**Pathopysiological Aspects of Other Neurodegenerative Diseases**

**Chapter 13**

**Other Dementias**

http://dx.doi.org/10.5772/53460

Uday Kishore

**1. Introduction**

are listed in Table 1.

gression to VaD [8].

**2. Vascular dementia**

Abhishek Shastri, Domenico Marco Bonifati and

The non-Alzheimer dementias (NAD) are a group of disorders that account for approxi‐ mately 30 to 40 per cent of dementias worldwide [1-3]. Some of the common types of NAD

The term vascular dementia (VaD) deals with cognitive impairment affecting daily activities required for living of vascular origin (ischemia, haemorrhage). However, VaD as a concept and disease entity is undergoing regular transformation. The term 'vascular cognitive im‐ pairment' (VCI) introduced in 1995 [4] is used to include any cognitive impairment from cerebrovascular disease (CVD) except major stroke. It was then proposed that the term VCI should include all forms of cognitive impairment associated with CVD [5] (Table 2). This term would include not only VaD but also mild cognitive impairment (MCI) with no de‐ mentia and dementia of mixed origin (Alzheimer's and vascular dementia) (see [6]). It has been argued that this classification does not fit the purpose of clinical differentiation and that this term should be restricted to MCI without dementia due to vascular cause [7]. How‐ ever, some scholars are of the opinion that VCI is a research terminology and that clinicians should identify the condition and deal with the associated risk factors thereby avoiding pro‐

The diagnostic criteria that characterise cognitive syndromes associated with vascular dis‐ ease are usually based on two factors: demonstration of presence of a cognitive disorder by neuropsychological testing and history of clinical stroke or presence of vascular disease by

and reproduction in any medium, provided the original work is properly cited.

© 2013 Shastri et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

Additional information is available at the end of the chapter

### **Chapter 13**

### **Other Dementias**

Abhishek Shastri, Domenico Marco Bonifati and Uday Kishore

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53460

**1. Introduction**

The non-Alzheimer dementias (NAD) are a group of disorders that account for approxi‐ mately 30 to 40 per cent of dementias worldwide [1-3]. Some of the common types of NAD are listed in Table 1.

### **2. Vascular dementia**

The term vascular dementia (VaD) deals with cognitive impairment affecting daily activities required for living of vascular origin (ischemia, haemorrhage). However, VaD as a concept and disease entity is undergoing regular transformation. The term 'vascular cognitive im‐ pairment' (VCI) introduced in 1995 [4] is used to include any cognitive impairment from cerebrovascular disease (CVD) except major stroke. It was then proposed that the term VCI should include all forms of cognitive impairment associated with CVD [5] (Table 2). This term would include not only VaD but also mild cognitive impairment (MCI) with no de‐ mentia and dementia of mixed origin (Alzheimer's and vascular dementia) (see [6]). It has been argued that this classification does not fit the purpose of clinical differentiation and that this term should be restricted to MCI without dementia due to vascular cause [7]. How‐ ever, some scholars are of the opinion that VCI is a research terminology and that clinicians should identify the condition and deal with the associated risk factors thereby avoiding pro‐ gression to VaD [8].

The diagnostic criteria that characterise cognitive syndromes associated with vascular dis‐ ease are usually based on two factors: demonstration of presence of a cognitive disorder by neuropsychological testing and history of clinical stroke or presence of vascular disease by

© 2013 Shastri et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

neuroimaging that suggests a link between the cognitive disorder and vascular disease. The term VCI is not used for patients who have an active diagnosis of drug or alcohol depend‐ ence or for patients with delirium [9].

• VCI-no dementia • Vascular dementia

• Mixed Alzheimer's disease and vascular dementia

1. Demographic

Lower educational level 2. Atherosclerosis Hypertension Cigarette smoking Myocardial infarction Diabetes mellitus Hyperlipidemia 3. Genetic CADASIL Apolipoprotein E 4. Stroke-related

Volume of cerebral tissue loss Bilateral cerebral infarction

White matter disease

**2.2. Clinical features and pathophysiology**

**Table 3.** Risk factors for vascular dementia according to reference [18]

Strategic infarction (thalamic, angular gyrus)

Firstly, to diagnose dementia, there should be a decline in memory and a decline in at least two cognitive skills such as orientation, social behaviour, verbal skills, attention, motor con‐ trol, praxis, emotional control and executive functions (goal-directed behaviour and prob‐ lem-solving skills). In VaD, the onset may be sudden or gradual, with stepwise progression. Since vascular component is involved, there may be focal neurological deficits such as hemi‐ paresis or swallowing disturbances and dysarthria (pseudobulbar lesion symptoms). A his‐ tory of transient ischaemic attacks is common. Depending on the site of the lesion, features such as motor aphasia, dyspraxia (due to left anterior cerebral artery ischemia) or psychosis (right middle cerebral artery) or amnesia and visual disturbances (posterior cerebral artery) may be seen. Other important associated features include gait disturbance which may be as‐ sociated with a history of unsteadiness as well as frequent falls. It is vital to distinguish de‐ mentia of vascular origin from degenerative form of dementia. This is because VaD, when diagnosed at an early stage provides for chances to prevent or delay progression. Thus, treatment strategies may vary. For this purpose, clinicians use a scoring system called Ha‐

Other Dementias

323

http://dx.doi.org/10.5772/53460

**Table 2.** Vascular cognitive impairment (VCI)

Age Male sex

#### **2.1. Epidemiology**

VaD is considered to be the second most prevalent type of dementia worldwide accounting for about 15 to 20 % of the dementia cases [10]. Prevalence of VaD in Japan has been report‐ ed to be as high as 47 % [11]. 16 % of all cases of late-onset dementia (65 years or after) [12] and 18 % of all cases of early-onset dementia (below 65 years) [13] was found to be VaD. However, it must be kept in mind that establishing the exact epidemiology of VaD is not an easy task mainly due to difficulty in diagnosing clinically [14] and overlap of AD neuropa‐ thology (see [15]).

Some of the risk factors for developing VaD are hypertension [16] and metabolic factors like diabetes and obesity. Males are considered to be at a significantly higher risk of developing VaD [17]. The incidence rate of VaD was found to be two times higher than Alzheimer's dis‐ ease for males in Japan [18]. The risk factors have been classified [19] and are listed in Table 3. Some of the protective factors found in the Canadian Study of Health and Aging include eating shellfish and regular exercise for women [20]. Antioxidants, which include vitamin E and C and also intake of fatty fish have been found to be protective against VCI [21].


**Table 1.** Types of non-Alzheimer dementia

a. Vascular dementia

• VCI-no dementia

neuroimaging that suggests a link between the cognitive disorder and vascular disease. The term VCI is not used for patients who have an active diagnosis of drug or alcohol depend‐

VaD is considered to be the second most prevalent type of dementia worldwide accounting for about 15 to 20 % of the dementia cases [10]. Prevalence of VaD in Japan has been report‐ ed to be as high as 47 % [11]. 16 % of all cases of late-onset dementia (65 years or after) [12] and 18 % of all cases of early-onset dementia (below 65 years) [13] was found to be VaD. However, it must be kept in mind that establishing the exact epidemiology of VaD is not an easy task mainly due to difficulty in diagnosing clinically [14] and overlap of AD neuropa‐

Some of the risk factors for developing VaD are hypertension [16] and metabolic factors like diabetes and obesity. Males are considered to be at a significantly higher risk of developing VaD [17]. The incidence rate of VaD was found to be two times higher than Alzheimer's dis‐ ease for males in Japan [18]. The risk factors have been classified [19] and are listed in Table 3. Some of the protective factors found in the Canadian Study of Health and Aging include eating shellfish and regular exercise for women [20]. Antioxidants, which include vitamin E

and C and also intake of fatty fish have been found to be protective against VCI [21].

ence or for patients with delirium [9].

**2.1. Epidemiology**

322 Neurodegenerative Diseases

thology (see [15]).

a. Vascular dementia

• Multi-infarct dementia

b. Dementia with Lewy Bodies c. Frontotemporal dementia d. Dementia in other diseases

• Creutzfeldt-Jakob disease • Huntington's disease • Parkinson's disease

• Pick's disease

• Alcohol-related

• Vascular dementia of acute onset (post-stroke)

• Human immunodeficiency virus (HIV) disease

• Neoplasia (glioma, meningioma, secondaries)

**Table 1.** Types of non-Alzheimer dementia

• Vitamin deficiencies (B12, folate, thiamine, nicotinic acid) • Metabolic and endocrine (liver disease, hypothyroidism)

e. Treatable or reversible dementias • Normal pressure hydrocephalus

• Subcortical vascular dementia (Binswanger's disease) • Mixed cortical and subcortical vascular dementia

• Other vascular dementia (CADASIL, vasculitis, post-cardiac arrest)

• Vascular dementia

• Mixed Alzheimer's disease and vascular dementia

**Table 2.** Vascular cognitive impairment (VCI)


**Table 3.** Risk factors for vascular dementia according to reference [18]

#### **2.2. Clinical features and pathophysiology**

Firstly, to diagnose dementia, there should be a decline in memory and a decline in at least two cognitive skills such as orientation, social behaviour, verbal skills, attention, motor con‐ trol, praxis, emotional control and executive functions (goal-directed behaviour and prob‐ lem-solving skills). In VaD, the onset may be sudden or gradual, with stepwise progression. Since vascular component is involved, there may be focal neurological deficits such as hemi‐ paresis or swallowing disturbances and dysarthria (pseudobulbar lesion symptoms). A his‐ tory of transient ischaemic attacks is common. Depending on the site of the lesion, features such as motor aphasia, dyspraxia (due to left anterior cerebral artery ischemia) or psychosis (right middle cerebral artery) or amnesia and visual disturbances (posterior cerebral artery) may be seen. Other important associated features include gait disturbance which may be as‐ sociated with a history of unsteadiness as well as frequent falls. It is vital to distinguish de‐ mentia of vascular origin from degenerative form of dementia. This is because VaD, when diagnosed at an early stage provides for chances to prevent or delay progression. Thus, treatment strategies may vary. For this purpose, clinicians use a scoring system called Ha‐ chinski ischaemic score [22]. A score of above six signifies dementia due to vascular cause. Some of the clinical criteria developed to assist in diagnosing VaD include State of Califor‐ nia Alzheimer Disease Diagnostic and Treatment Centers (ADDTC) criteria [23], Interna‐ tional Classification of Diseases (ICD-10) criteria [24], National Institute of Neurological Disorders and Stroke (NINDS)-Association Internationale pour la Recherche et l'Enseigne‐ ment en Neurosciences (AIREN) criteria [25] and Diagnostic and Statistical Manual for Men‐ tal Disorders (DSM-IV) criteria [26].

may be either large or small vessels or both. It is thought that the reason for multiple infarcts

Other Dementias

325

http://dx.doi.org/10.5772/53460

**Figure 1.** Brain MRI scan (DWI sequences) of a 59 years old man presenting with an acute onset of confusion, ideative and motor slowness and apathy with memory loss. A marked cognitive and motor slowness and apathy remained af‐ ter 15 days from onset. MRI scan showed ischemic lesions in the medial part of both thalami and in the midbrain (top

It is a type of subcortical ischaemic VaD. It is a progressive small vessel disease. Occlusion of small arteries (arterioles) leads to hypoperfusion and this in turn leads to white matter lacunes and necrosis [33]. Clinical features vary slightly where the patients develop a slowly progressing dementia. Brain imaging studies reveal increased white matter and periventric‐

**Figure 2.** Brain MRI (FLAIR sequences) of a 80 years old man with a multi-infarct progressive dementia with bulbar symptoms. Multiple cortical and subcortical infarct are seen together with periventricular white matter changes and

is due to underlying predisposing factors associated with VaD.

of the basilar syndrome).

*2.2.3. Binswanger's disease*

ular lesions (Figure 3).

corticola atrophy.

The most widely followed or accepted criteria for diagnosis of VaD is the NINDS-AIR‐ EN criteria. According to this, both clinical and radiological criteria must be fulfilled. Clinical criteria include presence of dementia and CVD as well as a relation between the two features i.e. dementia should develop after and within 3 months of the stroke. Radi‐ ological criteria are based on topography and severity of vascular lesions. There should be either a large vessel stroke or multiple lacunar infarcts in basal ganglia or white mat‐ ter lesions in periventricular regions. Large vessel lesions should be present in dominant hemisphere or in both the hemispheres while white matter lesions must involve at least 25 % of the cerebral white matter. However it was found that the neuroimaging criteria listed above does not always differentiate between stroke patients with and without de‐ mentia [27]. Definite vascular dementia is diagnosed by fulfilling the above mentioned criteria with histopathological evidence from brain biopsy or autopsy. Absence of other causes of dementia must be ruled out.

#### *2.2.1. Post-stroke dementia*

Post-stroke dementia (PSD) is the type of VaD developing after a stroke. Among patients who have experienced a first stroke, the prevalence of poststroke dementia (PSD) varies in relation to the interval after stroke, definition of dementia, location and size of the infarct. This includes a large-vessel lesion or single strategic lesion (thalamus or midbrain) (Figure 1). The cause of stroke may be haemorrhagic, or ischemic. The rate of dementia in people with stroke was found to be two times respect people without stroke [28]. Increasing age is significantly associated with PSD [29,30]. The severity of cognitive decline after a stroke is associated with increased risk of PSD [31]. Long-term mortality is 2 to 6 times higher in pa‐ tients with PSD after adjustment for demographic factors, associated cardiac diseases, stroke severity, and stroke recurrence (for review, see [32]). Silent cerebral infarcts, white matter changes, and global and medial temporal lobe atrophy are associated with increased risk of PSD [32]. Dementia is severe in lesions involving thalamus or midbrain. After stroke, recov‐ ery of patient involving both physical and cognitive functions is variable.

#### *2.2.2. Multi-infarct dementia*

As the name suggests, there are multiple strokes occurring in the same patient (Figure 2). Sometimes these may even go undetected and may be noticed only after a major stroke. This causes the characteristic step-wise progression of the disease where there may be deteriora‐ tion in cognitive abilities but also there may be periods of stability or even improvement of the patient. The severity of dementia increases with each stroke. The type of vessel involved may be either large or small vessels or both. It is thought that the reason for multiple infarcts is due to underlying predisposing factors associated with VaD.

**Figure 1.** Brain MRI scan (DWI sequences) of a 59 years old man presenting with an acute onset of confusion, ideative and motor slowness and apathy with memory loss. A marked cognitive and motor slowness and apathy remained af‐ ter 15 days from onset. MRI scan showed ischemic lesions in the medial part of both thalami and in the midbrain (top of the basilar syndrome).

#### *2.2.3. Binswanger's disease*

chinski ischaemic score [22]. A score of above six signifies dementia due to vascular cause. Some of the clinical criteria developed to assist in diagnosing VaD include State of Califor‐ nia Alzheimer Disease Diagnostic and Treatment Centers (ADDTC) criteria [23], Interna‐ tional Classification of Diseases (ICD-10) criteria [24], National Institute of Neurological Disorders and Stroke (NINDS)-Association Internationale pour la Recherche et l'Enseigne‐ ment en Neurosciences (AIREN) criteria [25] and Diagnostic and Statistical Manual for Men‐

The most widely followed or accepted criteria for diagnosis of VaD is the NINDS-AIR‐ EN criteria. According to this, both clinical and radiological criteria must be fulfilled. Clinical criteria include presence of dementia and CVD as well as a relation between the two features i.e. dementia should develop after and within 3 months of the stroke. Radi‐ ological criteria are based on topography and severity of vascular lesions. There should be either a large vessel stroke or multiple lacunar infarcts in basal ganglia or white mat‐ ter lesions in periventricular regions. Large vessel lesions should be present in dominant hemisphere or in both the hemispheres while white matter lesions must involve at least 25 % of the cerebral white matter. However it was found that the neuroimaging criteria listed above does not always differentiate between stroke patients with and without de‐ mentia [27]. Definite vascular dementia is diagnosed by fulfilling the above mentioned criteria with histopathological evidence from brain biopsy or autopsy. Absence of other

Post-stroke dementia (PSD) is the type of VaD developing after a stroke. Among patients who have experienced a first stroke, the prevalence of poststroke dementia (PSD) varies in relation to the interval after stroke, definition of dementia, location and size of the infarct. This includes a large-vessel lesion or single strategic lesion (thalamus or midbrain) (Figure 1). The cause of stroke may be haemorrhagic, or ischemic. The rate of dementia in people with stroke was found to be two times respect people without stroke [28]. Increasing age is significantly associated with PSD [29,30]. The severity of cognitive decline after a stroke is associated with increased risk of PSD [31]. Long-term mortality is 2 to 6 times higher in pa‐ tients with PSD after adjustment for demographic factors, associated cardiac diseases, stroke severity, and stroke recurrence (for review, see [32]). Silent cerebral infarcts, white matter changes, and global and medial temporal lobe atrophy are associated with increased risk of PSD [32]. Dementia is severe in lesions involving thalamus or midbrain. After stroke, recov‐

As the name suggests, there are multiple strokes occurring in the same patient (Figure 2). Sometimes these may even go undetected and may be noticed only after a major stroke. This causes the characteristic step-wise progression of the disease where there may be deteriora‐ tion in cognitive abilities but also there may be periods of stability or even improvement of the patient. The severity of dementia increases with each stroke. The type of vessel involved

ery of patient involving both physical and cognitive functions is variable.

tal Disorders (DSM-IV) criteria [26].

324 Neurodegenerative Diseases

causes of dementia must be ruled out.

*2.2.1. Post-stroke dementia*

*2.2.2. Multi-infarct dementia*

It is a type of subcortical ischaemic VaD. It is a progressive small vessel disease. Occlusion of small arteries (arterioles) leads to hypoperfusion and this in turn leads to white matter lacunes and necrosis [33]. Clinical features vary slightly where the patients develop a slowly progressing dementia. Brain imaging studies reveal increased white matter and periventric‐ ular lesions (Figure 3).

**Figure 2.** Brain MRI (FLAIR sequences) of a 80 years old man with a multi-infarct progressive dementia with bulbar symptoms. Multiple cortical and subcortical infarct are seen together with periventricular white matter changes and corticola atrophy.

**2.4. Management**

*2.4.1. Investigations*

*2.4.2. Treatment*

**2.5. Prognosis**

Routine blood investigations and biochemistry including lipid and glucose levels as well as liver enzymes must be done in order to rule out treatable causes of dementia and identify risk factors such as hyperlipidemia and diabetes. The Mini-Mental State Examination is a brief but good way of screening for dementia. Executive function may be tested by Clock-Drawing Task. A proper history from the patient and/or informant must be obtained and should include history for unprovoked falls, TIA and urinary incontinence also. Computed tomography (CT) and Magnetic Resonance Imaging (MRI) are useful investigations to check for both large and small infarcts and white matter lesions. Other imaging techniques like Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomogra‐ phy (PET) may be done to assess blood flow. Population MRI studies have revealed high prevalence of overt small-vessel disease in the elderly population (23 % for silent lacunes and 95 % for incidental hyperintensities). These lesions are associated with an increased risk for stroke and dementia [39]. A thorough and complete neurological examination must be done to confirm signs of stroke. It is extremely important to conduct a good cardiovascular examination including measuring blood pressure and examining for presence of murmurs.

Other Dementias

327

http://dx.doi.org/10.5772/53460

Since there are several risk factors associated with developing VaD, it is important to treat them or keep them in check. In people at risk for VCI, smoking cessation is mandatory. Life‐ style modification such as eating a low-fat diet, moderation in alcohol intake and regular ex‐ ercise are reasonably effective. Hypertension, hyperglycemia and hypercholesterolaemia must be treated. Antiplatelet therapy is used and is effective in preventing further strokes. Primary prevention with antihypertensive drugs perindopril and indapamide has been shown to be effective in reducing risk of dementia and cognitive decline in patients with re‐ current stroke [40]. Treatment of VaD is usually symptomatic. No specific drug has yet been recommended. Cholinesterase inhibitors (ChEI) such as donepezil have been found to be beneficial in improving cognition [41] but other ChEI such as galantamine[42] and rivastig‐ mine [43] have been found to be ineffective. N-methyl-D-aspartate antagonist like meman‐

The prognosis of VaD is generally poor. Most patients die within few years from onset. Death may be due to CVD or complications of dementia. Since there is no specific treatment recommended, it is very important to diagnose the disease at an early stage and stop it from

Electrocardiogram to look for presence of fibrillation is essential.

tine has been tried in trials but was also found to be ineffective [44].

progressing further. Preventive measures are also vital.

**Figure 3.** White matter changes and periventricular lesions observed in a 82 years old man with loss of memory and slowly progressive cognitive impairment. Brain atrophy is also present (mixed dementia)

#### *2.2.4. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)*

CADASIL is a familial form of vascular dementia. It is associated with migraine and is a subcortical ischaemic type of dementia. It is due to mutation in the *NOTCH3* gene on chro‐ mosome 19. It is the most common genetic form of VaD. The disease has an autosomal dom‐ inant type of inheritance. From the pathological point of view vascular lesions occur not only in vessels of the brain but also other organs. Hence, it can be diagnosed by skin biopsy and confirmed by immunohistochemistry with *NOTCH3* monoclonal antibody [34]. Brain imaging shows white matter lesions of necrosis and lacunae. A recessive form has also been described and mutations in the HTRA1 gene identified [35,36].

#### **2.3. Neuropathology**

The types of lesions seen in VaD are mainly infarctions. The infarctions may be present in the cortex and subcortical regions (complete infarctions) as well as the white matter and basal ganglia (lacunar infarctions). Cerebral amyloid angiopathy may be observed. Atrophy and sclerosis of hippocampus are also common [37]. A study was conducted on 135 post-mortem brains with dementia to conceptualize the natural history of cere‐ brovascular lesions (CVL) and operationalize it into a cerebrovascular staging system [38]. The authors rated the following CVL; in the frontal and temporal lobes: arterioscle‐ rosis, amyloid angiopathy, perivascular hemosiderin leakage, perivascular spaces dilata‐ tion in deep and juxtacortical white matter, myelin loss and cortical infarcts; in the hippocampus: neuronal loss, perivascular spaces dilatation and presence of micro- and large infarcts; in the basal ganglia: arteriosclerosis, perivascular spaces dilatation, density of micro- and large infarcts, either lacunar or territorial.

#### **2.4. Management**

#### *2.4.1. Investigations*

Routine blood investigations and biochemistry including lipid and glucose levels as well as liver enzymes must be done in order to rule out treatable causes of dementia and identify risk factors such as hyperlipidemia and diabetes. The Mini-Mental State Examination is a brief but good way of screening for dementia. Executive function may be tested by Clock-Drawing Task. A proper history from the patient and/or informant must be obtained and should include history for unprovoked falls, TIA and urinary incontinence also. Computed tomography (CT) and Magnetic Resonance Imaging (MRI) are useful investigations to check for both large and small infarcts and white matter lesions. Other imaging techniques like Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomogra‐ phy (PET) may be done to assess blood flow. Population MRI studies have revealed high prevalence of overt small-vessel disease in the elderly population (23 % for silent lacunes and 95 % for incidental hyperintensities). These lesions are associated with an increased risk for stroke and dementia [39]. A thorough and complete neurological examination must be done to confirm signs of stroke. It is extremely important to conduct a good cardiovascular examination including measuring blood pressure and examining for presence of murmurs. Electrocardiogram to look for presence of fibrillation is essential.

#### *2.4.2. Treatment*

**Figure 3.** White matter changes and periventricular lesions observed in a 82 years old man with loss of memory and

CADASIL is a familial form of vascular dementia. It is associated with migraine and is a subcortical ischaemic type of dementia. It is due to mutation in the *NOTCH3* gene on chro‐ mosome 19. It is the most common genetic form of VaD. The disease has an autosomal dom‐ inant type of inheritance. From the pathological point of view vascular lesions occur not only in vessels of the brain but also other organs. Hence, it can be diagnosed by skin biopsy and confirmed by immunohistochemistry with *NOTCH3* monoclonal antibody [34]. Brain imaging shows white matter lesions of necrosis and lacunae. A recessive form has also been

The types of lesions seen in VaD are mainly infarctions. The infarctions may be present in the cortex and subcortical regions (complete infarctions) as well as the white matter and basal ganglia (lacunar infarctions). Cerebral amyloid angiopathy may be observed. Atrophy and sclerosis of hippocampus are also common [37]. A study was conducted on 135 post-mortem brains with dementia to conceptualize the natural history of cere‐ brovascular lesions (CVL) and operationalize it into a cerebrovascular staging system [38]. The authors rated the following CVL; in the frontal and temporal lobes: arterioscle‐ rosis, amyloid angiopathy, perivascular hemosiderin leakage, perivascular spaces dilata‐ tion in deep and juxtacortical white matter, myelin loss and cortical infarcts; in the hippocampus: neuronal loss, perivascular spaces dilatation and presence of micro- and large infarcts; in the basal ganglia: arteriosclerosis, perivascular spaces dilatation, density

slowly progressive cognitive impairment. Brain atrophy is also present (mixed dementia)

described and mutations in the HTRA1 gene identified [35,36].

of micro- and large infarcts, either lacunar or territorial.

*Leukoencephalopathy (CADASIL)*

326 Neurodegenerative Diseases

**2.3. Neuropathology**

*2.2.4. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and*

Since there are several risk factors associated with developing VaD, it is important to treat them or keep them in check. In people at risk for VCI, smoking cessation is mandatory. Life‐ style modification such as eating a low-fat diet, moderation in alcohol intake and regular ex‐ ercise are reasonably effective. Hypertension, hyperglycemia and hypercholesterolaemia must be treated. Antiplatelet therapy is used and is effective in preventing further strokes. Primary prevention with antihypertensive drugs perindopril and indapamide has been shown to be effective in reducing risk of dementia and cognitive decline in patients with re‐ current stroke [40]. Treatment of VaD is usually symptomatic. No specific drug has yet been recommended. Cholinesterase inhibitors (ChEI) such as donepezil have been found to be beneficial in improving cognition [41] but other ChEI such as galantamine[42] and rivastig‐ mine [43] have been found to be ineffective. N-methyl-D-aspartate antagonist like meman‐ tine has been tried in trials but was also found to be ineffective [44].

#### **2.5. Prognosis**

The prognosis of VaD is generally poor. Most patients die within few years from onset. Death may be due to CVD or complications of dementia. Since there is no specific treatment recommended, it is very important to diagnose the disease at an early stage and stop it from progressing further. Preventive measures are also vital.

### **3. Dementia with lewy bodies**

Dementia with Lewy Bodies (DLB) is a degenerative type of dementia (like AD). It is the sec‐ ond most common type of degenerative dementia (after AD). Lewy Bodies are inclusion bodies present in the cytoplasm containing a protein called ubiquitin. The first cases of DLB with cortical involvement were reported in 1961 [45]. The Lewy Body was seen in autopsy by neuropathological staining only as far as 1989 [46]. Over the years, DLB has been given several terminologies, namely diffuse Lewy body Disease [47], Lewy body dementia [48], Lewy body variant of AD [49], senile dementia of Lewy body type [50] and dementia associ‐ ated with cortical Lewy bodies [51].

**3.3. Management**

*3.3.1. Investigations*

in diagnosis of LBD [71].

*3.3.2. Treatment*

**3.4. Prognosis**

of disease progression [78].

**4.1. Epidemiology**

**4. Frontotemporal dementia**

Clinically, dementia must be diagnosed. Other neuropsychiatric features such as depression, hallucinations and sleep disturbances must be identified. Proper history from carer or fami‐ ly member must be obtained. A complete psychiatric and neurological evaluation must be carried out. There are no specific diagnostic tests. MRI may show preservation of medial temporal lobe [67] or reduced amygdala volume [62]. SPECT may show hypoperfusion in occipital lobe [68]. Using SPECT with dopamine transporter imaging is turning out to be promising [69,70]. Imaging and findings of global amyloid deposition may also give a clue

Other Dementias

329

http://dx.doi.org/10.5772/53460

Drugs used in treatment include levodopa viz. usually used to treat Parkinson's disease. A one year follow-up study has shown it to be acutely effective [72] but its use is debatable as it also lead to adverse effects most notably being hallucinations [73]. Another promising drug is memantine which was also found to be well tolerated [74]. A Cochrane review found cholinesterase inhibitors to be not useful in patients with DLB [75]. Other measures

The prognosis in DLB can be variable. Initial health and well-being may play a role in decid‐ ing the prognosis. When compared to AD, the prognosis has been found to be similar [76] as well as more severe [77]. No single factor have been identified that may dictate the outcome

Frontotemporal dementia (FTD) is considered to be the second most common type of earlyonset (before the age of 65) dementia. There is pathological involvement of frontal and tem‐ poral lobes of the brain. FTD consists of a behavioural variant (bvFTD) and a language variant. The language variant can be further divided into semantic dementia (SD) and pro‐ gressive non-fluent aphasia (PNFA). Overlap of FTD with motor neuron disease (MND) is also seen clinically, pathologically and genetically [79]. The whole clinico-pathological spec‐

The prevalence of FTD was found to be about 15 in 100,000 in UK involving age groups 45-64 years [80] while in the Netherlands it was found to be 9.4 per 100,000 in the age group 60-69 years [81]. The prevalence of early-onset AD and FTD was (be consistent between past

include education of carers and also reality orientation of patients.

trum is often referred to as frontotemporal lobar degeneration.

#### **3.1. Epidemiology**

The prevalence of DLB is about 0.1 to 5 % in the general population and about 10 to 20 % of all dementia cases [52-54]. The incidence is about 0.1 % a year in the general population and about 3 % a year of all new dementia diagnosed cases [55]. A French cohort study found that the incidence of DLB increases with age [56].

#### **3.2. Clinical features and pathophysiology**

The main feature is the presence of dementia which means impairment of cognition affect‐ ing normal day to day and social activities. Guidelines [57] suggest the core features as be‐ ing fluctuation in level of cognition, detailed visual hallucinations that are recurrent and parkinsonism that is spontaneous. Any two of these core features indicate probable DLB while the presence of only one of the core features indicates possible DLB. Other psychiatric features may include depression, anxiety or apathy. There may also be a history of repeated falls given by the carers. Another interesting feature is the presence of Rapid Eye Movement sleep behaviour disorder (RBD) [58, 59]. RBD is a sleep disorder and is characterized by loss of muscle atonia during rapid eye movement as well as movement of limbs, with or without vocalization and dreaming. Carers often give a history that it is as though the patient is act‐ ing out his or her dreams. A recent study [60] found that inclusion of RBD as a core feature may help improve diagnosis of DLB.

On pathological examination, LB contain ubiquitin which is examined by immunohisto‐ chemistry. Increased presence of LB in the parahippocampus has been linked to increase in the severity of dementia [61]. DLB patholgy has been shown to be related to plaques in hippocampus and amygdala [62]. Another biomarker for diagnosis is α-synuclein (AS) immunohistochemistry [63]. Genetic mutation of AS has also been associated with DLB [64]. Diagnosis with AS staining was found to be more sensitive and more specific than ubiquitin staining [65]. Presence of LB in the temporal lobe has been shown to be relat‐ ed to visual hallucinations [66].

#### **3.3. Management**

**3. Dementia with lewy bodies**

ated with cortical Lewy bodies [51].

the incidence of DLB increases with age [56].

**3.2. Clinical features and pathophysiology**

may help improve diagnosis of DLB.

ed to visual hallucinations [66].

**3.1. Epidemiology**

328 Neurodegenerative Diseases

Dementia with Lewy Bodies (DLB) is a degenerative type of dementia (like AD). It is the sec‐ ond most common type of degenerative dementia (after AD). Lewy Bodies are inclusion bodies present in the cytoplasm containing a protein called ubiquitin. The first cases of DLB with cortical involvement were reported in 1961 [45]. The Lewy Body was seen in autopsy by neuropathological staining only as far as 1989 [46]. Over the years, DLB has been given several terminologies, namely diffuse Lewy body Disease [47], Lewy body dementia [48], Lewy body variant of AD [49], senile dementia of Lewy body type [50] and dementia associ‐

The prevalence of DLB is about 0.1 to 5 % in the general population and about 10 to 20 % of all dementia cases [52-54]. The incidence is about 0.1 % a year in the general population and about 3 % a year of all new dementia diagnosed cases [55]. A French cohort study found that

The main feature is the presence of dementia which means impairment of cognition affect‐ ing normal day to day and social activities. Guidelines [57] suggest the core features as be‐ ing fluctuation in level of cognition, detailed visual hallucinations that are recurrent and parkinsonism that is spontaneous. Any two of these core features indicate probable DLB while the presence of only one of the core features indicates possible DLB. Other psychiatric features may include depression, anxiety or apathy. There may also be a history of repeated falls given by the carers. Another interesting feature is the presence of Rapid Eye Movement sleep behaviour disorder (RBD) [58, 59]. RBD is a sleep disorder and is characterized by loss of muscle atonia during rapid eye movement as well as movement of limbs, with or without vocalization and dreaming. Carers often give a history that it is as though the patient is act‐ ing out his or her dreams. A recent study [60] found that inclusion of RBD as a core feature

On pathological examination, LB contain ubiquitin which is examined by immunohisto‐ chemistry. Increased presence of LB in the parahippocampus has been linked to increase in the severity of dementia [61]. DLB patholgy has been shown to be related to plaques in hippocampus and amygdala [62]. Another biomarker for diagnosis is α-synuclein (AS) immunohistochemistry [63]. Genetic mutation of AS has also been associated with DLB [64]. Diagnosis with AS staining was found to be more sensitive and more specific than ubiquitin staining [65]. Presence of LB in the temporal lobe has been shown to be relat‐

#### *3.3.1. Investigations*

Clinically, dementia must be diagnosed. Other neuropsychiatric features such as depression, hallucinations and sleep disturbances must be identified. Proper history from carer or fami‐ ly member must be obtained. A complete psychiatric and neurological evaluation must be carried out. There are no specific diagnostic tests. MRI may show preservation of medial temporal lobe [67] or reduced amygdala volume [62]. SPECT may show hypoperfusion in occipital lobe [68]. Using SPECT with dopamine transporter imaging is turning out to be promising [69,70]. Imaging and findings of global amyloid deposition may also give a clue in diagnosis of LBD [71].

#### *3.3.2. Treatment*

Drugs used in treatment include levodopa viz. usually used to treat Parkinson's disease. A one year follow-up study has shown it to be acutely effective [72] but its use is debatable as it also lead to adverse effects most notably being hallucinations [73]. Another promising drug is memantine which was also found to be well tolerated [74]. A Cochrane review found cholinesterase inhibitors to be not useful in patients with DLB [75]. Other measures include education of carers and also reality orientation of patients.

#### **3.4. Prognosis**

The prognosis in DLB can be variable. Initial health and well-being may play a role in decid‐ ing the prognosis. When compared to AD, the prognosis has been found to be similar [76] as well as more severe [77]. No single factor have been identified that may dictate the outcome of disease progression [78].

#### **4. Frontotemporal dementia**

Frontotemporal dementia (FTD) is considered to be the second most common type of earlyonset (before the age of 65) dementia. There is pathological involvement of frontal and tem‐ poral lobes of the brain. FTD consists of a behavioural variant (bvFTD) and a language variant. The language variant can be further divided into semantic dementia (SD) and pro‐ gressive non-fluent aphasia (PNFA). Overlap of FTD with motor neuron disease (MND) is also seen clinically, pathologically and genetically [79]. The whole clinico-pathological spec‐ trum is often referred to as frontotemporal lobar degeneration.

#### **4.1. Epidemiology**

The prevalence of FTD was found to be about 15 in 100,000 in UK involving age groups 45-64 years [80] while in the Netherlands it was found to be 9.4 per 100,000 in the age group 60-69 years [81]. The prevalence of early-onset AD and FTD was (be consistent between past and present verbs) found to be similar [80,82]. The incidence was found to be about 3.5 cases per 100000 person-years [83]. Average age of onset is around 50-60 years [80,81].

#### **4.2. Clinical Features and pathophysiology**

The core features are an insidious onset, decline in personal and social conduct as well as early emotional blunting and loss of insight [84]. The most common presenting symptoms are then changes in behaviour. Decrease in cognitive functions involving executive functions and speech is also observed. bvFTD is the most common of the subtypes [85] and is consid‐ ered to be the most typical of FTD. It is associated with degeneration of frontal and temporal lobes [86] Other important features include behavioural disinhibition, apathy and loss of empathy [87]. SD is characterised by loss of ability to name and recognise words, objects and faces. It is associated with atrophy of left temporal lobe [88]. However, at least initially, speech in SD may be unhampered, fluent and grammatically correct [89]. In PNFA, speech is hampered and is grammatically incorrect but usually comprehension is preserved. This is associated with problems in language expression [89] and also with left temporal lobe atro‐ phy and Broca's area degeneration [84,90]. FTD associated with MND has similar clinical presentations involving areas of language, memory and behavioural changes[91]. Genetic studies involving families where some members have FTD and others have MND have shown a repeat of hexanucleotide sequence GGGGCC in chromosome 9 open reading frame 72 region (*C9ORF72*) [92,93].

**Figure 4.** MRI brain scan (FLAIR and T2 sequences) of a 75 old woman with progressive FTD with mainly behavioural disturbances showing frontal and temporal lobe atrophy along with minor periventricular hyperintensities. She had

Other Dementias

331

http://dx.doi.org/10.5772/53460

No known or effective treatment exists for FTD. Treatment is mainly supportive or pallia‐ tive. Multi-disciplinary management involving psychiatrist, physician, clinical psychologist

The prognosis varies and to some extent depends on the type of FTD. The severity of the disease is more and clinical progression is faster in bvFTD [100]. In the language variant, the disease progression is slow with mainly impairment of language component

Pick's disease (PD) is a neurodegenerative disease. From the clinical point of view it over‐ laps with FTD but it is characterised by the presence of Pick bodies. These Pick bodies are argyrophilic, intraneuronal, cytoplasmic inclusions made up of three-repeat tau. Other fea‐

deficit in executive and attention functions, aggressive behaviour and obsessive-compulsive disorder.

and specialist nurse may be an effective way to treat patients with FTD.

*4.3.2. Treatment*

**4.4. Prognosis**

for several years [89].

**5. Dementia in other diseases**

**5.1. Dementia in Pick's disease**

FTLD shows atrophy or degeneration of frontal and/or temporal lobes along with microva‐ cuolation and neuronal loss in the cerebral cortex [94]. By the use of immunohistochemistry, FTLD is associated with the accumulation of microtubule-associated protein tau and trans‐ active response DNA-binding protein 43 (TDP-43). It can also be divided into two types (1) FTLD with tau-positive inclusions (FLTD-tau) and (2) FTLD with ubiquitin-positive and TDP-43-positive but tau-negative inclusions (FLTD-TDP) [95]. FLTD-tau mainly present as PNFA and overlap with Pick's disease while FLTD-TDP present mainly as SD and is associ‐ ated with MND. Patients with bvFTD can show either of the two types of pathology [96,97]. Apart from TDP-43 involvement in MND, another protein called fused in sarcoma (FUS) is also associated with familial cases of dementia and MND [98].

#### **4.3. Management**

#### *4.3.1. Investigations*

MRI is the most useful investigation. Features of lobar atrophy may be observed. In bvFTD, there is involvement of frontal, temporal, cortical and subcortical areas (Figure 4). Hypoper‐ fusion of these areas is also seen with SPECT and hypometabolism with PET. In the lan‐ guage variant, left temporal grey matter involvement is observed. Orbitofrontal cortex involvement is associated with behavioural changes in these patients. Also, cortical and sub‐ cortical hyoperfusion is found to be more marked on the left side [99]. A complete neuro‐ psychological battery is necessary to fully characterise clinically these patients.

**Figure 4.** MRI brain scan (FLAIR and T2 sequences) of a 75 old woman with progressive FTD with mainly behavioural disturbances showing frontal and temporal lobe atrophy along with minor periventricular hyperintensities. She had deficit in executive and attention functions, aggressive behaviour and obsessive-compulsive disorder.

#### *4.3.2. Treatment*

and present verbs) found to be similar [80,82]. The incidence was found to be about 3.5 cases

The core features are an insidious onset, decline in personal and social conduct as well as early emotional blunting and loss of insight [84]. The most common presenting symptoms are then changes in behaviour. Decrease in cognitive functions involving executive functions and speech is also observed. bvFTD is the most common of the subtypes [85] and is consid‐ ered to be the most typical of FTD. It is associated with degeneration of frontal and temporal lobes [86] Other important features include behavioural disinhibition, apathy and loss of empathy [87]. SD is characterised by loss of ability to name and recognise words, objects and faces. It is associated with atrophy of left temporal lobe [88]. However, at least initially, speech in SD may be unhampered, fluent and grammatically correct [89]. In PNFA, speech is hampered and is grammatically incorrect but usually comprehension is preserved. This is associated with problems in language expression [89] and also with left temporal lobe atro‐ phy and Broca's area degeneration [84,90]. FTD associated with MND has similar clinical presentations involving areas of language, memory and behavioural changes[91]. Genetic studies involving families where some members have FTD and others have MND have shown a repeat of hexanucleotide sequence GGGGCC in chromosome 9 open reading frame

FTLD shows atrophy or degeneration of frontal and/or temporal lobes along with microva‐ cuolation and neuronal loss in the cerebral cortex [94]. By the use of immunohistochemistry, FTLD is associated with the accumulation of microtubule-associated protein tau and trans‐ active response DNA-binding protein 43 (TDP-43). It can also be divided into two types (1) FTLD with tau-positive inclusions (FLTD-tau) and (2) FTLD with ubiquitin-positive and TDP-43-positive but tau-negative inclusions (FLTD-TDP) [95]. FLTD-tau mainly present as PNFA and overlap with Pick's disease while FLTD-TDP present mainly as SD and is associ‐ ated with MND. Patients with bvFTD can show either of the two types of pathology [96,97]. Apart from TDP-43 involvement in MND, another protein called fused in sarcoma (FUS) is

MRI is the most useful investigation. Features of lobar atrophy may be observed. In bvFTD, there is involvement of frontal, temporal, cortical and subcortical areas (Figure 4). Hypoper‐ fusion of these areas is also seen with SPECT and hypometabolism with PET. In the lan‐ guage variant, left temporal grey matter involvement is observed. Orbitofrontal cortex involvement is associated with behavioural changes in these patients. Also, cortical and sub‐ cortical hyoperfusion is found to be more marked on the left side [99]. A complete neuro‐

psychological battery is necessary to fully characterise clinically these patients.

also associated with familial cases of dementia and MND [98].

per 100000 person-years [83]. Average age of onset is around 50-60 years [80,81].

**4.2. Clinical Features and pathophysiology**

330 Neurodegenerative Diseases

72 region (*C9ORF72*) [92,93].

**4.3. Management**

*4.3.1. Investigations*

No known or effective treatment exists for FTD. Treatment is mainly supportive or pallia‐ tive. Multi-disciplinary management involving psychiatrist, physician, clinical psychologist and specialist nurse may be an effective way to treat patients with FTD.

#### **4.4. Prognosis**

The prognosis varies and to some extent depends on the type of FTD. The severity of the disease is more and clinical progression is faster in bvFTD [100]. In the language variant, the disease progression is slow with mainly impairment of language component for several years [89].

#### **5. Dementia in other diseases**

#### **5.1. Dementia in Pick's disease**

Pick's disease (PD) is a neurodegenerative disease. From the clinical point of view it over‐ laps with FTD but it is characterised by the presence of Pick bodies. These Pick bodies are argyrophilic, intraneuronal, cytoplasmic inclusions made up of three-repeat tau. Other fea‐ tures include circumscribed atrophy of frontal and temporal lobes, gliosis and loss of neu‐ rons [101] as it has seen in FTD. Clinically, patients present with symptoms similar to FTD such as those of bvFTD, PNFA and SD as mentioned previously. Therefore, it is difficult to distinguish FTD from PD clinically. Post-mortem clinical correlation studies have shown that PD is associated more closely with behavioural and language associated symptoms and not with motor disturbances [102]. The age of onset is around 45 to 65 years [103, 104]. There are no known risk factors associated with PD. 'Knife-edge' atrophy is observed pathological‐ ly in the cortex which implies sharp, circumscribed degeneration (also referred to as 'dried walnut' appearance) [105]. There may also be the presence of swollen, ballooned neurons in the cortex called as Pick cells although they are not always present. No specific treatment is available at present for PD.

ease advances. Pathological features include neostriatal (caudate and putamen) atrophy in early stages of disease [118] and presence of intranuclear inclusions of mutant huntingtin in neurons of the striatum region of the brain [119]. Management includes genetic counselling, regular neurological and neuropsychiatric evaluation. Treatment is mainly symptomatic.

Other Dementias

333

http://dx.doi.org/10.5772/53460

Parkinson's disease (PD) is a neurodegenerative disease mainly associated with motor symptoms. However, dementia develops in about 40 % of the sufferers [120,121]. Dementia developing after diagnosis of PD is termed as Parkinson's disease dementia (PDD). The prevalence of PDD in PD after 8-10 years has been found to be nearly 75 % [122,123]. Risk factors for developing early dementia are old age and severity of motor symptoms [123]. Clinical diagnostic features associated with PDD are impairment in attention, executive functions and memory. Other behavioural features are apathy, hallucinations and delusions [124]. Sleep disorders like RBD may be present and has been found to be associated with increased risk of developing PDD [125]. There are no investigations to diagnose PDD but there is association with hippocampal and medial temporal lobe atrophy [126]. SPECT stud‐ ies have found abnormalities in dopamine transporter and occipital region hypoperfusion [127]. Cholinergic deficits are also observed and treatment with cholinesterase inhibitors has been found to be useful in PDD [128]. Treatment is otherwise symptomatic. Prognosis varies

but PDD sufferers have been found to have increased risk of mortality [129].

survival time after dementia found to be 6 months [131].

The HIV-1 virus is known to cause AIDS and also other neurological disorders. These neu‐ rological disorders are known as HIV-associated neurocognitive disorders (HAND). The most severe form of HAND is HIV-associated dementia (HAD) [130]. The annual incidence of HAD in 1990's was 7 % [131]. However, with the advent of highly active antiretroviral therapy (HAART), the incidence has decreased by more than half to about 2 to 4% [132-134]. The clinical features as part of the diagnostic criteriae include dementia, no evidence for presence of delirium nor any other cause for dementia [130]. Neuroinflammation in brain is observed. Viral proteins that are released from infected glial cells activate uninfected micro‐ glial cells and astrocytes to secrete cytokines and neurotoxins. This causes neuronal cell death i.e. neurodegeneration [135,136]. To help in detecting HAD, a rating scale has been de‐ veloped which tests timed fingertapping, alternating hand sequence test and recall of four items at 2 minutes [137]. HAART is used as treatment of HAD. The aim is to suppress the virus and its replication in plasma and CNS [138]. Some of the drugs used in HAART regi‐ men are a combination of efavirenz, lamivudine and zidovudine. Other medications like memantine, valproic acid and selegiline listed under adjunctive therapies have not been found to be useful in HAD [139]. HAD is associated with increased mortality with median

**5.4. Dementia in Parkinson's disease**

**5.5. Dementia in HIV disease**

#### **5.2. Dementia in Creutzfeldt-Jakob disease**

Creutzfeldt-Jakob disease (CJD) is a subacute fatal neurodegenerative disease. It is the most common of the prion diseases to affect humans. Prion proteins are infectious-like agents that cause diseases termed as transmissible spongiform encephalopathies. Prion proteins are found normally in the cells of central nervous system and immune system [106]. However, a misfolded form of this protein is considered to be pathologic. CJD occurs as sporadic, genet‐ ic, iatrogenic or juvenile variant forms. Clinical features associated with CJD are a rapidly progressive encephalopathy with dementia, cerebellar ataxia and myoclonus [107]. It pro‐ gresses to stupor and coma in few months. The sporadic form of CJD (sCJD) accounts for about 85 % of all CJD cases [108, 109]. The average age of onset is around 60 years. Median time to death is about 5 months and 85-90 % of patients die within 1 year of onset [110-112]. In the familial form, mutations in the gene *PNRP* that encodes the prion protein are seen. Autosomal dominant inheritance is observed. Disease progression is slower than sCJD. Ia‐ trogenic form of CJD occurs accidently during surgical or medical procedures. In the juve‐ nile variant form of CJD (vCJD), the age of onset is around 30 years. Other features include early psychiatric features (depression, anxiety, apathy), delay in dementia and duration of illness of more than 6 months [113,114]. Pathologically all cases of CJD have features of neu‐ ronal loss, spongiform changes (vacuolation in grey matter) and astrogliosis [107]. Patholog‐ ical prion proteins can be observed via immunohistochemistry [113].

#### **5.3. Dementia in Huntington's disease**

Huntington's disease (HD) is a genetic cause of dementia. It is inherited as an autosomaldominant trait. The mutation in the *huntingtin* gene (chromosome 4) producing the disease was identified in 1993 [115]. Mutant protein called huntingtin has an abnormal CAG repeats (at least 36) on the coding sequence of this gene. HD is characterised by chorea (involuntary, jerky movement of limbs spreading to all muscles of body), behavioural and psychiatric changes (mainly psychoses and depression) along with dementia. The onset is around mid‐ dle age (about 40 years). Cognitive changes mainly slowing of intellectual capabilities and decline of executive functions occur and may sometimes be detected even before onset of motor symptoms [116, 117]. Dementia is progressive and increases as the course of the dis‐ ease advances. Pathological features include neostriatal (caudate and putamen) atrophy in early stages of disease [118] and presence of intranuclear inclusions of mutant huntingtin in neurons of the striatum region of the brain [119]. Management includes genetic counselling, regular neurological and neuropsychiatric evaluation. Treatment is mainly symptomatic.

#### **5.4. Dementia in Parkinson's disease**

tures include circumscribed atrophy of frontal and temporal lobes, gliosis and loss of neu‐ rons [101] as it has seen in FTD. Clinically, patients present with symptoms similar to FTD such as those of bvFTD, PNFA and SD as mentioned previously. Therefore, it is difficult to distinguish FTD from PD clinically. Post-mortem clinical correlation studies have shown that PD is associated more closely with behavioural and language associated symptoms and not with motor disturbances [102]. The age of onset is around 45 to 65 years [103, 104]. There are no known risk factors associated with PD. 'Knife-edge' atrophy is observed pathological‐ ly in the cortex which implies sharp, circumscribed degeneration (also referred to as 'dried walnut' appearance) [105]. There may also be the presence of swollen, ballooned neurons in the cortex called as Pick cells although they are not always present. No specific treatment is

Creutzfeldt-Jakob disease (CJD) is a subacute fatal neurodegenerative disease. It is the most common of the prion diseases to affect humans. Prion proteins are infectious-like agents that cause diseases termed as transmissible spongiform encephalopathies. Prion proteins are found normally in the cells of central nervous system and immune system [106]. However, a misfolded form of this protein is considered to be pathologic. CJD occurs as sporadic, genet‐ ic, iatrogenic or juvenile variant forms. Clinical features associated with CJD are a rapidly progressive encephalopathy with dementia, cerebellar ataxia and myoclonus [107]. It pro‐ gresses to stupor and coma in few months. The sporadic form of CJD (sCJD) accounts for about 85 % of all CJD cases [108, 109]. The average age of onset is around 60 years. Median time to death is about 5 months and 85-90 % of patients die within 1 year of onset [110-112]. In the familial form, mutations in the gene *PNRP* that encodes the prion protein are seen. Autosomal dominant inheritance is observed. Disease progression is slower than sCJD. Ia‐ trogenic form of CJD occurs accidently during surgical or medical procedures. In the juve‐ nile variant form of CJD (vCJD), the age of onset is around 30 years. Other features include early psychiatric features (depression, anxiety, apathy), delay in dementia and duration of illness of more than 6 months [113,114]. Pathologically all cases of CJD have features of neu‐ ronal loss, spongiform changes (vacuolation in grey matter) and astrogliosis [107]. Patholog‐

Huntington's disease (HD) is a genetic cause of dementia. It is inherited as an autosomaldominant trait. The mutation in the *huntingtin* gene (chromosome 4) producing the disease was identified in 1993 [115]. Mutant protein called huntingtin has an abnormal CAG repeats (at least 36) on the coding sequence of this gene. HD is characterised by chorea (involuntary, jerky movement of limbs spreading to all muscles of body), behavioural and psychiatric changes (mainly psychoses and depression) along with dementia. The onset is around mid‐ dle age (about 40 years). Cognitive changes mainly slowing of intellectual capabilities and decline of executive functions occur and may sometimes be detected even before onset of motor symptoms [116, 117]. Dementia is progressive and increases as the course of the dis‐

ical prion proteins can be observed via immunohistochemistry [113].

available at present for PD.

332 Neurodegenerative Diseases

**5.2. Dementia in Creutzfeldt-Jakob disease**

**5.3. Dementia in Huntington's disease**

Parkinson's disease (PD) is a neurodegenerative disease mainly associated with motor symptoms. However, dementia develops in about 40 % of the sufferers [120,121]. Dementia developing after diagnosis of PD is termed as Parkinson's disease dementia (PDD). The prevalence of PDD in PD after 8-10 years has been found to be nearly 75 % [122,123]. Risk factors for developing early dementia are old age and severity of motor symptoms [123]. Clinical diagnostic features associated with PDD are impairment in attention, executive functions and memory. Other behavioural features are apathy, hallucinations and delusions [124]. Sleep disorders like RBD may be present and has been found to be associated with increased risk of developing PDD [125]. There are no investigations to diagnose PDD but there is association with hippocampal and medial temporal lobe atrophy [126]. SPECT stud‐ ies have found abnormalities in dopamine transporter and occipital region hypoperfusion [127]. Cholinergic deficits are also observed and treatment with cholinesterase inhibitors has been found to be useful in PDD [128]. Treatment is otherwise symptomatic. Prognosis varies but PDD sufferers have been found to have increased risk of mortality [129].

#### **5.5. Dementia in HIV disease**

The HIV-1 virus is known to cause AIDS and also other neurological disorders. These neu‐ rological disorders are known as HIV-associated neurocognitive disorders (HAND). The most severe form of HAND is HIV-associated dementia (HAD) [130]. The annual incidence of HAD in 1990's was 7 % [131]. However, with the advent of highly active antiretroviral therapy (HAART), the incidence has decreased by more than half to about 2 to 4% [132-134]. The clinical features as part of the diagnostic criteriae include dementia, no evidence for presence of delirium nor any other cause for dementia [130]. Neuroinflammation in brain is observed. Viral proteins that are released from infected glial cells activate uninfected micro‐ glial cells and astrocytes to secrete cytokines and neurotoxins. This causes neuronal cell death i.e. neurodegeneration [135,136]. To help in detecting HAD, a rating scale has been de‐ veloped which tests timed fingertapping, alternating hand sequence test and recall of four items at 2 minutes [137]. HAART is used as treatment of HAD. The aim is to suppress the virus and its replication in plasma and CNS [138]. Some of the drugs used in HAART regi‐ men are a combination of efavirenz, lamivudine and zidovudine. Other medications like memantine, valproic acid and selegiline listed under adjunctive therapies have not been found to be useful in HAD [139]. HAD is associated with increased mortality with median survival time after dementia found to be 6 months [131].

#### **6. Conclusions**

The NAD or other dementias form a vital part of the fight against dementia and its conse‐ quences. Even though AD forms the bulk of dementia cases, knowledge and understanding of NAD might play an important role in the much needed quest for cure or prevention of dementia. More cutting-edge research into these diseases and their pathogenesis will help combat the spread and probably even onset of dementia.

[7] Roman GC, Sachdev P, Royall DR, Bullock RA, Orgogozo JM, Lopez-Pousa S, et al. Vascular cognitive disorder: a new diagnostic category updating vascular cognitive

Other Dementias

335

http://dx.doi.org/10.5772/53460

[8] Bowler JV. Vascular cognitive impairment. J Neurol Neurosurg Psychiatry 2005 Dec;

[9] Chui HC, Mack W, Jackson JE, Mungas D, Reed BR, Tinklenberg J, et al. Clinical cri‐ teria for the diagnosis of vascular dementia: a multicenter study of comparability

[10] van der Flier WM, Scheltens P. Epidemiology and risk factors of dementia. J Neurol

[11] Ikeda M, Hokoishi K, Maki N, Nebu A, Tachibana N, Komori K, et al. Increased prevalence of vascular dementia in Japan: a community-based epidemiological

[12] Lobo A, Launer LJ, Fratiglioni L, Andersen K, Di Carlo A, Breteler MM, et al. Preva‐ lence of dementia and major subtypes in Europe: A collaborative study of popula‐ tion-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology

[13] Harvey RJ, Skelton-Robinson M, Rossor MN. The prevalence and causes of dementia in people under the age of 65 years. J Neurol Neurosurg Psychiatry 2003 Sep;74(9):

[14] Mathias JL, Burke J. Cognitive functioning in Alzheimer's and vascular dementia: a

[15] Kalaria RN, Ballard C. Overlap between pathology of Alzheimer disease and vascu‐ lar dementia. Alzheimer Dis Assoc Disord 1999 Oct-Dec;13 Suppl 3:S115-23.

[16] Sharp SI, Aarsland D, Day S, Sonnesyn H, Alzheimer's Society Vascular Dementia Systematic Review Group, Ballard C. Hypertension is a potential risk factor for vas‐ cular dementia: systematic review. Int J Geriatr Psychiatry 2011 Jul;26(7):661-669. [17] Di Carlo A, Baldereschi M, Amaducci L, Lepore V, Bracco L, Maggi S, et al. Incidence of dementia, Alzheimer's disease, and vascular dementia in Italy. The ILSA Study. J

[18] Yoshitake T, Kiyohara Y, Kato I, Ohmura T, Iwamoto H, Nakayama K, et al. Inci‐ dence and risk factors of vascular dementia and Alzheimer's disease in a defined eld‐ erly Japanese population: the Hisayama Study. Neurology 1995 Jun;45(6):1161-1168.

[19] Gorelick PB. Risk factors for vascular dementia and Alzheimer disease. Stroke 2004

[20] Hebert R, Lindsay J, Verreault R, Rockwood K, Hill G, Dubois MF. Vascular demen‐ tia : incidence and risk factors in the Canadian study of health and aging. Stroke 2000

impairment and vascular dementia. J Neurol Sci 2004 Nov 15;226(1-2):81-87.

and interrater reliability. Arch Neurol 2000 Feb;57(2):191-196.

Neurosurg Psychiatry 2005 Dec;76 Suppl 5:v2-7.

study. Neurology 2001 Sep 11;57(5):839-844.

meta-analysis. Neuropsychology 2009 Jul;23(4):411-423.

76 Suppl 5:v35-44.

2000;54(11 Suppl 5):S4-9.

Am Geriatr Soc 2002 Jan;50(1):41-48.

Nov;35(11 Suppl 1):2620-2622.

Jul;31(7):1487-1493.

1206-1209.

### **Author details**

Abhishek Shastri1\*, Domenico Marco Bonifati2 and Uday Kishore1

\*Address all correspondence to: abhishek.shastri@brunel.ac.uk

\*Address all correspondence to: domenicomarco.bonifati@apss.tn.it

1 Centre for Infection, Immunity and Disease Mechanisms, Brunel University, London, Unit‐ ed Kingdom

2 Unit of Neurology, Department of Neurosciences, Santa Chiara Hospital, Trento, Italy

#### **References**


[7] Roman GC, Sachdev P, Royall DR, Bullock RA, Orgogozo JM, Lopez-Pousa S, et al. Vascular cognitive disorder: a new diagnostic category updating vascular cognitive impairment and vascular dementia. J Neurol Sci 2004 Nov 15;226(1-2):81-87.

**6. Conclusions**

334 Neurodegenerative Diseases

**Author details**

ed Kingdom

**References**

The NAD or other dementias form a vital part of the fight against dementia and its conse‐ quences. Even though AD forms the bulk of dementia cases, knowledge and understanding of NAD might play an important role in the much needed quest for cure or prevention of dementia. More cutting-edge research into these diseases and their pathogenesis will help

1 Centre for Infection, Immunity and Disease Mechanisms, Brunel University, London, Unit‐

[1] Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB, et al. Prev‐ alence of dementia in the United States: the aging, demographics, and memory

[2] Kalaria RN, Maestre GE, Arizaga R, Friedland RP, Galasko D, Hall K, et al. Alzheim‐ er's disease and vascular dementia in developing countries: prevalence, manage‐

[3] Brookmeyer R, Evans DA, Hebert L, Langa KM, Heeringa SG, Plassman BL, et al. National estimates of the prevalence of Alzheimer's disease in the United States. Alz‐

[4] Bowler JV, Hachinski V. Vascular cognitive impairment: a new approach to vascular

[5] O'Brien JT, Erkinjuntti T, Reisberg B, Roman G, Sawada T, Pantoni L, et al. Vascular

[6] Moorhouse P, Rockwood K. Vascular cognitive impairment: current concepts and

2 Unit of Neurology, Department of Neurosciences, Santa Chiara Hospital, Trento, Italy

and Uday Kishore1

combat the spread and probably even onset of dementia.

\*Address all correspondence to: abhishek.shastri@brunel.ac.uk

study. Neuroepidemiology 2007;29(1-2):125-132.

heimers Dement 2011 Jan;7(1):61-73.

ment, and risk factors. Lancet Neurol 2008 Sep;7(9):812-826.

dementia. Baillieres Clin Neurol 1995 Aug;4(2):357-376.

cognitive impairment. Lancet Neurol 2003 Feb;2(2):89-98.

clinical developments. Lancet Neurol 2008 Mar;7(3):246-255.

\*Address all correspondence to: domenicomarco.bonifati@apss.tn.it

Abhishek Shastri1\*, Domenico Marco Bonifati2


[21] Perez L, Heim L, Sherzai A, Jaceldo-Siegl K, Sherzai A. Nutrition and vascular de‐ mentia. J Nutr Health Aging 2012 Apr;16(4):319-324.

[36] Fukutake T. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): from discovery to gene identification. J Stroke

Other Dementias

337

http://dx.doi.org/10.5772/53460

[37] Kalaria RN, Kenny RA, Ballard CG, Perry R, Ince P, Polvikoski T. Towards defining the neuropathological substrates of vascular dementia. J Neurol Sci 2004 Nov

[38] Deramecourt V, Slade JY, Oakley AE, Perry RH, Ince PG, Maurage CA, et al. Staging and natural history of cerebrovascular pathology in dementia. Neurology 2012 Apr

[39] Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteris‐

[40] PROGRESS Collaborative Group. Effects of a perindopril-based blood pressure low‐ ering regimen on cardiac outcomes among patients with cerebrovascular disease. Eur

[41] Roman GC, Salloway S, Black SE, Royall DR, Decarli C, Weiner MW, et al. Random‐ ized, placebo-controlled, clinical trial of donepezil in vascular dementia: differential

[42] Craig D, Birks J. Galantamine for vascular cognitive impairment. Cochrane Database

[43] Craig D, Birks J. Rivastigmine for vascular cognitive impairment. Cochrane Database

[44] Kavirajan H, Schneider LS. Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled tri‐

[45] Okazaki H, Lipkin LE, Aronson SM. Diffuse intracytoplasmic ganglionic inclusions (Lewy type) associated with progressive dementia and quadriparesis in flexion. J

[46] Lennox G, Lowe J, Landon M, Byrne EJ, Mayer RJ, Godwin-Austen RB. Diffuse Lewy body disease: correlative neuropathology using anti-ubiquitin immunocytochemis‐

[47] Kosaka K, Yoshimura M, Ikeda K, Budka H. Diffuse type of Lewy body disease: pro‐ gressive dementia with abundant cortical Lewy bodies and senile changes of varying

[48] Gibb WR, Esiri MM, Lees AJ. Clinical and pathological features of diffuse cortical Lewy body disease (Lewy body dementia). Brain 1987 Oct;110 ( Pt 5)(Pt 5):1131-1153.

[49] Hansen L, Salmon D, Galasko D, Masliah E, Katzman R, DeTeresa R, et al. The Lewy body variant of Alzheimer's disease: a clinical and pathologic entity. Neurology 1990

try. J Neurol Neurosurg Psychiatry 1989 Nov;52(11):1236-1247.

degree--a new disease? Clin Neuropathol 1984 Sep-Oct;3(5):185-192.

tics to therapeutic challenges. Lancet Neurol 2010 Jul;9(7):689-701.

effects by hippocampal size. Stroke 2010 Jun;41(6):1213-1221.

Cerebrovasc Dis 2011 Mar-Apr;20(2):85-93.

15;226(1-2):75-80.

3;78(14):1043-1050.

Jan;40(1):1-8.

Heart J 2003 Mar;24(5):475-484.

Syst Rev 2006 Jan 25;(1)(1):CD004746.

Syst Rev 2005 Apr 18;(2)(2):CD004744.

als. Lancet Neurol 2007 Sep;6(9):782-792.

Neuropathol Exp Neurol 1961 Apr;20:237-244.


[36] Fukutake T. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): from discovery to gene identification. J Stroke Cerebrovasc Dis 2011 Mar-Apr;20(2):85-93.

[21] Perez L, Heim L, Sherzai A, Jaceldo-Siegl K, Sherzai A. Nutrition and vascular de‐

[22] Hachinski VC, Iliff LD, Zilhka E, Du Boulay GH, McAllister VL, Marshall J, et al. Cer‐

[23] Chui HC, Victoroff JI, Margolin D, Jagust W, Shankle R, Katzman R. Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alz‐ heimer's Disease Diagnostic and Treatment Centers. Neurology 1992 Mar;42(3 Pt 1):

[24] Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 2007 Nov;10(11):1387-1394.

[25] Roman GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-

[26] Mathias JL, Burke J. Cognitive functioning in Alzheimer's and vascular dementia: a

[27] Ballard CG, Burton EJ, Barber R, Stephens S, Kenny RA, Kalaria RN, et al. NINDS AIREN neuroimaging criteria do not distinguish stroke patients with and without

[28] Ivan CS, Seshadri S, Beiser A, Au R, Kase CS, Kelly-Hayes M, et al. Dementia after

[29] Tatemichi TK, Desmond DW, Paik M, Figueroa M, Gropen TI, Stern Y, et al. Clinical determinants of dementia related to stroke. Ann Neurol 1993 Jun;33(6):568-575. [30] Pohjasvaara T, Erkinjuntti T, Ylikoski R, Hietanen M, Vataja R, Kaste M. Clinical de‐

[31] Henon H, Durieu I, Guerouaou D, Lebert F, Pasquier F, Leys D. Poststroke dementia: incidence and relationship to prestroke cognitive decline. Neurology 2001 Oct

[32] Leys D, Henon H, Mackowiak-Cordoliani MA, Pasquier F. Poststroke dementia. Lan‐

[33] Roman GC, Erkinjuntti T, Wallin A, Pantoni L, Chui HC. Subcortical ischaemic vas‐

[34] Joutel A, Favrole P, Labauge P, Chabriat H, Lescoat C, Andreux F, et al. Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet

[35] Hara K, Shiga A, Fukutake T, Nozaki H, Miyashita A, Yokoseki A, et al. Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. N Engl J

ebral blood flow in dementia. Arch Neurol 1975 Sep;32(9):632-637.

AIREN International Workshop. Neurology 1993 Feb;43(2):250-260.

stroke: the Framingham Study. Stroke 2004 Jun;35(6):1264-1268.

terminants of poststroke dementia. Stroke 1998 Jan;29(1):75-81.

cular dementia. Lancet Neurol 2002 Nov;1(7):426-436.

meta-analysis. Neuropsychology 2009 Jul;23(4):411-423.

dementia. Neurology 2004 Sep 28;63(6):983-988.

mentia. J Nutr Health Aging 2012 Apr;16(4):319-324.

473-480.

336 Neurodegenerative Diseases

9;57(7):1216-1222.

cet Neurol 2005 Nov;4(11):752-759.

2001 Dec 15;358(9298):2049-2051.

Med 2009 Apr 23;360(17):1729-1739.


[50] Perry RH, Irving D, Blessed G, Fairbairn A, Perry EK. Senile dementia of Lewy body type. A clinically and neuropathologically distinct form of Lewy body dementia in the elderly. J Neurol Sci 1990 Feb;95(2):119-139.

[64] Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann

Other Dementias

339

http://dx.doi.org/10.5772/53460

[65] Gomez-Tortosa E, Newell K, Irizarry MC, Sanders JL, Hyman BT. alpha-Synuclein immunoreactivity in dementia with Lewy bodies: morphological staging and com‐ parison with ubiquitin immunostaining. Acta Neuropathol 2000 Apr;99(4):352-357.

[66] Harding AJ, Broe GA, Halliday GM. Visual hallucinations in Lewy body disease re‐ late to Lewy bodies in the temporal lobe. Brain 2002 Feb;125(Pt 2):391-403.

[67] Watson R, Blamire AM, O'Brien JT. Magnetic resonance imaging in lewy body de‐

[68] Lobotesis K, Fenwick JD, Phipps A, Ryman A, Swann A, Ballard C, et al. Occipital hypoperfusion on SPECT in dementia with Lewy bodies but not AD. Neurology 2001

[69] McKeith I, O'Brien J, Walker Z, Tatsch K, Booij J, Darcourt J, et al. Sensitivity and spe‐ cificity of dopamine transporter imaging with 123I-FP-CIT SPECT in dementia with Lewy bodies: a phase III, multicentre study. Lancet Neurol 2007 Apr;6(4):305-313.

[70] O'Brien JT, McKeith IG, Walker Z, Tatsch K, Booij J, Darcourt J, et al. Diagnostic accu‐ racy of 123I-FP-CIT SPECT in possible dementia with Lewy bodies. Br J Psychiatry

[71] Gomperts SN, Rentz DM, Moran E, Becker JA, Locascio JJ, Klunk WE, et al. Imaging amyloid deposition in Lewy body diseases. Neurology 2008 Sep 16;71(12):903-910.

[72] Lucetti C, Logi C, Del Dotto P, Berti C, Ceravolo R, Baldacci F, et al. Levodopa re‐ sponse in dementia with lewy bodies: a 1-year follow-up study. Parkinsonism Relat

[73] Ballard C, Kahn Z, Corbett A. Treatment of dementia with Lewy bodies and Parkin‐

[74] Aarsland D, Ballard C, Walker Z, Bostrom F, Alves G, Kossakowski K, et al. Meman‐ tine in patients with Parkinson's disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial. Lancet Neurol 2009 Jul;8(7):

[75] Rolinski M, Fox C, Maidment I, McShane R. Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson's disease dementia and cognitive impairment in Par‐

[76] Ballard C, O'Brien J, Morris CM, Barber R, Swann A, Neill D, et al. The progression of cognitive impairment in dementia with Lewy bodies, vascular dementia and Alz‐

kinson's disease. Cochrane Database Syst Rev 2012 Mar 14;3:CD006504.

heimer's disease. Int J Geriatr Psychiatry 2001 May;16(5):499-503.

son's disease dementia. Drugs Aging 2011 Oct 1;28(10):769-777.

mentias. Dement Geriatr Cogn Disord 2009;28(6):493-506.

Neurol 2004 Feb;55(2):164-173.

Mar 13;56(5):643-649.

2009 Jan;194(1):34-39.

613-618.

Disord 2010 Sep;16(8):522-526.


[64] Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 2004 Feb;55(2):164-173.

[50] Perry RH, Irving D, Blessed G, Fairbairn A, Perry EK. Senile dementia of Lewy body type. A clinically and neuropathologically distinct form of Lewy body dementia in

[52] Yamada T, Hattori H, Miura A, Tanabe M, Yamori Y. Prevalence of Alzheimer's dis‐ ease, vascular dementia and dementia with Lewy bodies in a Japanese population.

[53] Stevens T, Livingston G, Kitchen G, Manela M, Walker Z, Katona C. Islington study of dementia subtypes in the community. Br J Psychiatry 2002 Mar;180:270-276.

[54] Rahkonen T, Eloniemi-Sulkava U, Rissanen S, Vatanen A, Viramo P, Sulkava R. De‐ mentia with Lewy bodies according to the consensus criteria in a general population

[55] Zaccai J, McCracken C, Brayne C. A systematic review of prevalence and incidence studies of dementia with Lewy bodies. Age Ageing 2005 Nov;34(6):561-566.

[56] Perez F, Helmer C, Dartigues JF, Auriacombe S, Tison F. A 15-year population-based cohort study of the incidence of Parkinson's disease and dementia with Lewy bodies in an elderly French cohort. J Neurol Neurosurg Psychiatry 2010 Jul;81(7):742-746.

[57] McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consorti‐

[58] Ferman TJ, Boeve BF, Smith GE, Silber MH, Lucas JA, Graff-Radford NR, et al. De‐ mentia with Lewy bodies may present as dementia and REM sleep behavior disorder without parkinsonism or hallucinations. J Int Neuropsychol Soc 2002 Nov;8(7):

[59] Boeve BF, Silber MH, Ferman TJ. REM sleep behavior disorder in Parkinson's disease and dementia with Lewy bodies. J Geriatr Psychiatry Neurol 2004 Sep;17(3):146-157.

[60] Ferman TJ, Boeve BF, Smith GE, Lin SC, Silber MH, Pedraza O, et al. Inclusion of RBD improves the diagnostic classification of dementia with Lewy bodies. Neurolo‐

[61] Harding AJ, Halliday GM. Cortical Lewy body pathology in the diagnosis of demen‐

[62] Burton EJ, Mukaetova-Ladinska EB, Perry RH, Jaros E, Barber R, O'Brien JT. Neuro‐ pathological correlates of volumetric MRI in autopsy-confirmed Lewy body demen‐

[63] Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-

synuclein in Lewy bodies. Nature 1997 Aug 28;388(6645):839-840.

aged 75 years or older. J Neurol Neurosurg Psychiatry 2003 Jun;74(6):720-724.

the elderly. J Neurol Sci 1990 Feb;95(2):119-139.

Psychiatry Clin Neurosci 2001 Feb;55(1):21-25.

um. Neurology 2005 Dec 27;65(12):1863-1872.

tia. Acta Neuropathol 2001 Oct;102(4):355-363.

tia. Neurobiol Aging 2012 Jul;33(7):1228-1236.

gy 2011 Aug 30;77(9):875-882.

907-914.

338 Neurodegenerative Diseases

[51] Stoll G, Jander S. Microglia. eLS: John Wiley & Sons, Ltd; 2001.


[77] Walker Z, Allen RL, Shergill S, Mullan E, Katona CL. Three years survival in patients with a clinical diagnosis of dementia with Lewy bodies. Int J Geriatr Psychiatry 2000 Mar;15(3):267-273.

[91] Lillo P, Hodges JR. Frontotemporal dementia and motor neurone disease: overlap‐ ping clinic-pathological disorders. J Clin Neurosci 2009 Sep;16(9):1131-1135.

Other Dementias

341

http://dx.doi.org/10.5772/53460

[92] Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-

[93] DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011 Oct 20;72(2):245-256.

[94] Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM, Hatanpaa KJ, et al. Neuro‐ pathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuro‐

[95] Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, et al. Nomencla‐ ture and nosology for neuropathologic subtypes of frontotemporal lobar degenera‐

[96] Piguet O, Hornberger M, Mioshi E, Hodges JR. Behavioural-variant frontotemporal dementia: diagnosis, clinical staging, and management. Lancet Neurol 2011 Feb;

[97] Rohrer JD, Lashley T, Schott JM, Warren JE, Mead S, Isaacs AM, et al. Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degenera‐

[98] Mackenzie IR, Rademakers R, Neumann M. TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol 2010 Oct;9(10):995-1007.

[99] Agosta F, Canu E, Sarro L, Comi G, Filippi M. Neuroimaging findings in frontotem‐ poral lobar degeneration spectrum of disorders. Cortex 2012 Apr;48(4):389-413.

[100] Mioshi E, Hsieh S, Savage S, Hornberger M, Hodges JR. Clinical staging and disease progression in frontotemporal dementia. Neurology 2010 May 18;74(20):1591-1597.

[101] McKhann GM, Albert MS, Grossman S, Miller B, Dickson D, Trojanowski JQ. Clinical and Pathological Diagnosis of Frontotemporal Dementia. Report of the Work Group on Frontotemporal Dementia and Pick's Disease. Arch Neurol 2001;58:1803-1809.

[102] Yokota O, Tsuchiya K, Arai T, Yagishita S, Matsubara O, Mochizuki A, et al. Clinico‐ pathological characterization of Pick's disease versus frontotemporal lobar degenera‐ tion with ubiquitin/TDP-43-positive inclusions. Acta Neuropathol 2009 Apr;117(4):

[103] Binetti G, Locascio JJ, Corkin S, Vonsattel JP, Growdon JH. Differences between Pick disease and Alzheimer disease in clinical appearance and rate of cognitive decline.

linked ALS-FTD. Neuron 2011 Oct 20;72(2):257-268.

tion: an update. Acta Neuropathol 2010 Jan;119(1):1-4.

tion. Brain 2011 Sep;134(Pt 9):2565-2581.

Arch Neurol 2000 Feb;57(2):225-232.

pathol 2007 Jul;114(1):5-22.

10(2):162-172.

429-444.


[91] Lillo P, Hodges JR. Frontotemporal dementia and motor neurone disease: overlap‐ ping clinic-pathological disorders. J Clin Neurosci 2009 Sep;16(9):1131-1135.

[77] Walker Z, Allen RL, Shergill S, Mullan E, Katona CL. Three years survival in patients with a clinical diagnosis of dementia with Lewy bodies. Int J Geriatr Psychiatry 2000

[78] McKeith I, Mintzer J, Aarsland D, Burn D, Chiu H, Cohen-Mansfield J, et al. Demen‐

[79] Burrell JR, Kiernan MC, Vucic S, Hodges JR. Motor neuron dysfunction in frontotem‐

[80] Ratnavalli E, Brayne C, Dawson K, Hodges JR. The prevalence of frontotemporal de‐

[81] Rosso SM, Donker Kaat L, Baks T, Joosse M, de Koning I, Pijnenburg Y, et al. Fronto‐ temporal dementia in The Netherlands: patient characteristics and prevalence esti‐

[82] Borroni B, Alberici A, Grassi M, Rozzini L, Turla M, Zanetti O, et al. Prevalence and demographic features of early-onset neurodegenerative dementia in Brescia County,

[83] Mercy L, Hodges JR, Dawson K, Barker RA, Brayne C. Incidence of early-onset de‐ mentias in Cambridgeshire, United Kingdom. Neurology 2008 Nov 4;71(19):

[84] Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998 Dec;

[85] Johnson JK, Diehl J, Mendez MF, Neuhaus J, Shapira JS, Forman M, et al. Frontotem‐ poral lobar degeneration: demographic characteristics of 353 patients. Arch Neurol

[86] Neary D, Snowden J, Mann D. Frontotemporal dementia. Lancet Neurol 2005 Nov;

[87] Rascovsky K, Hodges JR, Kipps CM, Johnson JK, Seeley WW, Mendez MF, et al. Di‐ agnostic criteria for the behavioral variant of frontotemporal dementia (bvFTD): cur‐ rent limitations and future directions. Alzheimer Dis Assoc Disord 2007 Oct-Dec;

[88] Hodges JR, Patterson K, Oxbury S, Funnell E. Semantic dementia. Progressive fluent aphasia with temporal lobe atrophy. Brain 1992 Dec;115 ( Pt 6)(Pt 6):1783-1806.

[89] Tambuyzer BR, Ponsaerts P, Nouwen EJ. Microglia: gatekeepers of central nervous

[90] Nestor PJ, Graham NL, Fryer TD, Williams GB, Patterson K, Hodges JR. Progressive non-fluent aphasia is associated with hypometabolism centred on the left anterior in‐

system immunology. J Leukoc Biol 2009 Mar;85(3):352-370.

sula. Brain 2003 Nov;126(Pt 11):2406-2418.

mates from a population-based study. Brain 2003 Sep;126(Pt 9):2016-2022.

tia with Lewy bodies. Lancet Neurol 2004 Jan;3(1):19-28.

Italy. Alzheimer Dis Assoc Disord 2011 Oct;25(4):341-344.

poral dementia. Brain 2011 Sep;134(Pt 9):2582-2594.

mentia. Neurology 2002 Jun 11;58(11):1615-1621.

Mar;15(3):267-273.

340 Neurodegenerative Diseases

1496-1499.

51(6):1546-1554.

4(11):771-780.

21(4):S14-8.

2005 Jun;62(6):925-930.


[104] Cohen BJ. Theory and Practice of Psychiatry. New York: Oxford University Press; 2003.

[120] Emre M. Dementia associated with Parkinson's disease. Lancet Neurol 2003 Apr;2(4):

Other Dementias

343

http://dx.doi.org/10.5772/53460

[121] Perez F, Helmer C, Foubert-Samier A, Auriacombe S, Dartigues JF, Tison F. Risk of dementia in an elderly population of Parkinson's disease patients: A 15-year popula‐

[122] Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-Sorensen P. Prevalence and char‐ acteristics of dementia in Parkinson disease: an 8-year prospective study. Arch Neu‐

[123] Aarsland D, Kurz MW. The epidemiology of dementia associated with Parkinson's

[124] Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y, et al. Clinical di‐ agnostic criteria for dementia associated with Parkinson's disease. Mov Disord 2007

[125] Postuma RB, Bertrand JA, Montplaisir J, Desjardins C, Vendette M, Rios Romenets S, et al. Rapid eye movement sleep behavior disorder and risk of dementia in Parkin‐

[126] Weintraub D, Doshi J, Koka D, Davatzikos C, Siderowf AD, Duda JE, et al. Neurode‐ generation across stages of cognitive decline in Parkinson disease. Arch Neurol 2011

[127] Rossi C, Volterrani D, Nicoletti V, Manca G, Frosini D, Kiferle L, Unti E, De Feo P, Bonuccelli U, Ceravolo R. "Parkinson-dementia" diseases: A comparison by double

[129] Levy G, Tang MX, Louis ED, Cote LJ, Alfaro B, Mejia H, et al. The association of inci‐ dent dementia with mortality in PD. Neurology 2002 Dec 10;59(11):1708-1713. [130] Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, et al. Updated re‐ search nosology for HIV-associated neurocognitive disorders. Neurology 2007 Oct

[131] McArthur JC, Hoover DR, Bacellar H, Miller EN, Cohen BA, Becker JT, et al. Demen‐ tia in AIDS patients: incidence and risk factors. Multicenter AIDS Cohort Study.

[132] Sacktor N. The epidemiology of human immunodeficiency virus-associated neuro‐ logical disease in the era of highly active antiretroviral therapy. J Neurovirol 2002

[133] Mocroft A, Katlama C, Johnson AM, Pradier C, Antunes F, Mulcahy F, et al. AIDS across Europe, 1994-98: the EuroSIDA study. Lancet 2000 Jul 22;356(9226):291-296.

tracer SPECT studies. Parkinsonism and Related Disorders 2009 (15)762-766. [128] Rolinski M, Fox C, Maidment I, McShane R. Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson's disease dementia and cognitive impairment in Par‐

kinson's disease. Cochrane Database Syst Rev 2012 Mar 14;3:CD006504.

son's disease: A prospective study. Mov Disord 2012 May;27(6):720-726.

tion-based study. Alzheimers Dement 2012 May 30.

disease. Brain Pathol 2010 May;20(3):633-639.

229-237.

rol 2003 Mar;60(3):387-392.

Sep 15;22(12):1689-707; quiz 1837.

Dec;68(12):1562-1568.

30;69(18):1789-1799.

Dec;8 Suppl 2:115-121.

Neurology 1993 Nov;43(11):2245-2252.


[120] Emre M. Dementia associated with Parkinson's disease. Lancet Neurol 2003 Apr;2(4): 229-237.

[104] Cohen BJ. Theory and Practice of Psychiatry. New York: Oxford University Press;

[105] Munoz DJ, Morris HR, Rossor M. Pick's Disease. In: Dickson DW, Weller RO (eds.) Neurodegeneration: The Molecular Pathology of Dementia and Movement Disor‐

[106] Aguzzi A, Heikenwalder M. Pathogenesis of prion diseases: current status and fu‐

[107] Sikorska B, Knight R, Ironside JW, Liberski PP. Creutzfeldt-Jakob Disease. In: Ahmad SI (ed.) Neurodegenerative Diseases. Landes Bioscience and Springer Science+Busi‐

[108] Rosenbloom MH, Atri A. The evaluation of rapidly progressive dementia. Neurolo‐

[109] Aguzzi A, Calella AM. Prions: protein aggregation and infectious diseases. Physiol

[110] Geschwind MD, Shu H, Haman A, Sejvar JJ, Miller BL. Rapidly progressive demen‐

[111] Brown P, Gibbs CJ,Jr, Rodgers-Johnson P, Asher DM, Sulima MP, Bacote A, et al. Hu‐ man spongiform encephalopathy: the National Institutes of Health series of 300 cases

[112] Johnson RT, Gibbs CJ,Jr. Creutzfeldt-Jakob disease and related transmissible spongi‐

[114] Heath CA, Cooper SA, Murray K, Lowman A, Henry C, MacLeod MA, et al. Valida‐ tion of diagnostic criteria for variant Creutzfeldt-Jakob disease. Ann Neurol 2010 Jun;

[115] A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Re‐

[116] Gil JM, Rego AC. Mechanisms of neurodegeneration in Huntington's disease. Eur J

[117] Lovestone S. Alzheimer's Disease and Other Dementias (Including Pseudodemen‐ tias). In: David AS, Fleminger S, Kopelman MD, Lovestone S, Mellers JDC (eds.) Lishman's Organic Psychiatry, Fourth Edition. Blackwell Publishing; 2009. p543-616.

[118] Sturrock A, Leavitt BR. The clinical and genetic features of Huntington disease. J

[119] Ross CA, Poirier MA. Protein aggregation and neurodegenerative disease. Nat Med

of experimentally transmitted disease. Ann Neurol 1994 May;35(5):513-529.

form encephalopathies. N Engl J Med 1998 Dec 31;339(27):1994-2004.

[113] Johnson RT. Prion diseases. Lancet Neurol 2005 Oct;4(10):635-642.

search Group. Cell 1993 Mar 26;72(6):971-983.

Geriatr Psychiatry Neurol 2010 Dec;23(4):243-259.

Neurosci 2008 Jun;27(11):2803-2820.

2004 Jul;10 Suppl:S10-7.

ders, Second Edition. Blackwell Publishing Ltd.; 2011. p156-164.

ture outlook. Nat Rev Microbiol 2006 Oct;4(10):765-775.

2003.

342 Neurodegenerative Diseases

ness Media; 2012. p76-90.

gist 2011 Mar;17(2):67-74.

67(6):761-770.

Rev 2009 Oct;89(4):1105-1152.

tia. Ann Neurol 2008 Jul;64(1):97-108.


[134] Heaton RK, Clifford DB, Franklin DR,Jr, Woods SP, Ake C, Vaida F, et al. HIV-associ‐ ated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 2010 Dec 7;75(23):2087-2096.

**Chapter 14**

**The Role of Epigenetics in Neurodegenerative Diseases**

Neurodegenerative disorders are among the greatest challenges and among the most serious health problems that will have to be faced by the modern societies across the world, especially in light of increasing population age. They are incurable, progressive conditions resulting from continuous degeneration and death of nerve cells. Most of these disorders become more common with advancing age, including Alzheimer's disease and Parkinson's disease. The burden of these neurodegenerative diseases is growing inexorably as the population ages, with incalculable economic and human costs. According to a collaborative study of the World Health Organization, the World Bank and the Harvard School of Public Health (the Global Burden of Disease Study) dementia and other neurodegenerative diseases will be the eighth cause of disease burden for developed regions in 2020 [1, 2]. Moreover, they will become the world's second leading cause of death by 2050, overtaking cancer [2]. These future projections are of course only estimates, but they in combination with current state certainly support the

Although a minor subset of these disorders is caused by clearly defined genetic factors, for example Huntington's disease, the largest proportion arise due to a complex interplay of genetic and environmental factors. For this reason, delineation of specific risk factors, useful biomarkers, potential new therapeutic targets and agents and even definite diagnosis still remains difficult. Pathological characteristics in brain during the process of neurodegeneration show considerable overlap among different types of neurodegenerative cognitive and motor impairment [3]. Moreover, pathological findings do not neccessarily correlate with clinical findings, meaning that extensive neuropathology does not definitely imply a severly impared neurological function and, on the other hand, minor pathology may entail significantly impaired neurological function [4, 5]. Namely, neuropathological processes are not necessarily

and reproduction in any medium, provided the original work is properly cited.

© 2013 Lovrečić et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

fact that neurodegenerative diseases are of an increasing public concern

Luca Lovrečić, Aleš Maver, Maja Zadel and

Additional information is available at the end of the chapter

Borut Peterlin

**1. Introduction**

http://dx.doi.org/10.5772/54744


### **The Role of Epigenetics in Neurodegenerative Diseases**

Luca Lovrečić, Aleš Maver, Maja Zadel and Borut Peterlin

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54744

#### **1. Introduction**

[134] Heaton RK, Clifford DB, Franklin DR,Jr, Woods SP, Ake C, Vaida F, et al. HIV-associ‐ ated neurocognitive disorders persist in the era of potent antiretroviral therapy:

[135] Nath A. Human immunodeficiency virus (HIV) proteins in neuropathogenesis of

[136] del Palacio M, Alvarez S, Munoz-Fernandez MA. HIV-1 infection and neurocognitive

[137] Sacktor NC, Wong M, Nakasujja N, Skolasky RL, Selnes OA, Musisi S, et al. The In‐ ternational HIV Dementia Scale: a new rapid screening test for HIV dementia. AIDS

[138] McArthur JC, Brew BJ, Nath A. Neurological complications of HIV infection. Lancet

[139] Uthman OA, Abdulmalik JO. Adjunctive therapies for AIDS dementia complex. Co‐

CHARTER Study. Neurology 2010 Dec 7;75(23):2087-2096.

HIV dementia. J Infect Dis 2002 Dec 1;186 Suppl 2:S193-8.

chrane Database Syst Rev 2008 Jul 16;(3)(3):CD006496.

2005 Sep 2;19(13):1367-1374.

344 Neurodegenerative Diseases

Neurol 2005 Sep;4(9):543-555.

impairment in the current era. Rev Med Virol 2012 Jan;22(1):33-45.

Neurodegenerative disorders are among the greatest challenges and among the most serious health problems that will have to be faced by the modern societies across the world, especially in light of increasing population age. They are incurable, progressive conditions resulting from continuous degeneration and death of nerve cells. Most of these disorders become more common with advancing age, including Alzheimer's disease and Parkinson's disease. The burden of these neurodegenerative diseases is growing inexorably as the population ages, with incalculable economic and human costs. According to a collaborative study of the World Health Organization, the World Bank and the Harvard School of Public Health (the Global Burden of Disease Study) dementia and other neurodegenerative diseases will be the eighth cause of disease burden for developed regions in 2020 [1, 2]. Moreover, they will become the world's second leading cause of death by 2050, overtaking cancer [2]. These future projections are of course only estimates, but they in combination with current state certainly support the fact that neurodegenerative diseases are of an increasing public concern

Although a minor subset of these disorders is caused by clearly defined genetic factors, for example Huntington's disease, the largest proportion arise due to a complex interplay of genetic and environmental factors. For this reason, delineation of specific risk factors, useful biomarkers, potential new therapeutic targets and agents and even definite diagnosis still remains difficult. Pathological characteristics in brain during the process of neurodegeneration show considerable overlap among different types of neurodegenerative cognitive and motor impairment [3]. Moreover, pathological findings do not neccessarily correlate with clinical findings, meaning that extensive neuropathology does not definitely imply a severly impared neurological function and, on the other hand, minor pathology may entail significantly impaired neurological function [4, 5]. Namely, neuropathological processes are not necessarily

© 2013 Lovrečić et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

the cause of the underlying disease at the early disease stages, but may merely be the reflection of fundamental disease processes, yet unknown in majority of neurodegenerative disorders. Later, as disease progresses, neuropathological changes probably contribute to disease progression in a positive feedback loop.

Ballard et all estimated in 2011[6] that 24 million people have dementia worldwide, majority attributable to AD. Namely, it is foreseen that more than 80 million people will have AD by 2040 [7], because of the population ageing and age-dependent incidence rate of AD. In order to improve development of disease-modifying treatment we need to understand the under‐ lying pathophysiology of the disease. It is a progressive neurodegenerative disease which predominantly affects cortical and hippocampal neurons and leads to their irreversible loss [8]. Major clinical signs and symptoms include progressive impairment in memory, judgment, decision making, orientation to physical surroundings, and language. There are several neuropathological features in AD, but only 2 are considered essential for the diagnosis - β amyloid containing extracellular senile plaques and neurofibrillary tangles, composed of a hyperphosphorylated form of the microtubular protein tau. Others include synapse loss, neuron loss, atrophy, gliosis, degenerative changes in white matter, granulovacuolar degen‐

The Role of Epigenetics in Neurodegenerative Diseases

http://dx.doi.org/10.5772/54744

347

PD was first described by James Parkinson in earyl 1800s as "shaking palsy". It is the second most prevalent neurodegenerative disease after AD. There are over 6 million people with PD worldwide (European Parkinson's Disease Association, EPDA). As elderly population increases, this estimate is predicted to double by the year 2040. The typical clinical signs are resting tremor, bradykinesia, muscle rigidity, and postural instability. The key neuropatho‐ logical characteristics are the loss of neurons in the substantia nigra and the presence of neuronal protein aggregates termed Lewy bodies [10]. It is believed that approximately 5-20% of patients have monogenic PD with more than 10 genes being identified as causative. These gene defects in familial PD highlight the importance of genetic influences in this disease, however the majority of PD cases are considered sporadic and idiopathic nad thus believed to be largely influenced also by other factors. The current consensus suggests that PD develops from multiple risk factors including aging, genetic predisposition, and environmental

Important future challenge in the management AD and PD remains the establishment of early diagnosis or even identification of individuals prior to the onset of dementia in AD or resting tremor in PD. This implicates advancement in understanding disease pathogenesis and development of diagnostic approaches, including disease/process specific biomarkers.

Huntington disease is a late onset, autosomal dominant genetic disease - its cause is invariably trinucleotide expansion mutation, known for almost 2 decades [12]. Typical clinical signs are progressive motor impairment, cognitive decline and various psychiatric symptoms with the age of onset between 30 and 50 years. The disease is fatal after 15-20 years of progressive neurodegeneration [13]. So far, no effective treatment has been available to cure the disease or to even efficiently slow its progression. Although hyperkinesias and psychiatric symptoms respond well to pharmacotherapy, neuropsychological deficits and dementia remain untreat‐ able [14]. There is no way of predicting the age at onset. Also, due to the insensitive clinical rating scales, it is not feasible to follow the disease progression over short time periods. Moreover, there are no specific measures to follow response to symptomatic treatment over

**2.2. Huntington disease – A model of genetic neurodegenerative disorder**

eration, other protein aggregates [9].

exposure [11].

Currently, there is no diagnostic test that can clearly indicate the presence, absence, or category of a neurodegenerative disease. Individual diagnosis is based on clinical evaluation of the symptoms and specific neuroimaging characteristics, and it often takes years to make one. The exceptions are monogenic diseases, such as Huntington's disease (HD), where specific genetic test confirms the diagnosis.

Another unexplained field is underlying mechanism in a majority of neurodegenerative diseases. Most are characterized by the aggregation of intracellular proteins, but it is not clear whether this is a primary mechanism or a consequence of another disturbed cell function. The potential mechanisms of neurodegeneration are innumerable, including primary effects of protein homeostasis, disturbed protein degradation, gene expression, transcriptional regula‐ tion, mitochondrial dysfunction, etc. There is the urgent need to better understand disease pathophysiology in order to improve early diagnosis and development of disease-modifying treatments.

In the recent decade, however, a role of epigenetic alterations in development of neurodege‐ nerative diseases has been increasingly discussed. Epigenetic constitution presents a landscape where environmental factors may interact with genetic make-up of an individual. Addition‐ ally, the development of high-throughput technologies for genomic, trancriptomic and epigenomic profiling now offers insight into epigenetic alterations in neurodegeneration, as well as opportunity for an integrative view of its interactions with various 'omic' levels. Interpretation of epigenomic profiling results in the context of neurodegeneration and the methodology for integration of heterogeneous 'omic' data opens an array of novel biological and bioinformatic challenges and requires the development of novel approaches towards analysis of these data.

### **2. Neurodegenerative disorders**

#### **2.1. Common neurodegenerative disorders – Alzheimer and Parkinson disease**

Parkinson's disease (PD) and Alzheimer disease (AD) are two most common neurodegenera‐ tive diseases. Both are very heterogeneous in regard to the causes (combination of genetic and environmental factors), wide range in the age at onset, vast variety in leading symptoms and presenting clinical manifestations, disease progression and responses to different therapies. Definitive clinical diagnosis is hard, although a number of clinical and neuropsychological tests are often employed when making it. AD is detected with approximately 85–90% accuracy and PD with approximately 75% accuracy. Despite endless number of research groups worldwide trying to uncover and explain the pathogenesis of both AD and PD, they still remain unexplained.

Ballard et all estimated in 2011[6] that 24 million people have dementia worldwide, majority attributable to AD. Namely, it is foreseen that more than 80 million people will have AD by 2040 [7], because of the population ageing and age-dependent incidence rate of AD. In order to improve development of disease-modifying treatment we need to understand the under‐ lying pathophysiology of the disease. It is a progressive neurodegenerative disease which predominantly affects cortical and hippocampal neurons and leads to their irreversible loss [8]. Major clinical signs and symptoms include progressive impairment in memory, judgment, decision making, orientation to physical surroundings, and language. There are several neuropathological features in AD, but only 2 are considered essential for the diagnosis - β amyloid containing extracellular senile plaques and neurofibrillary tangles, composed of a hyperphosphorylated form of the microtubular protein tau. Others include synapse loss, neuron loss, atrophy, gliosis, degenerative changes in white matter, granulovacuolar degen‐ eration, other protein aggregates [9].

the cause of the underlying disease at the early disease stages, but may merely be the reflection of fundamental disease processes, yet unknown in majority of neurodegenerative disorders. Later, as disease progresses, neuropathological changes probably contribute to disease

Currently, there is no diagnostic test that can clearly indicate the presence, absence, or category of a neurodegenerative disease. Individual diagnosis is based on clinical evaluation of the symptoms and specific neuroimaging characteristics, and it often takes years to make one. The exceptions are monogenic diseases, such as Huntington's disease (HD), where specific genetic

Another unexplained field is underlying mechanism in a majority of neurodegenerative diseases. Most are characterized by the aggregation of intracellular proteins, but it is not clear whether this is a primary mechanism or a consequence of another disturbed cell function. The potential mechanisms of neurodegeneration are innumerable, including primary effects of protein homeostasis, disturbed protein degradation, gene expression, transcriptional regula‐ tion, mitochondrial dysfunction, etc. There is the urgent need to better understand disease pathophysiology in order to improve early diagnosis and development of disease-modifying

In the recent decade, however, a role of epigenetic alterations in development of neurodege‐ nerative diseases has been increasingly discussed. Epigenetic constitution presents a landscape where environmental factors may interact with genetic make-up of an individual. Addition‐ ally, the development of high-throughput technologies for genomic, trancriptomic and epigenomic profiling now offers insight into epigenetic alterations in neurodegeneration, as well as opportunity for an integrative view of its interactions with various 'omic' levels. Interpretation of epigenomic profiling results in the context of neurodegeneration and the methodology for integration of heterogeneous 'omic' data opens an array of novel biological and bioinformatic challenges and requires the development of novel approaches towards

**2.1. Common neurodegenerative disorders – Alzheimer and Parkinson disease**

Parkinson's disease (PD) and Alzheimer disease (AD) are two most common neurodegenera‐ tive diseases. Both are very heterogeneous in regard to the causes (combination of genetic and environmental factors), wide range in the age at onset, vast variety in leading symptoms and presenting clinical manifestations, disease progression and responses to different therapies. Definitive clinical diagnosis is hard, although a number of clinical and neuropsychological tests are often employed when making it. AD is detected with approximately 85–90% accuracy and PD with approximately 75% accuracy. Despite endless number of research groups worldwide trying to uncover and explain the pathogenesis of both AD and PD, they still remain

progression in a positive feedback loop.

test confirms the diagnosis.

346 Neurodegenerative Diseases

treatments.

analysis of these data.

unexplained.

**2. Neurodegenerative disorders**

PD was first described by James Parkinson in earyl 1800s as "shaking palsy". It is the second most prevalent neurodegenerative disease after AD. There are over 6 million people with PD worldwide (European Parkinson's Disease Association, EPDA). As elderly population increases, this estimate is predicted to double by the year 2040. The typical clinical signs are resting tremor, bradykinesia, muscle rigidity, and postural instability. The key neuropatho‐ logical characteristics are the loss of neurons in the substantia nigra and the presence of neuronal protein aggregates termed Lewy bodies [10]. It is believed that approximately 5-20% of patients have monogenic PD with more than 10 genes being identified as causative. These gene defects in familial PD highlight the importance of genetic influences in this disease, however the majority of PD cases are considered sporadic and idiopathic nad thus believed to be largely influenced also by other factors. The current consensus suggests that PD develops from multiple risk factors including aging, genetic predisposition, and environmental exposure [11].

Important future challenge in the management AD and PD remains the establishment of early diagnosis or even identification of individuals prior to the onset of dementia in AD or resting tremor in PD. This implicates advancement in understanding disease pathogenesis and development of diagnostic approaches, including disease/process specific biomarkers.

#### **2.2. Huntington disease – A model of genetic neurodegenerative disorder**

Huntington disease is a late onset, autosomal dominant genetic disease - its cause is invariably trinucleotide expansion mutation, known for almost 2 decades [12]. Typical clinical signs are progressive motor impairment, cognitive decline and various psychiatric symptoms with the age of onset between 30 and 50 years. The disease is fatal after 15-20 years of progressive neurodegeneration [13]. So far, no effective treatment has been available to cure the disease or to even efficiently slow its progression. Although hyperkinesias and psychiatric symptoms respond well to pharmacotherapy, neuropsychological deficits and dementia remain untreat‐ able [14]. There is no way of predicting the age at onset. Also, due to the insensitive clinical rating scales, it is not feasible to follow the disease progression over short time periods. Moreover, there are no specific measures to follow response to symptomatic treatment over short time periods. In addition, in the presymptomatic period when preventive treatment and slowing of neurodegeneration might be most effective, there are no measures/markers to monitor those responses and benefits.

The function of normal huntingtin in the cells and mutation mechanism that leads to neuro‐ degeneration and typical signs are still not clear, despite the fact, that the responsible gene and mutation were already identified and characterized in 1993. Basic research created many different hypotheses about pathogenic mechanisms – they include disturbances in variety of biochemical pathways, such as accumulation of misfolded mutated proteins, apoptosis, protein degradation, intracellular signaling as well as oxidative stress, disturbed transcription regulation [15, 16] and epigenetic processes [17].

### **3. Epigenetic mechanisms**

Increasing interest in epigenetics which is currently one of the most rapidly expanding fields in biomedical research has been accompanied by several breakthroughs like finding new histone variants and modifications, the discovery of the CpG island shores and most of all possibility of genome-wide analysis of epigenetic marks – epigenomic analysis – at single nucleotide resolution. The recognition of the role of epigenetics and how important it could be in human disease was first discussed in oncology and further extended to neurodevelop‐ ment and neurodegenerative diseases.

**3. RNA-based mechanisms** have also recently been shown to impact the higher-order

The Role of Epigenetics in Neurodegenerative Diseases

http://dx.doi.org/10.5772/54744

349

This is the most widely studied epigenetic mechanism which consists of covalent addition of methyl group at the 5-position of cytosines followed by guanines (CpG dinucleotides) and is usually associated with gene silencing. CpG dinucleotides are generally clustered in regions called CpG islands defined as regions with G-C content of at least 50%. Human gene promoters are associated with CpG island in about 60%. In normal cells they are usually unmethylated and about 6% of them become methylated in a tissue-specific manner in differentiated tissue

DNA methylation is not present only at CpG islands. Recently, a new term has been coined, CpG island shores which are regions of lower CpG density that are located close (≈ 2kb) to the CpG islands. Additionally, it seems that methylation of CpG island shores is closely related to the inactivation of transcription and is also found that most of tissue-specific methylation of

DNA methylation can inhibit gene expression in direct or indirect ways. Indirect transcription inhibition is mediated through promoting activation of methyl-CpG-binding domain (MBD) proteins by methylated DNA, which inhibit transcription [23]. Direct transcriptional inhibition

A significant portion of methylated CpG islands is also found in repetitive elements. This methylation is functional and needed because of protection from reactivation of endoparasitic sequences which can cause chromosomal instability, gene disruption and translocations [24]. Eventhough DNA methylation occurs mostly in CpG islands in mammals, non-CG methyla‐ tion has recently been described in humans at CHG and CHH sites (H=A,C or T). The level of

is possible by interruption of activity of DNA binding proteins from their target sites.

structure of chromatin, such as small noncoding RNAs.

(Reproduced with permission, Yan, M. S. et al. J Appl Physiol 2010;109:916-926).

**Figure 1.** Schematic representation of 3 fundamental mechanisms of epigenetic gene regulation.

DNA occurs not at CpG islands but CpG island shores [22].

**3.1. DNA methylation**

or during early development [21].

Changes in gene expression which are heritable are not always due to alterations in DNA sequence but are also attributable to epigenetic mechanisms. This could explain many cases where different phenotypes arise from the same genotype, such as monozygotic twins which are identical at DNA sequence level but have different DNA methylation and histone modi‐ fication profiles [18] that possibly affect the penetrance for several complex diseases (cancer, autoimmune, neurodegenerative and cardiovascular diseases).

Studying epigenetic mechanisms made it possible to map epigenetic marks which are critical for regulating gene expression. The importance of epigenetics in maintaining normal devel‐ opment and in being one of the key factors in cellular differentiation can be explained by the observing how aberrant placement of epigenetic marks and mutations in the epigenetic machinery is involved in disease [19].

There are three distinct, yet highly interrelated, major mechanisms of epigenetic regulation (Figure 1) [20] :


(Reproduced with permission, Yan, M. S. et al. J Appl Physiol 2010;109:916-926).

**Figure 1.** Schematic representation of 3 fundamental mechanisms of epigenetic gene regulation.

**3. RNA-based mechanisms** have also recently been shown to impact the higher-order structure of chromatin, such as small noncoding RNAs.

#### **3.1. DNA methylation**

short time periods. In addition, in the presymptomatic period when preventive treatment and slowing of neurodegeneration might be most effective, there are no measures/markers to

The function of normal huntingtin in the cells and mutation mechanism that leads to neuro‐ degeneration and typical signs are still not clear, despite the fact, that the responsible gene and mutation were already identified and characterized in 1993. Basic research created many different hypotheses about pathogenic mechanisms – they include disturbances in variety of biochemical pathways, such as accumulation of misfolded mutated proteins, apoptosis, protein degradation, intracellular signaling as well as oxidative stress, disturbed transcription

Increasing interest in epigenetics which is currently one of the most rapidly expanding fields in biomedical research has been accompanied by several breakthroughs like finding new histone variants and modifications, the discovery of the CpG island shores and most of all possibility of genome-wide analysis of epigenetic marks – epigenomic analysis – at single nucleotide resolution. The recognition of the role of epigenetics and how important it could be in human disease was first discussed in oncology and further extended to neurodevelop‐

Changes in gene expression which are heritable are not always due to alterations in DNA sequence but are also attributable to epigenetic mechanisms. This could explain many cases where different phenotypes arise from the same genotype, such as monozygotic twins which are identical at DNA sequence level but have different DNA methylation and histone modi‐ fication profiles [18] that possibly affect the penetrance for several complex diseases (cancer,

Studying epigenetic mechanisms made it possible to map epigenetic marks which are critical for regulating gene expression. The importance of epigenetics in maintaining normal devel‐ opment and in being one of the key factors in cellular differentiation can be explained by the observing how aberrant placement of epigenetic marks and mutations in the epigenetic

There are three distinct, yet highly interrelated, major mechanisms of epigenetic regulation

**1. DNA methylation** refers to the addition of a methyl group to the 5-position of cytosine

**2. Histone modification** - The fundamental repeating unit of chromatin is the nucleosome comprised of an octamer of core histone proteins. Posttranslational modifications of the amino-terminal tails of histone proteins and the density of these proteins per unit length of DNA, can importantly affect chromatin structure and constitute a putative "histone

in the context of CpG dinucleotides to define the "fifth base of DNA."

monitor those responses and benefits.

348 Neurodegenerative Diseases

**3. Epigenetic mechanisms**

ment and neurodegenerative diseases.

machinery is involved in disease [19].

(Figure 1) [20] :

code."

autoimmune, neurodegenerative and cardiovascular diseases).

regulation [15, 16] and epigenetic processes [17].

This is the most widely studied epigenetic mechanism which consists of covalent addition of methyl group at the 5-position of cytosines followed by guanines (CpG dinucleotides) and is usually associated with gene silencing. CpG dinucleotides are generally clustered in regions called CpG islands defined as regions with G-C content of at least 50%. Human gene promoters are associated with CpG island in about 60%. In normal cells they are usually unmethylated and about 6% of them become methylated in a tissue-specific manner in differentiated tissue or during early development [21].

DNA methylation is not present only at CpG islands. Recently, a new term has been coined, CpG island shores which are regions of lower CpG density that are located close (≈ 2kb) to the CpG islands. Additionally, it seems that methylation of CpG island shores is closely related to the inactivation of transcription and is also found that most of tissue-specific methylation of DNA occurs not at CpG islands but CpG island shores [22].

DNA methylation can inhibit gene expression in direct or indirect ways. Indirect transcription inhibition is mediated through promoting activation of methyl-CpG-binding domain (MBD) proteins by methylated DNA, which inhibit transcription [23]. Direct transcriptional inhibition is possible by interruption of activity of DNA binding proteins from their target sites.

A significant portion of methylated CpG islands is also found in repetitive elements. This methylation is functional and needed because of protection from reactivation of endoparasitic sequences which can cause chromosomal instability, gene disruption and translocations [24]. Eventhough DNA methylation occurs mostly in CpG islands in mammals, non-CG methyla‐ tion has recently been described in humans at CHG and CHH sites (H=A,C or T). The level of of non-CpG methylation decrease during differentiation and mechanisms of non-CpG methylation actually remains unclear at the moment [25].

In addition to above described epigenetic mechanism, there is another mechanisms, tightly linked to both histone modifications and DNA methylation – **nucleosome positioning.**

The Role of Epigenetics in Neurodegenerative Diseases

http://dx.doi.org/10.5772/54744

351

Gene expression is also regulated by DNA packed into nucleosomes as these represent a barrier to transcription that blocks access of activators and transcription factors. For in‐ stance nucleosome displacement of about 30 bp at transcription start site (TSS) has been reported which leads to changes in RNA polymerase II activity [19]. Gene activation is highly correlated with loss of nucleosome directly upstream of the TSS, whereas the oc‐ clusion of TSS by a nucleosome is correlated with gene repression [33]. Nucleosomes can be destabilized or ejected in ATP-hydrolysis dependent manner by groups of large mac‐ romolecular complexes, known as chromatin remodeling complexes. There are four fami‐

In general very little is known about specific mechanisms of nucleosome positioning and

Proper differentiation and function of the central nervous system cells are subject to significant influence of a variety of epigenetic modifications. It has been shown that substantial reorgan‐ ization of the epigenome on the level of cytosine methylation and histone modifications occurs throughout early brain development and continuing through the process of aging [35].

Most notably, the association between epigenetic signature and neurologic disease has been established through observation of monogenic neurodevelopmental disorders resulting from mutations in genes coding for proteins directly involved in core processes of methylation and histone modification. While mutatations in the MECP2 gene, coding for Methyl-CpG-binding protein and related to Rett syndrome, are probably most widely known for association of dysfunctional epigenetic regulation and neurologic disease, mutations in several similar genes have recently been related to neurologic disesease occuring in a variety of age groups.

The role of epigenetic alterations in common neurodegenerative disorders, such as Hunting‐ ton's, Parkinson's and Alzheimer's disease, on the other hand, has not been considered until recently. Specific disturbed epigenetic mechanisms and changes in all three neurodegeneration

Surprisingly, it has been shown in the recent decade, that inhibition of histone deacetylase enzymes (HDACs) confers neuroprotective effects in invertebrate and mouse models of Huntington's disease [36]. It is thought that observed beneficial effects of HDAC inhibitors results from re-stabilization of gene transcription, owing to a shift of histone acetylation equilibrium towards increased acetylation of histones, relaxation of DNA-chromatin com‐ plexes and subsequent increase of gene transcription. In addition to putative alleviation of symptoms observed in Huntington's disease, the potential benefit of HDAC inhibitors has been considered in a range of neurologic diseases, from monogenic neurologic diseases to common

neurodegenerative disorders, such as Parkinson's and Alzheimer's disease[35].

lies – SWI/SNF, ISWI, CHD and INO80 [34].

NDG disorders are shown in Figure 2.

further investigation will give us more insights into these processes.

**4. Epigenetics and its role in neurodegeneration**

Other epigenetic regulators linked to DNA methylation are DNA methylation enzyme DNA methyltransferases (DNMT) [26]. DNMT enzyme family mediates DNA methylation by catalyzing the transfer of a methyl group from an S-adenosyl-L-methionine to cytosine. In mammals there are five membrs of the DNMT family, but only three of them have methyla‐ transferase activity – DNMT1, DNMT3a and DNMT3b.

The question that still remains unclear is how DNA methylation machinery is directed to specific sequences. Several proposed mechanisms imply there should be some interaction of DNMTs with other epigenetic factors.

#### **3.2. Histone modifications**

Another important epigenetic mark is histone modification. There are 4 groups of core histones H2A, H2B, H3 and H4 which form H2A and H2B dimers and one H3-H4 tetramer. Together they form nucleosome – fundamental unit of cromatin structure. These proteins provide a solid structure for DNA helix and also an interactive surface as N-terminal regions of histones protrude from the nucleosome and are susceptible to interactions with other proteins.

The residues at histone tails are subject to many post-translational modifications like acetyla‐ tion, methylation, phosphorylation, SUMOylation and ADP-ribosylation [27]. Post-transla‐ tional modifications are dynamic and reversible processes mediated by two antagonistic sets of enzyme-complexes that can attach or remove corresponding chemical groups. Acetylation at lysine residues is one of most thoroughly studied histone modifications and is associated with transcriptional activation [28]. Modifications are made by histone acetyl transferases (HATs) and can be reverted by histone deacetylase (HDACs).

As previously mentioned, there are interactions between all epigenetic marks. An interesting example of such interplay between histone modification and DNA methylation is relationship between DNA methyltransferase3 (DNMT3L) and H3K4 where DNMT3L specifically interacts with histone H3 tails inducing *de novo* DNA methylation [19].

#### **3.3. RNA-based mechanisms - Noncoding RNA-mediated modulation of gene expression**

RNA mediated post-transcriptional gene silencing (TGS) was first observed already in 1989 in tobacco plants [29] and later became known as an important epigenetic mechanism also in humans. It has also been shown in the last years that small RNAs are directed to the targeted promoter regions and this leads to modulation of silent state chromatin modifications [30]. In addition to gene silencing, there is evidence to suggest involvement of small RNAs in addi‐ tional aspects of transcriptional regulation. These molecules may also activate certain genes, when targeted to promoter regions low in GC content [31]. One subtype of small RNAs are microRNAs, which excert their role on post-transcriptional level, probably by influencing the stability, compartmentalization and translation of mRNAs. In this way, expression of numer‐ ous genes is regulated related to different key biological processes cellular processes such as proliferation, morphogenesis, apoptosis and differentiation [32].

In addition to above described epigenetic mechanism, there is another mechanisms, tightly linked to both histone modifications and DNA methylation – **nucleosome positioning.**

Gene expression is also regulated by DNA packed into nucleosomes as these represent a barrier to transcription that blocks access of activators and transcription factors. For in‐ stance nucleosome displacement of about 30 bp at transcription start site (TSS) has been reported which leads to changes in RNA polymerase II activity [19]. Gene activation is highly correlated with loss of nucleosome directly upstream of the TSS, whereas the oc‐ clusion of TSS by a nucleosome is correlated with gene repression [33]. Nucleosomes can be destabilized or ejected in ATP-hydrolysis dependent manner by groups of large mac‐ romolecular complexes, known as chromatin remodeling complexes. There are four fami‐ lies – SWI/SNF, ISWI, CHD and INO80 [34].

In general very little is known about specific mechanisms of nucleosome positioning and further investigation will give us more insights into these processes.

### **4. Epigenetics and its role in neurodegeneration**

of non-CpG methylation decrease during differentiation and mechanisms of non-CpG

Other epigenetic regulators linked to DNA methylation are DNA methylation enzyme DNA methyltransferases (DNMT) [26]. DNMT enzyme family mediates DNA methylation by catalyzing the transfer of a methyl group from an S-adenosyl-L-methionine to cytosine. In mammals there are five membrs of the DNMT family, but only three of them have methyla‐

The question that still remains unclear is how DNA methylation machinery is directed to specific sequences. Several proposed mechanisms imply there should be some interaction of

Another important epigenetic mark is histone modification. There are 4 groups of core histones H2A, H2B, H3 and H4 which form H2A and H2B dimers and one H3-H4 tetramer. Together they form nucleosome – fundamental unit of cromatin structure. These proteins provide a solid structure for DNA helix and also an interactive surface as N-terminal regions of histones protrude from the nucleosome and are susceptible to interactions with other proteins.

The residues at histone tails are subject to many post-translational modifications like acetyla‐ tion, methylation, phosphorylation, SUMOylation and ADP-ribosylation [27]. Post-transla‐ tional modifications are dynamic and reversible processes mediated by two antagonistic sets of enzyme-complexes that can attach or remove corresponding chemical groups. Acetylation at lysine residues is one of most thoroughly studied histone modifications and is associated with transcriptional activation [28]. Modifications are made by histone acetyl transferases

As previously mentioned, there are interactions between all epigenetic marks. An interesting example of such interplay between histone modification and DNA methylation is relationship between DNA methyltransferase3 (DNMT3L) and H3K4 where DNMT3L specifically interacts

**3.3. RNA-based mechanisms - Noncoding RNA-mediated modulation of gene expression** RNA mediated post-transcriptional gene silencing (TGS) was first observed already in 1989 in tobacco plants [29] and later became known as an important epigenetic mechanism also in humans. It has also been shown in the last years that small RNAs are directed to the targeted promoter regions and this leads to modulation of silent state chromatin modifications [30]. In addition to gene silencing, there is evidence to suggest involvement of small RNAs in addi‐ tional aspects of transcriptional regulation. These molecules may also activate certain genes, when targeted to promoter regions low in GC content [31]. One subtype of small RNAs are microRNAs, which excert their role on post-transcriptional level, probably by influencing the stability, compartmentalization and translation of mRNAs. In this way, expression of numer‐ ous genes is regulated related to different key biological processes cellular processes such as

methylation actually remains unclear at the moment [25].

transferase activity – DNMT1, DNMT3a and DNMT3b.

(HATs) and can be reverted by histone deacetylase (HDACs).

with histone H3 tails inducing *de novo* DNA methylation [19].

proliferation, morphogenesis, apoptosis and differentiation [32].

DNMTs with other epigenetic factors.

**3.2. Histone modifications**

350 Neurodegenerative Diseases

Proper differentiation and function of the central nervous system cells are subject to significant influence of a variety of epigenetic modifications. It has been shown that substantial reorgan‐ ization of the epigenome on the level of cytosine methylation and histone modifications occurs throughout early brain development and continuing through the process of aging [35].

Most notably, the association between epigenetic signature and neurologic disease has been established through observation of monogenic neurodevelopmental disorders resulting from mutations in genes coding for proteins directly involved in core processes of methylation and histone modification. While mutatations in the MECP2 gene, coding for Methyl-CpG-binding protein and related to Rett syndrome, are probably most widely known for association of dysfunctional epigenetic regulation and neurologic disease, mutations in several similar genes have recently been related to neurologic disesease occuring in a variety of age groups.

The role of epigenetic alterations in common neurodegenerative disorders, such as Hunting‐ ton's, Parkinson's and Alzheimer's disease, on the other hand, has not been considered until recently. Specific disturbed epigenetic mechanisms and changes in all three neurodegeneration NDG disorders are shown in Figure 2.

Surprisingly, it has been shown in the recent decade, that inhibition of histone deacetylase enzymes (HDACs) confers neuroprotective effects in invertebrate and mouse models of Huntington's disease [36]. It is thought that observed beneficial effects of HDAC inhibitors results from re-stabilization of gene transcription, owing to a shift of histone acetylation equilibrium towards increased acetylation of histones, relaxation of DNA-chromatin com‐ plexes and subsequent increase of gene transcription. In addition to putative alleviation of symptoms observed in Huntington's disease, the potential benefit of HDAC inhibitors has been considered in a range of neurologic diseases, from monogenic neurologic diseases to common neurodegenerative disorders, such as Parkinson's and Alzheimer's disease[35].

share pathogenetic mechanisms and be related to dysfunctions of methylation and histone modifications. It has been demonstrated that nuclei of brain cells from patients with Parkin‐ son's disease contain reduced amounts of methyltransferase enzymes (most notably Dnmt1), leading to dysfunctional methylation of several genes playing a key role in PD pathogenesis, including synuclein-α gene, whose accumulation is observed in plaques of patients with PD [37]. It is also hypothesized that mitochondrial function, commonly perturbed in brain cells of patients with neurodegenerative disorders, is affected by methylation patterns of mitochon‐

The Role of Epigenetics in Neurodegenerative Diseases

http://dx.doi.org/10.5772/54744

353

Moreover, it was shown that protein aggregates constituting plaques found in brain cells of patients with Alzheimer's disease and Huntington's disease, contain sequestred proteins with histone acetyltranferase activity (notably CBP protein), potentially leading to reduced histone acetylation [38]. Increase of histone proteins carrying H3K9 marks has also been detected in

This novel evidence substantiates that epigenetic modifications may play a significant role in the etiology of neurodegenerative diseases and pathogenetic mechanisms involved in their

Parkinson's disease (PD) is the second among most common neurodegenerative disorders and is characterized by progressive depletion of dopaminergic neurons within the substantia nigra, clinically manifesting as progressive symptoms of tremor, rigidity, bradykinesia and postural instability [40, 41]. PD belongs to a group of complex diseases and is hypothesized to arise consequentially to interaction of a multitude of genetic and environmental factors. Details of specific sites of genetic predisposition and environmental insults, however, remain largely unclear [42]. Nevertheless, discovery of monogenic forms of PD provided a great insight into specific physiologic pathways that, once perturbed, lead to destruction of dopaminergic neurons. A significant proportion of cases with familial forms of PD, following clear Mendelian inheritance has been identified. Here, causative mutations have been discovered, offering valuable insight into intricacies and key points of disease pathogenesis. To date, mutations in genes *SNCA* (encoding α-synuclein protein), *PARK2* (parkin), *PINK1* (PTEN-induced kinase protein 1), *UCHL1* (ubiquitin carboxyl-terminal hydrolase isozyme L1), *DJ1* (DJ-1 protein), and *LRRK2* (leucine-rich repeat serine/threonine-protein kinase 2) were identified as a cause of

Perhaps the most studied gene in light of potential epigenetic alterations in PD is SNCA gene. Depositions of misfolded α-synuclein constitute a pathologic hallmark of Parkinson's disease (Lewy bodies) and co-locate with sites of neuronal loss. As α-synuclein toxic effects are primarily exerted in neuronal nuclei, it has been hypothesized that it perturbs the distribution and organization of DNA and histone epigenetic modifications [43]. Indeed, recent studies have demonstrated α-synuclein associates with histones and inhibits their acetylation, doing so through its association with Sirtuin-2 (Sirt2) histone deacetylase. Interestingly, in a *Drosophila* model of PD, targeted down-regulation of Sirt2 resulted in reduced α-synuclein toxicity [44]. Additionally, other histonic modifications have been related to increased or

propagation and may also present a great opportunity for therapeutic interventions.

blood and brain tissues of patients with Huntington's disease [39].

**4.1. Epigenetics in Parkinson's disease**

drial DNA [35].

familial PD [41].

Other line of evidence stems from the fact that a multitude of monogenic disorders, resulting from mutations in genes essential for proper epigenetic regulation, are characterized by symptoms that arise late in the course of life, such as cerebellar ataxia and hereditary neuro‐ pathy. This observation rose a possibility that common neurodegenerative disorders may share pathogenetic mechanisms and be related to dysfunctions of methylation and histone modifications. It has been demonstrated that nuclei of brain cells from patients with Parkin‐ son's disease contain reduced amounts of methyltransferase enzymes (most notably Dnmt1), leading to dysfunctional methylation of several genes playing a key role in PD pathogenesis, including synuclein-α gene, whose accumulation is observed in plaques of patients with PD [37]. It is also hypothesized that mitochondrial function, commonly perturbed in brain cells of patients with neurodegenerative disorders, is affected by methylation patterns of mitochon‐ drial DNA [35].

Moreover, it was shown that protein aggregates constituting plaques found in brain cells of patients with Alzheimer's disease and Huntington's disease, contain sequestred proteins with histone acetyltranferase activity (notably CBP protein), potentially leading to reduced histone acetylation [38]. Increase of histone proteins carrying H3K9 marks has also been detected in blood and brain tissues of patients with Huntington's disease [39].

This novel evidence substantiates that epigenetic modifications may play a significant role in the etiology of neurodegenerative diseases and pathogenetic mechanisms involved in their propagation and may also present a great opportunity for therapeutic interventions.

#### **4.1. Epigenetics in Parkinson's disease**

Other line of evidence stems from the fact that a multitude of monogenic disorders, resulting from mutations in genes essential for proper epigenetic regulation, are characterized by symptoms that arise late in the course of life, such as cerebellar ataxia and hereditary neuro‐ pathy. This observation rose a possibility that common neurodegenerative disorders may

**Figure 2.** Key epigenetic changes in PD, AD and HD

352 Neurodegenerative Diseases

Parkinson's disease (PD) is the second among most common neurodegenerative disorders and is characterized by progressive depletion of dopaminergic neurons within the substantia nigra, clinically manifesting as progressive symptoms of tremor, rigidity, bradykinesia and postural instability [40, 41]. PD belongs to a group of complex diseases and is hypothesized to arise consequentially to interaction of a multitude of genetic and environmental factors. Details of specific sites of genetic predisposition and environmental insults, however, remain largely unclear [42]. Nevertheless, discovery of monogenic forms of PD provided a great insight into specific physiologic pathways that, once perturbed, lead to destruction of dopaminergic neurons. A significant proportion of cases with familial forms of PD, following clear Mendelian inheritance has been identified. Here, causative mutations have been discovered, offering valuable insight into intricacies and key points of disease pathogenesis. To date, mutations in genes *SNCA* (encoding α-synuclein protein), *PARK2* (parkin), *PINK1* (PTEN-induced kinase protein 1), *UCHL1* (ubiquitin carboxyl-terminal hydrolase isozyme L1), *DJ1* (DJ-1 protein), and *LRRK2* (leucine-rich repeat serine/threonine-protein kinase 2) were identified as a cause of familial PD [41].

Perhaps the most studied gene in light of potential epigenetic alterations in PD is SNCA gene. Depositions of misfolded α-synuclein constitute a pathologic hallmark of Parkinson's disease (Lewy bodies) and co-locate with sites of neuronal loss. As α-synuclein toxic effects are primarily exerted in neuronal nuclei, it has been hypothesized that it perturbs the distribution and organization of DNA and histone epigenetic modifications [43]. Indeed, recent studies have demonstrated α-synuclein associates with histones and inhibits their acetylation, doing so through its association with Sirtuin-2 (Sirt2) histone deacetylase. Interestingly, in a *Drosophila* model of PD, targeted down-regulation of Sirt2 resulted in reduced α-synuclein toxicity [44]. Additionally, other histonic modifications have been related to increased or decreased death of neurons in PD. Treatment with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahy‐ dropyridine), commonly used in animal models to provoke PD symptoms, has been assocated with increased presence of H3 histonic marks, which has been reverted after treatment with levo-dopa [45]. In a *C. elegans* model of PD, where overexpression of SNCA was stimulated, reduced expression of nine genes coding for histone proteins was observed [46]. In addition, a recent study has linked a mutation (A53T) in SNCA gene to monoallelic silencing of transcription form mutated allele, which was shown to result from histonic modifications at that site [47].

These lines of evidence provide support for the possibility that a proportion of pathways leading to PD could be better understood by incorporating epigenetic regulome into the our current disease models. In addition, epigenetic alterations provide novel treatment targets, allowing re-stabilization of perturbed cellular mechanisms. Most notably, histone deacetylase inhibitors (HDACIs), currently already approved for treatment of haematologic malignancies, have been shown to rescue α-synuclein- induced toxicity in models in vitro and in vivo. Several new forms of HDACIs and DNA-demethylating drugs are currently in preclinical testing stage

The Role of Epigenetics in Neurodegenerative Diseases

http://dx.doi.org/10.5772/54744

355

Alzheimer disease, as discussed above, is the leading couse of dementia world wide. It is characterized by dementia that typically begins with subtle and poorly recognized failure of memory and slowly becomes more severe and, eventually, incapacitating. Other findings include confusion, poor judgment, language disturbance, agitation, withdrawal, and halluci‐ nations. As is true for PD, AD is believed to be a complex disease, combining the effects of genetic and environmental factors. On the other hand, approximately 25% of all AD is familial, 95% of which is late-onset (age >60-65 years) and 5% is early-onset (age <60 years). In familial AD definite causative genes and mutations are known, offering important models for studying disease pathogenesis. To date, mutations in three genes are undoubtfully linked to AD – Presenilin-1 (*PSEN1*), Presenilin-2 (*PSEN2*) and Amyloid beta A4 protein (*APP*). Others remain to be discovered. This is also true for the cause of sporadic AD, which can in part be attributable

Epigenetics is an emerging field in the light of potential impact on development of neurode‐ generative diseases. It is a mechanism independant of DNA sequence with effects on gene transcription, yet in specific way it is heritable. It is well known that epigenetic modifications alter transcriptional activity of thousands of genes and simultaneously of many different cellular pathways in individually specific manner, dependant also on environmental factors and yet unknown co-factors. In this way epigenetics might constitute a crossroad for diverse pathophysiological mechanisms and risk factors contributing to development of Alzheimer disease. In addition, epigenetics may explain a part of mechanism by which AD in a first degree relative means an increased risk of "sporadic" disease, since epigenetic impressions are passed from generation to generation. Different mechanism have been implicated – DNA methylation,

An important suggestive evidence of the role of epigenetic modifications in AD was a study on monozygotic twins discordant for AD, where status of DNA methylation in temporal

It has been shown this year in genome-wide DNA methylation study that more than 900 CpG sites representing 918 unique genes might be associated with late onset AD. The best candidate gene turned out to be a Transmembrane Protein 59 (TMEM59), whose promoter was hypo‐

neocortex neuronal nuclei was significantly altered in the AD twin [61].

and provide an array of new opportunities to benefit patients with PD [60].

**4.2. Epigenetics in Alzheimer disease**

to epigenetic mechanisms.

histone acetylation, miRNAs.

*4.2.1. DNA methylation in AD*

On the other hand, the role of DNA methylation in PD is currently unclear. It has been shown that metabolism of one-carbon compounds required for normal methylation is perturbed in PD [48]. Several studies have already pointed to the possibility of altered SNCA promoter gene methylation in relation to neuropsychiatric disorders [49]. Methylation of SNCA intron 1 has been associated with decrease in SNCA transcription and reduction of methylation at this site was observed at several brain regions affected in PD (including *substantia nigra*) [50]. This observation was further substantiated in analyses of other parts of the gene, where hypome‐ thylation was also detected [51]. These results raise the possibility that increase in α-synuclein production may result from increased SNCA expression, potentially as a consequence of reduced methylation status of this gene. Additionally, α-synuclein has been shown to seques‐ ter DNA methyltransferase 1 (DNMT1), resulting in decreased overall methylation of genes in brain tissues of PD patients [37]. A study investigating larger set of genes, has revealed that other genes besides SNCA are characterized by differential methylation in PD (ARK16, GPNMB, and STX1B) [52]. Recently, these investigations have been expanded to global epigenomic scale of methylation in postmortem brain samples and a novel gene characterized by hypomethylation in PD was identified (CYP2E1, the cytochrome P450, family 2, subfamily E, polypeptide 1). In accordance, increased expression of the same gene has also been detected. Interestingly, CYP2E1 knock-out mice models have also been shown to be protected from MPTP toxic effects [53].

The role of miRNA regulatory system has also been implicated and surveyed in the context of PD. Initial study, performed by Kim et al, reported a detection of miRNA molecule (miR-133b) with expression specific to midbrain dopaminergic neurons and reduction of expression level in PD patients' midbrain tissue samples [54]. Differences in expression of several other microRNAs have been detected in early symptomatic mouse models of PD (miR-10a, -10b, -212, -132, -495) [55]. In addition, miR-7 has been found to repress expression of SNCA gene in two independent studies where it was demonstrated that its expression levels were reduced in MPTP cell culture and animal models [56, 57]. A global miRNA profiling approach in PD brain samples revealed downregulation of miR-34b/c, which has an important role in regula‐ tion of mitochondrial function. This deregulation was particularly notable in patients early in disease course, who have not yet been subjected to PD treatment modalities [58]. In another study, alterations of miRNAs could even be detected in blood samples from PD patients in regard to affection and pre- and post-treatment status. Their expression levels could be used to distinguish patients from controls based on blood expression profiles [59].

These lines of evidence provide support for the possibility that a proportion of pathways leading to PD could be better understood by incorporating epigenetic regulome into the our current disease models. In addition, epigenetic alterations provide novel treatment targets, allowing re-stabilization of perturbed cellular mechanisms. Most notably, histone deacetylase inhibitors (HDACIs), currently already approved for treatment of haematologic malignancies, have been shown to rescue α-synuclein- induced toxicity in models in vitro and in vivo. Several new forms of HDACIs and DNA-demethylating drugs are currently in preclinical testing stage and provide an array of new opportunities to benefit patients with PD [60].

#### **4.2. Epigenetics in Alzheimer disease**

decreased death of neurons in PD. Treatment with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahy‐ dropyridine), commonly used in animal models to provoke PD symptoms, has been assocated with increased presence of H3 histonic marks, which has been reverted after treatment with levo-dopa [45]. In a *C. elegans* model of PD, where overexpression of SNCA was stimulated, reduced expression of nine genes coding for histone proteins was observed [46]. In addition, a recent study has linked a mutation (A53T) in SNCA gene to monoallelic silencing of transcription form mutated allele, which was shown to result from histonic modifications at

On the other hand, the role of DNA methylation in PD is currently unclear. It has been shown that metabolism of one-carbon compounds required for normal methylation is perturbed in PD [48]. Several studies have already pointed to the possibility of altered SNCA promoter gene methylation in relation to neuropsychiatric disorders [49]. Methylation of SNCA intron 1 has been associated with decrease in SNCA transcription and reduction of methylation at this site was observed at several brain regions affected in PD (including *substantia nigra*) [50]. This observation was further substantiated in analyses of other parts of the gene, where hypome‐ thylation was also detected [51]. These results raise the possibility that increase in α-synuclein production may result from increased SNCA expression, potentially as a consequence of reduced methylation status of this gene. Additionally, α-synuclein has been shown to seques‐ ter DNA methyltransferase 1 (DNMT1), resulting in decreased overall methylation of genes in brain tissues of PD patients [37]. A study investigating larger set of genes, has revealed that other genes besides SNCA are characterized by differential methylation in PD (ARK16, GPNMB, and STX1B) [52]. Recently, these investigations have been expanded to global epigenomic scale of methylation in postmortem brain samples and a novel gene characterized by hypomethylation in PD was identified (CYP2E1, the cytochrome P450, family 2, subfamily E, polypeptide 1). In accordance, increased expression of the same gene has also been detected. Interestingly, CYP2E1 knock-out mice models have also been shown to be protected from

The role of miRNA regulatory system has also been implicated and surveyed in the context of PD. Initial study, performed by Kim et al, reported a detection of miRNA molecule (miR-133b) with expression specific to midbrain dopaminergic neurons and reduction of expression level in PD patients' midbrain tissue samples [54]. Differences in expression of several other microRNAs have been detected in early symptomatic mouse models of PD (miR-10a, -10b, -212, -132, -495) [55]. In addition, miR-7 has been found to repress expression of SNCA gene in two independent studies where it was demonstrated that its expression levels were reduced in MPTP cell culture and animal models [56, 57]. A global miRNA profiling approach in PD brain samples revealed downregulation of miR-34b/c, which has an important role in regula‐ tion of mitochondrial function. This deregulation was particularly notable in patients early in disease course, who have not yet been subjected to PD treatment modalities [58]. In another study, alterations of miRNAs could even be detected in blood samples from PD patients in regard to affection and pre- and post-treatment status. Their expression levels could be used

to distinguish patients from controls based on blood expression profiles [59].

that site [47].

354 Neurodegenerative Diseases

MPTP toxic effects [53].

Alzheimer disease, as discussed above, is the leading couse of dementia world wide. It is characterized by dementia that typically begins with subtle and poorly recognized failure of memory and slowly becomes more severe and, eventually, incapacitating. Other findings include confusion, poor judgment, language disturbance, agitation, withdrawal, and halluci‐ nations. As is true for PD, AD is believed to be a complex disease, combining the effects of genetic and environmental factors. On the other hand, approximately 25% of all AD is familial, 95% of which is late-onset (age >60-65 years) and 5% is early-onset (age <60 years). In familial AD definite causative genes and mutations are known, offering important models for studying disease pathogenesis. To date, mutations in three genes are undoubtfully linked to AD – Presenilin-1 (*PSEN1*), Presenilin-2 (*PSEN2*) and Amyloid beta A4 protein (*APP*). Others remain to be discovered. This is also true for the cause of sporadic AD, which can in part be attributable to epigenetic mechanisms.

Epigenetics is an emerging field in the light of potential impact on development of neurode‐ generative diseases. It is a mechanism independant of DNA sequence with effects on gene transcription, yet in specific way it is heritable. It is well known that epigenetic modifications alter transcriptional activity of thousands of genes and simultaneously of many different cellular pathways in individually specific manner, dependant also on environmental factors and yet unknown co-factors. In this way epigenetics might constitute a crossroad for diverse pathophysiological mechanisms and risk factors contributing to development of Alzheimer disease. In addition, epigenetics may explain a part of mechanism by which AD in a first degree relative means an increased risk of "sporadic" disease, since epigenetic impressions are passed from generation to generation. Different mechanism have been implicated – DNA methylation, histone acetylation, miRNAs.

#### *4.2.1. DNA methylation in AD*

An important suggestive evidence of the role of epigenetic modifications in AD was a study on monozygotic twins discordant for AD, where status of DNA methylation in temporal neocortex neuronal nuclei was significantly altered in the AD twin [61].

It has been shown this year in genome-wide DNA methylation study that more than 900 CpG sites representing 918 unique genes might be associated with late onset AD. The best candidate gene turned out to be a Transmembrane Protein 59 (TMEM59), whose promoter was hypo‐ methylated in AD [62]. Interestingly, TMEM59 was previously linked to amyloid precursor protein shedding, which is a central regulatory point in the production of amyloid β peptid in AD [63]. Regulation of amyloid precursor protein shedding is still not clear and mostly unknown at the molecular level.

model [77]. The author suggested that histone deacetylase inhibitors might be potential therapeutic agents for AD nad other neurodegenerative diseases where learning and

The Role of Epigenetics in Neurodegenerative Diseases

http://dx.doi.org/10.5772/54744

357

As it seems, histone modifications happen and have an important role in AD and AD animal models. Still, the underlying mechanisms and regulation and post-modification pathways are

Micro RNAs (miRNAs) are post-transcriptional regulators that bind to complementary sequences on target mRNAs. This usually results in translational repression or target degra‐ dation and gene silencing. It is assumed that human genome might encode approximatelly 1000 miRNAs. miRNAs have been linked to posttranscriptional control of amyloid precursor protein expression [78], namely negative regulatory control by miR-101 and miR-16 [79]. The study clearly demonstrated that amyloid precursor protein is a target of miR-16 and that abnormally low expression of miR-16 might directly lead to protein accumulation in AD mice. Also, miRNAs are equally involved in the regulation of neuronal mRNA alternative splicing [80]. Smith et al have shown that miR-124 is down-regulated in AD brain and at the same time, its underexpression in neurons is associated with inclusion of exons 7 and 8 to amyloid precursor protein. To contribute to this finding, they have also shown that ectopic expression

At present, miRNAs are hot topic and the full complement of miRNA that participate in the regulation of precursor protein expression, splicing and potential other steps in its accumula‐

Huntington's disease (HD) is caused by dominant mutation with expanded number of glutamine codons within an existing poly-glutamine (polyQ) repeat sequence of a gene encoding for protein huntingtin (htt). Normal htt has 36 polyQ repeats and aberrant has more than 39 polyQ repeats. In case of 36-39 polyQ repeats we have an "intermediate allele" with incomplete penetrance and greater probability of becoming pathogenic if there is family

It has been shown in brain of mouse models [16] and in blood and brain of patients with HD that changes in gene expression occur very early in the disease course [81]. Gene transcription is regulated by complex interplay of different protein complexes, including transcription factors and histones, which in turn are regulated by covalent modifications such as acetylation, methylation and phosphorylation. Histone acetylation, which promotes transcription, is reduced in models of HD [82] and, on the other hand, histone methylation, which inhibits transcription, is increased [83]. Moreover, histone methylation was shown to be increased in

Further evidence was provided by the use of histone acetylase inhibitors (HDACi), sodium butyrate and phenylbutyrate which increased survival of R6/2 mice. Also, improved motor

HD patients, suggesting important role in disease pathogenesis [39].

memory impairment is present.

*4.2.3. miRNA in AD*

tion are yet to be discovered.

history of Huntington's disease.

**4.3. Epigenetics in Huntington's disease**

complex and not fully understood yet.

of miR-124 reversed these effects in cultured neurons.

Another gene candidate shown to be differentially methylated is mRNA componentof telomerase HTERT (human telomerase reverse transcriptase), potentially involved in higher telomerase activity and immune dysfunctions in AD pathogenesis [64]. Disturbances in inflammatory regulation and response has been widely accepted and studied in AD for more than a decade. Numerous studies have proven this connection, for example, inflammatory mediators and signs of oxidative stress were described mostly in regions of beta-amyloid peptide deposits and neurofibrillary tangles [65]. Also, *in vitro* and *in vivo* studies on connection between pro-inflammatory cytokines and processing and production of the beta-amyloid peptid shown important influence [66]. In addition, whole genome expression studies showed widespread transcriptional alterations - decreased neurotrophic support and activated apoptotic and neuroinflammatory signaling in AD brain [67]. Specific studies on DNA methylation have added to this hypothesis by detecting hypomethylation of iNOS, IL-1, and TNF-α in the AD brain [65].

#### *4.2.2. Hystone modification in AD*

Another pathway of epigenetic regulation of transcription and other functions in cells is chromatin acetylation and deacetylation of histone proteins. Many studies associated histone hypoacetylation and transcriptional dysfunction with many different neurodegenerative conditions, including AD [68], Parkinson's disease [69] and Huntington's disease [70]. Direct evidence of disturbed histone modifications in AD was proposed in a study where elevated levels of phosphorylated histone H3 in AD hippocampal neurons were found and dislocalised to neuronal cytoplasm, as opposed to the nucleus as in actively dividing cells [71]. On the other hand, a recent study using novel proteomic approaches showed that histone acetylation is significantly lower in AD temporal lobe as compared to aged controls [72].

Using HDAC inhibitors to manipulate histone acetylation in several animal models of AD showed important potential of these molecules as treatment options. For example, valproic acid, which has HDAC1 inhibitor activity, decreased the production of amyloidbeta precursor protein and reduced plaque burden in the brains of Alzheimer's disease transgenic mouse model [73]. Another study reported beneficial role of phenylbuthyrate in cognitive impairment and neuropathology in AD. Using sodium 4-phenylbutyrate to treat Tg2576 mice it was shown that it reversed spatial memory loss and normalized lev‐ els of phosphorylated tau in the hippocampus. At the same time, it failed to change amy‐ loid-beta precursor level [74]. This is in concordance with earlier studies which have shown that changes in amyloid-beta precursor levels are not necessarily associated with improvement in learning and memory performance [75, 76].

Another important finding was that increased histone acetylation induced sprouting of dendrites, increased number of synapses and reinstated learning behaviour and access to long-term memories, after already present brain atrophy and neuronal loss in a mouse model [77]. The author suggested that histone deacetylase inhibitors might be potential therapeutic agents for AD nad other neurodegenerative diseases where learning and memory impairment is present.

As it seems, histone modifications happen and have an important role in AD and AD animal models. Still, the underlying mechanisms and regulation and post-modification pathways are complex and not fully understood yet.

#### *4.2.3. miRNA in AD*

methylated in AD [62]. Interestingly, TMEM59 was previously linked to amyloid precursor protein shedding, which is a central regulatory point in the production of amyloid β peptid in AD [63]. Regulation of amyloid precursor protein shedding is still not clear and mostly

Another gene candidate shown to be differentially methylated is mRNA componentof telomerase HTERT (human telomerase reverse transcriptase), potentially involved in higher telomerase activity and immune dysfunctions in AD pathogenesis [64]. Disturbances in inflammatory regulation and response has been widely accepted and studied in AD for more than a decade. Numerous studies have proven this connection, for example, inflammatory mediators and signs of oxidative stress were described mostly in regions of beta-amyloid peptide deposits and neurofibrillary tangles [65]. Also, *in vitro* and *in vivo* studies on connection between pro-inflammatory cytokines and processing and production of the beta-amyloid peptid shown important influence [66]. In addition, whole genome expression studies showed widespread transcriptional alterations - decreased neurotrophic support and activated apoptotic and neuroinflammatory signaling in AD brain [67]. Specific studies on DNA methylation have added to this hypothesis by detecting hypomethylation of iNOS, IL-1, and

Another pathway of epigenetic regulation of transcription and other functions in cells is chromatin acetylation and deacetylation of histone proteins. Many studies associated histone hypoacetylation and transcriptional dysfunction with many different neurodegenerative conditions, including AD [68], Parkinson's disease [69] and Huntington's disease [70]. Direct evidence of disturbed histone modifications in AD was proposed in a study where elevated levels of phosphorylated histone H3 in AD hippocampal neurons were found and dislocalised to neuronal cytoplasm, as opposed to the nucleus as in actively dividing cells [71]. On the other hand, a recent study using novel proteomic approaches showed that histone acetylation is

Using HDAC inhibitors to manipulate histone acetylation in several animal models of AD showed important potential of these molecules as treatment options. For example, valproic acid, which has HDAC1 inhibitor activity, decreased the production of amyloidbeta precursor protein and reduced plaque burden in the brains of Alzheimer's disease transgenic mouse model [73]. Another study reported beneficial role of phenylbuthyrate in cognitive impairment and neuropathology in AD. Using sodium 4-phenylbutyrate to treat Tg2576 mice it was shown that it reversed spatial memory loss and normalized lev‐ els of phosphorylated tau in the hippocampus. At the same time, it failed to change amy‐ loid-beta precursor level [74]. This is in concordance with earlier studies which have shown that changes in amyloid-beta precursor levels are not necessarily associated with

Another important finding was that increased histone acetylation induced sprouting of dendrites, increased number of synapses and reinstated learning behaviour and access to long-term memories, after already present brain atrophy and neuronal loss in a mouse

significantly lower in AD temporal lobe as compared to aged controls [72].

improvement in learning and memory performance [75, 76].

unknown at the molecular level.

356 Neurodegenerative Diseases

TNF-α in the AD brain [65].

*4.2.2. Hystone modification in AD*

Micro RNAs (miRNAs) are post-transcriptional regulators that bind to complementary sequences on target mRNAs. This usually results in translational repression or target degra‐ dation and gene silencing. It is assumed that human genome might encode approximatelly 1000 miRNAs. miRNAs have been linked to posttranscriptional control of amyloid precursor protein expression [78], namely negative regulatory control by miR-101 and miR-16 [79]. The study clearly demonstrated that amyloid precursor protein is a target of miR-16 and that abnormally low expression of miR-16 might directly lead to protein accumulation in AD mice. Also, miRNAs are equally involved in the regulation of neuronal mRNA alternative splicing [80]. Smith et al have shown that miR-124 is down-regulated in AD brain and at the same time, its underexpression in neurons is associated with inclusion of exons 7 and 8 to amyloid precursor protein. To contribute to this finding, they have also shown that ectopic expression of miR-124 reversed these effects in cultured neurons.

At present, miRNAs are hot topic and the full complement of miRNA that participate in the regulation of precursor protein expression, splicing and potential other steps in its accumula‐ tion are yet to be discovered.

#### **4.3. Epigenetics in Huntington's disease**

Huntington's disease (HD) is caused by dominant mutation with expanded number of glutamine codons within an existing poly-glutamine (polyQ) repeat sequence of a gene encoding for protein huntingtin (htt). Normal htt has 36 polyQ repeats and aberrant has more than 39 polyQ repeats. In case of 36-39 polyQ repeats we have an "intermediate allele" with incomplete penetrance and greater probability of becoming pathogenic if there is family history of Huntington's disease.

It has been shown in brain of mouse models [16] and in blood and brain of patients with HD that changes in gene expression occur very early in the disease course [81]. Gene transcription is regulated by complex interplay of different protein complexes, including transcription factors and histones, which in turn are regulated by covalent modifications such as acetylation, methylation and phosphorylation. Histone acetylation, which promotes transcription, is reduced in models of HD [82] and, on the other hand, histone methylation, which inhibits transcription, is increased [83]. Moreover, histone methylation was shown to be increased in HD patients, suggesting important role in disease pathogenesis [39].

Further evidence was provided by the use of histone acetylase inhibitors (HDACi), sodium butyrate and phenylbutyrate which increased survival of R6/2 mice. Also, improved motor performance and to some extend reversed alteration in gene expression and hypoacetylation at selected promoters in cerebellum of R6/2 mice was reported [82]. The exact mode of histone acetylation and methylation in HD is still unknown, but HDACs might be a potentially promissing treatment. One of HDAC inhibitors, sodium phenylbutyrate, is already approved in the treatment of urea cycle disorders and is under investigation for treatment of various refractory cancers, amyotrophic lateral sclerosis and spinobulbar muscular atrophy. A dosefinding study of this compound in human HD has already been conducted to determine the tolerability of the compound in patients with HD [84].

accepted that these epigenetic alterations with consequent transcriptional dysregulation might be an important marker of disease status and its progression in many neurodegenerative diseases. The disruption of normal transcriptional pathways through altered epigenetic status

The Role of Epigenetics in Neurodegenerative Diseases

http://dx.doi.org/10.5772/54744

359

In this chapter we have shortly reviewed epigenetic role in Parkinson's disease, Alzheimer disease and Huntington's diseases. Epigenetic characteristics show an important role and certain specifics in all three. Moreover, the epigenetic modifications that have been reported in PD and AD, are in some points similar to trends in normal aging. Therefore, in addition to giving us insight to pathogenesis of neurodegeneration, they might also explain why aging by

Instead of studying preselected genes or regions and their epigenetic characteristics, wholegenome epigenetic status, so-called epigenome should be studied. With the knowledge on direct impact of epigenetic to transcriptional dysregulation, it would be of great importance to conduct epigenomic studies in tandem with transcriptomic (genome-wide gene expression profiling) studies. Only with this approach is one able to directly validate functional effects of epigenetic changes on gene expression. True, research on the epigenetic components and mechanisms associated with neurodegeneration is still in its beginning and future will provide

Last but not least - epigenetic modification is a reversible characteristic while genetic mutation is not. Influencing and tightly regulating epigenetic modification is therefore theoretically very promising candidate method from a therapeutic perspective of neurodegenerative diseases. It is well known that certain therapeutic compounds can influence and change the DNA methylation status and transcriptional activity accordingly. Though, one has to bear in mind, that in general, epigenetic mechanisms exert effects on many genes simultaneously and the

triggers signaling cascades linked with a number of pathological mechanisms.

itself is a risk factor for developing neurodegenerative disorder.

same is also true for currently known effective epigenetic therapeutics.

, Aleš Maver, Maja Zadel and Borut Peterlin

Clinical Institute of Medical Genetics, University Medical Center Ljubljana, Slovenia

[1] C.J.L. Murray, A.D.L., *The Global Burden of Disease*, 1996, World Health Organisation:

\*Address all correspondence to: lucalovrecic@gmail.com

additional essential information.

**Author details**

Luca Lovrečić\*

**References**

Geneva.

Another epigenetic mechanism, implicated in HD, is also disturbed miRNAs levels. Several miRNAs are significantly misregulated in HD brains compared with healthy controls. Five miRNAs, miR-9, miR-9\*, miR-29b, miR-124a and miR-132 are significantly disregulated in HD cortex [85]. Interestingly, miR-9/miR9\* are important in regulation of transcriptional repressor REST, which is mislocalized in brains neurons of patients with HD [86]. Together with other transcriptional factors it acts to regulate neuronal gene expression. How this is related to HD progression and potential for treatment remains yet to be elucidated.

In addition to human HD, an important role of miRNAs has also been shown in cell models of HD and linked directly to mutated protein huntingtin. Huntingtin has been shown to be the target of several miRNAs, miR-214, miR-150, miR-146a and miR-125b. Their expression reduced the expression of mutated protein. This regulation of huntingtin by miRNAs might provide a new approach to modulate HD [87].

### **5. Conclusion**

Neurodegenerative diseases are becoming one of the most important public health issue in the developed world due to the population ageing. It is of paramount importance to improve our knowledge on pathophysiology of the group of these diseases with the aim to improve diagnostics, development of disease-modifying treatment and preventive measures. The most important field is early diagnosis with accurate risk estimates and potential preventive treatment. Numerous research groups and initiatives are working with this same goal in order to improve above mentioned issues.

Global epigenetic changes, with downstream effect on numerous genes and different biological pathways, appear to be involved in synchronous cellular response and alterations that direct development, aging, and, in some cases, even disease. Epigenetic modifications in the patho‐ psysiology of neurodegenerative diseases are lately becoming more and more important and widely discussed. This field is expected to provide important molecular mechanisms that will contribute to understanding of the pathogenesis, treatment response and even development of new therapeutic targets in the field of neurodegenerative disorders.

DNA methylation, histone modifications and small noncoding RNA regulation are different epigenetic mechanisms directly or indirectly linked to transcriptional activity and posttranslational modifications, such as alternative splicing. It has already been proposed and well accepted that these epigenetic alterations with consequent transcriptional dysregulation might be an important marker of disease status and its progression in many neurodegenerative diseases. The disruption of normal transcriptional pathways through altered epigenetic status triggers signaling cascades linked with a number of pathological mechanisms.

In this chapter we have shortly reviewed epigenetic role in Parkinson's disease, Alzheimer disease and Huntington's diseases. Epigenetic characteristics show an important role and certain specifics in all three. Moreover, the epigenetic modifications that have been reported in PD and AD, are in some points similar to trends in normal aging. Therefore, in addition to giving us insight to pathogenesis of neurodegeneration, they might also explain why aging by itself is a risk factor for developing neurodegenerative disorder.

Instead of studying preselected genes or regions and their epigenetic characteristics, wholegenome epigenetic status, so-called epigenome should be studied. With the knowledge on direct impact of epigenetic to transcriptional dysregulation, it would be of great importance to conduct epigenomic studies in tandem with transcriptomic (genome-wide gene expression profiling) studies. Only with this approach is one able to directly validate functional effects of epigenetic changes on gene expression. True, research on the epigenetic components and mechanisms associated with neurodegeneration is still in its beginning and future will provide additional essential information.

Last but not least - epigenetic modification is a reversible characteristic while genetic mutation is not. Influencing and tightly regulating epigenetic modification is therefore theoretically very promising candidate method from a therapeutic perspective of neurodegenerative diseases. It is well known that certain therapeutic compounds can influence and change the DNA methylation status and transcriptional activity accordingly. Though, one has to bear in mind, that in general, epigenetic mechanisms exert effects on many genes simultaneously and the same is also true for currently known effective epigenetic therapeutics.

### **Author details**

performance and to some extend reversed alteration in gene expression and hypoacetylation at selected promoters in cerebellum of R6/2 mice was reported [82]. The exact mode of histone acetylation and methylation in HD is still unknown, but HDACs might be a potentially promissing treatment. One of HDAC inhibitors, sodium phenylbutyrate, is already approved in the treatment of urea cycle disorders and is under investigation for treatment of various refractory cancers, amyotrophic lateral sclerosis and spinobulbar muscular atrophy. A dosefinding study of this compound in human HD has already been conducted to determine the

Another epigenetic mechanism, implicated in HD, is also disturbed miRNAs levels. Several miRNAs are significantly misregulated in HD brains compared with healthy controls. Five miRNAs, miR-9, miR-9\*, miR-29b, miR-124a and miR-132 are significantly disregulated in HD cortex [85]. Interestingly, miR-9/miR9\* are important in regulation of transcriptional repressor REST, which is mislocalized in brains neurons of patients with HD [86]. Together with other transcriptional factors it acts to regulate neuronal gene expression. How this is related to HD

In addition to human HD, an important role of miRNAs has also been shown in cell models of HD and linked directly to mutated protein huntingtin. Huntingtin has been shown to be the target of several miRNAs, miR-214, miR-150, miR-146a and miR-125b. Their expression reduced the expression of mutated protein. This regulation of huntingtin by miRNAs might

Neurodegenerative diseases are becoming one of the most important public health issue in the developed world due to the population ageing. It is of paramount importance to improve our knowledge on pathophysiology of the group of these diseases with the aim to improve diagnostics, development of disease-modifying treatment and preventive measures. The most important field is early diagnosis with accurate risk estimates and potential preventive treatment. Numerous research groups and initiatives are working with this same goal in order

Global epigenetic changes, with downstream effect on numerous genes and different biological pathways, appear to be involved in synchronous cellular response and alterations that direct development, aging, and, in some cases, even disease. Epigenetic modifications in the patho‐ psysiology of neurodegenerative diseases are lately becoming more and more important and widely discussed. This field is expected to provide important molecular mechanisms that will contribute to understanding of the pathogenesis, treatment response and even development

DNA methylation, histone modifications and small noncoding RNA regulation are different epigenetic mechanisms directly or indirectly linked to transcriptional activity and posttranslational modifications, such as alternative splicing. It has already been proposed and well

of new therapeutic targets in the field of neurodegenerative disorders.

tolerability of the compound in patients with HD [84].

provide a new approach to modulate HD [87].

to improve above mentioned issues.

**5. Conclusion**

358 Neurodegenerative Diseases

progression and potential for treatment remains yet to be elucidated.

Luca Lovrečić\* , Aleš Maver, Maja Zadel and Borut Peterlin

\*Address all correspondence to: lucalovrecic@gmail.com

Clinical Institute of Medical Genetics, University Medical Center Ljubljana, Slovenia

### **References**

[1] C.J.L. Murray, A.D.L., *The Global Burden of Disease*, 1996, World Health Organisation: Geneva.

[2] Menken, M., T.L. Munsat, and J.F. Toole, *The global burden of disease study: implications for neurology.* Arch Neurol, 2000. 57(3): p. 418-20.

[18] Kaminsky, Z.A., et al., *DNA methylation profiles in monozygotic and dizygotic twins.* Nat

The Role of Epigenetics in Neurodegenerative Diseases

http://dx.doi.org/10.5772/54744

361

[19] Portela, A. and M. Esteller, *Epigenetic modifications and human disease.* Nat Biotechnol,

[20] Yan, M.S., C.C. Matouk, and P.A. Marsden, *Epigenetics of the vascular endothelium.* J

[21] Straussman, R., et al., *Developmental programming of CpG island methylation profiles in*

[22] Irizarry, R.A., et al., *The human colon cancer methylome shows similar hypo- and hyperme‐ thylation at conserved tissue-specific CpG island shores.* Nat Genet, 2009. 41(2): p. 178-86.

[23] Esteller, M., *Epigenetic gene silencing in cancer: the DNA hypermethylome.* Hum Mol

[24] Esteller, M., *Cancer epigenomics: DNA methylomes and histone-modification maps.* Nat

[25] Laurent, L., et al., *Dynamic changes in the human methylome during differentiation.* Ge‐

[26] Espada, J., et al., *Epigenetic disruption of ribosomal RNA genes and nucleolar architecture in DNA methyltransferase 1 (Dnmt1) deficient cells.* Nucleic Acids Res, 2007. 35(7): p.

[27] Kouzarides, T., *Chromatin modifications and their function.* Cell, 2007. 128(4): p. 693-705.

[28] Santos-Rosa, H., et al., *Histone H3 tail clipping regulates gene expression.* Nat Struct Mol

[29] Matzke, M.A., et al., *Reversible methylation and inactivation of marker genes in sequential‐*

[30] Kim, D.H., et al., *Argonaute-1 directs siRNA-mediated transcriptional gene silencing in hu‐*

[31] Janowski, B.A., et al., *Activating gene expression in mammalian cells with promoter-target‐*

[32] Carthew, R.W., *Gene regulation by microRNAs.* Curr Opin Genet Dev, 2006. 16(2): p.

[33] Schones, D.E., et al., *Dynamic regulation of nucleosome positioning in the human genome.*

[34] Ho, L. and G.R. Crabtree, *Chromatin remodelling during development.* Nature, 2010.

*ly transformed tobacco plants.* EMBO J, 1989. 8(3): p. 643-9.

*man cells.* Nat Struct Mol Biol, 2006. 13(9): p. 793-7.

*ed duplex RNAs.* Nat Chem Biol, 2007. 3(3): p. 166-73.

*the human genome.* Nat Struct Mol Biol, 2009. 16(5): p. 564-71.

Genet, 2009. 41(2): p. 240-5.

Appl Physiol, 2010. 109(3): p. 916-26.

Genet, 2007. 16 Spec No 1: p. R50-9.

Rev Genet, 2007. 8(4): p. 286-98.

nome Res, 2010. 20(3): p. 320-31.

Biol, 2009. 16(1): p. 17-22.

Cell, 2008. 132(5): p. 887-98.

463(7280): p. 474-84.

2191-8.

203-8.

2010. 28(10): p. 1057-68.


[18] Kaminsky, Z.A., et al., *DNA methylation profiles in monozygotic and dizygotic twins.* Nat Genet, 2009. 41(2): p. 240-5.

[2] Menken, M., T.L. Munsat, and J.F. Toole, *The global burden of disease study: implications*

[3] Schneider, J.A., et al., *Mixed brain pathologies account for most dementia cases in commun‐*

[4] *Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Neuropathology Group of the Medical Research Council Cognitive*

[5] Prohovnik, I., et al., *Dissociation of neuropathology from severity of dementia in late-onset*

[7] Forlenza, O.V., B.S. Diniz, and W.F. Gattaz, *Diagnosis and biomarkers of predementia in*

[8] McKhann, G., et al., *Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADR‐ DA Work Group under the auspices of Department of Health and Human Services Task*

[9] Hyman, B.T., et al., *National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease.* Alzheimers Dement, 2012. 8(1): p.

[10] Spillantini, M.G., et al., *Alpha-synuclein in Lewy bodies.* Nature, 1997. 388(6645): p.

[11] Gao, H.M. and J.S. Hong, *Gene-environment interactions: key to unraveling the mystery of*

[12] *A novel gene containing a trinucleotide repeat that is expanded and unstable on Hunting‐ ton's disease chromosomes. The Huntington's Disease Collaborative Research Group.* Cell,

[13] Harper, P.S., *Huntington's disease*. Major Problems in Neurology1996, London: W.B.

[14] Bonelli, R.M. and P. Hofmann, *A systematic review of the treatment studies in Hunting‐*

[15] Harjes, P. and E.E. Wanker, *The hunt for huntingtin function: interaction partners tell*

[16] Sugars, K.L. and D.C. Rubinsztein, *Transcriptional abnormalities in Huntington disease.*

[17] He, F. and P.K. Todd, *Epigenetics in nucleotide repeat expansion disorders.* Semin Neurol,

*ton's disease since 1990.* Expert Opin Pharmacother, 2007. 8(2): p. 141-53.

*many different stories.* Trends Biochem Sci, 2003. 28(8): p. 425-33.

*Function and Ageing Study (MRC CFAS).* Lancet, 2001. 357(9251): p. 169-75.

*for neurology.* Arch Neurol, 2000. 57(3): p. 418-20.

*Alzheimer disease.* Neurology, 2006. 66(1): p. 49-55.

*Alzheimer's disease.* BMC Med. 8: p. 89.

1-13.

360 Neurodegenerative Diseases

839-40.

1993. 72(6): p. 971-83.

2011. 31(5): p. 470-83.

Saunders Company Ltd.

Trends Genet, 2003. 19(5): p. 233-8.

*ity-dwelling older persons.* Neurology, 2007. 69(24): p. 2197-204.

[6] Ballard, C., et al., *Alzheimer's disease.* Lancet. 377(9770): p. 1019-31.

*Force on Alzheimer's Disease.* Neurology, 1984. 34(7): p. 939-44.

*Parkinson's disease.* Prog Neurobiol, 2011. 94(1): p. 1-19.


[35] Jakovcevski, M. and S. Akbarian, *Epigenetic mechanisms in neurological disease.* Nat Med, 2012. 18(8): p. 1194-204.

[52] *A two-stage meta-analysis identifies several new loci for Parkinson's disease.* PLoS Genet,

The Role of Epigenetics in Neurodegenerative Diseases

http://dx.doi.org/10.5772/54744

363

[53] Kaut, O., I. Schmitt, and U. Wullner, *Genome-scale methylation analysis of Parkinson's disease patients' brains reveals DNA hypomethylation and increased mRNA expression of*

[54] Kim, J., et al., *A MicroRNA feedback circuit in midbrain dopamine neurons.* Science, 2007.

[55] Gillardon, F., et al., *MicroRNA and proteome expression profiling in early-symptomatic al‐ pha-synuclein(A30P)-transgenic mice.* Proteomics Clin Appl, 2008. 2(5): p. 697-705. [56] Junn, E., et al., *Repression of alpha-synuclein expression and toxicity by microRNA-7.* Proc

[57] Doxakis, E., *Post-transcriptional regulation of alpha-synuclein expression by mir-7 and*

[58] Minones-Moyano, E., et al., *MicroRNA profiling of Parkinson's disease brains identifies early downregulation of miR-34b/c which modulate mitochondrial function.* Hum Mol Gen‐

[59] Margis, R. and C.R. Rieder, *Identification of blood microRNAs associated to Parkinsonis*

[60] Kazantsev, A.G. and L.M. Thompson, *Therapeutic application of histone deacetylase in‐ hibitors for central nervous system disorders.* Nat Rev Drug Discov, 2008. 7(10): p. 854-68.

[61] Mastroeni, D., et al., *Epigenetic differences in cortical neurons from a pair of monozygotic*

[62] Bakulski, K.M., et al., *Genome-wide DNA methylation differences between late-onset Alz‐ heimer's disease and cognitively normal controls in human frontal cortex.* J Alzheimers Dis,

[63] Selkoe, D.J. and D. Schenk, *Alzheimer's disease: molecular understanding predicts amy‐*

[64] Silva, P.N., et al., *Promoter methylation analysis of SIRT3, SMARCA5, HTERT and CDH1 genes in aging and Alzheimer's disease.* J Alzheimers Dis, 2008. 13(2): p. 173-6. [65] Akiyama, H., et al., *Inflammation and Alzheimer's disease.* Neurobiol Aging, 2000. 21(3):

[66] Blasko, I., et al., *TNFalpha plus IFNgamma induce the production of Alzheimer beta-amy‐*

[67] Colangelo, V., et al., *Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor down-regulation and up-regulation of apoptotic*

*loid peptides and decrease the secretion of APPs.* FASEB J, 1999. 13(1): p. 63-8.

*and pro-inflammatory signaling.* J Neurosci Res, 2002. 70(3): p. 462-73.

*twins discordant for Alzheimer's disease.* PLoS One, 2009. 4(8): p. e6617.

*loid-based therapeutics.* Annu Rev Pharmacol Toxicol, 2003. 43: p. 545-84.

*cytochrome P450 2E1.* Neurogenetics, 2012. 13(1): p. 87-91.

Natl Acad Sci U S A, 2009. 106(31): p. 13052-7.

*mir-153.* J Biol Chem, 2010. 285(17): p. 12726-34.

*disease.* J Biotechnol, 2011. 152(3): p. 96-101.

2011. 7(6): p. e1002142.

317(5842): p. 1220-4.

et, 2011. 20(15): p. 3067-78.

2012. 29(3): p. 571-88.

p. 383-421.


[52] *A two-stage meta-analysis identifies several new loci for Parkinson's disease.* PLoS Genet, 2011. 7(6): p. e1002142.

[35] Jakovcevski, M. and S. Akbarian, *Epigenetic mechanisms in neurological disease.* Nat

[36] Steffan, J.S., et al., *Histone deacetylase inhibitors arrest polyglutamine-dependent neurode‐*

[37] Desplats, P., et al., *Alpha-synuclein sequesters Dnmt1 from the nucleus: a novel mechanism for epigenetic alterations in Lewy body diseases.* J Biol Chem, 2011. 286(11): p. 9031-7.

[38] Nucifora, F.C., Jr., et al., *Interference by huntingtin and atrophin-1 with cbp-mediated tran‐*

[39] Ryu, H., et al., *ESET/SETDB1 gene expression and histone H3 (K9) trimethylation in Hun‐*

[40] Lees, A.J., J. Hardy, and T. Revesz, *Parkinson's disease.* Lancet, 2009. 373(9680): p.

[41] Mayeux, R., *Epidemiology of neurodegeneration.* Annu Rev Neurosci, 2003. 26: p. 81-104.

[42] Klein, C. and A. Westenberger, *Genetics of Parkinson's disease.* Cold Spring Harb Per‐

[43] Kontopoulos, E., J.D. Parvin, and M.B. Feany, *Alpha-synuclein acts in the nucleus to in‐ hibit histone acetylation and promote neurotoxicity.* Hum Mol Genet, 2006. 15(20): p.

[44] Outeiro, T.F., et al., *Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models*

[45] Nicholas, A.P., et al., *Striatal histone modifications in models of levodopa-induced dyskine‐*

[46] Vartiainen, S., et al., *Identification of gene expression changes in transgenic C. elegans over‐*

[47] Voutsinas, G.E., et al., *Allelic imbalance of expression and epigenetic regulation within the alpha-synuclein wild-type and p.Ala53Thr alleles in Parkinson disease.* Hum Mutat, 2010.

[48] Obeid, R., et al., *Methylation status and neurodegenerative markers in Parkinson disease.*

[49] Qureshi, I.A. and M.F. Mehler, *Advances in epigenetics and epigenomics for neurodegener‐*

[50] Jowaed, A., et al., *Methylation regulates alpha-synuclein expression and is decreased in*

[51] Matsumoto, L., et al., *CpG demethylation enhances alpha-synuclein expression and affects*

*expressing human alpha-synuclein.* Neurobiol Dis, 2006. 22(3): p. 477-86.

*ative diseases.* Curr Neurol Neurosci Rep, 2011. 11(5): p. 464-73.

*Parkinson's disease patients' brains.* J Neurosci, 2010. 30(18): p. 6355-9.

*the pathogenesis of Parkinson's disease.* PLoS One, 2010. 5(11): p. e15522.

*of Parkinson's disease.* Science, 2007. 317(5837): p. 516-9.

*sia.* J Neurochem, 2008. 106(1): p. 486-94.

Clin Chem, 2009. 55(10): p. 1852-60.

*scription leading to cellular toxicity.* Science, 2001. 291(5512): p. 2423-8.

*tington's disease.* Proc Natl Acad Sci U S A, 2006. 103(50): p. 19176-81.

*generation in Drosophila.* Nature, 2001. 413(6857): p. 739-43.

Med, 2012. 18(8): p. 1194-204.

spect Med, 2012. 2(1): p. a008888.

2055-66.

362 Neurodegenerative Diseases

3012-23.

31(6): p. 685-91.


[68] Stilling, R.M. and A. Fischer, *The role of histone acetylation in age-associated memory im‐ pairment and Alzheimer's disease.* Neurobiol Learn Mem, 2011. 96(1): p. 19-26.

[83] Gardian, G., et al., *Neuroprotective effects of phenylbutyrate in the N171-82Q transgenic*

The Role of Epigenetics in Neurodegenerative Diseases

http://dx.doi.org/10.5772/54744

365

[84] Hogarth, P., L. Lovrecic, and D. Krainc, *Sodium phenylbutyrate in Huntington's disease:*

[85] Packer, A.N., et al., *The bifunctional microRNA miR-9/miR-9\* regulates REST and CoR‐ EST and is downregulated in Huntington's disease.* J Neurosci, 2008. 28(53): p. 14341-6.

[86] Zuccato, C., et al., *Widespread disruption of repressor element-1 silencing transcription fac‐ tor/neuron-restrictive silencer factor occupancy at its target genes in Huntington's disease.* J

[87] Sinha, M., J. Ghose, and N.P. Bhattarcharyya, *Micro RNA -214,-150,-146a and-125b tar‐*

*mouse model of Huntington's disease.* J Biol Chem, 2005. 280(1): p. 556-63.

*a dose-finding study.* Mov Disord, 2007. 22(13): p. 1962-4.

*get Huntingtin gene.* RNA Biol, 2011. 8(6): p. 1005-21.

Neurosci, 2007. 27(26): p. 6972-83.


[83] Gardian, G., et al., *Neuroprotective effects of phenylbutyrate in the N171-82Q transgenic mouse model of Huntington's disease.* J Biol Chem, 2005. 280(1): p. 556-63.

[68] Stilling, R.M. and A. Fischer, *The role of histone acetylation in age-associated memory im‐ pairment and Alzheimer's disease.* Neurobiol Learn Mem, 2011. 96(1): p. 19-26.

[69] Chuang, D.M., et al., *Multiple roles of HDAC inhibition in neurodegenerative conditions.*

[70] Sadri-Vakili, G. and J.H. Cha, *Mechanisms of disease: Histone modifications in Hunting‐*

[71] Ogawa, O., et al., *Ectopic localization of phosphorylated histone H3 in Alzheimer's disease:*

[72] Zhang, K., et al., *Targeted proteomics for quantification of histone acetylation in Alzheim‐*

[73] Su, Y., et al., *Lithium, a common drug for bipolar disorder treatment, regulates amyloid-beta*

[74] Ricobaraza, A., et al., *Phenylbutyrate ameliorates cognitive deficit and reduces tau patholo‐ gy in an Alzheimer's disease mouse model.* Neuropsychopharmacology, 2009. 34(7): p.

[75] Malm, T.M., et al., *Pyrrolidine dithiocarbamate activates Akt and improves spatial learning in APP/PS1 mice without affecting beta-amyloid burden.* J Neurosci, 2007. 27(14): p.

[76] Dodart, J.C., et al., *Immunization reverses memory deficits without reducing brain Abeta*

[77] Fischer, A., et al., *Recovery of learning and memory is associated with chromatin remodel‐*

[78] Long, J.M. and D.K. Lahiri, *Current drug targets for modulating Alzheimer's amyloid pre‐ cursor protein: role of specific micro-RNA species.* Curr Med Chem, 2011. 18(22): p.

[79] Liu, W., et al., *MicroRNA-16 targets amyloid precursor protein to potentially modulate Alz‐ heimer's-associated pathogenesis in SAMP8 mice.* Neurobiol Aging, 2012. 33(3): p.

[80] Smith, P., et al., *In vivo regulation of amyloid precursor protein neuronal splicing by micro‐*

[81] Borovecki, F., et al., *Genome-wide expression profiling of human blood reveals biomarkers for Huntington's disease.* Proc Natl Acad Sci U S A, 2005. 102(31): p. 11023-8.

[82] Ferrante, R.J., et al., *Histone deacetylase inhibition by sodium butyrate chemotherapy ameli‐ orates the neurodegenerative phenotype in Huntington's disease mice.* J Neurosci, 2003.

*burden in Alzheimer's disease model.* Nat Neurosci, 2002. 5(5): p. 452-7.

Trends Neurosci, 2009. 32(11): p. 591-601.

*er's disease.* Proteomics, 2012. 12(8): p. 1261-8.

*ling.* Nature, 2007. 447(7141): p. 178-82.

*RNAs.* J Neurochem, 2011. 116(2): p. 240-7.

1721-32.

364 Neurodegenerative Diseases

3712-21.

3314-21.

522-34.

23(28): p. 9418-27.

*ton's disease.* Nat Clin Pract Neurol, 2006. 2(6): p. 330-8.

*a mitotic catastrophe?* Acta Neuropathol, 2003. 105(5): p. 524-8.

*precursor protein processing.* Biochemistry, 2004. 43(22): p. 6899-908.


**Chapter 15**

**Plasma Membrane Channels Formed by Connexins or**

**Pannexins in Microglia: Possible Role in the Inflamed**

In a healthy brain, microglia exhibit a resting surveillance state associated with active explo‐ ration of their environment for exogenous or endogenous signals representing a threat to the homeostasis [1-5]. When physiological balance is impaired in the central nervous system (CNS), resting phenotype of microglia shift to a reactive phenotype with different degrees of activation according to the nature of the stimuli and the context. During intense CNS inflam‐ mation, rather than show a repair-orientated activity profile, reactive microglia constitute a source of toxic factors and participate in the recruitment of non-resident brain cells involved in the innate immune response, which worsen brain damage. The brain performs exception‐ ally complex and dynamic tasks that depend on the coordinated interaction of glial cells, therefore it is conceivable that impairment of intercellular signaling and coordination among microglia could play an important role on several CNS disorders. In vertebrate cells, this synchronization is in part mediated by gap junctions [6-10]. They are aggregates of in‐ tercellular channels termed gap junction channels that allow direct, but selective, cytoplas‐ mic continuity between contacting cells, promoting the exchange of ions (allowing eletrical coupling), metabolites (e.g., ADP, glucose, glutamate and glutathione) and second messen‐ gers (e.g., cAMP and IP3)[11-16]. Whereas a gap junction channel is formed by the serial docking of two hemichannels each one contributed by one of two adjacent cells, each hemi‐ channel is composed by six protein subunits termed connexins (Fig. 1). The latter belong to a highly conserved protein family encoded by 21 genes in human and 20 in mouse with ortho‐ logs in other vertebrate species [17-19]. Connexins are abundantly expressed in cells of the CNS, and they are named after their predicted molecular mass expressed in kDa, so that

> © 2013 Orellana; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

**Brain**

Juan A. Orellana

**1. Introduction**

http://dx.doi.org/10.5772/54306

Additional information is available at the end of the chapter

connexin43 (Cx43) has a molecular mass of ~43 kDa.

## **Plasma Membrane Channels Formed by Connexins or Pannexins in Microglia: Possible Role in the Inflamed Brain**

Juan A. Orellana

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54306

### **1. Introduction**

In a healthy brain, microglia exhibit a resting surveillance state associated with active explo‐ ration of their environment for exogenous or endogenous signals representing a threat to the homeostasis [1-5]. When physiological balance is impaired in the central nervous system (CNS), resting phenotype of microglia shift to a reactive phenotype with different degrees of activation according to the nature of the stimuli and the context. During intense CNS inflam‐ mation, rather than show a repair-orientated activity profile, reactive microglia constitute a source of toxic factors and participate in the recruitment of non-resident brain cells involved in the innate immune response, which worsen brain damage. The brain performs exception‐ ally complex and dynamic tasks that depend on the coordinated interaction of glial cells, therefore it is conceivable that impairment of intercellular signaling and coordination among microglia could play an important role on several CNS disorders. In vertebrate cells, this synchronization is in part mediated by gap junctions [6-10]. They are aggregates of in‐ tercellular channels termed gap junction channels that allow direct, but selective, cytoplas‐ mic continuity between contacting cells, promoting the exchange of ions (allowing eletrical coupling), metabolites (e.g., ADP, glucose, glutamate and glutathione) and second messen‐ gers (e.g., cAMP and IP3)[11-16]. Whereas a gap junction channel is formed by the serial docking of two hemichannels each one contributed by one of two adjacent cells, each hemi‐ channel is composed by six protein subunits termed connexins (Fig. 1). The latter belong to a highly conserved protein family encoded by 21 genes in human and 20 in mouse with ortho‐ logs in other vertebrate species [17-19]. Connexins are abundantly expressed in cells of the CNS, and they are named after their predicted molecular mass expressed in kDa, so that connexin43 (Cx43) has a molecular mass of ~43 kDa.

© 2013 Orellana; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

For a long time the main function attributed to connexin hemichannels was the formation of gap junction channels. Nevertheless, in the last decade, the presence of functional connexin hemichannels in nonjunctional membranes has been demonstrated by several experimental approaches [20-24]. These channels serve like aqueous pores permeable to ions and small molecules that permit diffusional exchange between the intra and extracellular compart‐ ments, allowing cellular release of relevant quantities of autocrine/paracrine signaling mole‐

Plasma Membrane Channels Formed by Connexins or Pannexins in Microglia: Possible Role in the Inflamed Brain

uptake of small molecules (e.g., glucose) [31]. One decade ago, a new gene family of gap junction proteins composed by three members was discovered in chordates [32, 33]. These proteins are the chordate homologs of innexins (the gap junction proteins of non chordates), and were denominated pannexins (panx1, 2 and 3) because apparently they are present in all eumetazoans except echinoderms [34] (Fig. 1). It has been suggested that gap junctional intercellular communication occur via Panx3 in osteoblasts [35], whereas other studies have shown that overexpression of exogenous Panx1 could form gap junctions *in vitro* [33, 36, 37]. Nevertheless, the absence of ultrastructural evidences for gap junction formation and dem‐ onstration of functional communication mediated by other endogenously expressed pannex‐

Current knowledge regarding brain hemichannels state that, under physiological condi‐ tions, they have a low activity, but enough to ensure the release of paracrine substances nec‐ essary for diverse functions of the CNS, including ischemic tolerance [39, 40], establishment of adhesive interactions [41]; fear memory consolidation [42], glucosensing [30], chemore‐ ception [43], blood-brain barrier permeability [44], neuronal migration [45, 46] and metabol‐ ic autocrine regulation [47]. Nevertheless, under acute or chronic neurodegeneration dysregulation of hemichannel properties could be critical on the beginning and maintenance of homeostatic imbalances observed in diverse brain diseases [48-50]. Pioneering findings from Paul and colleagues showed that Xenopus oocytes transfected with Cx46 mRNA ex‐ hibited non-selective cation currents associated to depolarization and cell lysis within 24 h [51]. From then on, several studies supported the idea that dysregulated opening of hemi‐ channels is incompatible with normal cell life. In the CNS, the first convincing evidence of hemichannel opening was provided by Contreras and colleagues, whose work showed that opening of Cx43 hemichannels accelerate astroglial cell death induced by ischemia-like con‐ ditions [52]. Such increased hemichannel activity induced by ischemia-like conditions has been observed in neurons [40, 53-55], oligodendrocytes [56], and also in brain cells subjected to other pro-inflammatory conditions [48]. Up to now, it is believed that sustained hemi‐

channel opening contributes to increased intracellular Ca2+ concentration ([Ca2+]i

turn may favor even more the hemichannel activity (De Vuyst et al., 2007, Schalper et al.,

Under these conditions, ionic (or electrolyte) imbalance leads to an osmotic imbalance that results in cell swelling and plasma membrane breakdown. Calcium overload induced in part by hemichannel opening may also activate phospholipase A2, with the subsequent gen‐ eration of arachidonic acid and activation of cyclooxygenase/lipoxygenase pathways leading to increased free radicals, lipid peroxidation and further plasma membrane damage. Possi‐

intracellular overload (Fig. 2).

ins indicate that they apparently act mainly as hemichannels [38].

and PGE2) to the extracellular milieu [25-30], as well as

http://dx.doi.org/10.5772/54306

369

), which in

cules (e.g., ATP, glutamate, NAD+

2008), inducing Ca2+ and Na+

**Figure 1.** Diagram illustrating basic structures of gap junction channels and hemichannels formed by connexins or pannexins in microglia. Connexins and pannexins share similar membrane topology, with four α-helical transmem‐ brane domains (M1-M4) connected by two extracellular loops (E1 and E2), one cytoplasmic loop (CL) where both ami‐ no (NH2)- and caboxy (COOH)-termini are intracellular. Top and bottom center show hemichannels formed by six connexin or pannexin subunits each, respectively. The middle center shows a connexin gap junction channel, at a close contact between two microglia. A hemichannel is formed by six connexins or pannexins that oligomerize lateral‐ ly leaving a central pore in the activated state (open). Under resting conditions hemichannels remain preferentially closed, but they can be activated by diverse physiological and pathological conditions, offering a diffusional trans‐ membrane route between the intra and extracellular milieu. In addition, it is depicted the types of hemichannels and gap junction channels expressed by microglia. This figure includes only the available information obtained under in vivo and/or in vitro studies using more than one experimental approach.

For a long time the main function attributed to connexin hemichannels was the formation of gap junction channels. Nevertheless, in the last decade, the presence of functional connexin hemichannels in nonjunctional membranes has been demonstrated by several experimental approaches [20-24]. These channels serve like aqueous pores permeable to ions and small molecules that permit diffusional exchange between the intra and extracellular compart‐ ments, allowing cellular release of relevant quantities of autocrine/paracrine signaling mole‐ cules (e.g., ATP, glutamate, NAD+ and PGE2) to the extracellular milieu [25-30], as well as uptake of small molecules (e.g., glucose) [31]. One decade ago, a new gene family of gap junction proteins composed by three members was discovered in chordates [32, 33]. These proteins are the chordate homologs of innexins (the gap junction proteins of non chordates), and were denominated pannexins (panx1, 2 and 3) because apparently they are present in all eumetazoans except echinoderms [34] (Fig. 1). It has been suggested that gap junctional intercellular communication occur via Panx3 in osteoblasts [35], whereas other studies have shown that overexpression of exogenous Panx1 could form gap junctions *in vitro* [33, 36, 37]. Nevertheless, the absence of ultrastructural evidences for gap junction formation and dem‐ onstration of functional communication mediated by other endogenously expressed pannex‐ ins indicate that they apparently act mainly as hemichannels [38].

Current knowledge regarding brain hemichannels state that, under physiological condi‐ tions, they have a low activity, but enough to ensure the release of paracrine substances nec‐ essary for diverse functions of the CNS, including ischemic tolerance [39, 40], establishment of adhesive interactions [41]; fear memory consolidation [42], glucosensing [30], chemore‐ ception [43], blood-brain barrier permeability [44], neuronal migration [45, 46] and metabol‐ ic autocrine regulation [47]. Nevertheless, under acute or chronic neurodegeneration dysregulation of hemichannel properties could be critical on the beginning and maintenance of homeostatic imbalances observed in diverse brain diseases [48-50]. Pioneering findings from Paul and colleagues showed that Xenopus oocytes transfected with Cx46 mRNA ex‐ hibited non-selective cation currents associated to depolarization and cell lysis within 24 h [51]. From then on, several studies supported the idea that dysregulated opening of hemi‐ channels is incompatible with normal cell life. In the CNS, the first convincing evidence of hemichannel opening was provided by Contreras and colleagues, whose work showed that opening of Cx43 hemichannels accelerate astroglial cell death induced by ischemia-like con‐ ditions [52]. Such increased hemichannel activity induced by ischemia-like conditions has been observed in neurons [40, 53-55], oligodendrocytes [56], and also in brain cells subjected to other pro-inflammatory conditions [48]. Up to now, it is believed that sustained hemi‐ channel opening contributes to increased intracellular Ca2+ concentration ([Ca2+]i ), which in turn may favor even more the hemichannel activity (De Vuyst et al., 2007, Schalper et al., 2008), inducing Ca2+ and Na+ intracellular overload (Fig. 2).

Under these conditions, ionic (or electrolyte) imbalance leads to an osmotic imbalance that results in cell swelling and plasma membrane breakdown. Calcium overload induced in part by hemichannel opening may also activate phospholipase A2, with the subsequent gen‐ eration of arachidonic acid and activation of cyclooxygenase/lipoxygenase pathways leading to increased free radicals, lipid peroxidation and further plasma membrane damage. Possi‐

**Figure 1.** Diagram illustrating basic structures of gap junction channels and hemichannels formed by connexins or pannexins in microglia. Connexins and pannexins share similar membrane topology, with four α-helical transmem‐ brane domains (M1-M4) connected by two extracellular loops (E1 and E2), one cytoplasmic loop (CL) where both ami‐ no (NH2)- and caboxy (COOH)-termini are intracellular. Top and bottom center show hemichannels formed by six connexin or pannexin subunits each, respectively. The middle center shows a connexin gap junction channel, at a close contact between two microglia. A hemichannel is formed by six connexins or pannexins that oligomerize lateral‐ ly leaving a central pore in the activated state (open). Under resting conditions hemichannels remain preferentially closed, but they can be activated by diverse physiological and pathological conditions, offering a diffusional trans‐ membrane route between the intra and extracellular milieu. In addition, it is depicted the types of hemichannels and gap junction channels expressed by microglia. This figure includes only the available information obtained under in

vivo and/or in vitro studies using more than one experimental approach.

368 Neurodegenerative Diseases

bly, exacerbated or uncontrolled hemichannel opening could lead to cellular damage by sev‐ eral ways: 1) High increase of [Ca2+]i by Ca2+ entry through hemichannels, 2) cellular swelling by increased entry of Na2+ and Cl through hemichannels, 3) release of metabolic products essential to cell viability as glucose, NAD+ or glutathione via hemichannels and 4) alternatively, spread of toxic molecules released by hemichannels (e.g., glutamate) could af‐ fect the viability of healthy neighboring cells.

damage by various mechanisms. (A) Ca2+ entry through hemichannels activate phospholipase A2, with the subsequent generation of arachidonic acid and activation of cyclooxygenase/lipoxygenase pathways leading to increased free radicals, lipid peroxidation and further plasma membrane damage. Note that increased levels of [Ca2+]i may activate even more hemichannel opening as demonstrated previously [57, 58]. (B) Na2+ and Cl- entry through hemichannels could produce cellular swelling by increased influx of H2O via aquoporins (green channels). (C) Release of essencial metabolic products via hemichannels (eg., glucose, NAD+ or glutathione) could increase cell vulnerability. (D) Release via hemichannels of molecules that in high amounts are toxic (e.g., ATP and glutamate) could affect the viability of

Plasma Membrane Channels Formed by Connexins or Pannexins in Microglia: Possible Role in the Inflamed Brain

http://dx.doi.org/10.5772/54306

371

Taking into account that hemichannels participate in the paracrine signaling among brain cells, the current chapter attempts to review and discuss the role of gap junction channels

In a resting surveillance state, microglia express almost undetectable levels of Cx43 and Cx36 [59-65]. Nevertheless, when microglia are subjected to pro-inflammatory conditions, they exhibit expression of Cx43 and are able to form gap junction channels among them, as evaluated by dye-coupling experiments. In fact, Cx43 expression and gap junctional com‐ munication is induced in microglia by LPS, TNF-α plus IFN-γ [61], calcium ionophore plus PMA [66], or Staphylococcus aureus-derived peptidoglycan [64]. Despite the above, cul‐ tured human or mouse microglia treated with LPS, granulocyte-macrophage colony-stimu‐ lating factor, INF-γ or TNF-α do not exhibit modifications in connexin expression [60, 63]. Recently has been showed that resting microglia exhibit detectable levels of surface and total Cx43, whereas upon treatment with amyloid-β peptide (Aβ) a high increase in Cx43 expres‐ sion is observed (Orellana 2011a). The discrepancy in the above mentioned studies may be related to different types of animal used to obtain brain tissue, dissimilar methods to take

The ability to establish gap junctional communication among microglia, requires a rise in [Ca2+]i [66], while cAMP, cGMP or activation of PKC have been ruled out as possible induc‐ tors gap junction-mediated coupling [66]. In this regard, different degrees of microglial acti‐ vation may trigger intracellular pathways that further result in a specific pattern of expression of gap juntion proteins. Communication via gap junctions may allow to activated microglia to recruit resting microglia at the site of injury, resulting in more damage or repair depending on the circumstances. Interestingly, microglia stimulated with cytokines or LPS exhibit reduced levels of Cx43 expression and gap junctional communication in astrocytes when both cell types are in co-culture or when conditioned media from activated microglia is used [31, 55, 59, 60, 67, 68]. Interestingly, gap junctions among dendritic cells ensure shar‐ ing of antigenic peptides [69-74], suggesting the possibility that these channels in microglia also could coordinate the CNS immune response. Importantly, recently it has been shown that the release of TNF-α and IL-1β by microglia depend on the activity of gap junction channels, because secretion of those cytokines was partially blocked by a gap junction block‐ er, α-glicirretinic acid [75]. Thus, it was proposed that gap junction channels play a key role

healthy neighboring cells and spread damage.

and hemichannels in microglia on normal and inflamed brain.

**2. Gap junction channels in microglia**

out cells and different culture conditions.

into coordinate the microglial mediated inflammation.

**Figure 2.** Dysregulated opening of hemichannels induces cell damage by different mechanisms. Under normal condi‐ tions, hemichannels (yellow channels) exhibit a low activity. However, upon exposure to inflammatory conditions, hemichannels undergo a dysregulation proccess leading to an uncontrolled opening which further results in cellular

damage by various mechanisms. (A) Ca2+ entry through hemichannels activate phospholipase A2, with the subsequent generation of arachidonic acid and activation of cyclooxygenase/lipoxygenase pathways leading to increased free radicals, lipid peroxidation and further plasma membrane damage. Note that increased levels of [Ca2+]i may activate even more hemichannel opening as demonstrated previously [57, 58]. (B) Na2+ and Cl- entry through hemichannels could produce cellular swelling by increased influx of H2O via aquoporins (green channels). (C) Release of essencial metabolic products via hemichannels (eg., glucose, NAD+ or glutathione) could increase cell vulnerability. (D) Release via hemichannels of molecules that in high amounts are toxic (e.g., ATP and glutamate) could affect the viability of healthy neighboring cells and spread damage.

Taking into account that hemichannels participate in the paracrine signaling among brain cells, the current chapter attempts to review and discuss the role of gap junction channels and hemichannels in microglia on normal and inflamed brain.

### **2. Gap junction channels in microglia**

bly, exacerbated or uncontrolled hemichannel opening could lead to cellular damage by sev‐

alternatively, spread of toxic molecules released by hemichannels (e.g., glutamate) could af‐

**Figure 2.** Dysregulated opening of hemichannels induces cell damage by different mechanisms. Under normal condi‐ tions, hemichannels (yellow channels) exhibit a low activity. However, upon exposure to inflammatory conditions, hemichannels undergo a dysregulation proccess leading to an uncontrolled opening which further results in cellular

by Ca2+ entry through hemichannels, 2) cellular

through hemichannels, 3) release of metabolic

or glutathione via hemichannels and 4)

eral ways: 1) High increase of [Ca2+]i

370 Neurodegenerative Diseases

swelling by increased entry of Na2+ and Cl-

fect the viability of healthy neighboring cells.

products essential to cell viability as glucose, NAD+

In a resting surveillance state, microglia express almost undetectable levels of Cx43 and Cx36 [59-65]. Nevertheless, when microglia are subjected to pro-inflammatory conditions, they exhibit expression of Cx43 and are able to form gap junction channels among them, as evaluated by dye-coupling experiments. In fact, Cx43 expression and gap junctional com‐ munication is induced in microglia by LPS, TNF-α plus IFN-γ [61], calcium ionophore plus PMA [66], or Staphylococcus aureus-derived peptidoglycan [64]. Despite the above, cul‐ tured human or mouse microglia treated with LPS, granulocyte-macrophage colony-stimu‐ lating factor, INF-γ or TNF-α do not exhibit modifications in connexin expression [60, 63]. Recently has been showed that resting microglia exhibit detectable levels of surface and total Cx43, whereas upon treatment with amyloid-β peptide (Aβ) a high increase in Cx43 expres‐ sion is observed (Orellana 2011a). The discrepancy in the above mentioned studies may be related to different types of animal used to obtain brain tissue, dissimilar methods to take out cells and different culture conditions.

The ability to establish gap junctional communication among microglia, requires a rise in [Ca2+]i [66], while cAMP, cGMP or activation of PKC have been ruled out as possible induc‐ tors gap junction-mediated coupling [66]. In this regard, different degrees of microglial acti‐ vation may trigger intracellular pathways that further result in a specific pattern of expression of gap juntion proteins. Communication via gap junctions may allow to activated microglia to recruit resting microglia at the site of injury, resulting in more damage or repair depending on the circumstances. Interestingly, microglia stimulated with cytokines or LPS exhibit reduced levels of Cx43 expression and gap junctional communication in astrocytes when both cell types are in co-culture or when conditioned media from activated microglia is used [31, 55, 59, 60, 67, 68]. Interestingly, gap junctions among dendritic cells ensure shar‐ ing of antigenic peptides [69-74], suggesting the possibility that these channels in microglia also could coordinate the CNS immune response. Importantly, recently it has been shown that the release of TNF-α and IL-1β by microglia depend on the activity of gap junction channels, because secretion of those cytokines was partially blocked by a gap junction block‐ er, α-glicirretinic acid [75]. Thus, it was proposed that gap junction channels play a key role into coordinate the microglial mediated inflammation.

#### **3. Hemichannels in microglia**

Up to now only few studies have documented the expression of functional hemichannels in microglia. Contrary to the expectations regarding as Cx43 the most possible protein to form hemichannels in microglia, TNF-α treatment was shown to induce release of gluta‐ mate through a pathway inhibited by a Cx32 (32Gap27), but not Cx43 (43Gap27) mimetic peptide [76]. Moreover, surface levels of Cx32 were increased in microglia treated with TNF-α. Noteworthy, the increased neuronal death associated with the release of gluta‐ mate was inhibited completely with the 32Gap27 mimetic peptide [76]. Later, the same group of authors proposed that glutamate released via Cx32 hemichannels play a key role in neuronal damage originated by brain ischemia [77] and experimental autoimmune en‐ cephalomyelitis [78]. Accordingly, microglial cells from Mecp2 null mice, a model of a neurodevelopmental disorder known as Rett syndrome, promote neuronal death through glutamate release via a cell membrane pathway inhibited by 32Gap27 and 32Gap24, two Cx32 hemichannel mimetic peptides [79]. It is relevant to kept in mind that these and oth‐ er mimetic peptides are homologous to extracellular domains of the respective connexin sequences, but their effects on hemichannel activity have not been documented, thereby some studies have questioned their specificity [80-82]. The use of cell cultures derived from connexin null mice and/or performing knockdown of the respective connexin, along the appropriate use of mimetic peptides could ensure the involvement of Cx32 hemichan‐ nels in these studies.

Almost two years ago, the opening of Cx43 and Panx1 hemichannels, evaluated by dye up‐ take and macroscopic cell membrane currents, were shown to be increased in microglia by Aβ25-35 exposure (Orellana et al. 2012a). These observations were confirmed by using micro‐ glial cultures from Cx43 KO mice and Panx1 mimetic peptides. These currents were record‐ ed at negative holding potential (-60 mV) in the presence of external divalent cations, suggesting that opening of microglial hemichannels may occur in Alzheimer's disease (AD). Importantly, ATP and glutamate released from microglia treated with Aβ25-35 trigger hemi‐ channel opening in neurons causing deleterious effects on them [83]. Supporting the idea of hemichannels as possible regulators in damage observed in AD, a novel putative hemichan‐ nel blocker (INI-0602) that crosses the blood brain barrier was recently shown to inhibit *in vivo* the LPS-induced glutamate release from microglia and to improve memory deficits in APP/PS1 mice [84]. Due the pharmacological pattern of this response," it was proposed the involvement of Cx32 hemichannels. However, the possible implication of other hemichannel forming proteins or even other channels was not ruled out and studies on the specificity of INI-0602 require further demonstration using, for example, *in vivo* experiments with Cx32-/ microglia or knockdown of Cx32. To demonstrate the participation of hemichannels in this disease it is necessary to analyze the functional state of microglial hemichannels in brain sli‐ ces from AD model mice (APP/PS1) by using patch-clamp and membrane permeability as‐ says.

**Figure 3.** Role of microglial cell hemichannels and gap junction channels during neuroinflammation. Chronic or acute inflammation increases hemichannel (HC) activity in microglia allowing the influx of Ca2+ (1) and its spread to neighbor

Plasma Membrane Channels Formed by Connexins or Pannexins in Microglia: Possible Role in the Inflamed Brain

inflammation in microglia leads to ATP release (3), which diffuses through the extracellular space and activates mem‐ brane purinergic (P2) receptors (4). High levels of [Ca2+]i (5) allow the release of glutamate through microglial cell HCs (6) and further activation of neuronal NMDA receptors (7). P2 and NMDA receptor activation in neurons increase the activity of neuronal Panx1 and Cx36 HCs, affecting electrochemical and Ca2+ imbalance in neurons, which leads to cell

). HC opening induced by

http://dx.doi.org/10.5772/54306

373

cells through gap junctions (GJCs) (2) raising the intracellular free Ca2+ concentration ([Ca2+]i

death (8).

Plasma Membrane Channels Formed by Connexins or Pannexins in Microglia: Possible Role in the Inflamed Brain http://dx.doi.org/10.5772/54306 373

**3. Hemichannels in microglia**

372 Neurodegenerative Diseases

nels in these studies.

says.

Up to now only few studies have documented the expression of functional hemichannels in microglia. Contrary to the expectations regarding as Cx43 the most possible protein to form hemichannels in microglia, TNF-α treatment was shown to induce release of gluta‐ mate through a pathway inhibited by a Cx32 (32Gap27), but not Cx43 (43Gap27) mimetic peptide [76]. Moreover, surface levels of Cx32 were increased in microglia treated with TNF-α. Noteworthy, the increased neuronal death associated with the release of gluta‐ mate was inhibited completely with the 32Gap27 mimetic peptide [76]. Later, the same group of authors proposed that glutamate released via Cx32 hemichannels play a key role in neuronal damage originated by brain ischemia [77] and experimental autoimmune en‐ cephalomyelitis [78]. Accordingly, microglial cells from Mecp2 null mice, a model of a neurodevelopmental disorder known as Rett syndrome, promote neuronal death through glutamate release via a cell membrane pathway inhibited by 32Gap27 and 32Gap24, two Cx32 hemichannel mimetic peptides [79]. It is relevant to kept in mind that these and oth‐ er mimetic peptides are homologous to extracellular domains of the respective connexin sequences, but their effects on hemichannel activity have not been documented, thereby some studies have questioned their specificity [80-82]. The use of cell cultures derived from connexin null mice and/or performing knockdown of the respective connexin, along the appropriate use of mimetic peptides could ensure the involvement of Cx32 hemichan‐

Almost two years ago, the opening of Cx43 and Panx1 hemichannels, evaluated by dye up‐ take and macroscopic cell membrane currents, were shown to be increased in microglia by Aβ25-35 exposure (Orellana et al. 2012a). These observations were confirmed by using micro‐ glial cultures from Cx43 KO mice and Panx1 mimetic peptides. These currents were record‐ ed at negative holding potential (-60 mV) in the presence of external divalent cations, suggesting that opening of microglial hemichannels may occur in Alzheimer's disease (AD). Importantly, ATP and glutamate released from microglia treated with Aβ25-35 trigger hemi‐ channel opening in neurons causing deleterious effects on them [83]. Supporting the idea of hemichannels as possible regulators in damage observed in AD, a novel putative hemichan‐ nel blocker (INI-0602) that crosses the blood brain barrier was recently shown to inhibit *in vivo* the LPS-induced glutamate release from microglia and to improve memory deficits in APP/PS1 mice [84]. Due the pharmacological pattern of this response," it was proposed the involvement of Cx32 hemichannels. However, the possible implication of other hemichannel forming proteins or even other channels was not ruled out and studies on the specificity of INI-0602 require further demonstration using, for example, *in vivo* experiments with Cx32-/ microglia or knockdown of Cx32. To demonstrate the participation of hemichannels in this disease it is necessary to analyze the functional state of microglial hemichannels in brain sli‐ ces from AD model mice (APP/PS1) by using patch-clamp and membrane permeability as‐

**Figure 3.** Role of microglial cell hemichannels and gap junction channels during neuroinflammation. Chronic or acute inflammation increases hemichannel (HC) activity in microglia allowing the influx of Ca2+ (1) and its spread to neighbor cells through gap junctions (GJCs) (2) raising the intracellular free Ca2+ concentration ([Ca2+]i ). HC opening induced by inflammation in microglia leads to ATP release (3), which diffuses through the extracellular space and activates mem‐ brane purinergic (P2) receptors (4). High levels of [Ca2+]i (5) allow the release of glutamate through microglial cell HCs (6) and further activation of neuronal NMDA receptors (7). P2 and NMDA receptor activation in neurons increase the activity of neuronal Panx1 and Cx36 HCs, affecting electrochemical and Ca2+ imbalance in neurons, which leads to cell death (8).

#### **4. Conclusions**

Microglial cells are known to play a relevant role in neuronal survival [3]. In pathological situations, dysregulation of connexin- and pannexin-based channels expressed by microglia, contribute importantly to determine the neuronal fate [48, 50]. Microgliosis and brain in‐ flammation are associated with most, if not all, brain injuries and pathologies. Hemichannel activation in microglia could play a crucial role in the reinforcement of the neuronal death, due to their capacity to release glutamate and ATP (Fig. 3) [55, 76, 83, 85]. Opening of Cx43, Cx32 and Panx1 hemichannels could increase [Ca2+]i in microglia, which further propagate Ca2+ waves via gap junction channels to neighbor cells (Fig. 3). Moreover, in distant micro‐ glia, Ca2+ waves can activate hemichannels, as demonstrated previously [57, 58, 86]. Then, opening of neuronal Panx1 hemichannels could be triggered by the rise in [Ca2+]i via activa‐ tion of NMDA and P2X receptors by glutamate and ATP, respectively. Panx1 hemichannels are likely to contribute to the intracellular Ca2+ overload that activates neurotoxic intracellu‐ lar cascades during excitotoxicity [87] (Fig. 3). Thus, the prevention of hemichannel activa‐ tion under pro-inflammatory conditions may represent an unexplored strategy to prevent neuronal damage and death. Altogether these observations strengthen the emerging concept that unregulated membrane permeability through enhanced hemichannel permeability and dysfunctional gap junction channels may contribute to the development of CNS pathologies and connexins as well as pannexins might represent potential and alternative targets for therapeutic intervention in neuroinflammatory diseases.

[3] Block, M. L, Zecca, L, & Hong, J. S. *Microglia-mediated neurotoxicity: uncovering the mo‐*

Plasma Membrane Channels Formed by Connexins or Pannexins in Microglia: Possible Role in the Inflamed Brain

http://dx.doi.org/10.5772/54306

375

[5] Streit, W. J. *Microglia as neuroprotective, immunocompetent cells of the CNS.* Glia, (2002). ,

[6] Saez, J. C, et al. *Plasma membrane channels formed by connexins: their regulation and func‐*

[7] Sohl, G, & Willecke, K. *Gap junctions and the connexin protein family.* Cardiovasc Res,

[8] Laird, D. W. *The gap junction proteome and its relationship to disease.* Trends Cell Biol,

[9] Goodenough, D. A, & Paul, D. L. *Gap junctions.* Cold Spring Harb Perspect Biol,

[10] Evans, W. H, De Vuyst, E, & Leybaert, L. *The gap junction cellular internet: connexin*

[11] Saez, J. C, et al. *cAMP delays disappearance of gap junctions between pairs of rat hepato‐*

[12] Connors, B. W, & Long, M. A. *Electrical synapses in the mammalian brain.* Annu Rev

[13] Goldberg, G. S, Lampe, P. D, & Nicholson, B. J. *Selective transfer of endogenous metabo‐ lites through gap junctions composed of different connexins.* Nat Cell Biol, (1999). ,

[14] Kam, Y, et al. *Transfer of second messengers through gap junction connexin 43 channels re‐*

[15] Lawrence, T. S, Beers, W. H, & Gilula, N. B. *Transmission of hormonal stimulation by*

[16] Niessen, H, et al. *Selective permeability of different connexin channels to the second messen‐*

[17] Cruciani, V, & Mikalsen, S. O. *The connexin gene family in mammals.* Biol Chem,

[18] Abascal, F, & Zardoya, R. *Evolutionary analyses of gap junction protein families.* Biochim

[19] Willecke, K, et al. *Structural and functional diversity of connexin genes in the mouse and*

[20] Goodenough, D. A, & Paul, D. L. *Beyond the gap: functions of unpaired connexon chan‐*

*hemichannels enter the signalling limelight.* Biochem J, (2006). , 1-14.

*constituted in liposomes.* Biochim Biophys Acta, (1998). , 384-388.

*ger inositol 1,4,5-trisphosphate.* J Cell Sci, (2000). Pt 8): , 1365-1372.

*cell-to-cell communication.* Nature, (1978). , 501-506.

*human genome.* Biol Chem, (2002). , 725-737.

*nels.* Nat Rev Mol Cell Biol, (2003). , 285-294.

*cytes in primary culture.* Am J Physiol, (1989). Pt 1): , C1-11.

[4] Hanisch, U. K. *Microglia as a source and target of cytokines.* Glia, (2002). , 140-155.

*lecular mechanisms.* Nat Rev Neurosci, (2007). , 57-69.

*tions.* Physiol Rev, (2003). , 1359-1400.

133-139.

(2004). , 228-232.

(2010). , 92-101.

(2009). , a002576.

457-459.

(2005). , 325-332.

Biophys Acta, (2012).

Neurosci, (2004). , 393-418.

#### **Acknowledgements**

This work was partially supported by CONICYT 79090028 and FONDECYT 11121133 (to JAO) grants.

### **Author details**

Juan A. Orellana

Departamento de Neurología; Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

#### **References**


**4. Conclusions**

374 Neurodegenerative Diseases

Cx32 and Panx1 hemichannels could increase [Ca2+]i

therapeutic intervention in neuroinflammatory diseases.

**Acknowledgements**

JAO) grants.

**Author details**

Juan A. Orellana

**References**

Chile, Santiago, Chile

Microglial cells are known to play a relevant role in neuronal survival [3]. In pathological situations, dysregulation of connexin- and pannexin-based channels expressed by microglia, contribute importantly to determine the neuronal fate [48, 50]. Microgliosis and brain in‐ flammation are associated with most, if not all, brain injuries and pathologies. Hemichannel activation in microglia could play a crucial role in the reinforcement of the neuronal death, due to their capacity to release glutamate and ATP (Fig. 3) [55, 76, 83, 85]. Opening of Cx43,

Ca2+ waves via gap junction channels to neighbor cells (Fig. 3). Moreover, in distant micro‐ glia, Ca2+ waves can activate hemichannels, as demonstrated previously [57, 58, 86]. Then,

tion of NMDA and P2X receptors by glutamate and ATP, respectively. Panx1 hemichannels are likely to contribute to the intracellular Ca2+ overload that activates neurotoxic intracellu‐ lar cascades during excitotoxicity [87] (Fig. 3). Thus, the prevention of hemichannel activa‐ tion under pro-inflammatory conditions may represent an unexplored strategy to prevent neuronal damage and death. Altogether these observations strengthen the emerging concept that unregulated membrane permeability through enhanced hemichannel permeability and dysfunctional gap junction channels may contribute to the development of CNS pathologies and connexins as well as pannexins might represent potential and alternative targets for

This work was partially supported by CONICYT 79090028 and FONDECYT 11121133 (to

Departamento de Neurología; Escuela de Medicina, Pontificia Universidad Católica de

[2] Block, M. L, & Hong, J. S. *Microglia and inflammation-mediated neurodegeneration: multi‐*

[1] Kettenmann, H, et al. *Physiology of microglia.* Physiol Rev, (2011). , 461-553.

*ple triggers with a common mechanism.* Prog Neurobiol, (2005). , 77-98.

opening of neuronal Panx1 hemichannels could be triggered by the rise in [Ca2+]i

in microglia, which further propagate

via activa‐


[21] Stout, C, Goodenough, D. A, & Paul, D. L. *Connexins: functions without junctions.* Curr Opin Cell Biol, (2004). , 507-512.

[38] MacVicarB.A. and R.J. Thompson, *Non-junction functions of pannexin-1 channels.*

Plasma Membrane Channels Formed by Connexins or Pannexins in Microglia: Possible Role in the Inflamed Brain

http://dx.doi.org/10.5772/54306

377

[39] Lin, J. H, et al. *A central role of connexin 43 in hypoxic preconditioning.* J Neurosci,

[40] Schock, S. C, et al. *ATP release by way of connexin 36 hemichannels mediates ischemic tol‐*

[41] Cotrina, M. L, Lin, J. H, & Nedergaard, M. *Adhesive properties of connexin hemichannels.*

[42] Stehberg, J, et al. *Release of gliotransmitters through astroglial connexin 43 hemichannels is necessary for fear memory consolidation in the basolateral amygdala.* FASEB J, (2012). [43] Wenker, I. C, et al. *Regulation of ventral surface CO2/H+-sensitive neurons by purinergic*

[44] De Bock, M, et al. *Connexin channels provide a target to manipulate brain endothelial calci‐ um dynamics and blood-brain barrier permeability.* J Cereb Blood Flow Metab, (2011). ,

[45] Liu, X, et al. *Gap junctions/hemichannels modulate interkinetic nuclear migration in the*

[46] Liu, X, et al. *Connexin 43 controls the multipolar phase of neuronal migration to the cerebral*

[47] Kawamura, M, Jr, D. N, & Ruskin, S. A. Masino, *Metabolic autocrine regulation of neu‐ rons involves cooperation among pannexin hemichannels, adenosine receptors, and KATP*

[48] Orellana, J. A, et al. *Modulation of brain hemichannels and gap junction channels by proinflammatory agents and their possible role in neurodegeneration.* Antioxid Redox Signal,

[49] Orellana, J. A, et al. *Hemichannels in the neurovascular unit and white matter under nor‐ mal and inflamed conditions.* CNS Neurol Disord Drug Targets, (2011). , 404-414. [50] Orellana, J. A, et al. *Glial hemichannels and their involvement in aging and neurodegenera‐*

[51] Paul, D. L, et al. *Connexin46, a novel lens gap junction protein, induces voltage-gated cur‐ rents in nonjunctional plasma membrane of Xenopus oocytes.* J Cell Biol, (1991). ,

[52] Contreras, J. E, et al. *Metabolic inhibition induces opening of unapposed connexin 43 gap junction hemichannels and reduces gap junctional communication in cortical astrocytes in*

[53] Thompson, R. J, & Zhou, N. and B.A. MacVicar, *Ischemia opens neuronal gap junction*

*erance in vitro.* Biochem Biophys Res Commun, (2008). , 138-144.

Trends Neurosci, (2010). , 93-102.

*signalling.* J Physiol, (2012). Pt 9): , 2137-2150.

*forebrain precursors.* J Neurosci, (2010). , 4197-4209.

*cortex.* Proc Natl Acad Sci U S A, (2012). , 8280-8285.

*channels.* J Neurosci, (2010). , 3886-3895.

*tive diseases.* Rev Neurosci, (2012). , 163-177.

*culture.* Proc Natl Acad Sci U S A, (2002). , 495-500.

*hemichannels.* Science, (2006). , 924-927.

(2008). , 681-695.

1942-1957.

(2009). , 369-399.

1077-1089.

Glia, (2008). , 1791-1798.


[38] MacVicarB.A. and R.J. Thompson, *Non-junction functions of pannexin-1 channels.* Trends Neurosci, (2010). , 93-102.

[21] Stout, C, Goodenough, D. A, & Paul, D. L. *Connexins: functions without junctions.* Curr

[22] Saez, J. C, et al. *Connexin-based gap junction hemichannels: gating mechanisms.* Biochim

[23] Schalper, K. A, et al. *Currently used methods for identification and characterization of hem‐*

[24] Saez, J. C, et al. *Cell membrane permeabilization via connexin hemichannels in living and*

[25] Bruzzone, S, et al. *Connexin 43 hemi channels mediate Ca2+-regulated transmembrane*

[26] Ye, Z. C, et al. *Functional hemichannels in astrocytes: a novel mechanism of glutamate re‐*

[27] Cherian, P. P, et al. *Mechanical strain opens connexin 43 hemichannels in osteocytes: a nov‐ el mechanism for the release of prostaglandin.* Mol Biol Cell, (2005). , 3100-3106.

[28] Stout, C. E, et al. *Intercellular calcium signaling in astrocytes via ATP release through con‐*

[29] Braet, K, et al. *Pharmacological sensitivity of ATP release triggered by photoliberation of in‐ ositol-1,4,5-trisphosphate and zero extracellular calcium in brain endothelial cells.* J Cell

[30] Orellana, J. A, et al. *Glucose increases intracellular free Ca(2+) in tanycytes via ATP re‐*

[31] Retamal, M. A, et al. *Cx43 hemichannels and gap junction channels in astrocytes are regu‐ lated oppositely by proinflammatory cytokines released from activated microglia.* J Neurosci,

[32] Panchin, Y, et al. *A ubiquitous family of putative gap junction molecules.* Curr Biol,

[33] Bruzzone, R, et al. *Pannexins, a family of gap junction proteins expressed in brain.* Proc

[34] Shestopalov, V. I, & Panchin, Y. *Pannexins and gap junction protein diversity.* Cell Mol

[35] Ishikawa, M, et al. *Pannexin 3 functions as an ER Ca(2+) channel, hemichannel, and gap*

[36] Lai, C. P, et al. *Tumor-suppressive effects of pannexin 1 in C6 glioma cells.* Cancer Res,

[37] Vanden AbeeleF., et al., *Functional implications of calcium permeability of the channel*

*junction to promote osteoblast differentiation.* J Cell Biol, (2011). , 1257-1274.

Opin Cell Biol, (2004). , 507-512.

376 Neurodegenerative Diseases

Biophys Acta, (2005). , 215-224.

*ichannels.* Cell Commun Adhes, (2008). , 207-218.

*NAD+ fluxes in intact cells.* FASEB J, (2001). , 10-12.

*nexin hemichannels.* J Biol Chem, (2002). , 10482-10488.

*leased through connexin 43 hemichannels.* Glia, (2012). , 53-68.

*dying cells.* Exp Cell Res, (2010). , 2377-2389.

*lease.* J Neurosci, (2003). , 3588-3596.

Physiol, (2003). , 205-213.

(2007). , 13781-13792.

(2000). , R473-R474.

Life Sci, (2008). , 376-394.

(2007). , 1545-1554.

Natl Acad Sci U S A, (2003). , 13644-13649.

*formed by pannexin 1.* J Cell Biol, (2006). , 535-546.


[54] Thompson, R. J, et al. *Activation of pannexin-1 hemichannels augments aberrant bursting in the hippocampus.* Science, (2008). , 1555-1559.

[70] Matsue, H, et al. *Gap junction-mediated intercellular communication between dendritic cells (DCs) is required for effective activation of DCs.* J Immunol, (2006). , 181-190.

Plasma Membrane Channels Formed by Connexins or Pannexins in Microglia: Possible Role in the Inflamed Brain

http://dx.doi.org/10.5772/54306

379

[71] Corvalan, L. A, et al. *Injury of skeletal muscle and specific cytokines induce the expression of gap junction channels in mouse dendritic cells.* J Cell Physiol, (2007). , 649-660.

[72] Handel, A, et al. *Gap junction-mediated antigen transport in immune responses.* Trends

[73] Mendoza-naranjo, A, et al. *Functional gap junctions facilitate melanoma antigen ransfer and cross-presentation between human dendritic cells.* J Immunol, (2007). , 6949-6957.

[74] Pang, B, et al. *Direct antigen presentation and gap junction mediated cross-presentation*

[75] Eugenin, E. A, et al. *The Role of Gap Junction Channels During Physiologic and Pathologic Conditions of the Human Central Nervous System.* J Neuroimmune Pharmacol, (2012).

[76] Takeuchi, H, et al. *Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner.* J Biol Chem, (2006). ,

[77] Takeuchi, H, et al. *Blockade of microglial glutamate release protects against ischemic brain*

[78] Shijie, J, et al. *Blockade of glutamate release from microglia attenuates experimental autoim‐*

[79] Maezawa, I, et al. *Rett syndrome astrocytes are abnormal and spread MeCP2 deficiency*

[80] Wang, J, et al. *Modulation of membrane channel currents by gap junction protein mimetic*

[81] Dahl, G. *Gap junction-mimetic peptides do work, but in unexpected ways.* Cell Commun

[82] Evans, W. H, & Leybaert, L. *Mimetic peptides as blockers of connexin channel-facilitated*

[83] Orellana, J. A, et al. *Amyloid beta-induced death in neurons involves glial and neuronal*

[84] Takeuchi, H, et al. *Blockade of gap junction hemichannel suppresses disease progression in mouse models of amyotrophic lateral sclerosis and Alzheimer's disease.* PLoS One, (2011). ,

[85] Kang, J, et al. *Connexin 43 hemichannels are permeable to ATP.* J Neurosci, (2008). ,

*mune encephalomyelitis in mice.* Tohoku J Exp Med, (2009). , 87-92.

*peptides: size matters.* Am J Physiol Cell Physiol, (2007). , C1112-C1119.

*intercellular communication.* Cell Commun Adhes, (2007). , 265-273.

*through gap junctions.* J Neurosci, (2009). , 5051-5061.

*hemichannels.* J Neurosci, (2011). , 4962-4977.

Immunol, (2007). , 463-466.

21362-21368.

*during apoptosis.* J Immunol, (2009). , 1083-1090.

*injury.* Exp Neurol, (2008). , 144-146.

Adhes, (2007). , 259-264.

e21108.

4702-4711.


[70] Matsue, H, et al. *Gap junction-mediated intercellular communication between dendritic cells (DCs) is required for effective activation of DCs.* J Immunol, (2006). , 181-190.

[54] Thompson, R. J, et al. *Activation of pannexin-1 hemichannels augments aberrant bursting*

[55] Orellana, J. A, et al. *ATP and glutamate released via astroglial connexin 43 hemichannels mediate neuronal death through activation of pannexin 1 hemichannels.* J Neurochem,

[56] Domercq, M, et al. receptors *mediate ischemic damage to oligodendrocytes*. Glia, (2010). p.

[57] Schalper, K. A, et al. *Connexin 43 hemichannels mediate the Ca2+ influx induced by extrac‐*

[58] De Vuyst, E, et al. *Connexin hemichannels and gap junction channels are differentially in‐ fluenced by lipopolysaccharide and basic fibroblast growth factor.* Mol Biol Cell, (2007). ,

[59] Rouach, N, et al. *Brain macrophages inhibit gap junctional communication and downregu‐ late connexin 43 expression in cultured astrocytes.* Eur J Neurosci, (2002). , 403-407. [60] Meme, W, et al. *Proinflammatory cytokines released from microglia inhibit gap junctions in*

[61] Eugenin, E. A, et al. *Microglia at brain stab wounds express connexin 43 and in vitro form functional gap junctions after treatment with interferon-gamma and tumor necrosis factor-*

[62] Parenti, R, et al. *Immunocytochemical and RT-PCR analysis of connexin36 in cultures of*

[63] Dobrenis, K, et al. *Human and mouse microglia express connexin36, and functional gap junctions are formed between rodent microglia and neurons.* J Neurosci Res, (2005). ,

[64] Garg, S, & Md, M. Syed, and T. Kielian, *Staphylococcus aureus-derived peptidoglycan in‐ duces Cx43 expression and functional gap junction intercellular communication in microglia.*

[65] Lee, I. H, et al. *Glial and neuronal connexin expression patterns in the rat spinal cord dur‐*

[66] Martinez, A. D, et al. *Identification of second messengers that induce expression of func‐ tional gap junctions in microglia cultured from newborn rats.* Brain Res, (2002). , 191-201.

[67] Faustmann, P. M, et al. *Microglia activation influences dye coupling and Cx43 expression*

[68] Hinkerohe, D, et al. *Effects of cytokines on microglial phenotypes and astroglial coupling in*

[69] Neijssen, J, et al. *Cross-presentation by intercellular peptide transfer through gap junctions.*

*ing development and following injury.* J Comp Neurol, (2005). , 1-10.

*ellular alkalinization.* Am J Physiol Cell Physiol, (2010). , C1504-C1515.

*astrocytes: potentiation by beta-amyloid.* FASEB J, (2006). , 494-496.

*alpha.* Proc Natl Acad Sci U S A, (2001). , 4190-4195.

*mammalian glial cells.* Arch Ital Biol, (2002). , 101-108.

*in the hippocampus.* Science, (2008). , 1555-1559.

(2011). , 826-840.

730-40., 2X7.

378 Neurodegenerative Diseases

34-46.

306-315.

J Neurochem, (2005). , 475-483.

Nature, (2005). , 83-88.

*of the astrocytic network.* Glia, (2003). , 101-108.

*an inflammatory coculture model.* Glia, (2005). , 85-97.


[86] Sanchez, H. A, et al. *Metabolic inhibition increases activity of connexin-32 hemichannels permeable to Ca2+ in transfected HeLa cells.* Am J Physiol Cell Physiol, (2009). , C665- C678.

**Chapter 16**

**Influence of Obesity on Neurodegenerative Diseases**

Obesity is one of the greatest public health challenges of the 21st century. Obesity preva‐ lence has been increasing globally at an alarming rate, particularly among children. The pro‐ gressively increased prevalence of obesity over the past decades among children, as well as adults, is not limited to the US and other industrialized nations but is also evident in devel‐ oping countries [1].The World Health Organization (WHO) estimated the prevalence of obe‐ sity at more than 1 billion overweight adults, with at least 500 million reaching the level of obese. As this continues to increase, by 2015, WHO estimates the number of overweighed adults will balloon to 2.3 billion with more than 700 million obese. Worldwide, obesity is currently responsible for 2–8% of health care costs and approximately 10–13% of deaths [2]. Fundamental causes of the current obesity epidemic are associated with sedentary lifestyles, increased consumption of energy-dense foods high in saturated fats and sugars and reduced physical activity. All of which correlate with the profound changes occurring in behavioral patterns of communities across societies as a consequence of increased urbanization and in‐ dustrialization and often the disappearance of traditional lifestyles [3]. However, it is now appreciated that the progression to obesity represents a complex interaction of genetics, me‐

Clinically, obesity is defined by measurements of body mass index [4] or waist circumfer‐ ence and waist to hip ratio [5]. Body mass index (BMI) is a simple index weight-to-height defined as a person's weight in kilograms divided by the square of his/her height in meters

accumulation of fat in adipose tissue in the form of triglycerides, which can negatively affect health. Obesity is associated with number of metabolic disorders, increased expression of

and reproduction in any medium, provided the original work is properly cited.

or higher identifies an individual as obese. Physiologically, obesity is an excessive

distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 Awada et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

identifies overweight and a BMI of

Rana Awada , Avinash Parimisetty and

Additional information is available at the end of the chapter

tabolism, as well as diet and physical activity level.

). According to WHO guidelines, a BMI 25 kg/m2

Christian Lefebvre d'Hellencourt

http://dx.doi.org/10.5772/53671

**1. Introduction**

(kg/m2

30 kg/m2

[87] Szydlowska, K, & Tymianski, M. *Calcium, ischemia and excitotoxicity.* Cell Calcium, (2010). , 122-129.

### **Influence of Obesity on Neurodegenerative Diseases**

Rana Awada , Avinash Parimisetty and Christian Lefebvre d'Hellencourt

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53671

#### **1. Introduction**

[86] Sanchez, H. A, et al. *Metabolic inhibition increases activity of connexin-32 hemichannels*

[87] Szydlowska, K, & Tymianski, M. *Calcium, ischemia and excitotoxicity.* Cell Calcium,

C678.

380 Neurodegenerative Diseases

(2010). , 122-129.

*permeable to Ca2+ in transfected HeLa cells.* Am J Physiol Cell Physiol, (2009). , C665-

Obesity is one of the greatest public health challenges of the 21st century. Obesity preva‐ lence has been increasing globally at an alarming rate, particularly among children. The pro‐ gressively increased prevalence of obesity over the past decades among children, as well as adults, is not limited to the US and other industrialized nations but is also evident in devel‐ oping countries [1].The World Health Organization (WHO) estimated the prevalence of obe‐ sity at more than 1 billion overweight adults, with at least 500 million reaching the level of obese. As this continues to increase, by 2015, WHO estimates the number of overweighed adults will balloon to 2.3 billion with more than 700 million obese. Worldwide, obesity is currently responsible for 2–8% of health care costs and approximately 10–13% of deaths [2].

Fundamental causes of the current obesity epidemic are associated with sedentary lifestyles, increased consumption of energy-dense foods high in saturated fats and sugars and reduced physical activity. All of which correlate with the profound changes occurring in behavioral patterns of communities across societies as a consequence of increased urbanization and in‐ dustrialization and often the disappearance of traditional lifestyles [3]. However, it is now appreciated that the progression to obesity represents a complex interaction of genetics, me‐ tabolism, as well as diet and physical activity level.

Clinically, obesity is defined by measurements of body mass index [4] or waist circumfer‐ ence and waist to hip ratio [5]. Body mass index (BMI) is a simple index weight-to-height defined as a person's weight in kilograms divided by the square of his/her height in meters (kg/m2 ). According to WHO guidelines, a BMI 25 kg/m2 identifies overweight and a BMI of 30 kg/m2 or higher identifies an individual as obese. Physiologically, obesity is an excessive accumulation of fat in adipose tissue in the form of triglycerides, which can negatively affect health. Obesity is associated with number of metabolic disorders, increased expression of

© 2013 Awada et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

pro-inflammatory markers and elevated risk for various disease including type 2 diabetes, cardiovascular disease, gastrointestinal disorders, respiratory difficulties, and various types of cancer [6]. In a more general nature, it has been suggested that obesity may accelerate the normal process of aging [7] (figure 1).

within an air conditioned room as this was not observed when patients were in a warm en‐ vironment. White adipose tissue (WAT) is a source of energy involved in heat insulation and mechanical cushion. WAT represents around 15-20% of body weight and in obese indi‐ viduals it increases up to 50%. WAT is composed of several different cell types, including preadipocytes, mature adipocytes, macrophages, endothelial cells which are involved in WAT homeostasis (Figure 3) [13, 14]. It is worth noting the presence of stem cells in the WAT, which are extensively studied for their potential in therapeutic reparation and even

Influence of Obesity on Neurodegenerative Diseases

http://dx.doi.org/10.5772/53671

383

for the treatment of obesity and metabolic disorders [15-17].

**Figure 2.** Brown fat (A) and white fat (B) tissue distribution in adult from [10, 11]

Different functional properties have been identified for WAT depending upon location in the subcutaneous or visceral areas. For example, a correlation exists between visceral obesity and increased risk of insulin resistance and cardiovascular diseases, while an increase of subcutaneous fat is associated with favorable plasma lipid profiles [11]. Adipose tissue was not usually thought of as an immune or inflammatory organ based upon studies demon‐ strating that loss of adipose tissue is associated with a decrease in markers of inflammation. It is now well accepted however, that adipose tissue is a key player in the development of inflammation [19]. Excess fat tissue in the obese environment contributes to a low-grade chronic inflammation [20] with elevated production of pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNFα), interleukin -6 (IL-6) and IL-1 [21, 22]. The visceral adi‐

**Figure 1.** Obesity accelerates age and age related pathologies. Adapted from [8]

#### **2. Obesity and inflammatory mediators**

Adipose tissue has long been regarded as tissue storage of fat in the form of triglycerides; however, it is now recognized as an endocrine tissue producing a number of different fac‐ tors, including inflammatory-related factors, acting at a physiological level [9].

Two forms of adipose tissues exist in mammals: the brown fat and the white fat (figure 2).

Brown adipose tissue is involved in the regulation of the body temperature. In humans, un‐ til recently, it was thought that brown fat was only present in the newborn and infant [12]. The extensive use of positron emission tomography (PET) in cancer medical imaging has changed this dogma. An evaluation of fluorodeoxyglucose PET (FDG PET) data from adult cancer patients indicated a high level of glucose consumption in specific body regions corre‐ sponding to brown fat [10], presumably in order to maintain normal body temperature within an air conditioned room as this was not observed when patients were in a warm en‐ vironment. White adipose tissue (WAT) is a source of energy involved in heat insulation and mechanical cushion. WAT represents around 15-20% of body weight and in obese indi‐ viduals it increases up to 50%. WAT is composed of several different cell types, including preadipocytes, mature adipocytes, macrophages, endothelial cells which are involved in WAT homeostasis (Figure 3) [13, 14]. It is worth noting the presence of stem cells in the WAT, which are extensively studied for their potential in therapeutic reparation and even for the treatment of obesity and metabolic disorders [15-17].

pro-inflammatory markers and elevated risk for various disease including type 2 diabetes, cardiovascular disease, gastrointestinal disorders, respiratory difficulties, and various types of cancer [6]. In a more general nature, it has been suggested that obesity may accelerate the

normal process of aging [7] (figure 1).

382 Neurodegenerative Diseases

**Figure 1.** Obesity accelerates age and age related pathologies. Adapted from [8]

Adipose tissue has long been regarded as tissue storage of fat in the form of triglycerides; however, it is now recognized as an endocrine tissue producing a number of different fac‐

Two forms of adipose tissues exist in mammals: the brown fat and the white fat (figure 2). Brown adipose tissue is involved in the regulation of the body temperature. In humans, un‐ til recently, it was thought that brown fat was only present in the newborn and infant [12]. The extensive use of positron emission tomography (PET) in cancer medical imaging has changed this dogma. An evaluation of fluorodeoxyglucose PET (FDG PET) data from adult cancer patients indicated a high level of glucose consumption in specific body regions corre‐ sponding to brown fat [10], presumably in order to maintain normal body temperature

tors, including inflammatory-related factors, acting at a physiological level [9].

**2. Obesity and inflammatory mediators**

**Figure 2.** Brown fat (A) and white fat (B) tissue distribution in adult from [10, 11]

Different functional properties have been identified for WAT depending upon location in the subcutaneous or visceral areas. For example, a correlation exists between visceral obesity and increased risk of insulin resistance and cardiovascular diseases, while an increase of subcutaneous fat is associated with favorable plasma lipid profiles [11]. Adipose tissue was not usually thought of as an immune or inflammatory organ based upon studies demon‐ strating that loss of adipose tissue is associated with a decrease in markers of inflammation. It is now well accepted however, that adipose tissue is a key player in the development of inflammation [19]. Excess fat tissue in the obese environment contributes to a low-grade chronic inflammation [20] with elevated production of pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNFα), interleukin -6 (IL-6) and IL-1 [21, 22]. The visceral adi‐ pocytes significantly contribute in this role as they are metabolically active and produce a higher level of pro-inflammatory cytokines [11, 23-25].

WAT is considered as an important organ in the regulation of many pathological processes by producing several inflammatory factors including, chemokines, cytokines and adipo‐ kines (also named adipocytokines). During the development of obesity expression of these

Influence of Obesity on Neurodegenerative Diseases

http://dx.doi.org/10.5772/53671

385

Adipocytes secrete various chemo-attractants that recruit monocytes into the WAT. Obese adipose tissue exhibits an increased expression of Monocyte Chemoattractant Protein 1 (MCP-1) and of its receptor CCR2. The signaling of MCP1 / CCR2 has a direct impact on the development of obesity (for review see [36]). CCL-2, another chemokine with capability to recruit macrophages, has also a high level of expression in obese adipose tissue; however, it does not appear to be critical for adipose tissue macrophage recruitment [37]. Several other chemokines are also likely to play a role in the recruitment of monocytes/macrophages into the adipose tissue, such as MCP2, MCP4, migration inhibitory factor (MIF), macrophage in‐ flammatory protein-1α (MIP-1α), MIP-1β, or MIP2-α [26, 38]. The adipocytes are not alone in the elevated inflammatory condition of obesity in that the number of macrophages is also higher in the obese environment thus, providing an additional cellular source of inflamma‐

Experimental animal studies have served a critical role in advancing our knowledge with regards to the biological relationship between adipose tissue, obesity, and inflammation. The first study to show a link between obesity and inflammation was the work of Hotamisli‐ gil and colleagues in 1993 in which they demonstrated that TNFα expression was up-regu‐ lated in adipose tissue of genetically obese mice [39]. Additional work reported that the number of bone-marrow derived macrophages present in white adipose tissue directly cor‐ related with obesity [19]. In addition to macrophages, it has been demonstrated that pre-adi‐ pocytes and mature adipocytes also produce inflammatory factors. The mechanisms that initiate and trigger the inflammation are not yet totally elucidated, but different hypothesis have been proposed. A number of factors could trigger an inflammatory response and among them the saturated fatty acids may play a contributing role. For example, palmitate, an abundant nutritional fatty acid, could bind to the inflammation-related toll like receptors (TLR) leading to activation of a signalling cascade and the activation of the transcription fac‐ tor NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) [40]. NF-kB is in‐ volved in many cellular processes including immune and inflammatory responses. Upon activation and nuclear translocation, NF-kB can further induce the production of inflamma‐ tory cytokines, including TNF and IL-1. An alternative, but as relevant a process, is the rec‐ ognition of a diverse range of stress and damage signals by inflammasomes. These are a group of protein complexes including the Nod-Like Receptor (NLR) proteins that can direct‐ ly activate caspase-1 leading to the secretion of pro-inflammatory cytokines and pyroptotic

Recently inflammasomes and their activation of down-stream events have been shown to play a major role in the development of obesity, insulin resistance, and diabetes [42, 43]. Another hypothesis linking inflammation and obesity is supported by Burcelin's group and involves the intestinal flora equilibrium. In this model, a high fat diet is proposed to

factors is modified (figure 4).

tory factors [19].

cell death (for review see [41]).

**Figure 3.** Cells present in the fat tissue adapted from [13, 18]

**Figure 4.** Inflammatory factors produced by WAT in obese situations. [26-35]

WAT is considered as an important organ in the regulation of many pathological processes by producing several inflammatory factors including, chemokines, cytokines and adipo‐ kines (also named adipocytokines). During the development of obesity expression of these factors is modified (figure 4).

pocytes significantly contribute in this role as they are metabolically active and produce a

higher level of pro-inflammatory cytokines [11, 23-25].

384 Neurodegenerative Diseases

**Figure 3.** Cells present in the fat tissue adapted from [13, 18]

**Figure 4.** Inflammatory factors produced by WAT in obese situations. [26-35]

Adipocytes secrete various chemo-attractants that recruit monocytes into the WAT. Obese adipose tissue exhibits an increased expression of Monocyte Chemoattractant Protein 1 (MCP-1) and of its receptor CCR2. The signaling of MCP1 / CCR2 has a direct impact on the development of obesity (for review see [36]). CCL-2, another chemokine with capability to recruit macrophages, has also a high level of expression in obese adipose tissue; however, it does not appear to be critical for adipose tissue macrophage recruitment [37]. Several other chemokines are also likely to play a role in the recruitment of monocytes/macrophages into the adipose tissue, such as MCP2, MCP4, migration inhibitory factor (MIF), macrophage in‐ flammatory protein-1α (MIP-1α), MIP-1β, or MIP2-α [26, 38]. The adipocytes are not alone in the elevated inflammatory condition of obesity in that the number of macrophages is also higher in the obese environment thus, providing an additional cellular source of inflamma‐ tory factors [19].

Experimental animal studies have served a critical role in advancing our knowledge with regards to the biological relationship between adipose tissue, obesity, and inflammation. The first study to show a link between obesity and inflammation was the work of Hotamisli‐ gil and colleagues in 1993 in which they demonstrated that TNFα expression was up-regu‐ lated in adipose tissue of genetically obese mice [39]. Additional work reported that the number of bone-marrow derived macrophages present in white adipose tissue directly cor‐ related with obesity [19]. In addition to macrophages, it has been demonstrated that pre-adi‐ pocytes and mature adipocytes also produce inflammatory factors. The mechanisms that initiate and trigger the inflammation are not yet totally elucidated, but different hypothesis have been proposed. A number of factors could trigger an inflammatory response and among them the saturated fatty acids may play a contributing role. For example, palmitate, an abundant nutritional fatty acid, could bind to the inflammation-related toll like receptors (TLR) leading to activation of a signalling cascade and the activation of the transcription fac‐ tor NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) [40]. NF-kB is in‐ volved in many cellular processes including immune and inflammatory responses. Upon activation and nuclear translocation, NF-kB can further induce the production of inflamma‐ tory cytokines, including TNF and IL-1. An alternative, but as relevant a process, is the rec‐ ognition of a diverse range of stress and damage signals by inflammasomes. These are a group of protein complexes including the Nod-Like Receptor (NLR) proteins that can direct‐ ly activate caspase-1 leading to the secretion of pro-inflammatory cytokines and pyroptotic cell death (for review see [41]).

Recently inflammasomes and their activation of down-stream events have been shown to play a major role in the development of obesity, insulin resistance, and diabetes [42, 43]. Another hypothesis linking inflammation and obesity is supported by Burcelin's group and involves the intestinal flora equilibrium. In this model, a high fat diet is proposed to increase the gram-negative bacteria proportion in the intestine; this increases intestine per‐ meability and the absorption of lipopolysacharide (LPS; the wall component of the gramnegative bacteria). Upon this increased absorption, TLR activation leads to an upregulation of the inflammatory response [44, 45]. These two hypotheses are not mutually exclusive but rather it is likely that the two mechanisms coexist. While the classic localiza‐ tion of TLRs is on macrophages our laboratory and others have shown the presence of functional Toll-like receptors (TLRs) on human adipocytes including the expression of TLR type 2 (TLR2) and TLR type 4 (TLR4) [46, 47] providing evidence for the potential of an adipocyte receptor-mediated response.

differentiation, and migration acting via specific G-protein coupled receptors [65]. The LPA strongly influences proliferation and differentiation of pre-adipocytes *via* the activation of LPA1 receptor [66, 67]. Anti-inflammatory properties for LPA have been suggested based upon the ability to inhibit, in mice, the LPS-induced inflammatory response of macrophages [68]. The expression of ATX is up-regulated during adipogenesis [69, 70] as well as in adipo‐ cytes from obese-diabetic db/db mice and in adipose tissue obtained from glucose-intolerant obese women subjects [69, 71]. The role of ATX in inflammation is less clear, but LPA seems to demonstrate some anti-inflammatory properties as it inhibits LPS-induced inflammation in cultured macrophages and in mice. Based upon these findings, it has been suggested that in addition to its role in cancer and LPA production, ATX may be involved in adipose tissue

Influence of Obesity on Neurodegenerative Diseases

http://dx.doi.org/10.5772/53671

387

It is only relatively recently that the concept that obesity could have an effect on the brain has been emerging. Associations between obesity and various neurological disorders have been reported including sleep apnea, anxiety, manic depressive disorders, increased risk of developing cerebrovascular accident (CVA), and other neurological disorders [18, 72]. Addi‐ tional consideration has been raised that obesity may be linked to various progressive and aging-related neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease

Over the last decade, a number of magnetic resonance imaging (MRI) and computed tomog‐ raphy (CT) studies have reported alterations in brain morphology of overweight/obese indi‐ viduals. Initial studies demonstrated a higher BMI and/or waist-to-hip ratio in middle-aged individuals associated with a reduction in whole brain volume [73-75]. A similar association was observed with temporal lobe atrophy in elderly women [76] with additional evidence of hippocampal atrophy [77]. Debette et al. [78] reported a link between abdominal fat and re‐ duced brain volume in otherwise healthy middle-aged adults. This study reported an in‐ verse association between various obesity indicators (BMI, waist circumference, waist-to-hip ratio, and abdominal fat) and brain volume as determined by structural MRI of 733 partici‐ pants. Independent of other obesity indicators, waist-to-hip ratio was found to be associated with increased temporal horn volume. Pannacciulli et al., 2006 reported gray matter reduc‐ tions in the left postcentral gyrus, bilateral putamen, and right cerebellar regions in obese individuals as detected using voxel-based morphometry [79]. Gender differences have been suggested with a male-specific association between increasing BMI and smaller cerebellum, midbrain, frontal, termporal, and parietal cortex [74]. In a cohort of 95 obese women be‐ tween the ages of 52 and 92, gray matter reductions were reported in the left orbitofrontal, right inferior frontal, right precentral gyri, and right cerebellar regions [80]. In contrast, in‐ creased volumes in white matter in the frontal, temporal, and parietal lobes were also re‐ ported [80]. In a cross-sectional study of normal elderly individuals showing no sign of

development and/or obesity-associated pathologies such as diabetes.

(AD), and autoimmune nervous system diseases like multiple sclerosis.

**3. Influence of obesity on CNS**

Adipokines are defined as soluble mediators that are mainly, but not exclusively, produced by adipocytes and exert their biological function in an autocrine, paracrine or systemic man‐ ner. Over 50 adipokines have been identified, and they generally function as hormones to influence energy homeostasis and feeding [22, 48]. The following sections will focus on a re‐ view of two specific adipokines (leptin and adiponectin) and an additional factor (autotaxin) produced by WAT. Information is presented supporting that these factors and their activa‐ tion may provide an important link between obesity and related inflammatory disorders.

Leptin was identified in 1994 as the 16 kDa protein product of the obese (ob) gene [49]. It displays immune-regulatory effects by increasing the production of pro-inflammatory cyto‐ kines by macrophages [50]. It is best known as an important regulator of energy balance through its actions in the brain to suppress appetite and increase energy expenditure [51]. Leptin in the blood enters the brain via a transport mechanism that can be saturated [52]. Upon entry it is believed to act primarily on the hypothalamic centers thus possibly provid‐ ing a target for its effects upon appetite. In addition to the hypothalamus, leptin receptors (OBR) are widely expressed in numerous extra-hypothalamic regions of the brain, including the hippocampus, cerebellum, amygdala, and brain stem [53]. There are many splice var‐ iants of the receptor; those with short cytoplasmic domains are expressed in multiple tissues while the one with long cytoplasmic domains (OB-Rb) are expressed in specific brain re‐ gions. OB-Rb stimulates the JAK/STAT3 pathway and PI3K which are necessary for the lep‐ tin effects on food intake and hepatic glucose metabolism [54, 55].

Adiponectin, a prototypic adipocytokine is an anti-inflammatory adipokine secreted by adi‐ pocytes [56-58]. It plays a major role in regulation of insulin sensitivity and in obesity the lev‐ els of adiponectin are diminished due to a decreased release from WAT [59]. A deficiency in adiponectin is associated with exaggerated inflammatory response in patients with critical ill‐ ness, including sepsis [32, 60] and with the development of a proinflammatory phenotype in in animal models of polymicrobial sepsis [61, 62]. Further studies demonstrated that adipo‐ nectin deficiency is associated with increased leukocyte and platelet adhesion as well as blood brain barrier dysfunction with cecal ligation and puncture induced sepsis in mice [63].

Autotaxin (ATX), also known as ectonucleotide pyrophosphatase phosphodiesterase-2 (ENPP2), is a secreted enzyme with lysophospholipase D (lysoPLD) activity involved in hy‐ drolysis of lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA) [64]. LPA is bio‐ active phospholipid involved in numerous biological activities, including cell proliferation, differentiation, and migration acting via specific G-protein coupled receptors [65]. The LPA strongly influences proliferation and differentiation of pre-adipocytes *via* the activation of LPA1 receptor [66, 67]. Anti-inflammatory properties for LPA have been suggested based upon the ability to inhibit, in mice, the LPS-induced inflammatory response of macrophages [68]. The expression of ATX is up-regulated during adipogenesis [69, 70] as well as in adipo‐ cytes from obese-diabetic db/db mice and in adipose tissue obtained from glucose-intolerant obese women subjects [69, 71]. The role of ATX in inflammation is less clear, but LPA seems to demonstrate some anti-inflammatory properties as it inhibits LPS-induced inflammation in cultured macrophages and in mice. Based upon these findings, it has been suggested that in addition to its role in cancer and LPA production, ATX may be involved in adipose tissue development and/or obesity-associated pathologies such as diabetes.

### **3. Influence of obesity on CNS**

increase the gram-negative bacteria proportion in the intestine; this increases intestine per‐ meability and the absorption of lipopolysacharide (LPS; the wall component of the gramnegative bacteria). Upon this increased absorption, TLR activation leads to an upregulation of the inflammatory response [44, 45]. These two hypotheses are not mutually exclusive but rather it is likely that the two mechanisms coexist. While the classic localiza‐ tion of TLRs is on macrophages our laboratory and others have shown the presence of functional Toll-like receptors (TLRs) on human adipocytes including the expression of TLR type 2 (TLR2) and TLR type 4 (TLR4) [46, 47] providing evidence for the potential of an

Adipokines are defined as soluble mediators that are mainly, but not exclusively, produced by adipocytes and exert their biological function in an autocrine, paracrine or systemic man‐ ner. Over 50 adipokines have been identified, and they generally function as hormones to influence energy homeostasis and feeding [22, 48]. The following sections will focus on a re‐ view of two specific adipokines (leptin and adiponectin) and an additional factor (autotaxin) produced by WAT. Information is presented supporting that these factors and their activa‐ tion may provide an important link between obesity and related inflammatory disorders. Leptin was identified in 1994 as the 16 kDa protein product of the obese (ob) gene [49]. It displays immune-regulatory effects by increasing the production of pro-inflammatory cyto‐ kines by macrophages [50]. It is best known as an important regulator of energy balance through its actions in the brain to suppress appetite and increase energy expenditure [51]. Leptin in the blood enters the brain via a transport mechanism that can be saturated [52]. Upon entry it is believed to act primarily on the hypothalamic centers thus possibly provid‐ ing a target for its effects upon appetite. In addition to the hypothalamus, leptin receptors (OBR) are widely expressed in numerous extra-hypothalamic regions of the brain, including the hippocampus, cerebellum, amygdala, and brain stem [53]. There are many splice var‐ iants of the receptor; those with short cytoplasmic domains are expressed in multiple tissues while the one with long cytoplasmic domains (OB-Rb) are expressed in specific brain re‐ gions. OB-Rb stimulates the JAK/STAT3 pathway and PI3K which are necessary for the lep‐

Adiponectin, a prototypic adipocytokine is an anti-inflammatory adipokine secreted by adi‐ pocytes [56-58]. It plays a major role in regulation of insulin sensitivity and in obesity the lev‐ els of adiponectin are diminished due to a decreased release from WAT [59]. A deficiency in adiponectin is associated with exaggerated inflammatory response in patients with critical ill‐ ness, including sepsis [32, 60] and with the development of a proinflammatory phenotype in in animal models of polymicrobial sepsis [61, 62]. Further studies demonstrated that adipo‐ nectin deficiency is associated with increased leukocyte and platelet adhesion as well as blood

brain barrier dysfunction with cecal ligation and puncture induced sepsis in mice [63].

Autotaxin (ATX), also known as ectonucleotide pyrophosphatase phosphodiesterase-2 (ENPP2), is a secreted enzyme with lysophospholipase D (lysoPLD) activity involved in hy‐ drolysis of lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA) [64]. LPA is bio‐ active phospholipid involved in numerous biological activities, including cell proliferation,

tin effects on food intake and hepatic glucose metabolism [54, 55].

adipocyte receptor-mediated response.

386 Neurodegenerative Diseases

It is only relatively recently that the concept that obesity could have an effect on the brain has been emerging. Associations between obesity and various neurological disorders have been reported including sleep apnea, anxiety, manic depressive disorders, increased risk of developing cerebrovascular accident (CVA), and other neurological disorders [18, 72]. Addi‐ tional consideration has been raised that obesity may be linked to various progressive and aging-related neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease (AD), and autoimmune nervous system diseases like multiple sclerosis.

Over the last decade, a number of magnetic resonance imaging (MRI) and computed tomog‐ raphy (CT) studies have reported alterations in brain morphology of overweight/obese indi‐ viduals. Initial studies demonstrated a higher BMI and/or waist-to-hip ratio in middle-aged individuals associated with a reduction in whole brain volume [73-75]. A similar association was observed with temporal lobe atrophy in elderly women [76] with additional evidence of hippocampal atrophy [77]. Debette et al. [78] reported a link between abdominal fat and re‐ duced brain volume in otherwise healthy middle-aged adults. This study reported an in‐ verse association between various obesity indicators (BMI, waist circumference, waist-to-hip ratio, and abdominal fat) and brain volume as determined by structural MRI of 733 partici‐ pants. Independent of other obesity indicators, waist-to-hip ratio was found to be associated with increased temporal horn volume. Pannacciulli et al., 2006 reported gray matter reduc‐ tions in the left postcentral gyrus, bilateral putamen, and right cerebellar regions in obese individuals as detected using voxel-based morphometry [79]. Gender differences have been suggested with a male-specific association between increasing BMI and smaller cerebellum, midbrain, frontal, termporal, and parietal cortex [74]. In a cohort of 95 obese women be‐ tween the ages of 52 and 92, gray matter reductions were reported in the left orbitofrontal, right inferior frontal, right precentral gyri, and right cerebellar regions [80]. In contrast, in‐ creased volumes in white matter in the frontal, temporal, and parietal lobes were also re‐ ported [80]. In a cross-sectional study of normal elderly individuals showing no sign of cognitive deficit, tensor-based morphometry unveiled atrophy in the white and gray matter of the frontal lobes, anterior cingulate gyrus, hippocampus, and thalamus in both male and female subjects with a high BMI (BMI > 30) as compared to individuals with a normal BMI (18.5–25) [81]. Upon further investigation, the brain volume reduction in gray and white matter was found to be associated with a common variant of the fat mass and obesity associ‐ ated (*FTO*) gene [82]. Three-dimensional MRI brain maps of 206 healthy elderly participants showed an association between brain volume and the risk allele of the *FTO* gene known to be strongly associated with higher body-mass index. Participants who carried at least one copy of the allele had marked reductions in the volume of various brain structures com‐ pared to average volumes in non-carriers and in the general population. Carriers of the al‐ lele had, on average, an 8% deficit in the frontal lobe, 12% deficit in the occipital lobe (percentage units are expressed in terms of the average volumes seen in the general popula‐ tion of carriers and non-carriers). A reduction in temporal lobe volume was observed in par‐ ticipants with a higher BMI, but not in carriers of the risk allele. A pronounced effect of BMI was seen in carriers of the FTO allele showing volume deficits in all the other lobes of the brain, as well as in the brain stem and cerebellum. The authors proposed as a strong hypoth‐ esis that "BMI affects brain structure and that FTO exerts some additive detectable effect over and above whatever the BMI of the person happens to be" [82].

The possible relationship between neurodegeneration and obesity in animal models and in humans has been studied now for over a decade with a primary focus on the possibility that obesity and related metabolic disorders exacerbate neurodegeneration and thereby, promote cognitive decline and increase vulnerability to brain injury [73]. Based upon the identifica‐ tion of hereditary neurodegenerative disorders associated with obesity such as Alstrom, Bardet-Biedl or Prader-Willi syndromes, some studies have addressed the possibility that neurodegeneration in the brain may be a causal factor for obesity [83]. A more recent associ‐ ation between obesity and neurological function is based upon correlations with biological processes of oxidative stress and inflammation. While the causal nature of these processes to neurodegeneration has not been definitively established, it is widely accepted that neuroin‐ flammation and oxidative stress responses occur with clinical manifestation of the disease. Given the recent reports of adipokines within the body fat and the elevation of these inflam‐ matory factors with stimulation, a more direct linkage between obesity and various human diseases, including neurodegenerative disease, has been hypothesized. In the past decade, a linkage has been demonstrated between being overweight in middle age and increased risk for AD and other forms of dementia [84, 85]. However, as to date, the exact nature of the elevated risk has not been identified and characterized. There however, have been a number of hypotheses put forth, many including a role for inflammation. As previously stated, WAT can produce an array of inflammatory-related factors, for which expression levels may be modified in obesity. It has been proposed that an obesity-related chronic low-grade inflam‐ mation can serve to change the environment leading to a priming the brain for subsequent insults leading to a heightened inflammatory response and possibly exacerbation of the damage (figure 5).

**Figure 5.** low grade chronic inflammation affect the response of the brain to later injury.

complex network.

Obesity has a major negative impact on cognitive function due to vascular defects, impaired insulin metabolism and signaling pathway or a defect in glucose transport mechanisms in brain [86]. As shown in figure 4, leptin level is increased in obesity but there is also evidence that leptin signaling may become less effective in obesity, provoking a leptin-resistance sta‐ tus [87-89]. Thus, obesity, as it relates to leptin, may be due to a lack of leptin or of its recep‐ tor(s) but may also be a consequence of a signaling defect. Interestingly, leptin has protective effects in the brain both *in vitro* and *in vivo* and thus, has been suggested to be a good candidate as a link between obesity and neurodegeneration [90]. Similar to leptin, ATX is increased in obesity. LPA receptors are present in the CNS but the potential effect of ATX on oxidative stress or neuroinflammation was not known. In a recent study, Awada et al. [91] demonstrated that ATX synthesis and secretion by the brain immune cell, the microglia, have a protective effect by mitigating intracellular oxidation. These data suggests a novel anti-oxidant role for ATX in the brain. In contrast, adiponectin level is lowered with obesity [92]. In the CNS, adiponectin has been shown to improve cerebrovascular injury in mice [93, 94]. A deficiency in adiponectin in the mouse increases the severity of seizure activity [95] while presence of adiponectin provides a level of protection to hippocampal neurons against kainic acid-induced excitotoxicity [96]. It is likely that other factors produced by the WAT could have some effects on the CNS and further investigations are needed to decipher this

Influence of Obesity on Neurodegenerative Diseases

http://dx.doi.org/10.5772/53671

389

**Figure 5.** low grade chronic inflammation affect the response of the brain to later injury.

cognitive deficit, tensor-based morphometry unveiled atrophy in the white and gray matter of the frontal lobes, anterior cingulate gyrus, hippocampus, and thalamus in both male and female subjects with a high BMI (BMI > 30) as compared to individuals with a normal BMI (18.5–25) [81]. Upon further investigation, the brain volume reduction in gray and white matter was found to be associated with a common variant of the fat mass and obesity associ‐ ated (*FTO*) gene [82]. Three-dimensional MRI brain maps of 206 healthy elderly participants showed an association between brain volume and the risk allele of the *FTO* gene known to be strongly associated with higher body-mass index. Participants who carried at least one copy of the allele had marked reductions in the volume of various brain structures com‐ pared to average volumes in non-carriers and in the general population. Carriers of the al‐ lele had, on average, an 8% deficit in the frontal lobe, 12% deficit in the occipital lobe (percentage units are expressed in terms of the average volumes seen in the general popula‐ tion of carriers and non-carriers). A reduction in temporal lobe volume was observed in par‐ ticipants with a higher BMI, but not in carriers of the risk allele. A pronounced effect of BMI was seen in carriers of the FTO allele showing volume deficits in all the other lobes of the brain, as well as in the brain stem and cerebellum. The authors proposed as a strong hypoth‐ esis that "BMI affects brain structure and that FTO exerts some additive detectable effect

The possible relationship between neurodegeneration and obesity in animal models and in humans has been studied now for over a decade with a primary focus on the possibility that obesity and related metabolic disorders exacerbate neurodegeneration and thereby, promote cognitive decline and increase vulnerability to brain injury [73]. Based upon the identifica‐ tion of hereditary neurodegenerative disorders associated with obesity such as Alstrom, Bardet-Biedl or Prader-Willi syndromes, some studies have addressed the possibility that neurodegeneration in the brain may be a causal factor for obesity [83]. A more recent associ‐ ation between obesity and neurological function is based upon correlations with biological processes of oxidative stress and inflammation. While the causal nature of these processes to neurodegeneration has not been definitively established, it is widely accepted that neuroin‐ flammation and oxidative stress responses occur with clinical manifestation of the disease. Given the recent reports of adipokines within the body fat and the elevation of these inflam‐ matory factors with stimulation, a more direct linkage between obesity and various human diseases, including neurodegenerative disease, has been hypothesized. In the past decade, a linkage has been demonstrated between being overweight in middle age and increased risk for AD and other forms of dementia [84, 85]. However, as to date, the exact nature of the elevated risk has not been identified and characterized. There however, have been a number of hypotheses put forth, many including a role for inflammation. As previously stated, WAT can produce an array of inflammatory-related factors, for which expression levels may be modified in obesity. It has been proposed that an obesity-related chronic low-grade inflam‐ mation can serve to change the environment leading to a priming the brain for subsequent insults leading to a heightened inflammatory response and possibly exacerbation of the

over and above whatever the BMI of the person happens to be" [82].

damage (figure 5).

388 Neurodegenerative Diseases

Obesity has a major negative impact on cognitive function due to vascular defects, impaired insulin metabolism and signaling pathway or a defect in glucose transport mechanisms in brain [86]. As shown in figure 4, leptin level is increased in obesity but there is also evidence that leptin signaling may become less effective in obesity, provoking a leptin-resistance sta‐ tus [87-89]. Thus, obesity, as it relates to leptin, may be due to a lack of leptin or of its recep‐ tor(s) but may also be a consequence of a signaling defect. Interestingly, leptin has protective effects in the brain both *in vitro* and *in vivo* and thus, has been suggested to be a good candidate as a link between obesity and neurodegeneration [90]. Similar to leptin, ATX is increased in obesity. LPA receptors are present in the CNS but the potential effect of ATX on oxidative stress or neuroinflammation was not known. In a recent study, Awada et al. [91] demonstrated that ATX synthesis and secretion by the brain immune cell, the microglia, have a protective effect by mitigating intracellular oxidation. These data suggests a novel anti-oxidant role for ATX in the brain. In contrast, adiponectin level is lowered with obesity [92]. In the CNS, adiponectin has been shown to improve cerebrovascular injury in mice [93, 94]. A deficiency in adiponectin in the mouse increases the severity of seizure activity [95] while presence of adiponectin provides a level of protection to hippocampal neurons against kainic acid-induced excitotoxicity [96]. It is likely that other factors produced by the WAT could have some effects on the CNS and further investigations are needed to decipher this complex network.

### **4. Susceptibility of the CNS to obesity in animal studies**

Animal models of obesity have been very useful and important for understanding the regu‐ lation of food intake and imbalance in energy expenditure. The initial models examined spontaneous single gene mutations leading to the loss of the gene function [97]. The first of these models described is the agouti mouse [98, 99]. In addition to rats, other species have been used to study obesity related issues. These include, pigs, chicken, and even bats [97, 100, 101]. As several genes have been found to be involved in energy balance regulation, the advancement of methods for the overexpression or silencing of genes has allowed for a dra‐ matic increase in the number of mouse models of obesity.

**5. Conclusion**

**Acknowledgements**

**Author details**

**References**

miol 2006; 35(1) 93-9

obesity. 2008

It is now well accepted that obesity is associated with several pathologies including neuro‐ pathies and the ability of the nervous system to repair following injury. While further re‐ search is needed in characterizing the nature of the effect of obesity on the nervous system there are current studies suggesting that such effects can be modified. For example, resvera‐ trol or ursolic acid have been shown to attenuate obesity-associated nervous system inflam‐ mation resulting in an improvement of memory deficits in mice fed a high-fat diet. [125, 126]. Given the accelerated increase in obesity and neurodegenerative diseases as well as the influence of childhood health status and adult disease, there is a critical need to better un‐ derstand the relationship between obesity and the nervous system. Identification of the criti‐ cal factors underlying the various changes seen in the brain and its response to injury as a function of age, nutritional status, and body mass, i.e., obesity will lay the foundation for developing therapeutic interventions that will be applicable to the human population.

Influence of Obesity on Neurodegenerative Diseases

http://dx.doi.org/10.5772/53671

391

We would like to thanks Dr. G. Jean Harry (NTP/NIEHS/NIH) for her comments and edi‐ tion. We would like to thank the 'Region La Reunion', Europe (CPER/FEDER) for its fund‐

ing supports. AP is funded by fellowships from 'Conseil Régional de La Réunion'.

Rana Awada , Avinash Parimisetty and Christian Lefebvre d'Hellencourt\*

CYROI, UFR Santé, Université de La Réunion, Ile de La Réunion, France

tion. World Health Organ Tech Rep Ser 2000; 894(i-xii, 1-253

\*Address all correspondence to: Christian.Lefebvre-d-Hellencourt@univ-reunion.fr

Groupe d'Etude sur l'Inflammation Chronique et l'Obesité (GEICO), EA 4516, Plateforme

[1] Prentice AM. The emerging epidemic of obesity in developing countries. Int J Epide‐

[2] World Health Organisation (WHO). Obesity in Europe. http://www.euro.who.int/

[3] Obesity: preventing and managing the global epidemic. Report of a WHO consulta‐

There is a growing body of evidence that nutrition could affect the inflammatory status of the brain [102, 103]. High dietary fat is a significant risk for cerebral oxidative stress devel‐ opment, neuronal inflammation, vascular dementia, AD, and Parkinson disease [104-108]. High fat diet induces a rapid (24 hours) temporary inflammation in the CNS, which can po‐ tentially progress to a chronic condition in obese mice as well as in human and leads to glio‐ sis and mediobasal hypothalamus neuronal injury [109].

In genetic murine model of obesity, an increased susceptibility of CNS to trauma has been observed; obesity is an aggravating factor in chemical-induced neurodegeneration. In mice deficient for the leptin gene (ob/ob), the effects of two neurotoxicants are exacerbated, methamphetamine (METH), which affects dopaminergic neurons and kainic acid (KA), af‐ fecting the hippocampus [110]. The ob/ob mice are also more susceptible to seizure in‐ duced by the gamma-aminobutyric acid A receptor (GABAAR) antagonist, pentylenetetrazol (PTZ) [111].

It is now known that in distinct neurogenic sites of the brain the presence of stem/progenitor cells allows for the generation of new neurons over the full lifespan [112]. This process is influenced by a number of factors including cytokines, hormones, growth factors, and exer‐ cise [112-116]. The regulatory effects of growth factors demonstrate a level of specificity for brain regions with brain-derived neurotrophic factor (BDNF) showing prominent effects in the hippocampus while ciliary neurotrophic factor (CNTF) induces neurogenesis in the hy‐ pothalamus. In this case the neurogenesis occurs in the satiety centers inducing a persistent weight loss [117]. More importantly, with regards to inflammatory factors, injury to the brain such as ischemia [118], epilepsy [119], or chemically induced neurodegeneration [120] induce an increase in neurogenesis. This induction has been termed "injury-induced neuro‐ genesis". A relationship between adult neurogenesis and obesity has been demonstrated in the decrease in the turnover of new neurons in the hypothalamic arcuate nucleus (region playing a key role in body weight regulation) in obese mice (high fat diet or ob/ob) [121]. While the research effort targeted toward this area of the effects of nutrition or obesity on adult neurogenesis is in its infancy, it is likely that a link similar to what has been found with neurodegeneration, may be found for molecules such as Omega 3 fatty acids, flavo‐ noids, and polyphenols [122-124].

### **5. Conclusion**

**4. Susceptibility of the CNS to obesity in animal studies**

matic increase in the number of mouse models of obesity.

sis and mediobasal hypothalamus neuronal injury [109].

pentylenetetrazol (PTZ) [111].

390 Neurodegenerative Diseases

noids, and polyphenols [122-124].

Animal models of obesity have been very useful and important for understanding the regu‐ lation of food intake and imbalance in energy expenditure. The initial models examined spontaneous single gene mutations leading to the loss of the gene function [97]. The first of these models described is the agouti mouse [98, 99]. In addition to rats, other species have been used to study obesity related issues. These include, pigs, chicken, and even bats [97, 100, 101]. As several genes have been found to be involved in energy balance regulation, the advancement of methods for the overexpression or silencing of genes has allowed for a dra‐

There is a growing body of evidence that nutrition could affect the inflammatory status of the brain [102, 103]. High dietary fat is a significant risk for cerebral oxidative stress devel‐ opment, neuronal inflammation, vascular dementia, AD, and Parkinson disease [104-108]. High fat diet induces a rapid (24 hours) temporary inflammation in the CNS, which can po‐ tentially progress to a chronic condition in obese mice as well as in human and leads to glio‐

In genetic murine model of obesity, an increased susceptibility of CNS to trauma has been observed; obesity is an aggravating factor in chemical-induced neurodegeneration. In mice deficient for the leptin gene (ob/ob), the effects of two neurotoxicants are exacerbated, methamphetamine (METH), which affects dopaminergic neurons and kainic acid (KA), af‐ fecting the hippocampus [110]. The ob/ob mice are also more susceptible to seizure in‐ duced by the gamma-aminobutyric acid A receptor (GABAAR) antagonist,

It is now known that in distinct neurogenic sites of the brain the presence of stem/progenitor cells allows for the generation of new neurons over the full lifespan [112]. This process is influenced by a number of factors including cytokines, hormones, growth factors, and exer‐ cise [112-116]. The regulatory effects of growth factors demonstrate a level of specificity for brain regions with brain-derived neurotrophic factor (BDNF) showing prominent effects in the hippocampus while ciliary neurotrophic factor (CNTF) induces neurogenesis in the hy‐ pothalamus. In this case the neurogenesis occurs in the satiety centers inducing a persistent weight loss [117]. More importantly, with regards to inflammatory factors, injury to the brain such as ischemia [118], epilepsy [119], or chemically induced neurodegeneration [120] induce an increase in neurogenesis. This induction has been termed "injury-induced neuro‐ genesis". A relationship between adult neurogenesis and obesity has been demonstrated in the decrease in the turnover of new neurons in the hypothalamic arcuate nucleus (region playing a key role in body weight regulation) in obese mice (high fat diet or ob/ob) [121]. While the research effort targeted toward this area of the effects of nutrition or obesity on adult neurogenesis is in its infancy, it is likely that a link similar to what has been found with neurodegeneration, may be found for molecules such as Omega 3 fatty acids, flavo‐

It is now well accepted that obesity is associated with several pathologies including neuro‐ pathies and the ability of the nervous system to repair following injury. While further re‐ search is needed in characterizing the nature of the effect of obesity on the nervous system there are current studies suggesting that such effects can be modified. For example, resvera‐ trol or ursolic acid have been shown to attenuate obesity-associated nervous system inflam‐ mation resulting in an improvement of memory deficits in mice fed a high-fat diet. [125, 126]. Given the accelerated increase in obesity and neurodegenerative diseases as well as the influence of childhood health status and adult disease, there is a critical need to better un‐ derstand the relationship between obesity and the nervous system. Identification of the criti‐ cal factors underlying the various changes seen in the brain and its response to injury as a function of age, nutritional status, and body mass, i.e., obesity will lay the foundation for developing therapeutic interventions that will be applicable to the human population.

### **Acknowledgements**

We would like to thanks Dr. G. Jean Harry (NTP/NIEHS/NIH) for her comments and edi‐ tion. We would like to thank the 'Region La Reunion', Europe (CPER/FEDER) for its fund‐ ing supports. AP is funded by fellowships from 'Conseil Régional de La Réunion'.

### **Author details**

Rana Awada , Avinash Parimisetty and Christian Lefebvre d'Hellencourt\*

\*Address all correspondence to: Christian.Lefebvre-d-Hellencourt@univ-reunion.fr

Groupe d'Etude sur l'Inflammation Chronique et l'Obesité (GEICO), EA 4516, Plateforme CYROI, UFR Santé, Université de La Réunion, Ile de La Réunion, France

#### **References**


[4] Mei Z, Grummer-Strawn LM, Pietrobelli A, Goulding A, Goran MI and Dietz WH. Validity of body mass index compared with other body-composition screening in‐ dexes for the assessment of body fatness in children and adolescents. Am J Clin Nutr 2002; 75(6) 978-85

[20] Greenberg AS and Obin MS. Obesity and the role of adipose tissue in inflammation

Influence of Obesity on Neurodegenerative Diseases

http://dx.doi.org/10.5772/53671

393

[21] Moschen AR, Kaser A, Enrich B, Mosheimer B, Theurl M, Niederegger H and Tilg H. Visfatin, an adipocytokine with proinflammatory and immunomodulating proper‐

[22] Tilg H and Moschen AR. Adipocytokines: mediators linking adipose tissue, inflam‐

[23] Van Harmelen V, Reynisdottir S, Eriksson P, Thorne A, Hoffstedt J, Lonnqvist F and Arner P. Leptin secretion from subcutaneous and visceral adipose tissue in women.

[24] Fain JN, Madan AK, Hiler ML, Cheema P and Bahouth SW. Comparison of the re‐ lease of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from vis‐ ceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology

[25] Lafontan M and Langin D. Lipolysis and lipid mobilization in human adipose tissue.

[26] Tilg H and Moschen AR. Role of adiponectin and PBEF/visfatin as regulators of in‐ flammation: involvement in obesity-associated diseases. Clin Sci (Lond) 2008; 114(4)

[27] Berndt J, Kloting N, Kralisch S, Kovacs P, Fasshauer M, Schon MR, Stumvoll M and Bluher M. Plasma visfatin concentrations and fat depot-specific mRNA expression in

[28] Azuma K, Katsukawa F, Oguchi S, Murata M, Yamazaki H, Shimada A and Saruta T. Correlation between serum resistin level and adiposity in obese individuals. Obes

[29] Sartipy P and Loskutoff DJ. Monocyte chemoattractant protein 1 in obesity and insu‐

[30] Madani R, Karastergiou K, Ogston NC, Miheisi N, Bhome R, Haloob N, Tan GD, Karpe F, Malone-Lee J, Hashemi M, Jahangiri M and Mohamed-Ali V. RANTES re‐ lease by human adipose tissue in vivo and evidence for depot-specific differences.

[31] Chiellini C, Santini F, Marsili A, Berti P, Bertacca A, Pelosini C, Scartabelli G, Pardini E, Lopez-Soriano J, Centoni R, Ciccarone AM, Benzi L, Vitti P, Del Prato S, Pinchera A and Maffei M. Serum haptoglobin: a novel marker of adiposity in humans. J Clin

lin resistance. Proc Natl Acad Sci U S A 2003; 100(12) 7265-70

Am J Physiol Endocrinol Metab 2009; 296(6) E1262-8

and metabolism. Am J Clin Nutr 2006; 83(2) 461S-5S

mation and immunity. Nat Rev Immunol 2006; 6(10) 772-83

ties. J Immunol 2007; 178(3) 1748-58

Diabetes 1998; 47(6) 913-7

Prog Lipid Res 2009; 48(5) 275-97

humans. Diabetes 2005; 54(10) 2911-6

Endocrinol Metab 2004; 89(6) 2678-83

Res 2003; 11(8) 997-1001

2004; 145(5) 2273-82

275-88


[20] Greenberg AS and Obin MS. Obesity and the role of adipose tissue in inflammation and metabolism. Am J Clin Nutr 2006; 83(2) 461S-5S

[4] Mei Z, Grummer-Strawn LM, Pietrobelli A, Goulding A, Goran MI and Dietz WH. Validity of body mass index compared with other body-composition screening in‐ dexes for the assessment of body fatness in children and adolescents. Am J Clin Nutr

[5] Eckel RH, Grundy SM and Zimmet PZ. The metabolic syndrome. Lancet 2005;

[7] Tzanetakou IP, Katsilambros NL, Benetos A, Mikhailidis DP and Perrea DN. "Is obe‐ sity linked to aging?": adipose tissue and the role of telomeres. Ageing Res Rev 2012;

[8] Granholm AC, Boger H and Emborg ME. Mood, memory and movement: an age-re‐

[9] Harwood HJ, Jr. The adipocyte as an endocrine organ in the regulation of metabolic

[10] Nedergaard J, Bengtsson T and Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 2007; 293(2) E444-52

[11] Wronska A and Kmiec Z. Structural and biochemical characteristics of various white

[12] Cannon B and Nedergaard J. Brown adipose tissue: function and physiological sig‐

[13] Hauner H. Secretory factors from human adipose tissue and their functional role.

[14] Hauner H. The new concept of adipose tissue function. Physiology & Behavior 2004;

[15] Cawthorn WP, Scheller EL and MacDougald OA. Adipose tissue stem cells meet pre‐ adipocyte commitment: going back to the future. J Lipid Res 2011; 53(2) 227-46

[16] Tran TT and Kahn CR. Transplantation of adipose tissue and stem cells: role in me‐

[17] Roche R, Hoareau L, Mounet F and Festy F. Adult stem cells for cardiovascular dis‐

[18] Palaniyandi R, Awada R, Harry GJ and Lefebvre d'Hellencourt C. White fat tissue, obesity and possible role in neurodegeneration in Harry GJ and Tilson HA (ed)

[19] Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL and Ferrante AW, Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest

eases: the adipose tissue potential. Expert Opin Biol Ther 2007; 7(6) 791-8

White fat tissue, obesity and possible role in neurodegeneration. Book 2010

[6] Haslam DW and James WP. Obesity. Lancet 2005; 366(9492) 1197-209

lated neurodegenerative complex? Curr Aging Sci 2008; 1(2) 133-9

adipose tissue depots. Acta Physiol (Oxf) 2012; 205(2) 194-208

tabolism and disease. Nat Rev Endocrinol 2010; 6(4) 195-213

homeostasis. Neuropharmacology 2012; 63(1) 57-75

nificance. Physiol Rev 2004; 84(1) 277-359

Proc Nutr Soc 2005; 64(2) 163-9

2002; 75(6) 978-85

392 Neurodegenerative Diseases

365(9468) 1415-28

11(2) 220-9

83(4) 653-8

2003; 112(12) 1796-808


[32] Hillenbrand A, Knippschild U, Weiss M, Schrezenmeier H, Henne-Bruns D, Huber-Lang M and Wolf AM. Sepsis induced changes of adipokines and cytokines - septic patients compared to morbidly obese patients. BMC Surg 2010; 10(26

[45] Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W and Pettersson S. Host-gut microbiota metabolic interactions. Science 2012; 336(6086) 1262-7

Influence of Obesity on Neurodegenerative Diseases

http://dx.doi.org/10.5772/53671

395

[46] Bes-Houtmann S, Roche R, Hoareau L, Gonthier MP, Festy F, Caillens H, Gasque P, Lefebvre d'Hellencourt C and Cesari M. Presence of functional TLR2 and TLR4 on

[47] Meijer K, de Vries M, Al-Lahham S, Bruinenberg M, Weening D, Dijkstra M, Kloos‐ terhuis N, van der Leij RJ, van der Want H, Kroesen BJ, Vonk R and Rezaee F. Hu‐ man primary adipocytes exhibit immune cell function: adipocytes prime

[49] Zhang Y, Proenca R, Maffei M, Barone M, Leopold L and Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372(6505)

[50] Loffreda S, Yang SQ, Lin HZ, Karp CL, Brengman ML, Wang DJ, Klein AS, Bulkley GB, Bao C, Noble PW, Lane MD and Diehl AM. Leptin regulates proinflammatory

[51] Friedman JM and Halaas JL. Leptin and the regulation of body weight in mammals.

[52] Banks WA, Kastin AJ, Huang W, Jaspan JB and Maness LM. Leptin enters the brain

[53] Elmquist JK, Bjorbaek C, Ahima RS, Flier JS and Saper CB. Distributions of leptin re‐ ceptor mRNA isoforms in the rat brain. J Comp Neurol 1998; 395(4) 535-47

[54] Buettner C, Pocai A, Muse ED, Etgen AM, Myers MG, Jr. and Rossetti L. Critical role

[55] Gautron L and Elmquist JK. Sixteen years and counting: an update on leptin in ener‐

[56] Ohashi K, Ouchi N and Matsuzawa Y. Anti-inflammatory and anti-atherogenic prop‐

[57] Ouchi N and Walsh K. Adiponectin as an anti-inflammatory factor. Clin Chim Acta

[58] Robinson K, Prins J and Venkatesh B. Clinical review: adiponectin biology and its

[59] Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimo‐ mura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T and Matsuzawa Y. Paradoxical

by a saturable system independent of insulin. Peptides 1996; 17(2) 305-11

of STAT3 in leptin's metabolic actions. Cell Metab 2006; 4(1) 49-60

role in inflammation and critical illness. Crit Care 2011; 15(2) 221

inflammation independent of macrophages. PLoS ONE 2011; 6(3) e17154

[48] Ahima RS and Osei SY. Adipokines in obesity. Front Horm Res 2008; 36(182-97

human adipocytes. Histochem Cell Biol 2007; 127(2) 131-7

immune responses. Faseb J 1998; 12(1) 57-65

gy balance. J Clin Invest 2011; 121(6) 2087-93

erties of adiponectin. Biochimie 2012;

2007; 380(1-2) 24-30

Nature 1998; 395(6704) 763-70

425-32


[45] Nicholson JK, Holmes E, Kinross J, Burcelin R, Gibson G, Jia W and Pettersson S. Host-gut microbiota metabolic interactions. Science 2012; 336(6086) 1262-7

[32] Hillenbrand A, Knippschild U, Weiss M, Schrezenmeier H, Henne-Bruns D, Huber-Lang M and Wolf AM. Sepsis induced changes of adipokines and cytokines - septic

[33] Bell LN, Ward JL, Degawa-Yamauchi M, Bovenkerk JE, Jones R, Cacucci BM, Gupta CE, Sheridan C, Sheridan K, Shankar SS, Steinberg HO, March KL and Considine RV. Adipose tissue production of hepatocyte growth factor contributes to elevated serum

[34] Fain JN. Release of inflammatory mediators by human adipose tissue is enhanced in obesity and primarily by the nonfat cells: a review. Mediators Inflamm 2010;

[35] Meier CA, Bobbioni E, Gabay C, Assimacopoulos-Jeannet F, Golay A and Dayer JM. IL-1 receptor antagonist serum levels are increased in human obesity: a possible link

[36] Panee J. Monocyte Chemoattractant Protein 1 (MCP-1) in obesity and diabetes. Cyto‐

[37] Clement S, Juge-Aubry C, Sgroi A, Conzelmann S, Pazienza V, Pittet-Cuenod B, Mei‐ er CA and Negro F. Monocyte chemoattractant protein-1 secreted by adipose tissue induces direct lipid accumulation in hepatocytes. Hepatology 2008; 48(3) 799-807

[38] Gonzalez-Castejon M and Rodriguez-Casado A. Dietary phytochemicals and their

[39] Hotamisligil GS, Shargill NS and Spiegelman BM. Adipose expression of tumor ne‐ crosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993;

[40] Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H and Flier JS. TLR4 links innate im‐ munity and fatty acid-induced insulin resistance. J Clin Invest 2006; 116(11) 3015-25

[41] Strowig T, Henao-Mejia J, Elinav E and Flavell R. Inflammasomes in health and dis‐

[42] Stienstra R, Tack CJ, Kanneganti TD, Joosten LA and Netea MG. The inflammasome

[43] Stienstra R, van Diepen JA, Tack CJ, Zaki MH, van de Veerdonk FL, Perera D, Neale GA, Hooiveld GJ, Hijmans A, Vroegrijk I, van den Berg S, Romijn J, Rensen PC, Joos‐ ten LA, Netea MG and Kanneganti TD. Inflammasome is a central player in the in‐ duction of obesity and insulin resistance. Proc Natl Acad Sci U S A 2011; 108(37)

[44] Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM and Burcelin R. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008; 57(6) 1470-81

puts obesity in the danger zone. Cell Metab 2012; 15(1) 10-8

potential effects on obesity: a review. Pharmacol Res 2011; 64(5) 438-55

patients compared to morbidly obese patients. BMC Surg 2010; 10(26

HGF in obesity. Am J Physiol Endocrinol Metab 2006; 291(4) E843-8

to the resistance to leptin? J Clin Endocrinol Metab 2002; 87(3) 1184-8

2010(513948

394 Neurodegenerative Diseases

kine 2012;

259(5091) 87-91

15324-9

ease. Nature 481(7381) 278-86


decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999; 257(1) 79-83

synthesis, and activates preadipocyte proliferation. Up-regulated expression with

Influence of Obesity on Neurodegenerative Diseases

http://dx.doi.org/10.5772/53671

397

[70] Gesta S, Simon MF, Rey A, Sibrac D, Girard A, Lafontan M, Valet P and Saulnier-Blache JS. Secretion of a lysophospholipase D activity by adipocytes: involvement in

[71] Boucher J, Quilliot D, Praderes JP, Simon MF, Gres S, Guigne C, Prevot D, Ferry G, Boutin JA, Carpene C, Valet P and Saulnier-Blache JS. Potential involvement of adi‐ pocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophos‐

[72] Whitmer RA. The epidemiology of adiposity and dementia. Curr Alzheimer Res

[73] Bruce-Keller AJ, Keller JN and Morrison CD. Obesity and vulnerability of the CNS.

[74] Taki Y, Kinomura S, Sato K, Inoue K, Goto R, Okada K, Uchida S, Kawashima R and Fukuda H. Relationship between body mass index and gray matter volume in 1,428

[75] Ward MA, Carlsson CM, Trivedi MA, Sager MA and Johnson SC. The effect of body mass index on global brain volume in middle-aged adults: a cross sectional study.

[76] Gustafson D, Lissner L, Bengtsson C, Bjorkelund C and Skoog I. A 24-year follow-up of body mass index and cerebral atrophy. Neurology 2004; 63(10) 1876-81

[77] Jagust W, Harvey D, Mungas D and Haan M. Central obesity and the aging brain.

[78] Debette S, Beiser A, Hoffmann U, Decarli C, O'Donnell CJ, Massaro JM, Au R, Himali JJ, Wolf PA, Fox CS and Seshadri S. Visceral fat is associated with lower brain vol‐

[79] Pannacciulli N, Del Parigi A, Chen K, Le DS, Reiman EM and Tataranni PA. Brain abnormalities in human obesity: a voxel-based morphometric study. Neuroimage

[80] Walther K, Birdsill AC, Glisky EL and Ryan L. Structural brain differences and cogni‐ tive functioning related to body mass index in older females. Hum Brain Mapp 2010;

[81] Raji CA, Ho AJ, Parikshak NN, Becker JT, Lopez OL, Kuller LH, Hua X, Leow AD, Toga AW and Thompson PM. Brain structure and obesity. Hum Brain Mapp 2010;

[82] Ho AJ, Stein JL, Hua X, Lee S, Hibar DP, Leow AD, Dinov ID, Toga AW, Saykin AJ, Shen L, Foroud T, Pankratz N, Huentelman MJ, Craig DW, Gerber JD, Allen AN,

ume in healthy middle-aged adults. Ann Neurol 2010; 68(2) 136-44

adipocyte differentiation and obesity. J Biol Chem 2003; 278(20) 18162-9

lysophosphatidic acid synthesis. J Lipid Res 2002; 43(6) 904-10

pholipase D/autotaxin expression. Diabetologia 2005; 48(3) 569-77

healthy individuals. Obesity (Silver Spring) 2008; 16(1) 119-24

Biochim Biophys Acta 2009; 1792(5) 395-400

2007; 4(2) 117-22

BMC Neurol 2005; 5(23

2006; 31(4) 1419-25

31(7) 1052-64

31(3) 353-64

Arch Neurol 2005; 62(10) 1545-8


synthesis, and activates preadipocyte proliferation. Up-regulated expression with adipocyte differentiation and obesity. J Biol Chem 2003; 278(20) 18162-9

[70] Gesta S, Simon MF, Rey A, Sibrac D, Girard A, Lafontan M, Valet P and Saulnier-Blache JS. Secretion of a lysophospholipase D activity by adipocytes: involvement in lysophosphatidic acid synthesis. J Lipid Res 2002; 43(6) 904-10

decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res

[60] Venkatesh B, Hickman I, Nisbet J, Cohen J and Prins J. Changes in serum adiponectin concentrations in critical illness: a preliminary investigation. Crit Care 2009; 13(4)

[61] Uji Y, Yamamoto H, Tsuchihashi H, Maeda K, Funahashi T, Shimomura I, Shimizu T, Endo Y and Tani T. Adiponectin deficiency is associated with severe polymicrobial sepsis, high inflammatory cytokine levels, and high mortality. Surgery 2009; 145(5)

[62] Teoh H, Quan A, Bang KW, Wang G, Lovren F, Vu V, Haitsma JJ, Szmitko PE, Al-Omran M, Wang CH, Gupta M, Peterson MD, Zhang H, Chan L, Freedman J, Swee‐ ney G and Verma S. Adiponectin deficiency promotes endothelial activation and profoundly exacerbates sepsis-related mortality. Am J Physiol Endocrinol Metab

[63] Vachharajani V, Cunningham C, Yoza B, Carson J, Jr., Vachharajani TJ and McCall C. Adiponectin-deficiency exaggerates sepsis-induced microvascular dysfunction in the

[64] Umezu-Goto M, Kishi Y, Taira A, Hama K, Dohmae N, Takio K, Yamori T, Mills GB, Inoue K, Aoki J and Arai H. Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production. J Cell Biol 2002;

[65] Ishii I, Fukushima N, Ye X and Chun J. Lysophospholipid receptors: signaling and

[66] Simon MF, Daviaud D, Pradere JP, Gres S, Guigne C, Wabitsch M, Chun J, Valet P and Saulnier-Blache JS. Lysophosphatidic acid inhibits adipocyte differentiation via lysophosphatidic acid 1 receptor-dependent down-regulation of peroxisome prolifer‐

[67] Valet P, Pages C, Jeanneton O, Daviaud D, Barbe P, Record M, Saulnier-Blache JS and Lafontan M. Alpha2-adrenergic receptor-mediated release of lysophosphatidic acid by adipocytes. A paracrine signal for preadipocyte growth. J Clin Invest 1998; 101(7)

[68] Fan H, Zingarelli B, Harris V, Tempel GE, Halushka PV and Cook JA. Lysophospha‐ tidic acid inhibits bacterial endotoxin-induced pro-inflammatory response: potential

[69] Ferry G, Tellier E, Try A, Gres S, Naime I, Simon MF, Rodriguez M, Boucher J, Tack I, Gesta S, Chomarat P, Dieu M, Raes M, Galizzi JP, Valet P, Boutin JA and Saulnier-Blache JS. Autotaxin is released from adipocytes, catalyzes lysophosphatidic acid

ator-activated receptor gamma2. J Biol Chem 2005; 280(15) 14656-62

anti-inflammatory signaling pathways. Mol Med 2008; 14(7-8) 422-8

mouse brain. Obesity (Silver Spring) 2012; 20(3) 498-504

biology. Annu Rev Biochem 2004; 73(321-54

Commun 1999; 257(1) 79-83

R105

396 Neurodegenerative Diseases

550-7

2008; 295(3) E658-64

158(2) 227-33

1431-8


Corneveaux JJ, Stephan DA, DeCarli CS, DeChairo BM, Potkin SG, Jack CR, Jr., Weiner MW, Raji CA, Lopez OL, Becker JT, Carmichael OT and Thompson PM. A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly. Proc Natl Acad Sci U S A 2010; 107(18) 8404-9

[96] Jeon BT, Shin HJ, Kim JB, Kim YK, Lee DH, Kim KH, Kim HJ, Kang SS, Cho GJ, Choi WS and Roh GS. Adiponectin protects hippocampal neurons against kainic acid-in‐

Influence of Obesity on Neurodegenerative Diseases

http://dx.doi.org/10.5772/53671

399

[97] Speakman J, Hambly C, Mitchell S and Krol E. Animal models of obesity. Obes Rev

[98] Dickies MM. A new viable yellow mutation in the house mouse. J Hered 1962;

[99] Yen TT, Gill AM, Frigeri LG, Barsh GS and Wolff GL. Obesity, diabetes, and neopla‐ sia in yellow A(vy)/- mice: ectopic expression of the agouti gene. Faseb J 1994; 8(8)

[100] Dietrich HM. Housing, breeding and selecting chickens of the Obese strain (OS) with

[101] Hen G, Yosefi S, Simchaev V, Shinder D, Hruby VJ and Friedman-Einat M. The mela‐ nocortin circuit in obese and lean strains of chicks. J Endocrinol 2006; 190(2) 527-35

[102] Keller JN. Special issue: Reciprocal interactions between diet, metabolism, and the

[103] Zhang L, Bruce-Keller AJ, Dasuri K, Nguyen AT, Liu Y and Keller JN. Diet-induced metabolic disturbances as modulators of brain homeostasis. Biochim Biophys Acta

[104] Kalmijn S. Fatty acid intake and the risk of dementia and cognitive decline: a review of clinical and epidemiological studies. J Nutr Health Aging 2000; 4(4) 202-7

[105] Hida K, Wada J, Eguchi J, Zhang H, Baba M, Seida A, Hashimoto I, Okada T, Yasu‐ hara A, Nakatsuka A, Shikata K, Hourai S, Futami J, Watanabe E, Matsuki Y, Hira‐ matsu R, Akagi S, Makino H and Kanwar YS. Visceral adipose tissue-derived serine protease inhibitor: a unique insulin-sensitizing adipocytokine in obesity. Proc Natl

[106] Bousquet M, St-Amour I, Vandal M, Julien P, Cicchetti F and Calon F. High-fat diet exacerbates MPTP-induced dopaminergic degeneration in mice. Neurobiol Dis 2012;

[107] Choi JY, Jang EH, Park CS and Kang JH. Enhanced susceptibility to 1-methyl-4-phe‐ nyl-1,2,3,6-tetrahydropyridine neurotoxicity in high-fat diet-induced obesity. Free

[108] Morris JK, Bomhoff GL, Stanford JA and Geiger PC. Neurodegeneration in an animal model of Parkinson's disease is exacerbated by a high-fat diet. Am J Physiol Regul

[109] Thaler JP, Yi CX, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, Zhao X, Sarruf DA, Izgur V, Maravilla KR, Nguyen HT, Fischer JD, Matsen ME, Wisse BE, Morton

spontaneous autoimmune thyroiditis. Lab Anim 1989; 23(4) 345-52

nervous system. Foreword. Biochim Biophys Acta 2009; 1792(5) 393-4

duced excitotoxicity. Brain Res Rev 2009; 61(2) 81-8

2007; 8 Suppl 1(55-61

2009; 1792(5) 417-22

45(1) 529-38

Acad Sci U S A 2005; 102(30) 10610-5

Radic Biol Med 2005; 38(6) 806-16

Integr Comp Physiol 299(4) R1082-90

53(84-6

479-88


[96] Jeon BT, Shin HJ, Kim JB, Kim YK, Lee DH, Kim KH, Kim HJ, Kang SS, Cho GJ, Choi WS and Roh GS. Adiponectin protects hippocampal neurons against kainic acid-in‐ duced excitotoxicity. Brain Res Rev 2009; 61(2) 81-8

Corneveaux JJ, Stephan DA, DeCarli CS, DeChairo BM, Potkin SG, Jack CR, Jr., Weiner MW, Raji CA, Lopez OL, Becker JT, Carmichael OT and Thompson PM. A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly. Proc Natl Acad Sci U S A 2010; 107(18) 8404-9 [83] Ristow M. Neurodegenerative disorders associated with diabetes mellitus. J Mol

[84] Gustafson D. Adiposity indices and dementia. Lancet Neurol 2006; 5(8) 713-20

[85] Gustafson D, Rothenberg E, Blennow K, Steen B and Skoog I. An 18-year follow-up of overweight and risk of Alzheimer disease. Arch Intern Med 2003; 163(13) 1524-8

[86] Naderali EK, Ratcliffe SH and Dale MC. Obesity and Alzheimer's disease: a link be‐ tween body weight and cognitive function in old age. Am J Alzheimers Dis Other

[87] Myers MG, Jr., Heymsfield SB, Haft C, Kahn BB, Laughlin M, Leibel RL, Tschop MH and Yanovski JA. Challenges and opportunities of defining clinical leptin resistance.

[88] St-Pierre J and Tremblay ML. Modulation of leptin resistance by protein tyrosine

[89] Shimizu H, Oh IS, Okada S and Mori M. Leptin resistance and obesity. Endocr J 2007;

[90] Doherty GH. Obesity and the ageing brain: could leptin play a role in neurodegener‐

[91] Awada R, Rondeau P, Gres S, Saulnier-Blache JS, Lefebvre d'Hellencourt C and Bour‐ don E. Autotaxin protects microglial cells against oxidative stress. Free Radic Biol

[92] Hu E, Liang P and Spiegelman BM. AdipoQ is a novel adipose-specific gene dysre‐

[93] Chen B, Liao WQ, Xu N, Xu H, Wen JY, Yu CA, Liu XY, Li CL, Zhao SM and Camp‐ bell W. Adiponectin protects against cerebral ischemia-reperfusion injury through

[94] Nishimura M, Izumiya Y, Higuchi A, Shibata R, Qiu J, Kudo C, Shin HK, Moskowitz MA and Ouchi N. Adiponectin prevents cerebral ischemic injury through endothelial

[95] Lee EB, Warmann G, Dhir R and Ahima RS. Metabolic dysfunction associated with adiponectin deficiency enhances kainic acid-induced seizure severity. J Neurosci

nitric oxide synthase dependent mechanisms. Circulation 2008; 117(2) 216-23

Med 2004; 82(8) 510-29

398 Neurodegenerative Diseases

Demen 2009; 24(6) 445-9

Cell Metab 2012; 15(2) 150-6

Med 2012; 52(2) 516-26

2012; 31(40) 14361-6

54(1) 17-26

phosphatases. Cell Metab 2012; 15(3) 292-7

ation? Curr Gerontol Geriatr Res 2011; 2011(708154

gulated in obesity. J Biol Chem 1996; 271(18) 10697-703

anti-inflammatory action. Brain Res 2009; 1273(129-37


GJ, Horvath TL, Baskin DG, Tschop MH and Schwartz MW. Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 2012; 122(1) 153-62

campal neurogenesis: molecular mechanisms and behavioural effects on depression

Influence of Obesity on Neurodegenerative Diseases

http://dx.doi.org/10.5772/53671

401

[123] Stangl D and Thuret S. Impact of diet on adult hippocampal neurogenesis. Genes

[124] Zainuddin MS and Thuret S. Nutrition, adult hippocampal neurogenesis and mental

[125] Jeon BT, Jeong EA, Shin HJ, Lee Y, Lee DH, Kim HJ, Kang SS, Cho GJ, Choi WS and Roh GS. Resveratrol attenuates obesity-associated peripheral and central inflamma‐ tion and improves memory deficit in mice fed a high-fat diet. Diabetes 2012; 61(6)

[126] Lu J, Wu DM, Zheng YL, Hu B, Cheng W, Zhang ZF and Shan Q. Ursolic acid im‐ proves high fat diet-induced cognitive impairments by blocking endoplasmic reticu‐ lum stress and IkappaB kinase beta/nuclear factor-kappaB-mediated inflammatory

and anxiety. Oxid Med Cell Longev 2012; 2012(541971

pathways in mice. Brain Behav Immun 2011; 25(8) 1658-67

Nutr 2009; 4(4) 271-82

1444-54

health. Br Med Bull 2012;


campal neurogenesis: molecular mechanisms and behavioural effects on depression and anxiety. Oxid Med Cell Longev 2012; 2012(541971

[123] Stangl D and Thuret S. Impact of diet on adult hippocampal neurogenesis. Genes Nutr 2009; 4(4) 271-82

GJ, Horvath TL, Baskin DG, Tschop MH and Schwartz MW. Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 2012; 122(1) 153-62

[110] Sriram K, Benkovic SA, Miller DB and O'Callaghan JP. Obesity exacerbates chemical‐

[111] Erbayat-Altay E, Yamada KA, Wong M and Thio LL. Increased severity of pentylene‐ tetrazol induced seizures in leptin deficient ob/ob mice. Neurosci Lett 2008; 433(2)

[112] Ming GL and Song H. Adult neurogenesis in the mammalian brain: significant an‐

[113] Anderson MF, Aberg MA, Nilsson M and Eriksson PS. Insulin-like growth factor-I and neurogenesis in the adult mammalian brain. Brain Res Dev Brain Res 2002;

[114] Ciaroni S, Cuppini R, Cecchini T, Ferri P, Ambrogini P, Cuppini C and Del Grande P. Neurogenesis in the adult rat dentate gyrus is enhanced by vitamin E deficiency. J

[115] Valente T, Hidalgo J, Bolea I, Ramirez B, Angles N, Reguant J, Morello JR, Gutierrez C, Boada M and Unzeta M. A diet enriched in polyphenols and polyunsaturated fat‐ ty acids, LMN diet, induces neurogenesis in the subventricular zone and hippocam‐

[116] van Praag H, Christie BR, Sejnowski TJ and Gage FH. Running enhances neurogene‐ sis, learning, and long-term potentiation in mice. Proc Natl Acad Sci U S A 1999;

[117] Kokoeva MV, Yin H and Flier JS. Neurogenesis in the hypothalamus of adult mice:

[118] Bachner D, Ahrens M, Betat N, Schroder D and Gross G. Developmental expression

[119] Bengzon J, Kokaia Z, Elmer E, Nanobashvili A, Kokaia M and Lindvall O. Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seiz‐

[120] Harry GJ, McPherson CA, Wine RN, Atkinson K and Lefebvre d'Hellencourt C. Tri‐ methyltin-induced neurogenesis in the murine hippocampus. Neurotox Res 2004;

[121] McNay DE, Briancon N, Kokoeva MV, Maratos-Flier E and Flier JS. Remodeling of the arcuate nucleus energy-balance circuit is inhibited in obese mice. J Clin Invest

[122] Dias GP, Cavegn N, Nix A, do Nascimento Bevilaqua MC, Stangl D, Zainuddin MS, Nardi AE, Gardino PF and Thuret S. The role of dietary polyphenols on adult hippo‐

ly induced neurodegeneration. Neuroscience 2002; 115(4) 1335-46

swers and significant questions. Neuron 2011; 70(4) 687-702

pus of adult mouse brain. J Alzheimers Dis 2009; 18(4) 849-65

potential role in energy balance. Science 2005; 310(5748) 679-83

analysis of murine autotaxin (ATX). Mech Dev 1999; 84(1-2) 121-5

ures. Proc Natl Acad Sci U S A 1997; 94(19) 10432-7

82-6

400 Neurodegenerative Diseases

134(1-2) 115-22

96(23) 13427-31

5(8) 623-7

2012; 122(1) 142-52

Comp Neurol 1999; 411(3) 495-502


**Chapter 17**

**Electro-Physiological Approaches to Monitoring Neuro-**

Electrical brain activity is recorded by means of a variety of techniques, including different approaches, for instance surface field electrodes among others. Additionally, specific local neuronal responses are suitable for recording. As an example, those known as evoked response potentials allow to determine whether neural pathways and neuronal groups are performing

Neuro-degenerative diseases involve lost of integrity of a number of neuronal nuclei; in turn, this represents significant changes in electrical brain activity that might be compared with unaltered individuals. Several experiments have shown the potential usefulness of evoked response potentials ERP brain correlates as bio-markers, diagnostic and prognostic tools of some neurodegenerative diseases. Also, neuropsychological tests have demonstrated correla‐ tions with electrophysiological findings, and are helpful to detect early cognitive decline or

Electrodiagnostic examination should make available useful information for researchers and physicians. Furthermore, it could help to the correct diagnosis of the illness, its differential diagnosis to the identification of the pathophysiological abnormalities probably responsible

> © 2013 Rojas et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

**Degenerative Diseases**

http://dx.doi.org/10.5772/55228

**1. Introduction**

properly.

for the pathology

Manuel J. Rojas, Camilo Orozco and Francisco Olea

Additional information is available at the end of the chapter

disease progression in neurodegenerative diseases.

**2. Electro-physiological techniques**

**•** Surface electrode cortical EEG:

## **Electro-Physiological Approaches to Monitoring Neuro-Degenerative Diseases**

Manuel J. Rojas, Camilo Orozco and Francisco Olea

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55228

### **1. Introduction**

Electrical brain activity is recorded by means of a variety of techniques, including different approaches, for instance surface field electrodes among others. Additionally, specific local neuronal responses are suitable for recording. As an example, those known as evoked response potentials allow to determine whether neural pathways and neuronal groups are performing properly.

Neuro-degenerative diseases involve lost of integrity of a number of neuronal nuclei; in turn, this represents significant changes in electrical brain activity that might be compared with unaltered individuals. Several experiments have shown the potential usefulness of evoked response potentials ERP brain correlates as bio-markers, diagnostic and prognostic tools of some neurodegenerative diseases. Also, neuropsychological tests have demonstrated correla‐ tions with electrophysiological findings, and are helpful to detect early cognitive decline or disease progression in neurodegenerative diseases.

Electrodiagnostic examination should make available useful information for researchers and physicians. Furthermore, it could help to the correct diagnosis of the illness, its differential diagnosis to the identification of the pathophysiological abnormalities probably responsible for the pathology

### **2. Electro-physiological techniques**

**•** Surface electrode cortical EEG:

© 2013 Rojas et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The electroencephalogram EEG is usually described in terms of its rhythmic activity, which is helpful in relating the EEG to the brain function [1]. Neuronal activity during information processing is represented by oscillations within local or widespread neuronal networks. These oscillations can be recorded by means of surface electrodes over the skull. The rhythmic activity in EEG is commonly divided in specific frequency bands: 0.5–4Hz (delta), 4–8Hz (theta), 8– 10Hz (alpha 1), 10–12Hz (alpha 2), 12–30Hz (beta), and 30–100Hz (gamma) [2]. The FFT decomposes the EEG time series into a voltage by frequency spectral graph commonly called the "power spectrum", with power being the square of the EEG magnitude, and magnitude being the integral average of the amplitude of the EEG signal, measured from(+) peak-to- (-)peak), across the time sampled, or epoch [3]. As a result of this procedure the quantitative electroencephalogram QEEG is obtained [4], [5].

**3. Alzheimer electroencephalographic patterns**

is low in AD patients [10].

nerative pathologies [12].

left fronto-parietal EEG [16].

The electroencephalogram EEG measures neuronal activity, and is an objective way to assess the degree of cognitive disturbance. Researchers have investigated how well cognitive function in dementia assessed by psychometric tests correlates with electrical brain activity (EEG). Results from such an experimental approach shows a slowing of the EEG, and an increase of dipole strength in the slow frequency bands, a more anterior equivalent dipole of alpha- and

Electro-Physiological Approaches to Monitoring Neuro-Degenerative Diseases

http://dx.doi.org/10.5772/55228

405

Relative power in different EEG frequency bands from EEG signals have been used in order to improve the diagnosis of AD. Frequency bands between 4 and 30 Hz have been systematically tested; the relative power of a certain frequency band is obtained by dividing the power of this frequency band by the power of the total frequency band. The frequen‐ cy band 4-7 Hz is the optimal frequency range for detecting AD [9]. Progressive atrophy of hippocampus correlates with decreased cortical alpha power in AD patients. More‐ over, the small hippocampal volume is measured in magnetic resonance imaging of the AD subjects [10], [11]. Additionally, the power of occipital, parietal, and temporal alpha sources

A promising study by Kann demonstrated the implication of the fast neuronal network oscillations in the gamma range (~30-90 Hz) in complex brain functions. Sensory processing, memory formation and, consciousness are brain functions highly vulnerable to neurodege‐

Cortical pathology in AD is related to decreasing fast frequency power; whereas in‐ creased slow frequency EEG power is observed in mixed dementia compared to AD. The quantitative EEG contributes to a better understanding of the electrical brain pattern in AD [13]. Slowing on qEEG is a marker for subsequent rate of cognitive and functional decline in mildly demented AD patients. Frequency bands analysis of EEG recordings from AD subjects shows lower parieto-occipital beta values, and higher frontocentral and parietooccipital theta values. Additionally, lower parieto-occipital beta values are related to more decline in activities of daily living [14], [15]. Also, connectivity between frontal and parietal sites in AD patients is reduced, thus, resulting in significant decreased of coherence in the

In some cases there is no correlation between the increase of delta waves in the electroence‐ phalogram, and the severity of mental deterioration of the AD patients, but this facts correlate by taking in account the intensity of delta waves rather than just their presence. The delta waves generated with participation of the cortex, thalamus, and brainstem seems to be more variable in different stages of AD. Measures of the theta activity discriminated between mild, marked, and severe cases of AD to some extent. The cognitive and EEG changes are probably

EEG recordings at rest and during visual stimulation processed by means of Fast Fourier Transform (FFT) are helpful to determine intra- and inter-hemispheric coherence in AD patients. Those studies have shown statistically significant phase dispersion especially at

related to atrophy of the cholinergic neurons in the hippocampal structures [17].

beta-activity, correlated with increasing cognitive deterioration in AD patients [8].

**•** Recording deep brain electrodes

Local field potential and action potentials can be captured by means of very fine conductive electrodes for research and surgical monitoring purposes [6], [7]. In addition, deep brain electrodes implanted into the brain are used to apply electrical stimulation in order to treat disorders that have electrical generators [6].

<sup>\*</sup>Figure authorized for publication by the corresponding author from: Rodriguez-Oroz MC et al. Brain. 2011 Jan;134(Pt 1):36-49.

**Figure 1.** Deep brain electrodes to treat Parkinson's disease: (A) Electrode with four active contacts (0, 1, 2 and 3 from ventral to dorsal and each 1.5 mm high at 0.5 mm intervals; total length 7.5 mm) was placed at the selected coordi‐ nates in the subthalamic nucleus with the most ventral contact (contact 0) placed in the ventral part of the nucleus \*

### **3. Alzheimer electroencephalographic patterns**

The electroencephalogram EEG is usually described in terms of its rhythmic activity, which is helpful in relating the EEG to the brain function [1]. Neuronal activity during information processing is represented by oscillations within local or widespread neuronal networks. These oscillations can be recorded by means of surface electrodes over the skull. The rhythmic activity in EEG is commonly divided in specific frequency bands: 0.5–4Hz (delta), 4–8Hz (theta), 8– 10Hz (alpha 1), 10–12Hz (alpha 2), 12–30Hz (beta), and 30–100Hz (gamma) [2]. The FFT decomposes the EEG time series into a voltage by frequency spectral graph commonly called the "power spectrum", with power being the square of the EEG magnitude, and magnitude being the integral average of the amplitude of the EEG signal, measured from(+) peak-to- (-)peak), across the time sampled, or epoch [3]. As a result of this procedure the quantitative

Local field potential and action potentials can be captured by means of very fine conductive electrodes for research and surgical monitoring purposes [6], [7]. In addition, deep brain electrodes implanted into the brain are used to apply electrical stimulation in order to treat

\*Figure authorized for publication by the corresponding author from: Rodriguez-Oroz MC et al. Brain. 2011 Jan;134(Pt

**Figure 1.** Deep brain electrodes to treat Parkinson's disease: (A) Electrode with four active contacts (0, 1, 2 and 3 from ventral to dorsal and each 1.5 mm high at 0.5 mm intervals; total length 7.5 mm) was placed at the selected coordi‐ nates in the subthalamic nucleus with the most ventral contact (contact 0) placed in the ventral part of the nucleus \*

electroencephalogram QEEG is obtained [4], [5].

disorders that have electrical generators [6].

**•** Recording deep brain electrodes

404 Neurodegenerative Diseases

1):36-49.

The electroencephalogram EEG measures neuronal activity, and is an objective way to assess the degree of cognitive disturbance. Researchers have investigated how well cognitive function in dementia assessed by psychometric tests correlates with electrical brain activity (EEG). Results from such an experimental approach shows a slowing of the EEG, and an increase of dipole strength in the slow frequency bands, a more anterior equivalent dipole of alpha- and beta-activity, correlated with increasing cognitive deterioration in AD patients [8].

Relative power in different EEG frequency bands from EEG signals have been used in order to improve the diagnosis of AD. Frequency bands between 4 and 30 Hz have been systematically tested; the relative power of a certain frequency band is obtained by dividing the power of this frequency band by the power of the total frequency band. The frequen‐ cy band 4-7 Hz is the optimal frequency range for detecting AD [9]. Progressive atrophy of hippocampus correlates with decreased cortical alpha power in AD patients. More‐ over, the small hippocampal volume is measured in magnetic resonance imaging of the AD subjects [10], [11]. Additionally, the power of occipital, parietal, and temporal alpha sources is low in AD patients [10].

A promising study by Kann demonstrated the implication of the fast neuronal network oscillations in the gamma range (~30-90 Hz) in complex brain functions. Sensory processing, memory formation and, consciousness are brain functions highly vulnerable to neurodege‐ nerative pathologies [12].

Cortical pathology in AD is related to decreasing fast frequency power; whereas in‐ creased slow frequency EEG power is observed in mixed dementia compared to AD. The quantitative EEG contributes to a better understanding of the electrical brain pattern in AD [13]. Slowing on qEEG is a marker for subsequent rate of cognitive and functional decline in mildly demented AD patients. Frequency bands analysis of EEG recordings from AD subjects shows lower parieto-occipital beta values, and higher frontocentral and parietooccipital theta values. Additionally, lower parieto-occipital beta values are related to more decline in activities of daily living [14], [15]. Also, connectivity between frontal and parietal sites in AD patients is reduced, thus, resulting in significant decreased of coherence in the left fronto-parietal EEG [16].

In some cases there is no correlation between the increase of delta waves in the electroence‐ phalogram, and the severity of mental deterioration of the AD patients, but this facts correlate by taking in account the intensity of delta waves rather than just their presence. The delta waves generated with participation of the cortex, thalamus, and brainstem seems to be more variable in different stages of AD. Measures of the theta activity discriminated between mild, marked, and severe cases of AD to some extent. The cognitive and EEG changes are probably related to atrophy of the cholinergic neurons in the hippocampal structures [17].

EEG recordings at rest and during visual stimulation processed by means of Fast Fourier Transform (FFT) are helpful to determine intra- and inter-hemispheric coherence in AD patients. Those studies have shown statistically significant phase dispersion especially at occipital and parietal regions in AD [18]. Coherence analysis of the EEG during photic stimulation also is low in AD patients, irrespective of the stimulus frequency, due to a failure of normal stimulation-related brain activation. What is more, when coherence analysis is done from recordings of the brain´s left hemisphere and the right one, impairment of interhemi‐ spheric functional connectivity is found [15].

AD. In the theta band the significant decrease in relative power of the left temporal region. In the beta band, all separate cortical regions demonstrated a significant decrease of relative power in AD [25]. Furthermore, the auto mutual information (AMI) provides a measure of future points predictability from past points in the magnetoencephalogram (MEG). Studies analyzing the (MEG) background activity in patients with AD, using the AMI reveals that the absolute values of the averaged decline rate of AMI is lower in AD patients than in control subjects. Thus, based on this kind of analysis is suggested that neuronal dysfunction in AD is associated with differences in the dynamical processes underlying the MEG recording [26]. REM sleep is a behavioral state characterized by atonia, and high frequency-low amplitude EEG among other features. Polysomnographic studies have found AD patients with REM sleep with-out atonia. The lack of atonia during REM sleep might involve alteration of the extrap‐ yramidal motor control [27]. During quiet sleep in healthy human EEG there are components that consist of a brief negative high-voltage peak, usually greater than 100 µV, followed by a slower positive complex around 350 and 550 ms and at 900 ms a final negative peak, known as K-complex [28]; they are generated in response to external stimuli such as sounds, touches on the skin [29], and internal ones such as inspiratory interruptions [30]. They also occur in widespread cortical locations [28] though they tend to predominate over the frontal parts of the brain [31]. K-complexes synchronize the thalamocortical network during sleep, producing sleep oscillations such as spindles and delta waves [32]. Additionally, it has been suggested that K-complexes play an important role in memory consolidation [33]. In patients with Alzheimer disease, the electroencephalogram during wakefulness shows pathologic signs of abundant, delta activity. AD patients produced significantly fewer evoked K-complexes and had substantially smaller N550 amplitudes than controls. Even though observed increases in pathologic delta-frequency electroencephalographic activity, patients with Alzheimer disease have an impaired capacity to generate normal physiologic delta responses such as K-com‐

Electro-Physiological Approaches to Monitoring Neuro-Degenerative Diseases

http://dx.doi.org/10.5772/55228

407

The progressive deterioration of AD patient progresses is caused by the loss of functional connectivity within neocortical association areas. Much more sensitive methods to identify early alterations of neuronal networks makes possible to predict the onset of AD. Diffuse slowing is correlated with the cognitive decline. This is a method to extract meaningful EEG parameters for the early diagnosis and staging of Alzheimer's disease [35]. Also, a clear difference between AD patients carrying the ApoE epsilon4 allele and no carriers is detected in the EEG; neurophysiological endophenotype of non-demented individuals at genetic risk for AD have increased excitability and dysfunction of deep brain and alpha rhythm-generating structures even decades before the first clinical symptoms of presumable dementia. Under hyperventilation the presence of the epsilon4 allele in AD relatives is associated with the manifestation of synchronous high-voltage delta-, theta-activity and sharp-waves, pro‐ nounced decrease in alpha and increase in delta and theta relative powers [36]. Mildly demented AD patients have an increase of relative delta power in the left side, and a decrease

plexes during quiet sleep [34].

**5. Alzheimer early detection**

### **4. Alzheimer diagnosis**

A combination of computed techniques to analyze EEG recordings, such as the Higuchi fractal dimension (HFD), spectral entropy (SE), spectral centroid (SC), spectral roll-off (SR), and zerocrossing rate (ZCR), results in a AD diagnostic accuracy of 78%. HFD is a quantitative measure of time series complexity derived from fractal theory. Among spectral measures, SE measures the level of disorder in the spectrum, SC is a measure of spectral shape, and SR is frequency sample below which a specified percent of the spectral magnitude distribution is contained. Lastly, ZCR is simply the rate at which the signal changes signs. Even though, the individual accuracies ranged from 60-66%, that itself is not enough to be clinically useful alone. Combin‐ ing these features and training a support vector machine (SVM) represent a novel alternative computed technique to reach high diagnostic accuracy for AD [19].

An electrophysiological marker in the early detection of neurodegeneration is found in the EEG pattern during stimulation for visual evoked potentials (VEP) in mild AD patients. In mild AD the altered activity concentrates on deep structures of the left hemisphere, say hippocampus and midbrain [20]. Visual evoked potentials in diagnosed Alzheimer patients (ApoE epsilon4 carriers) have significantly longer peak latencies and a trend to higher interpeak latencies of late potential components. However, potential amplitudes are similar in carriers and no carriers. It appears that the ApoE epsilon4 allele mainly promotes neuronal dysfunction [21]. In an ERPs lexical-decision task AD patients do not display repetition priming for words repeated at long lags [22].

Neuropathological findings in AD correlate with sensory-affective dissociation. Pain antici‐ pation and autonomic reactivity depend on both the cognitive status and the frequency bands of the electroencephalogram, especially delta and theta frequencies. The painful stimulation perception is well preserved in AD, however, the affective and cognitive functions, which are related to both anticipation and autonomic reactivity are very affected [23].

A helpful tool to confirm an AD diagnosis is the electrophysiological correlate of minipoly‐ myoclonus and a bi-frontal negativity in the EEG that precedes the myoclonic jerk. This electrophysiological fact may reflect activity of a subcortical generator. [24].

Quantitative relative power analysis of magnetoencephalography recordings can find widespread abnormalities in oscillatory brain dynamics in AD patients. In the delta band the AD patients have a consistently higher relative power, especially in the right occipital area. Delta activity is increased in AD patients, whereas alpha, and beta activity was decreased. Particularly the beta band (13–30 Hz) shows a very significant decrease in relative power in AD. In the theta band the significant decrease in relative power of the left temporal region. In the beta band, all separate cortical regions demonstrated a significant decrease of relative power in AD [25]. Furthermore, the auto mutual information (AMI) provides a measure of future points predictability from past points in the magnetoencephalogram (MEG). Studies analyzing the (MEG) background activity in patients with AD, using the AMI reveals that the absolute values of the averaged decline rate of AMI is lower in AD patients than in control subjects. Thus, based on this kind of analysis is suggested that neuronal dysfunction in AD is associated with differences in the dynamical processes underlying the MEG recording [26].

REM sleep is a behavioral state characterized by atonia, and high frequency-low amplitude EEG among other features. Polysomnographic studies have found AD patients with REM sleep with-out atonia. The lack of atonia during REM sleep might involve alteration of the extrap‐ yramidal motor control [27]. During quiet sleep in healthy human EEG there are components that consist of a brief negative high-voltage peak, usually greater than 100 µV, followed by a slower positive complex around 350 and 550 ms and at 900 ms a final negative peak, known as K-complex [28]; they are generated in response to external stimuli such as sounds, touches on the skin [29], and internal ones such as inspiratory interruptions [30]. They also occur in widespread cortical locations [28] though they tend to predominate over the frontal parts of the brain [31]. K-complexes synchronize the thalamocortical network during sleep, producing sleep oscillations such as spindles and delta waves [32]. Additionally, it has been suggested that K-complexes play an important role in memory consolidation [33]. In patients with Alzheimer disease, the electroencephalogram during wakefulness shows pathologic signs of abundant, delta activity. AD patients produced significantly fewer evoked K-complexes and had substantially smaller N550 amplitudes than controls. Even though observed increases in pathologic delta-frequency electroencephalographic activity, patients with Alzheimer disease have an impaired capacity to generate normal physiologic delta responses such as K-com‐ plexes during quiet sleep [34].

### **5. Alzheimer early detection**

occipital and parietal regions in AD [18]. Coherence analysis of the EEG during photic stimulation also is low in AD patients, irrespective of the stimulus frequency, due to a failure of normal stimulation-related brain activation. What is more, when coherence analysis is done from recordings of the brain´s left hemisphere and the right one, impairment of interhemi‐

A combination of computed techniques to analyze EEG recordings, such as the Higuchi fractal dimension (HFD), spectral entropy (SE), spectral centroid (SC), spectral roll-off (SR), and zerocrossing rate (ZCR), results in a AD diagnostic accuracy of 78%. HFD is a quantitative measure of time series complexity derived from fractal theory. Among spectral measures, SE measures the level of disorder in the spectrum, SC is a measure of spectral shape, and SR is frequency sample below which a specified percent of the spectral magnitude distribution is contained. Lastly, ZCR is simply the rate at which the signal changes signs. Even though, the individual accuracies ranged from 60-66%, that itself is not enough to be clinically useful alone. Combin‐ ing these features and training a support vector machine (SVM) represent a novel alternative

An electrophysiological marker in the early detection of neurodegeneration is found in the EEG pattern during stimulation for visual evoked potentials (VEP) in mild AD patients. In mild AD the altered activity concentrates on deep structures of the left hemisphere, say hippocampus and midbrain [20]. Visual evoked potentials in diagnosed Alzheimer patients (ApoE epsilon4 carriers) have significantly longer peak latencies and a trend to higher interpeak latencies of late potential components. However, potential amplitudes are similar in carriers and no carriers. It appears that the ApoE epsilon4 allele mainly promotes neuronal dysfunction [21]. In an ERPs lexical-decision task AD patients do not display repetition

Neuropathological findings in AD correlate with sensory-affective dissociation. Pain antici‐ pation and autonomic reactivity depend on both the cognitive status and the frequency bands of the electroencephalogram, especially delta and theta frequencies. The painful stimulation perception is well preserved in AD, however, the affective and cognitive functions, which are

A helpful tool to confirm an AD diagnosis is the electrophysiological correlate of minipoly‐ myoclonus and a bi-frontal negativity in the EEG that precedes the myoclonic jerk. This

Quantitative relative power analysis of magnetoencephalography recordings can find widespread abnormalities in oscillatory brain dynamics in AD patients. In the delta band the AD patients have a consistently higher relative power, especially in the right occipital area. Delta activity is increased in AD patients, whereas alpha, and beta activity was decreased. Particularly the beta band (13–30 Hz) shows a very significant decrease in relative power in

related to both anticipation and autonomic reactivity are very affected [23].

electrophysiological fact may reflect activity of a subcortical generator. [24].

computed technique to reach high diagnostic accuracy for AD [19].

spheric functional connectivity is found [15].

priming for words repeated at long lags [22].

**4. Alzheimer diagnosis**

406 Neurodegenerative Diseases

The progressive deterioration of AD patient progresses is caused by the loss of functional connectivity within neocortical association areas. Much more sensitive methods to identify early alterations of neuronal networks makes possible to predict the onset of AD. Diffuse slowing is correlated with the cognitive decline. This is a method to extract meaningful EEG parameters for the early diagnosis and staging of Alzheimer's disease [35]. Also, a clear difference between AD patients carrying the ApoE epsilon4 allele and no carriers is detected in the EEG; neurophysiological endophenotype of non-demented individuals at genetic risk for AD have increased excitability and dysfunction of deep brain and alpha rhythm-generating structures even decades before the first clinical symptoms of presumable dementia. Under hyperventilation the presence of the epsilon4 allele in AD relatives is associated with the manifestation of synchronous high-voltage delta-, theta-activity and sharp-waves, pro‐ nounced decrease in alpha and increase in delta and theta relative powers [36]. Mildly demented AD patients have an increase of relative delta power in the left side, and a decrease for relative alpha power in the right side; this preserves a linear correlation, and allows to predicting activity daily living ADL loss timing, and general behavioral and cognitive deterioration in mild Alzheimer's disease [5]. The delta relative power in the left side predicts both the loss of ADL and death, whereas right theta predicted the onset of incontinence [37]. In addition, the qEEG measures is correlated with neuropsychological test scores related to abilities that are impaired in the early stages of disease, such as delayed recall and verbal fluency [11].

campus and midbrain). Mild AD and MCI were more active for beta and gamma band, but at the same time beta and alpha band are more active than theta band. Elderly controls showed dominance of gamma and beta band in all significant areas. Mild AD and MCI have different neural patterns but show virtually similar frequency band activations, while elderly people

Electro-Physiological Approaches to Monitoring Neuro-Degenerative Diseases

http://dx.doi.org/10.5772/55228

409

\* Figure authorized for publication by the corresponding author from: Cheng PJ, Pai MC. Clin Neurophysiol. 2010 Sep;

**Figure 2.** Event-related potential study: Comparison between alzheimer diseases patients and normal control pa‐ tients: (A) N170 at the four electrode sites; (B) the amplitudes of N170 between groups and types, AD: Alzheimer's

Visual ERP features have shown that different neural regions are responsible for the early visual processing in the structural encoding of scenes and faces. P100 is a part of the evoked response suitable to examine basic visual processing, N170 brings information about structural encoding, and N250 is related to familiarity. The pattern of P100 and that of N170 suggest that mild Alzheimer disease patients maintain basic visual processing and structural encoding abilities, and scene recognition is impaired earlier than face recognition in the course of

differ from them in space and frequency bands [20].

121(9):1519-25

disease. \*

Prognosis of early AD onset can be done by means of calculating the REO/REC power ratio; this tool takes the spectral analysis of the EEG recorded under awake resting eyes closed (REC) and open (REO) conditions. Demented AD patients show an increased REO/REC power ratio in the 6.5-12 Hz band. Patients lacking a dominant peak in the 6.5-12 Hz band, but with high power in 1-6.5 Hz band have an earlier age of disease onset [38].

Increased risk of mortality in AD is associated with higher theta, lower alpha, and lower beta activity in the parieto-occipital EEG. Also, higher theta activity in the fronto-central EEG has a prognosis value. Decreases of beta and alpha activity on quantitative spectral EEG are independent predictors of mortality in patients with early Alzheimer disease [39].

IFAST (implicit function as squashing time) is an artificial neural networks (ANNs) assembly; it is capable of compressing the temporal sequence of EEG data into spatial invariants. This model represents spatial features of the EEG patterns at scalp surface by means of filtering EEG tracks according to four different frequency ranges (0.12 Hz, 12.2 - 29.8 Hz; 30.2 - 40 Hz, and Notch Filter 48 - 50 Hz). The spatial content of the EEG voltage is extracted by IFAST stepwise procedure using ANNs. The data input for the classification operated by ANNs are the connections weights of a nonlinear auto-associative ANN trained to reproduce the recorded EEG tracks. This method allows distinguish between mild cognitive impairment (MCI) stable and MCI subjects who will convert to Alzheimer's disease (MCI/AD), with a high degree of accuracy. Eyes-closed resting EEG data in individual MCI/AD subjects show significant differences in the 10-12 Hz band when compared to MCI subjects [40].

Event-modulated EEG dynamic analysis makes it possible to investigate the functional activation of neocortical circuits [41]. Evoked Response Potentials (ERP) brain correlates are useful preclinical markers to identify individuals at risk for AD. Additionally, the ERP measures can predict its presence. Asymptomatic PSEN1 mutation carriers have greater occipital positivity, but less positivity in frontal regions than control subjects. Those differences are more evident during the 200-300 msec period of the ERP. It seems like carriers rely more upon perceptual details of the items to distinguish between them, while control subjects may use frontally mediated processes to distinguish between studied and unstudied visual items [42].

An electrophysiological marker in the early detection of neurodegeneration is found in the EEG pattern during stimulation for visual evoked potentials VEP in mild AD patients compared to Elderly controls, and MCI. Elderly controls have a neural pattern with a right– left dominance; in MCI this pattern seems to be displaced from right hemisphere to the left one, while in mild AD the activity concentrates on deep structures of this hemisphere (hippo‐ campus and midbrain). Mild AD and MCI were more active for beta and gamma band, but at the same time beta and alpha band are more active than theta band. Elderly controls showed dominance of gamma and beta band in all significant areas. Mild AD and MCI have different neural patterns but show virtually similar frequency band activations, while elderly people differ from them in space and frequency bands [20].

for relative alpha power in the right side; this preserves a linear correlation, and allows to predicting activity daily living ADL loss timing, and general behavioral and cognitive deterioration in mild Alzheimer's disease [5]. The delta relative power in the left side predicts both the loss of ADL and death, whereas right theta predicted the onset of incontinence [37]. In addition, the qEEG measures is correlated with neuropsychological test scores related to abilities that are impaired in the early stages of disease, such as delayed recall and verbal

Prognosis of early AD onset can be done by means of calculating the REO/REC power ratio; this tool takes the spectral analysis of the EEG recorded under awake resting eyes closed (REC) and open (REO) conditions. Demented AD patients show an increased REO/REC power ratio in the 6.5-12 Hz band. Patients lacking a dominant peak in the 6.5-12 Hz band, but with high

Increased risk of mortality in AD is associated with higher theta, lower alpha, and lower beta activity in the parieto-occipital EEG. Also, higher theta activity in the fronto-central EEG has a prognosis value. Decreases of beta and alpha activity on quantitative spectral EEG are

IFAST (implicit function as squashing time) is an artificial neural networks (ANNs) assembly; it is capable of compressing the temporal sequence of EEG data into spatial invariants. This model represents spatial features of the EEG patterns at scalp surface by means of filtering EEG tracks according to four different frequency ranges (0.12 Hz, 12.2 - 29.8 Hz; 30.2 - 40 Hz, and Notch Filter 48 - 50 Hz). The spatial content of the EEG voltage is extracted by IFAST stepwise procedure using ANNs. The data input for the classification operated by ANNs are the connections weights of a nonlinear auto-associative ANN trained to reproduce the recorded EEG tracks. This method allows distinguish between mild cognitive impairment (MCI) stable and MCI subjects who will convert to Alzheimer's disease (MCI/AD), with a high degree of accuracy. Eyes-closed resting EEG data in individual MCI/AD subjects show significant

Event-modulated EEG dynamic analysis makes it possible to investigate the functional activation of neocortical circuits [41]. Evoked Response Potentials (ERP) brain correlates are useful preclinical markers to identify individuals at risk for AD. Additionally, the ERP measures can predict its presence. Asymptomatic PSEN1 mutation carriers have greater occipital positivity, but less positivity in frontal regions than control subjects. Those differences are more evident during the 200-300 msec period of the ERP. It seems like carriers rely more upon perceptual details of the items to distinguish between them, while control subjects may use frontally mediated processes to distinguish between studied and

An electrophysiological marker in the early detection of neurodegeneration is found in the EEG pattern during stimulation for visual evoked potentials VEP in mild AD patients compared to Elderly controls, and MCI. Elderly controls have a neural pattern with a right– left dominance; in MCI this pattern seems to be displaced from right hemisphere to the left one, while in mild AD the activity concentrates on deep structures of this hemisphere (hippo‐

independent predictors of mortality in patients with early Alzheimer disease [39].

differences in the 10-12 Hz band when compared to MCI subjects [40].

unstudied visual items [42].

power in 1-6.5 Hz band have an earlier age of disease onset [38].

fluency [11].

408 Neurodegenerative Diseases

**Figure 2.** Event-related potential study: Comparison between alzheimer diseases patients and normal control pa‐ tients: (A) N170 at the four electrode sites; (B) the amplitudes of N170 between groups and types, AD: Alzheimer's disease. \*

Visual ERP features have shown that different neural regions are responsible for the early visual processing in the structural encoding of scenes and faces. P100 is a part of the evoked response suitable to examine basic visual processing, N170 brings information about structural encoding, and N250 is related to familiarity. The pattern of P100 and that of N170 suggest that mild Alzheimer disease patients maintain basic visual processing and structural encoding abilities, and scene recognition is impaired earlier than face recognition in the course of Alzheimer disease [43]. There is a diminished N400 component during a semantic categori‐ zation task in elderly subjects which suggest that due to the difficulty in accessing information there are deficient associative connections within the semantic network [44]. Auditory sensory and cognitive cortical potentials in persons with familial Alzheimer disease (FAD) mutations are abnormal approximately 10 years before dementia will be manifest. FAD mutation carriers had significantly longer latencies of the N100, P200, N200, and P300 components, and smaller slow wave amplitudes. Longer event-related potential latencies suggest slowing of cortical information processing in FAD mutation carriers [45]. The P300 latency is very useful in diagnosis, since it is found to be altered in cases with AD at an early stage, with very little cognitive degeneration [46].

symptoms developed. Thus, causality between the emergence of synchronous oscillations in the pallidum and main parkinsonian motor symptoms seems unlikely. Consequently, the pathological disruption of movement-related activity in the basal ganglia appears to be a better correlate at least to bradykinesia and is probably the best responsible candidate for this motor

Electro-Physiological Approaches to Monitoring Neuro-Degenerative Diseases

http://dx.doi.org/10.5772/55228

411

The observation of a voluntary movement executed by another person is associated with an alpha and beta EEG desynchronization over the motor cortex, thought to reflect activity from the human "mirror neuron" system. Movement observation is accompanied by bilateral beta reduction in subthalamic power and cortico-STN coherence in PD, which is smaller than the decrease observed during movement execution, but significant when compared with control conditions. Movement observation is accompanied by changes in the beta oscillatory activity of the STN, similar to those observed in the EEG. These changes suggest that the basal ganglia

The difficulty that patients have in initiating voluntary movement in the absence of any external cues might be due to the fact that the amplitude of movement-related cortical potential is equal to those prior to random-choice movements. The implication is that processes involved

Parkinson disease patients show deficits in simple visuo-perceptual functions. Moreover, PD patients had impairment in tasks requiring set shifting from one reaction to another that may suggest frontal lobe dysfunction. The memory deficit in PD may derive from lowered moti‐

Looking for electrophysiological correlates of perceptual categorization in Parkinson's disease, visual event-related potentials (ERPs) in a natural scene categorization task become a suitable tool. In healthy control subjects, there is a significant early difference (150-250 ms poststimulus) between ERPs elicited by pictures containing animals and scenes without animals. In spite of relatively preserved basic-level visual functions, this is not the case in untreated PD patients. These results move up the possibility for striatal contributions to visual categorization and

It has been reported an oscillatory theta-alpha activity in the ventral subthalamic nucleus associated with impulse control disorders ICD in patients with Parkinson's disease. This activity is distinct from that associated with L-dopa-induced dyskinesias LID and is also coherent with EEG activity recorded in frontal areas. The activity recorded in PD patients with impulse control disorders come out from the associative-limbic area (ventral subthalamic area), which is coherent with premotor frontal cortical activity. Patients with impulse control disorders display theta-alpha (4-10 Hz) activity (mean peak: 6.71 Hz) that is generated 2-8 mm below the intercommissural line. In PD the oscillatory activity of the subthalamic nucleus recorded through the electrodes implanted for deep brain stimulation displays dopaminedependent changes whereby the OFF to ON motor state is signalled by a marked reduction in beta band activity [55]. Thus, dopaminergic side effects in Parkinson's disease are associated with oscillatory activity in the theta-alpha band, but at different frequencies and with different topography for the motor (dyskinesias) and behavioural (abnormal impulsivity) manifesta‐

might be engaged by the activity of the human mirror system [51].

in self-selection of movement are abnormal in Parkinson's disease [52].

may present a novel protocol for further clinical studies [54].

symptom [50].

vation or initiating behavior [53].

### **6. Parkinson electroencephalographic patterns**

Recordings in humans as a result of functional neurosurgery have revealed a tendency for basal ganglia neurons to oscillate and synchronize their activity, giving rise to a rhythmic population activity, manifest as oscillatory local field potentials. The most important activity is synchronized oscillation in the beta band (13-30 Hz), which has been picked up at various sites within the basal ganglia-cortical loop in PD. Dopaminergic medication and move‐ ment suppress this activity, with the timing and degree of suppression closely correlating with behavioral performance. for that reason synchronization in the beta band has been hypothesized to be essentially antikinetic in nature and pathophysiologically relevant to bradykinesia [47].

Post-movement beta synchronization is an increase in EEG beta power after movement termination. Parkinson patients have longer movement duration than controls, and also execute longer movement with their left hand, unrelated to the side of tremor. In Parkin‐ son patients post-movement beta synchronization is significantly smaller contralateral to the tremulous hand movement. The post-movement beta synchronization has anterior shifting in Parkinson-patients; whilst in tremor dominant Parkinson's disease the asymmet‐ ric decrease of post-move beta synchronization is related to the laterality of tremor rather than bradykinesia [48].

Local Field Potentials LFP recording beta oscillatory activity is generated largely within the dorsal portion of the sub thalamic nucleus STN and can produce synchronous oscillatory activity of the local neuronal population. Recent studies suggest that beta (15-30 Hz) oscillatory activity in the subthalamic nucleus (STN) is severely increased in PD, and may interfere with movement execution [49].

Parkinson's disease is known to result from basal ganglia dysfunction. Electrophysiological recordings show abnormal synchronous oscillatory activity in the cortico-basal ganglia network in parkinsonian patients and animals. Also, it has been recorded an altered response pattern during movement execution in the pallidum of parkinsonian animals. In Parkinson animal models, spontaneous correlated activity increased later, after animals became severely bradykinetic, whereas synchronous oscillatory activity appeared only after major motor symptoms developed. Thus, causality between the emergence of synchronous oscillations in the pallidum and main parkinsonian motor symptoms seems unlikely. Consequently, the pathological disruption of movement-related activity in the basal ganglia appears to be a better correlate at least to bradykinesia and is probably the best responsible candidate for this motor symptom [50].

Alzheimer disease [43]. There is a diminished N400 component during a semantic categori‐ zation task in elderly subjects which suggest that due to the difficulty in accessing information there are deficient associative connections within the semantic network [44]. Auditory sensory and cognitive cortical potentials in persons with familial Alzheimer disease (FAD) mutations are abnormal approximately 10 years before dementia will be manifest. FAD mutation carriers had significantly longer latencies of the N100, P200, N200, and P300 components, and smaller slow wave amplitudes. Longer event-related potential latencies suggest slowing of cortical information processing in FAD mutation carriers [45]. The P300 latency is very useful in diagnosis, since it is found to be altered in cases with AD at an early stage, with very little

Recordings in humans as a result of functional neurosurgery have revealed a tendency for basal ganglia neurons to oscillate and synchronize their activity, giving rise to a rhythmic population activity, manifest as oscillatory local field potentials. The most important activity is synchronized oscillation in the beta band (13-30 Hz), which has been picked up at various sites within the basal ganglia-cortical loop in PD. Dopaminergic medication and move‐ ment suppress this activity, with the timing and degree of suppression closely correlating with behavioral performance. for that reason synchronization in the beta band has been hypothesized to be essentially antikinetic in nature and pathophysiologically relevant to

Post-movement beta synchronization is an increase in EEG beta power after movement termination. Parkinson patients have longer movement duration than controls, and also execute longer movement with their left hand, unrelated to the side of tremor. In Parkin‐ son patients post-movement beta synchronization is significantly smaller contralateral to the tremulous hand movement. The post-movement beta synchronization has anterior shifting in Parkinson-patients; whilst in tremor dominant Parkinson's disease the asymmet‐ ric decrease of post-move beta synchronization is related to the laterality of tremor rather

Local Field Potentials LFP recording beta oscillatory activity is generated largely within the dorsal portion of the sub thalamic nucleus STN and can produce synchronous oscillatory activity of the local neuronal population. Recent studies suggest that beta (15-30 Hz) oscillatory activity in the subthalamic nucleus (STN) is severely increased in PD, and may interfere with

Parkinson's disease is known to result from basal ganglia dysfunction. Electrophysiological recordings show abnormal synchronous oscillatory activity in the cortico-basal ganglia network in parkinsonian patients and animals. Also, it has been recorded an altered response pattern during movement execution in the pallidum of parkinsonian animals. In Parkinson animal models, spontaneous correlated activity increased later, after animals became severely bradykinetic, whereas synchronous oscillatory activity appeared only after major motor

cognitive degeneration [46].

410 Neurodegenerative Diseases

bradykinesia [47].

than bradykinesia [48].

movement execution [49].

**6. Parkinson electroencephalographic patterns**

The observation of a voluntary movement executed by another person is associated with an alpha and beta EEG desynchronization over the motor cortex, thought to reflect activity from the human "mirror neuron" system. Movement observation is accompanied by bilateral beta reduction in subthalamic power and cortico-STN coherence in PD, which is smaller than the decrease observed during movement execution, but significant when compared with control conditions. Movement observation is accompanied by changes in the beta oscillatory activity of the STN, similar to those observed in the EEG. These changes suggest that the basal ganglia might be engaged by the activity of the human mirror system [51].

The difficulty that patients have in initiating voluntary movement in the absence of any external cues might be due to the fact that the amplitude of movement-related cortical potential is equal to those prior to random-choice movements. The implication is that processes involved in self-selection of movement are abnormal in Parkinson's disease [52].

Parkinson disease patients show deficits in simple visuo-perceptual functions. Moreover, PD patients had impairment in tasks requiring set shifting from one reaction to another that may suggest frontal lobe dysfunction. The memory deficit in PD may derive from lowered moti‐ vation or initiating behavior [53].

Looking for electrophysiological correlates of perceptual categorization in Parkinson's disease, visual event-related potentials (ERPs) in a natural scene categorization task become a suitable tool. In healthy control subjects, there is a significant early difference (150-250 ms poststimulus) between ERPs elicited by pictures containing animals and scenes without animals. In spite of relatively preserved basic-level visual functions, this is not the case in untreated PD patients. These results move up the possibility for striatal contributions to visual categorization and may present a novel protocol for further clinical studies [54].

It has been reported an oscillatory theta-alpha activity in the ventral subthalamic nucleus associated with impulse control disorders ICD in patients with Parkinson's disease. This activity is distinct from that associated with L-dopa-induced dyskinesias LID and is also coherent with EEG activity recorded in frontal areas. The activity recorded in PD patients with impulse control disorders come out from the associative-limbic area (ventral subthalamic area), which is coherent with premotor frontal cortical activity. Patients with impulse control disorders display theta-alpha (4-10 Hz) activity (mean peak: 6.71 Hz) that is generated 2-8 mm below the intercommissural line. In PD the oscillatory activity of the subthalamic nucleus recorded through the electrodes implanted for deep brain stimulation displays dopaminedependent changes whereby the OFF to ON motor state is signalled by a marked reduction in beta band activity [55]. Thus, dopaminergic side effects in Parkinson's disease are associated with oscillatory activity in the theta-alpha band, but at different frequencies and with different topography for the motor (dyskinesias) and behavioural (abnormal impulsivity) manifesta‐ tions [6]. Diffuse lesions correlate with slowing of the EEG in patients with severe cognitive impairment [56], [57], [58]. All patients with dementia have an increase in slow waves in all the EEEG electrodes recording. In addition, all PD patients present diffuse slowing in the EEG with increased delta power [57].

point, most individuals probably cross the threshold to the symptomatic phase of the illness, the pathologic process comes to involve the neocortex, and the disease is manifested in all its clinical magnitude. These diffuse lesions correlate with slowing of the EEG in patients with

Electro-Physiological Approaches to Monitoring Neuro-Degenerative Diseases

http://dx.doi.org/10.5772/55228

413

The auditory evoked potentials of different latencies are useful in the evaluation of cognitive changes associated to PD. Middle latency auditory evoked potentials are abnormal in most PD patient. P300 is absent significantly more often in PD patients with cognitive impairment [64].

Spectral ratio is the sum of the power values in the alpha and beta waves divided by the sum of the values in the slow waves. Since, all patients with dementia have an increase in slow waves in all the EEEG electrodes recording, the spectral ratios decrease have significant predictive value in PD at all electrode locations except for the frontal pole. In addition, all PD patients present diffuse slowing in the EEG giving to delta power significance as predictive electrophysiological biomarker for dementia in PD [57]. ERP is also useful tool for the evalu‐ ation of neuropsychological impairments in PD. In the classic oddball task P300 is elicited by target. Even though, P300b findings in PD have shown inconsistent results, prolonged P300b

The hazard of developing dementia is 13 times higher for those with low background rhythm frequency (lower than the grand median of 8.5 Hz) than for those with high background rhythm frequency. The QEEG measures of background rhythm frequency and relative power

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder, with neurodegeneration mainly affecting the striatum. In Nogo as opposed to Go trials two fronto-central ERP components are elicited: the Nogo-N2 and Nogo-P3. These components are supposed to depend on (medial) prefrontal regions, especially the anterior cingulate cortex (ACC). In HD the Nogo-P3 demonstrates a strong attenuation, while the Nogo-N2 does not differ from controls. The decline in inhibition is likely mediated via a dysfunction in the ACC, which is known to be dysfunctional in HD. Moreover, the decline in response inhibition in HD is gene-associated. The differentially affected Nogo-components suggest that they rely on different neuronal circuits, even within the ACC. For HD this suggests that this structure is

Cognition is affected early in Huntington disease, and in HD animal models there is evidence that this reflects abnormal synaptic plasticity. HD gene carriers and controls respond differ‐ ently to theta burst stimulation, with controls having more inhibition than HD gene carriers. However, there is no difference between pre-manifest and early symptomatic HD gene carriers. Motor cortex plasticity is abnormal in HD gene carriers but is not closely linked to the development of motor signs of HD [67]. In vivo recording of field potentials in the dorsomedial

latency in PD patients with dementia have been consistently observed [65].

**8. Huntington electroencephalographic patterns**

in the band are potential predictive biomarkers for dementia incidence in PD [57].

severe cognitive impairment [56], [57], [58].

Parkinson Early Detection:

not entirely dysfunctional [66].

Movement disorders in PD are due to the imbalance of inhibitory and excitatory processes involving motor cortical and subcortical neuronal circuits together with a nigrostriatal dopamine deficit [59]. A paired-pulse paradigm is usually used to study postexcitatory inhibition effect related to sensory gating mechanisms and synaptic processes in neurotrans‐ mitters release. There are two mechanisms that might explain paired-pulse inhibition phe‐ nomena. The first mechanism is the decrease in release probability of excitatory neurotransmitters from terminals of afferent axons. Another possible mechanism of the decrement of the second response on paired stimulation is connected with synaptically released GABA from terminals of inhibitory interneurons [60]. As the paired-pulse facilitation, paired-pulse inhibition is considered to be a form of a short-term synaptic plasticity. The investigation of cortical evoked potentials to paired-pulse sensory stimulation may provide additional information about mechanisms of neurological disturbances in PD [60].

### **7. Parkinson diagnosis**

When individuals performed a reaching motor task (catching a ball in free fall), beta band asymmetry is observed. This result show a pattern of asymmetry in the somatosensory cortex, associated with a preparatory mechanism. With respect to task moment, after the ball's fall, the asymmetry is reduced. Moreover, the difference in asymmetry between the regions is related to a supposed specialization of areas (i.e., temporal and central). The temporal region is associated with cognitive processes involved in the motor action (i.e., explicit knowledge). On the other hand, the central sites are related to the motor control mechanisms per se (i.e., implicit knowledge). The premotor cortex shows a decrease on neural activity in the contrala‐ teral hemisphere (i.e., to the right hand). This finding is in agreement with others suggesting a participation of the frontal cortex in the planning of the apprehension task. This sensorimotor paradigm may be added to the inventory of tasks used to study clinical conditions such as depression, alzheimer and Parkinson diseases [61].

The corpus callosum (CC) is the morphological correlate of inter-hemispheric connectivity. Its integrity is of great importance for motor function and inter-hemispheric coordination of bimanual movements. Callosal fiber tracts are highly vulnerable as they are involved in number of neurodegenerative disease like parkinsonian syndromes and amyotrophic lateral sclerosis, even at early stages of the diseases. Transcraneal magnetic stimulation of the transcallosal inhibition may be performed by measurement of the ipsilateral silent period (iSP). The most common finding is a loss or a prolongation of the iSP latency [62].

As PD progresses, components of the autonomic, limbic, and somatomotor systems become damaged [63]. The substantia nigra and other regions of nuclear gray matter in the midbrain and forebrain become the focus of initially slight and then severe pathologic changes. At certain point, most individuals probably cross the threshold to the symptomatic phase of the illness, the pathologic process comes to involve the neocortex, and the disease is manifested in all its clinical magnitude. These diffuse lesions correlate with slowing of the EEG in patients with severe cognitive impairment [56], [57], [58].

The auditory evoked potentials of different latencies are useful in the evaluation of cognitive changes associated to PD. Middle latency auditory evoked potentials are abnormal in most PD patient. P300 is absent significantly more often in PD patients with cognitive impairment [64].

Parkinson Early Detection:

tions [6]. Diffuse lesions correlate with slowing of the EEG in patients with severe cognitive impairment [56], [57], [58]. All patients with dementia have an increase in slow waves in all the EEEG electrodes recording. In addition, all PD patients present diffuse slowing in the EEG

Movement disorders in PD are due to the imbalance of inhibitory and excitatory processes involving motor cortical and subcortical neuronal circuits together with a nigrostriatal dopamine deficit [59]. A paired-pulse paradigm is usually used to study postexcitatory inhibition effect related to sensory gating mechanisms and synaptic processes in neurotrans‐ mitters release. There are two mechanisms that might explain paired-pulse inhibition phe‐ nomena. The first mechanism is the decrease in release probability of excitatory neurotransmitters from terminals of afferent axons. Another possible mechanism of the decrement of the second response on paired stimulation is connected with synaptically released GABA from terminals of inhibitory interneurons [60]. As the paired-pulse facilitation, paired-pulse inhibition is considered to be a form of a short-term synaptic plasticity. The investigation of cortical evoked potentials to paired-pulse sensory stimulation may provide

additional information about mechanisms of neurological disturbances in PD [60].

When individuals performed a reaching motor task (catching a ball in free fall), beta band asymmetry is observed. This result show a pattern of asymmetry in the somatosensory cortex, associated with a preparatory mechanism. With respect to task moment, after the ball's fall, the asymmetry is reduced. Moreover, the difference in asymmetry between the regions is related to a supposed specialization of areas (i.e., temporal and central). The temporal region is associated with cognitive processes involved in the motor action (i.e., explicit knowledge). On the other hand, the central sites are related to the motor control mechanisms per se (i.e., implicit knowledge). The premotor cortex shows a decrease on neural activity in the contrala‐ teral hemisphere (i.e., to the right hand). This finding is in agreement with others suggesting a participation of the frontal cortex in the planning of the apprehension task. This sensorimotor paradigm may be added to the inventory of tasks used to study clinical conditions such as

The corpus callosum (CC) is the morphological correlate of inter-hemispheric connectivity. Its integrity is of great importance for motor function and inter-hemispheric coordination of bimanual movements. Callosal fiber tracts are highly vulnerable as they are involved in number of neurodegenerative disease like parkinsonian syndromes and amyotrophic lateral sclerosis, even at early stages of the diseases. Transcraneal magnetic stimulation of the transcallosal inhibition may be performed by measurement of the ipsilateral silent period (iSP).

As PD progresses, components of the autonomic, limbic, and somatomotor systems become damaged [63]. The substantia nigra and other regions of nuclear gray matter in the midbrain and forebrain become the focus of initially slight and then severe pathologic changes. At certain

The most common finding is a loss or a prolongation of the iSP latency [62].

with increased delta power [57].

412 Neurodegenerative Diseases

**7. Parkinson diagnosis**

depression, alzheimer and Parkinson diseases [61].

Spectral ratio is the sum of the power values in the alpha and beta waves divided by the sum of the values in the slow waves. Since, all patients with dementia have an increase in slow waves in all the EEEG electrodes recording, the spectral ratios decrease have significant predictive value in PD at all electrode locations except for the frontal pole. In addition, all PD patients present diffuse slowing in the EEG giving to delta power significance as predictive electrophysiological biomarker for dementia in PD [57]. ERP is also useful tool for the evalu‐ ation of neuropsychological impairments in PD. In the classic oddball task P300 is elicited by target. Even though, P300b findings in PD have shown inconsistent results, prolonged P300b latency in PD patients with dementia have been consistently observed [65].

The hazard of developing dementia is 13 times higher for those with low background rhythm frequency (lower than the grand median of 8.5 Hz) than for those with high background rhythm frequency. The QEEG measures of background rhythm frequency and relative power in the band are potential predictive biomarkers for dementia incidence in PD [57].

### **8. Huntington electroencephalographic patterns**

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder, with neurodegeneration mainly affecting the striatum. In Nogo as opposed to Go trials two fronto-central ERP components are elicited: the Nogo-N2 and Nogo-P3. These components are supposed to depend on (medial) prefrontal regions, especially the anterior cingulate cortex (ACC). In HD the Nogo-P3 demonstrates a strong attenuation, while the Nogo-N2 does not differ from controls. The decline in inhibition is likely mediated via a dysfunction in the ACC, which is known to be dysfunctional in HD. Moreover, the decline in response inhibition in HD is gene-associated. The differentially affected Nogo-components suggest that they rely on different neuronal circuits, even within the ACC. For HD this suggests that this structure is not entirely dysfunctional [66].

Cognition is affected early in Huntington disease, and in HD animal models there is evidence that this reflects abnormal synaptic plasticity. HD gene carriers and controls respond differ‐ ently to theta burst stimulation, with controls having more inhibition than HD gene carriers. However, there is no difference between pre-manifest and early symptomatic HD gene carriers. Motor cortex plasticity is abnormal in HD gene carriers but is not closely linked to the development of motor signs of HD [67]. In vivo recording of field potentials in the dorsomedial striatum evoked by stimulation of the prelimbic cortex in rats shows an altered plasticity, with higher paired-pulse facilitation, enhanced short-term depression, as well as stronger long-term potentiation after theta burst stimulation. This is a behavioral and electrophysiological evidence of a presymptomatic alteration of prefrontostriatal processing in an animal model for Huntington disease and suggests that supra-second timing may be the earliest cognitive dysfunction in HD [68].

**Author details**

Manuel J. Rojas\*

**References**

Sep;92(1-2):141-7.

1383-401.

Nov;16(6):566-73.

291(1):R189-96.

Sect. 1995;99(1-3):55-62.

IEEE Eng Med Biol Soc. 2011;2011:6087-91.

, Camilo Orozco and Francisco Olea

Animal Health Department, National University of Colombia, Bogota, Colombia

[1] Brismar T. The human EEG--physiological and clinical studies. Physiol Behav. 2007

Electro-Physiological Approaches to Monitoring Neuro-Degenerative Diseases

http://dx.doi.org/10.5772/55228

415

[2] Nunez PL, Srinivasan R. A theoretical basis for standing and traveling brain waves measured with human EEG with implications for an integrated consciousness. Clin

[3] Murali S, Vladimir KV. Analysis of fractal and fast fourier transform spectra of hu‐ man electroencephalograms induced by odors. Int J Neurosci. 2007 Oct;117(10):

[4] Soininen H, Reinikainen K, Partanen J, Mervaala E, Paljärvi L, Helkala EL, et al. Slowing of the dominant occipital rhythm in electroencephalogram is associated with low concentration of noradrenaline in the thalamus in patients with Alzheimer's dis‐

[5] Nobili F, Copello F, Vitali P, Prastaro T, Carozzo S, Perego G, et al. Timing of disease progression by quantitative EEG in Alzheimer' s patients. J Clin Neurophysiol. 1999

[6] Rodriguez-Oroz MC, López-Azcárate J, Garcia-Garcia D, Alegre M, Toledo J, Valen‐ cia M, et al. Involvement of the subthalamic nucleus in impulse control disorders as‐

[7] Rojas MJ, Navas JA, Rector DM. Evoked response potential markers for anesthetic and behavioral states. Am J Physiol Regul Integr Comp Physiol. 2006 Jul;

[8] Dierks T, Frölich L, Ihl R, Maurer K. Correlation between cognitive brain function and electrical brain activity in dementia of Alzheimer type. J Neural Transm Gen

[9] Elgendi M, Vialatte F, Cichocki A, Latchoumane C, Jeong J, Dauwels J. Optimization of EEG frequency bands for improved diagnosis of Alzheimer disease. Conf Proc

sociated with Parkinson's disease. Brain. 2011 Jan;134(Pt 1):36-49.

\*Address all correspondence to: marojasba@unal.edu.co

Neurophysiol. 2006 Nov;117(11):2424-35.

ease. Neurosci Lett. 1992 Mar;137(1):5-8.

The onset of Huntington disease (HD) might be atypical. Rarely, there is severe cognitive impairment and diffuse cortical atrophy before the onset of motor manifestations or symptoms of an extrapyramidal movement disorder. Thus, especial consideration must there be for patients with early dementia of unknown etiology [69].

The visually evoked potential is abnormal in patients with Huntington disease. Both early and late wave components are affected, and the averaged amplitude for the patients is reduced in comparison with normal control subjects. Despite striking attenuation and disorganization of the complex, latency of initial wave components is normal. The abnormality is not present in patients with a variety of other nonfocal cerebral disorders nor in children of patients with Huntington disease [70]. There are marked impairments of patients with HD in early visual sensory processing (early components). The early visual components show a significant latency shift (delay of about 50 milliseconds) in HD. In the search paradigms the P3 compo‐ nents differentiating target and standard stimuli is virtually absent in HD as is the ERP effect indexing word recognition. This is accompanied by a marked delay in search times and lower hit rates in the search tasks and grossly reduced recognition accuracy in the memory task. Deficits in visual search might be due to an impairment to deploy attentional resources across the visual field and/or an inability to control eye movements [71].

#### **9. Huntington diagnosis**

Huntington disease usually causes cognitive decline previously to motor symptoms. Studies performed in a HD animal model to assess this issue suggest that normal plasticity in pre‐ frontostriatal circuits may be necessary for reliable and precise timing behavior. Furthermore, the behavioral analysis revealed poorer temporal sensitivity as early as 4 months of age, well before detection of overt motor deficits. At a later symptomatic age, animals were impaired in their temporal discriminative behavior [68].

### **10. Huntington early detection**

It is well known that HD affects cognition earlier than motor system. The motor-evoked potential to burst stimulation is a suitable tool to evaluate motor synaptic plasticity. This might bring out clues about motor control decline related to HD before having symptoms of abnormal motor behavior [67].

### **Author details**

striatum evoked by stimulation of the prelimbic cortex in rats shows an altered plasticity, with higher paired-pulse facilitation, enhanced short-term depression, as well as stronger long-term potentiation after theta burst stimulation. This is a behavioral and electrophysiological evidence of a presymptomatic alteration of prefrontostriatal processing in an animal model for Huntington disease and suggests that supra-second timing may be the earliest cognitive

The onset of Huntington disease (HD) might be atypical. Rarely, there is severe cognitive impairment and diffuse cortical atrophy before the onset of motor manifestations or symptoms of an extrapyramidal movement disorder. Thus, especial consideration must there be for

The visually evoked potential is abnormal in patients with Huntington disease. Both early and late wave components are affected, and the averaged amplitude for the patients is reduced in comparison with normal control subjects. Despite striking attenuation and disorganization of the complex, latency of initial wave components is normal. The abnormality is not present in patients with a variety of other nonfocal cerebral disorders nor in children of patients with Huntington disease [70]. There are marked impairments of patients with HD in early visual sensory processing (early components). The early visual components show a significant latency shift (delay of about 50 milliseconds) in HD. In the search paradigms the P3 compo‐ nents differentiating target and standard stimuli is virtually absent in HD as is the ERP effect indexing word recognition. This is accompanied by a marked delay in search times and lower hit rates in the search tasks and grossly reduced recognition accuracy in the memory task. Deficits in visual search might be due to an impairment to deploy attentional resources across

Huntington disease usually causes cognitive decline previously to motor symptoms. Studies performed in a HD animal model to assess this issue suggest that normal plasticity in pre‐ frontostriatal circuits may be necessary for reliable and precise timing behavior. Furthermore, the behavioral analysis revealed poorer temporal sensitivity as early as 4 months of age, well before detection of overt motor deficits. At a later symptomatic age, animals were impaired in

It is well known that HD affects cognition earlier than motor system. The motor-evoked potential to burst stimulation is a suitable tool to evaluate motor synaptic plasticity. This might bring out clues about motor control decline related to HD before having symptoms of abnormal

dysfunction in HD [68].

414 Neurodegenerative Diseases

**9. Huntington diagnosis**

their temporal discriminative behavior [68].

**10. Huntington early detection**

motor behavior [67].

patients with early dementia of unknown etiology [69].

the visual field and/or an inability to control eye movements [71].

Manuel J. Rojas\* , Camilo Orozco and Francisco Olea

\*Address all correspondence to: marojasba@unal.edu.co

Animal Health Department, National University of Colombia, Bogota, Colombia

### **References**


[10] Babiloni C, Frisoni GB, Pievani M, Vecchio F, Lizio R, Buttiglione M, et al. Hippo‐ campal volume and cortical sources of EEG alpha rhythms in mild cognitive impair‐ ment and Alzheimer disease. Neuroimage. 2009 Jan;44(1):123-35.

[22] Schnyer DM, Allen JJ, Kaszniak AW, Forster KI. An event-related potential examina‐ tion of masked and unmasked repetition priming in Alzheimer's disease: implica‐

Electro-Physiological Approaches to Monitoring Neuro-Degenerative Diseases

http://dx.doi.org/10.5772/55228

417

tions for theories of implicit memory. Neuropsychology. 1999 Jul;13(3):323-37.

electrical activity deterioration. Pain. 2004 Sep;111(1-2):22-9.

Adv Neurol. 1986;43:399-405.

Sleep. 2006 Oct;29(10):1321-5.

Neuroscience. 1998 Feb;82(3):671-86.

Aug;25(4):187-93.

1084-7.

385-402.

1727-35.

Feb;10(1):49-62.

Sleep. 2005 Jul;28(7):865-70.

[23] Benedetti F, Arduino C, Vighetti S, Asteggiano G, Tarenzi L, Rainero I. Pain reactivi‐ ty in Alzheimer patients with different degrees of cognitive impairment and brain

[24] Hallett M, Wilkins DE. Myoclonus in Alzheimer's disease and minipolymyoclonus.

[25] de Haan W, Stam CJ, Jones BF, Zuiderwijk IM, van Dijk BW, Scheltens P. Restingstate oscillatory brain dynamics in Alzheimer disease. J Clin Neurophysiol. 2008

[26] Gómez C, Hornero R, Fernández A, Abasolo D, Escudero J, López M. Magnetoence‐ phalogram background activity analysis in Alzheimer's disease patients using auto

[27] Gagnon JF, Petit D, Fantini ML, Rompré S, Gauthier S, Panisset M, et al. REM sleep behavior disorder and REM sleep without atonia in probable Alzheimer disease.

[28] Cash SS, Halgren E, Dehghani N, Rossetti AO, Thesen T, Wang C, et al. The human K-complex represents an isolated cortical down-state. Science. 2009 May;324(5930):

[29] ROTH M, SHAW J, GREEN J. The form voltage distribution and physiological signif‐ icance of the K-complex. Electroencephalogr Clin Neurophysiol. 1956 Aug;8(3):

[30] Webster KE, Colrain IM. Multichannel EEG analysis of respiratory evoked-potential components during wakefulness and NREM sleep. J Appl Physiol. 1998 Nov;85(5):

[31] McCormick L, Nielsen T, Nicolas A, Ptito M, Montplaisir J. Topographical distribu‐ tion of spindles and K-complexes in normal subjects. Sleep. 1997 Nov;20(11):939-41.

[32] Amzica F, Steriade M. Cellular substrates and laminar profile of sleep K-complex.

[33] Tononi G, Cirelli C. Sleep function and synaptic homeostasis. Sleep Med Rev. 2006

[34] Crowley K, Sullivan EV, Adalsteinsson E, Pfefferbaum A, Colrain IM. Differentiating pathologic delta from healthy physiologic delta in patients with Alzheimer disease.

[35] Strik WK, Chiaramonti R, Muscas GC, Paganini M, Mueller TJ, Fallgatter AJ, et al. Decreased EEG microstate duration and anteriorisation of the brain electrical fields

mutual information. Conf Proc IEEE Eng Med Biol Soc. 2006;1:6181-4.


[22] Schnyer DM, Allen JJ, Kaszniak AW, Forster KI. An event-related potential examina‐ tion of masked and unmasked repetition priming in Alzheimer's disease: implica‐ tions for theories of implicit memory. Neuropsychology. 1999 Jul;13(3):323-37.

[10] Babiloni C, Frisoni GB, Pievani M, Vecchio F, Lizio R, Buttiglione M, et al. Hippo‐ campal volume and cortical sources of EEG alpha rhythms in mild cognitive impair‐

[11] Duffy FH, McAnulty GB, Albert MS. Temporoparietal electrophysiological differen‐ ces characterize patients with Alzheimer's disease: a split-half replication study. Cer‐

[12] Kann O, Huchzermeyer C, Kovács R, Wirtz S, Schuelke M. Gamma oscillations in the hippocampus require high complex I gene expression and strong functional perform‐

[13] Schreiter Gasser U, Rousson V, Hentschel F, Sattel H, Gasser T. Alzheimer disease versus mixed dementias: an EEG perspective. Clin Neurophysiol. 2008 Oct;119(10):

[14] Claus JJ, Kwa VI, Teunisse S, Walstra GJ, van Gool WA, Koelman JH, et al. Slowing on quantitative spectral EEG is a marker for rate of subsequent cognitive and func‐ tional decline in early Alzheimer disease. Alzheimer Dis Assoc Disord. 1998 Sep;

[15] Wada Y, Nanbu Y, Koshino Y, Yamaguchi N, Hashimoto T. Reduced interhemi‐ spheric EEG coherence in Alzheimer disease: analysis during rest and photic stimula‐

[16] Güntekin B, Saatçi E, Yener G. Decrease of evoked delta, theta and alpha coherences in Alzheimer patients during a visual oddball paradigm. Brain Res. 2008 Oct;

[17] Kowalski JW, Gawel M, Pfeffer A, Barcikowska M. The diagnostic value of EEG in Alzheimer disease: correlation with the severity of mental impairment. J Clin Neuro‐

[18] Celesia GG, Villa AE, Brigell M, Rubboli G, Bolcioni G, Fiori MG. An electrophysio‐ logical study of visual processing in Alzheimer's disease. Electroencephalogr Clin

[19] Staudinger T, Polikar R. Analysis of complexity based EEG features for the diagnosis of Alzheimer's disease. Conf Proc IEEE Eng Med Biol Soc. 2011;2011:2033-6.

[20] Haupt M, González-Hernández JA, Scherbaum WA. Regions with different evoked frequency band responses during early-stage visual processing distinguish mild Alz‐ heimer dementia from mild cognitive impairment and normal aging. Neurosci Lett.

[21] Rosengarten B, Paulsen S, Burr O, Kaps M. Effect of ApoE epsilon4 allele on visual evoked potentials and resultant flow coupling in patients with Alzheimer. J Geriatr

ment and Alzheimer disease. Neuroimage. 2009 Jan;44(1):123-35.

eb Cortex. 1995 1995 May-Jun;5(3):215-21.

2255-9.

416 Neurodegenerative Diseases

12(3):167-74.

1235:109-16.

physiol. 2001 Nov;18(6):570-5.

2008 Sep;442(3):273-8.

Neurophysiol. 1993 Sep;87(3):97-104.

Psychiatry Neurol. 2010 Sep;23(3):165-70.

ance of mitochondria. Brain. 2011 Feb;134(Pt 2):345-58.

tion. Alzheimer Dis Assoc Disord. 1998 Sep;12(3):175-81.


in mild and moderate dementia of the Alzheimer type. Psychiatry Res. 1997 Oct; 75(3):183-91.

[48] Szirmai I, Tamás G, Takáts A, Pálvölgyi L, Kamondi A. [Electrophysiologic investiga‐ tion of cerebral cortex in the subtypes of Parkinson disease]. Ideggyogy Sz. 2002

Electro-Physiological Approaches to Monitoring Neuro-Degenerative Diseases

http://dx.doi.org/10.5772/55228

419

[49] Weinberger M, Mahant N, Hutchison WD, Lozano AM, Moro E, Hodaie M, et al. Be‐ ta oscillatory activity in the subthalamic nucleus and its relation to dopaminergic re‐

[50] Leblois A, Meissner W, Bioulac B, Gross CE, Hansel D, Boraud T. Late emergence of synchronized oscillatory activity in the pallidum during progressive Parkinsonism.

[51] Alegre M, Rodríguez-Oroz MC, Valencia M, Pérez-Alcázar M, Guridi J, Iriarte J, et al. Changes in subthalamic activity during movement observation in Parkinson's dis‐ ease: is the mirror system mirrored in the basal ganglia? Clin Neurophysiol. 2010

[52] Touge T, Werhahn KJ, Rothwell JC, Marsden CD. Movement-related cortical poten‐ tials preceding repetitive and random-choice hand movements in Parkinson's dis‐

[53] Hartikainen P, Helkala EL, Soininen H, Riekkinen P. Cognitive and memory deficits in untreated Parkinson's disease and amyotrophic lateral sclerosis patients: a compa‐

[54] Antal A, Kéri S, Dibó G, Benedek G, Janka Z, Vécsei L, et al. Electrophysiological cor‐ relates of visual categorization: evidence for cognitive dysfunctions in early Parkin‐

[55] Brown P. Oscillatory nature of human basal ganglia activity: relationship to the path‐

[56] Morita A, Kamei S, Mizutani T. Relationship between slowing of the EEG and cogni‐ tive impairment in Parkinson disease. J Clin Neurophysiol. 2011 Aug;28(4):384-7.

[57] Klassen BT, Hentz JG, Shill HA, Driver-Dunckley E, Evidente VG, Sabbagh MN, et al. Quantitative EEG as a predictive biomarker for Parkinson disease dementia. Neu‐

[58] Serizawa K, Kamei S, Morita A, Hara M, Mizutani T, Yoshihashi H, et al. Compari‐ son of quantitative EEGs between Parkinson disease and age-adjusted normal con‐

[59] Ridding MC, Inzelberg R, Rothwell JC. Changes in excitability of motor cortical cir‐ cuitry in patients with Parkinson's disease. Ann Neurol. 1995 Feb;37(2):181-8.

[60] Chu Z, Hablitz JJ. GABA(B) receptor-mediated heterosynaptic depression of excitato‐ ry synaptic transmission in rat frontal neocortex. Brain Res. 2003 Jan;959(1):39-49.

rative study. J Neural Transm Park Dis Dement Sect. 1993;6(2):127-37.

ophysiology of Parkinson's disease. Mov Disord. 2003 Apr;18(4):357-63.

son's disease. Brain Res Cogn Brain Res. 2002 Apr;13(2):153-8.

sponse in Parkinson's disease. J Neurophysiol. 2006 Dec;96(6):3248-56.

May;55(5-6):182-9.

Mar;121(3):414-25.

Eur J Neurosci. 2007 Sep;26(6):1701-13.

ease. Ann Neurol. 1995 Jun;37(6):791-9.

rology. 2011 Jul;77(2):118-24.

trols. J Clin Neurophysiol. 2008 Dec;25(6):361-6.


[48] Szirmai I, Tamás G, Takáts A, Pálvölgyi L, Kamondi A. [Electrophysiologic investiga‐ tion of cerebral cortex in the subtypes of Parkinson disease]. Ideggyogy Sz. 2002 May;55(5-6):182-9.

in mild and moderate dementia of the Alzheimer type. Psychiatry Res. 1997 Oct;

[36] Ponomareva NV, Korovaitseva GI, Rogaev EI. EEG alterations in non-demented indi‐ viduals related to apolipoprotein E genotype and to risk of Alzheimer disease. Neu‐

[37] Rodriguez G, Nobili F, Arrigo A, Priano F, De Carli F, Francione S, et al. Prognostic significance of quantitative electroencephalography in Alzheimer patients: prelimi‐ nary observations. Electroencephalogr Clin Neurophysiol. 1996 Aug;99(2):123-8.

[38] Signorino M, Pucci E, Belardinelli N, Nolfe G, Angeleri F. EEG spectral analysis in vascular and Alzheimer dementia. Electroencephalogr Clin Neurophysiol. 1995 May;

[39] Claus JJ, Ongerboer de Visser BW, Walstra GJ, Hijdra A, Verbeeten B, van Gool WA. Quantitative spectral electroencephalography in predicting survival in patients with

[40] Buscema M, Grossi E, Capriotti M, Babiloni C, Rossini P. The I.F.A.S.T. model allows the prediction of conversion to Alzheimer disease in patients with mild cognitive im‐ pairment with high degree of accuracy. Curr Alzheimer Res. 2010 Mar;7(2):173-87.

[41] Giannakopoulos P, Missonnier P, Kövari E, Gold G, Michon A. Electrophysiological markers of rapid cognitive decline in mild cognitive impairment. Front Neurol Neu‐

[42] Quiroz YT, Ally BA, Celone K, McKeever J, Ruiz-Rizzo AL, Lopera F, et al. Eventrelated potential markers of brain changes in preclinical familial Alzheimer disease.

[43] Cheng PJ, Pai MC. Dissociation between recognition of familiar scenes and of faces in patients with very mild Alzheimer disease: an event-related potential study. Clin

[44] Castañeda M, Ostrosky-Solis F, Pérez M, Bobes MA, Rangel LE. ERP assessment of semantic memory in Alzheimer's disease. Int J Psychophysiol. 1997 Dec;27(3):201-14.

[45] Golob EJ, Ringman JM, Irimajiri R, Bright S, Schaffer B, Medina LD, et al. Cortical event-related potentials in preclinical familial Alzheimer disease. Neurology. 2009

[46] Fernández- Lastra A, Morales-Rodríguez M, Penzol-Díaz J. [Neurophysiological study and use of P300 evoked potentials for investigation in the diagnosis and of fol‐ low-up of patients with Alzheimer s disease]. Rev Neurol. 2001 2001 Mar 16-31;32(6):

[47] Brown P. Bad oscillations in Parkinson's disease. J Neural Transm Suppl. 2006 (70):

early Alzheimer disease. Arch Neurol. 1998 Aug;55(8):1105-11.

75(3):183-91.

418 Neurodegenerative Diseases

94(5):313-25.

rosci. 2009;24:39-46.

Nov;73(20):1649-55.

525-8.

27-30.

Neurology. 2011 Aug;77(5):469-75.

Neurophysiol. 2010 Sep;121(9):1519-25.

robiol Aging. 2008 Jun;29(6):819-27.


[61] Velasques B, Machado S, Portella CE, Silva JG, Basile LF, Cagy M, et al. Electrophy‐ siological analysis of a sensorimotor integration task. Neurosci Lett. 2007 Oct;426(3): 155-9.

**Chapter 18**

**Oxidative Changes and Possible Effects of**

**Polymorphism of Antioxidant Enzymes in**

Frequency of neurodegenerative diseases increase significantly with the age. In the present, average age is increasing and the number of people over 60 years increases as well. Ageing is a physiological process; however it seems to be linked with an increasing risk of origin and development of several diseases including neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Exact mechanisms of ageing are still unclear but experimental evidences support a hypothesis that ageing changes are consequen‐ ces of increasing oxidative damage of organs, tissues, cells and all biomolecules. Oxidative damage is elevated when production of reactive oxygen species is increased compared to the physiological condition or a defence ability of organism against attacks of reactive oxygen species is decreased. Oxidation of specific proteins could play a key role in age associated damage. A relationship between protein aggregation, oxidative stress and neurodegeneration remains unclear although neurodegenerative diseases are connected with an origin of protein deposits. It assumes that protein oxidation and generation of protein aggregates generate a base for a loss of cell function and a reduced ability aged organisms to resist to physiological stress. Accumulation of modified proteins, disturbance of ion homeostasis, lipid and DNA modifications, and impairment of energy production are some of the crucial mechanisms linking ageing to neurodegeneration. In addition mitochondrial dysfunction plays a key role in neurology. Damage of mitochondrial electron transport may be an important factor in the pathogenesis of neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Hunting‐

> © 2013 Babusikova et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

**Neurodegenerative Disease**

Dusan Dobrota and Jana Jurecekova

http://dx.doi.org/10.5772/54619

**1. Introduction**

ton's diseases.

Eva Babusikova, Andrea Evinova, Jozef Hatok,

Additional information is available at the end of the chapter


### **Chapter 18**
