**3. Neurological diseases associated with aging**

#### **3.1. Stroke**

According to World Health Organization (WHO), stroke is defined as "rapidly developing clinical signs of focal (or global) disturbance of cerebral function, lasting more than 24 hours or leading to death, with no apparent cause other than that of vascular origin" [23]. There are two main types of stroke, ischemic and hemorrhagic, which have different pathogenesis.

#### *3.1.1. Ischemic and hemorrhagic stroke*

In an ischemic stroke, the blood supply to some brain areas is reduced due to narrowing or complete occlusion of arteries, which leads to dysfunction of this part of the brain tissue. The molecular mechanisms involved in the pathomechanism of ischemic stroke include progressive damage of the blood-brain barrier (BBB) due to loss of integrity, degeneration or death of neurons, glial reaction, and infiltration of immune cells. Ischemic stroke represents 85–90% cases of stroke [24, 25]. Age-related changes in WM are thought to increase the risk for stroke, poststroke death [26], and ischemic injury after stroke [27]. One of the molecular features of ischemic stroke in the elderly is excitotoxicity due to changes in protein expression (e.g. increase in GLT-1, a transporter for glutamate) and production of ROS. The generation of ROS leads to the death of oligodendrocytes and to the disruption of axons within WM. In the aged brain, the functional decline of mitochondria and antioxidant systems is associated with greater oxidative stress and worsen the WM injury upon ischemia [21].

Hemorrhagic stroke may be caused by cerebral hemorrhage and subarachnoid hemorrhage as a result of damage to the brain's blood vessels by chronic hypertension, cerebral arteriovenous malformation, intracranial aneurysm, disambiguation, cerebral amyloid angiopathy, or drug-induced bleeding. The molecular basis of such a hemorrhage is represented by cytotoxicity of blood, hypermetabolism, excitotoxicity, oxidative stress, and inflammation [28, 29].

#### *3.1.2. Senescence, civilization diseases, and stroke*

The American Heart Association has reported that stroke is the fifth cause of death in the United States [30]. The risk factors of stroke are divided into modifiable (e.g. hypertension and other cardiovascular diseases, migraine, diabetes, dyslipidemia, diet, addictions) and unmodifiable (age, sex, race, genetic factors). Among the unmodifiable risk factors, the most important is age [31]. The risk of stroke increases exponentially with age in both men and women. It is estimated that the incidence of stroke doubles with each decade of life after the age of 55 and affects as many as 5% of people over the age of 65 [32]. It is known that the majority of modifiable risk factors, such as hypertension, atrial fibrillation, hyperhomocysteinemia (HHcy), and inflammatory processes (e.g. periodontal disease, infections, increased hs-CRP), are more common in the elderly. The effect of aging on the cardiovascular system is cumulative [33]. Atrial fibrillation occurs in 5% of individuals aged 70 or above and is a cause of one quarter of stroke incidents in patients at the age of 80. The risk of stroke can be decreased by antithrombotic therapies [34].

The serum total homocysteine (Hcy) concentration is another independent risk factor of ischemic stroke in the elderly, as it correlates with thrombosis. The population attributable risk of stroke incidence in high Hcy levels (>17.4 μmol/L) changes with age and was estimated at 21 and 26% for age 40–59 years (men and women, respectively) and at 35 and 37% for individuals over 60 years of age (men and women, respectively) [35]. HHcy (level of Hcy more than 15.0 μmol/L) promotes the development of atherosclerosis. Clinical studies have shown that HHcy has a toxic impact on both the vascular and nervous systems and may be observed not only in stroke but also in PD, mild cognitive impairment (MCI), and epilepsy [36]. Supplementation of folate and vitamin B12 is essential in the treatment of HHcy, but folate alone does not reduce the risk of stroke [37].

Two thirds of the population aged over 65 years suffers from hypertension [31]. Hypertension has been proven to increase fourfold the risk of stroke; as the blood pressure increases, so does the probability of suffering stroke. Fortunately, a blood pressure reduction of about 10/5 mmHg decreases the risk of stroke by about 35% [33]. Hypertension is often linked with obesity, abnormalities in lipid profile, and type 2 diabetes. Together, these comorbidities contribute to atherosclerosis and thromboembolic stroke.

Diabetes has been found to have a greater impact in developing stroke in women than in men. Diabetes is a significant independent contributor of stroke in older women [38, 39]. However, the risk of stroke in diabetic patients can be decreased with proper intervention and treatment. The Systolic Hypertension in the Elderly Program has shown that antihypertensive treatment in individuals with diabetes can reduce the risk of stroke by about 20% [40].

of ischemic stroke in the elderly is excitotoxicity due to changes in protein expression (e.g. increase in GLT-1, a transporter for glutamate) and production of ROS. The generation of ROS leads to the death of oligodendrocytes and to the disruption of axons within WM. In the aged brain, the functional decline of mitochondria and antioxidant systems is associated with

Hemorrhagic stroke may be caused by cerebral hemorrhage and subarachnoid hemorrhage as a result of damage to the brain's blood vessels by chronic hypertension, cerebral arteriovenous malformation, intracranial aneurysm, disambiguation, cerebral amyloid angiopathy, or drug-induced bleeding. The molecular basis of such a hemorrhage is represented by cytotoxicity of blood, hypermetabolism, excitotoxicity, oxidative stress, and inflammation

The American Heart Association has reported that stroke is the fifth cause of death in the United States [30]. The risk factors of stroke are divided into modifiable (e.g. hypertension and other cardiovascular diseases, migraine, diabetes, dyslipidemia, diet, addictions) and unmodifiable (age, sex, race, genetic factors). Among the unmodifiable risk factors, the most important is age [31]. The risk of stroke increases exponentially with age in both men and women. It is estimated that the incidence of stroke doubles with each decade of life after the age of 55 and affects as many as 5% of people over the age of 65 [32]. It is known that the majority of modifiable risk factors, such as hypertension, atrial fibrillation, hyperhomocysteinemia (HHcy), and inflammatory processes (e.g. periodontal disease, infections, increased hs-CRP), are more common in the elderly. The effect of aging on the cardiovascular system is cumulative [33]. Atrial fibrillation occurs in 5% of individuals aged 70 or above and is a cause of one quarter of stroke incidents in patients at the age of 80. The risk of stroke can be

The serum total homocysteine (Hcy) concentration is another independent risk factor of ischemic stroke in the elderly, as it correlates with thrombosis. The population attributable risk of stroke incidence in high Hcy levels (>17.4 μmol/L) changes with age and was estimated at 21 and 26% for age 40–59 years (men and women, respectively) and at 35 and 37% for individuals over 60 years of age (men and women, respectively) [35]. HHcy (level of Hcy more than 15.0 μmol/L) promotes the development of atherosclerosis. Clinical studies have shown that HHcy has a toxic impact on both the vascular and nervous systems and may be observed not only in stroke but also in PD, mild cognitive impairment (MCI), and epilepsy [36]. Supplementation of folate and vitamin B12 is essential in the treatment of HHcy, but

Two thirds of the population aged over 65 years suffers from hypertension [31]. Hypertension has been proven to increase fourfold the risk of stroke; as the blood pressure increases, so does the probability of suffering stroke. Fortunately, a blood pressure reduction of about 10/5 mmHg decreases the risk of stroke by about 35% [33]. Hypertension is often linked with obesity, abnormalities in lipid profile, and type 2 diabetes. Together, these comorbidities

greater oxidative stress and worsen the WM injury upon ischemia [21].

*3.1.2. Senescence, civilization diseases, and stroke*

decreased by antithrombotic therapies [34].

folate alone does not reduce the risk of stroke [37].

contribute to atherosclerosis and thromboembolic stroke.

[28, 29].

68 Senescence - Physiology or Pathology

Disturbances in the lipid profile should be regularly reviewed and treated as necessary, as they are another contributor to stroke. Independent studies have shown that high levels of total cholesterol (in the 240–270 mg/dL range) [41–43] and triglycerides [44, 45] as well as a low level of high-density lipoproteins (HDL, up to 35 mg/dL) [43, 46, 47] increase the incidence of ischemic stroke. According to the Heart Protection Study, statin therapy in the elderly group can reduce the risk of a first stroke by 29% [48]. Another side of the coin is obesity, defined as body mass index (BMI) >30 kg/m2 , or abdominal obesity, defined by a waist circumference >102 cm (men) and >88 cm (women) [33]. It is known that abdominal obesity is a stronger predictor of stroke than BMI [49].

Moreover, it has been observed that infection with some pathogens may cause acute stroke within a week; these pathogens are *Chlamydophila pneumoniae*, *Haemophilus influenzae*, *Mycoplasma pneumoniae*, *Helicobacter pylori*, Cytomegalovirus, Epstein-Barr virus, and Herpes simplex virus types I and II. This occurs due to the activation of leukocytes and increased tendency for thrombosis at the site of atherosclerotic plaque. Because of immune deficiencies, the elderly are more susceptible to infections and, therefore, to postinfection complications [33].

It should be mentioned that controlling and regulating the modifiable risk factors is extremely important in stroke prevention. Older people tend to pay more attention to stroke avoidance. Epidemiological studies performed in the USA assumed that, in the last decade, the stroke death rate declined more in subjects after the age of 65 than in the younger population [30].

Stroke is a heterogeneous syndrome, with possible genetic background. Single-gene diseases may cause rare, hereditary disorders for which stroke may be a primary manifestation. Recent studies suggest that common and rare genetic polymorphisms that induce diabetes, hyperlipidemia, or hypertension may activate specific stroke mechanisms causing dangerous angiopathies [50]. For instance, the genetic variation at chromosome 16 (locus q24.2) had been shown to induce small vessel stroke. Traylor et al. using modern GWAS method have found that rare variant rs12445022 in *ZCCHC14* gene may induce small vessels dysfunction, thus greatly increase the risk of stroke [51]. Another interesting genetic factor studied in stroke is a polymorphism in *BDNF* gene (rs6265), which results in amino acid change (Val→Met) in the precursor protein, causing a reduction in brain-derived neurotrophic factor (BDNF) activity, which plays a role in rehabilitation after stroke. The studies show that concentrations of BDNF were decreased in acute ischemic-stroke patients compared to controls. BDNF signaling is dependent on the genetic variation which could affect an individual's response to recovery after stroke. The rs6265 polymorphism may also affect the risk of ischemic stroke, post-stroke outcomes and the efficacy of the various forms of rehabilitation [52] (**Figure 1**).

#### **3.2. Epilepsy**

Epilepsy is one of the most common neurological diseases, with approximately 50 million sufferers worldwide. Epilepsy is a collection of somatic, vegetative, and/or mental symptoms, which may be the result of morphological or metabolic changes in the brain. Although the disease has a chronic character and had long been thought to be connected with events in infancy or childhood, epidemiological studies have revealed that there is pronounced incidence of epilepsy in people over 65 years of age [53, 54]. To date, many various causative factors have been associated with epilepsy. However, the etiology of the disease remains unknown in 65–75% of patients [55].

Epilepsy that develops after the age of 60 is symptomatic in the vast majority, although generalized epilepsy may also rarely manifest in the elderly [56]. Epileptic seizures are often underdiagnosed in that age group. The symptoms are usually recognized as memory disorders or mental changes of uncertain origin [57]. Risk factors for epilepsy and seizure etiology vary with age. The most common mechanism of pathogenesis of new-onset epilepsy and seizures in the elderly may be associated with cerebrovascular diseases (CVDs), neuron degenerative disorders, intracerebral tumors, and traumatic head injury [58, 59].

#### *3.2.1. Epilepsy and cerebrovascular diseases*

CVDs account for 30–50% of all identified causes of epilepsy in the elderly [60, 61]. Epilepsy attacks may be affected by a stroke and may occur immediately after an ischemic event or be delayed. Seizures may also be the first clinical manifestation of brain ischemia or hemorrhage, increasing the risk to develop epilepsy within the first year after the vascular episode by 20 times. The study of Alberti et al. [62] showed that hemorrhagic transformation of an ischemic stroke is a predictive factor for epilepsy and may also be related to the disruption of the BBB [63]. Numerous genetic factors may be engaged in epileptogenesis. According to Yang et al. [64], mitochondrial aldehyde dehydrogenase 2 (ALDH2, encoded by the *ALDH2* gene) has a protective effect in CVDs. Nevertheless, allele A of the rs671 polymorphism in the *ALDH2* gene was shown to be connected with post-stroke epilepsy due to decreased activity of ALDH2 leading to accumulation of the potential ALDH2 substrate—4-hydroxynonenal (4-HNE), considered to be a specific marker of oxidative stress and involved in myocardial and cerebral ischemia. Zhang et al. [65] suggest that the T allele of the -1C/T polymorphism in the *CD40* gene may be associated with susceptibility to poststroke epilepsy (**Figure 1**). The proposed mechanism includes raised plasma concentrations of sCD40L, which is involved in the inflammatory response. Moreover, poststroke epileptogenesis was shown to be associated with lifestyle factors (alcohol use), acute metabolic disturbances (hyperglycemia), non-CNS comorbidities (type 1 or 2 diabetes, hypertension, coronary heart disease or myocardial infarction, as well as peripheral infections), CNS diseases (early seizures, depression or use of antidepressants, dementia), and pharmacotherapy (statins) [66].

#### *3.2.2. Epilepsy due to head trauma*

Another causative factor of epilepsy in the elderly may be head trauma. Due to an increased likelihood of imbalance, older people are more prone to falls causing head injuries. Acute events, such as skull fractures, subdural hematoma, brain contusion, accidental injury, concussion, or loss of consciousness, were shown to be associated with increased risk of posttraumatic epilepsy [67]. Moreover, various genetic factors were shown to be associated with head injury as a risk factor for late posttraumatic seizures. Diaz-Arrastia et al. [68] showed that carriers of the pathogenic *APOE* E4 allele were more likely to develop epilepsy after suffering acute head trauma (**Figure 1**).

#### *3.2.3. Epilepsy due to brain tumor*

**3.2. Epilepsy**

70 Senescence - Physiology or Pathology

Epilepsy is one of the most common neurological diseases, with approximately 50 million sufferers worldwide. Epilepsy is a collection of somatic, vegetative, and/or mental symptoms, which may be the result of morphological or metabolic changes in the brain. Although the disease has a chronic character and had long been thought to be connected with events in infancy or childhood, epidemiological studies have revealed that there is pronounced incidence of epilepsy in people over 65 years of age [53, 54]. To date, many various causative factors have been associated with epilepsy. However, the etiology of the disease remains unknown in 65–75% of patients [55]. Epilepsy that develops after the age of 60 is symptomatic in the vast majority, although generalized epilepsy may also rarely manifest in the elderly [56]. Epileptic seizures are often underdiagnosed in that age group. The symptoms are usually recognized as memory disorders or mental changes of uncertain origin [57]. Risk factors for epilepsy and seizure etiology vary with age. The most common mechanism of pathogenesis of new-onset epilepsy and seizures in the elderly may be associated with cerebrovascular diseases (CVDs), neuron degenerative

CVDs account for 30–50% of all identified causes of epilepsy in the elderly [60, 61]. Epilepsy attacks may be affected by a stroke and may occur immediately after an ischemic event or be delayed. Seizures may also be the first clinical manifestation of brain ischemia or hemorrhage, increasing the risk to develop epilepsy within the first year after the vascular episode by 20 times. The study of Alberti et al. [62] showed that hemorrhagic transformation of an ischemic stroke is a predictive factor for epilepsy and may also be related to the disruption of the BBB [63]. Numerous genetic factors may be engaged in epileptogenesis. According to Yang et al. [64], mitochondrial aldehyde dehydrogenase 2 (ALDH2, encoded by the *ALDH2* gene) has a protective effect in CVDs. Nevertheless, allele A of the rs671 polymorphism in the *ALDH2* gene was shown to be connected with post-stroke epilepsy due to decreased activity of ALDH2 leading to accumulation of the potential ALDH2 substrate—4-hydroxynonenal (4-HNE), considered to be a specific marker of oxidative stress and involved in myocardial and cerebral ischemia. Zhang et al. [65] suggest that the T allele of the -1C/T polymorphism in the *CD40* gene may be associated with susceptibility to poststroke epilepsy (**Figure 1**). The proposed mechanism includes raised plasma concentrations of sCD40L, which is involved in the inflammatory response. Moreover, poststroke epileptogenesis was shown to be associated with lifestyle factors (alcohol use), acute metabolic disturbances (hyperglycemia), non-CNS comorbidities (type 1 or 2 diabetes, hypertension, coronary heart disease or myocardial infarction, as well as peripheral infections), CNS diseases (early seizures, depression or use of

Another causative factor of epilepsy in the elderly may be head trauma. Due to an increased likelihood of imbalance, older people are more prone to falls causing head injuries. Acute events,

disorders, intracerebral tumors, and traumatic head injury [58, 59].

antidepressants, dementia), and pharmacotherapy (statins) [66].

*3.2.2. Epilepsy due to head trauma*

*3.2.1. Epilepsy and cerebrovascular diseases*

Epileptic seizures are common symptoms of brain tumors (BTs) in 20–40% of patients. The study of de Assis et al. [69] demonstrates that BTs related to epilepsy include primary CNS lymphoma, meningioma, anaplastic ependymoma, and anaplastic astrocytoma. The highest incidence of epilepsy occurs in low-grade tumors like primary astrocytoma, oligodendroglioma, mixed astrocytoma WHO grade I and II, as well as meningiomas. It seems that the incidence of seizures is inversely correlated to the grade of the malignancy. Age is a risk factor for increased mortality in those BT patients who develop seizures. Epilepsy attacks also appear in 67% of patients with melanocytic brain metastases, in 48% patients with lung cancer metastases, in 33% patients with breast cancer, and in 55% of patients in whom the primary cancer type was unknown. Unfortunately, BT-related epilepsy is characterized by pharmacological resistance [69, 70].

#### *3.2.4. Biochemical factors in epilepsy*

Hcy seems to have additional and interesting significance for the development of epilepsy. As stated earlier, HHcy has demonstrated an association with several disorders, including epilepsy [71]. High Hcy concentration has been shown to be related to numerous factors, including lifestyle (smoking, high consumption of alcohol, caffeine), age (due to the weakening of the excretory function of the kidneys, malabsorption of vitamin B12 in the stomach, hormonal disorders, e.g. in women during and after menopause), comorbid diseases, pharmacotherapy (e.g. antidiabetic drugs or fibrates), or unbalanced diet (deficiency of vitamin B12 or folic acid) [72–75]. Moreover, Schwaninger et al. [76] demonstrated that prolonged treatment with antiepileptic drugs (AEDs) may increase the plasma concentration of Hcy. On the other hand, the authors were not able to conclude whether the HHcy in epilepsy patients was a sole effect of pharmacotherapy or a causative factor of the disease.

Seizures may also occur in metabolic disorders, because of multiple comorbidities and polypharmacy. There should be a high index of suspicion for electrolyte imbalance, especially hyponatremia and hypoglycemia, in this group of patients. Other metabolic disorders, such as hyperglycemia and uremic or hepatic encephalopathy, are less specific to this age group [77]. The role of alcohol appears to be less important in the elderly than in young adults, but should not be neglected [78], as it may intensify the number of calcium channels and promote seizure activity by increasing the concentration of neurotransmitters [79].

#### *3.2.5. Epilepsy in degenerative diseases*

AD is a significant risk factor of epilepsy in the elderly. Imfeld et al. [80] suggested that patients with a longer history of AD (≥3 years) may have a higher risk of developing seizures or epilepsy than those with a shorter duration of disease. Similar results were presented by Amatniek et al. [81], who observed that the incidence of seizures increased as the disease progressed; the cumulative incidence over 7 years was 8%. The risk of seizure onset is higher in AD patients with hyperlipidemia and severe dementia [82]. The epileptogenetic mechanism has not yet been elucidated in patients with neurodegeneration. It might be associated with β-amyloid (Aβ) deposition, neuronal loss and gliosis, and antidementia drugs [83, 84]. High levels of Aβ are considered a cause of AD, but they are also related to synaptic activity. Aβ serves as a potent regulator of synaptic transmission, causing presynaptic facilitation at relatively low Aβ concentrations and postsynaptic depression with higher Aβ levels. The modulation of synaptic transmission has an important effect on producing epileptiform activity [85].

Another degenerative disorder which may potentially induce seizures is MS, a chronic disease of the CNS. MS usually occurs in young adults (aged 20 to 40 years). However, 1.1–12% of MS patients experience the first symptoms of the disease after the age of 50 [86]. The prevalence of seizures among MS patients was shown to be higher than the general population, which may indicate the relationship between seizures and MS [87]. One possible explanation is that MS lesions act as epileptogenic sites [88]. Generally, a small fraction (2.5%) of MS patients develop seizures [89]. The study of epilepsy in the elderly among MS patients is inconclusive, but clinicians should be aware of the risk of epilepsy in people with MS [88].

#### **3.3. Aging and dementia**

Dementia—as a form of cognitive decline—is strongly associated with old age. Almost 10% of those older than 65 years suffer from some kind of memory impairment. The most common causes of dementia include AD and vascular dementia (VaD). The prevalence of dementia increases with age, affecting nearly 50% of the population over 85 years of age. Dementia is a progressive disorder, finally leading to severe disability and complete dependence of sufferers on caregivers [90].

#### *3.3.1. Vascular dementia*

VaD was initially understood to be an advanced effect of repetitive brain lesions [91]. The development of brain imaging techniques revealed that silent ischemic lesions appeared to be quite common and later became known as a significant cause of dementia [92, 93]. Epidemiological studies have shown that vascular dysfunction causes 10–20% dementia cases [94, 95]. The frequency of VaD in the general population varies from 1.2 to 4.2% of individuals over 65 years, depending on the methodological approach [94, 96]. The prevalence of VaD is strongly connected with age. A Canadian study described that frequency of vascular cognitive impairment increased from 2.0% in those aged 65 to 74 years to 13.7% in those over 85 years of age [97]. A meta-analysis from 1998, synthesizing the results of 23 studies from around the world, confirmed the trend of increasing incidence of VaD in senescence [98]. Increasing longevity in many populations has also increased the importance and burden of vascularrelated memory deficits. A long-term survey demonstrated that the incidence of post-stroke dementia between 1984 and 2001 had doubled [99].

Several studies have analyzed the risk factors, other than age, of CNS vascular lesions. They identified hypertension, heart disease, diabetes with insulin resistance, and dyslipidemia to be related to an increased risk to develop VaD. It is important to note that the results obtained by different authors occasionally contradict each other [100–109]. The cluster of cardiovascular risk factors, also called "metabolic syndrome," that include dyslipidemia, obesity, hypertension, and insulin resistance, has also been shown to be associated with VaD [110, 111]. Additionally, patients with fully symptomatic metabolic syndrome obtained lesser scores in neuropsychological testing [112]. Moreover, HHcy, previously associated with vascular diseases and stroke, was shown to be associated with VaD [113].

Many studies have also demonstrated that a symptomatic stroke incident, occurring mostly in the elderly, may inflict memory deficits in 6 to 32% of patients, depending on the followup period (3 months—20 years) [114–128]. MCI preceding stroke increases the probability of post-stroke dementia [129, 130], and memory decline seemed to progress more rapidly with later stroke episodes [131]. Similarly, recurrent stroke was associated with greater cognitive impairment when compared with patients with a single vascular incident [122] (**Figure 1**).

#### *3.3.2. Alzheimer's disease*

or epilepsy than those with a shorter duration of disease. Similar results were presented by Amatniek et al. [81], who observed that the incidence of seizures increased as the disease progressed; the cumulative incidence over 7 years was 8%. The risk of seizure onset is higher in AD patients with hyperlipidemia and severe dementia [82]. The epileptogenetic mechanism has not yet been elucidated in patients with neurodegeneration. It might be associated with β-amyloid (Aβ) deposition, neuronal loss and gliosis, and antidementia drugs [83, 84]. High levels of Aβ are considered a cause of AD, but they are also related to synaptic activity. Aβ serves as a potent regulator of synaptic transmission, causing presynaptic facilitation at relatively low Aβ concentrations and postsynaptic depression with higher Aβ levels. The modulation of synaptic transmission has an important effect on producing epileptiform

Another degenerative disorder which may potentially induce seizures is MS, a chronic disease of the CNS. MS usually occurs in young adults (aged 20 to 40 years). However, 1.1–12% of MS patients experience the first symptoms of the disease after the age of 50 [86]. The prevalence of seizures among MS patients was shown to be higher than the general population, which may indicate the relationship between seizures and MS [87]. One possible explanation is that MS lesions act as epileptogenic sites [88]. Generally, a small fraction (2.5%) of MS patients develop seizures [89]. The study of epilepsy in the elderly among MS patients is inconclusive,

Dementia—as a form of cognitive decline—is strongly associated with old age. Almost 10% of those older than 65 years suffer from some kind of memory impairment. The most common causes of dementia include AD and vascular dementia (VaD). The prevalence of dementia increases with age, affecting nearly 50% of the population over 85 years of age. Dementia is a progressive disorder, finally leading to severe disability and complete dependence of suffer-

VaD was initially understood to be an advanced effect of repetitive brain lesions [91]. The development of brain imaging techniques revealed that silent ischemic lesions appeared to be quite common and later became known as a significant cause of dementia [92, 93]. Epidemiological studies have shown that vascular dysfunction causes 10–20% dementia cases [94, 95]. The frequency of VaD in the general population varies from 1.2 to 4.2% of individuals over 65 years, depending on the methodological approach [94, 96]. The prevalence of VaD is strongly connected with age. A Canadian study described that frequency of vascular cognitive impairment increased from 2.0% in those aged 65 to 74 years to 13.7% in those over 85 years of age [97]. A meta-analysis from 1998, synthesizing the results of 23 studies from around the world, confirmed the trend of increasing incidence of VaD in senescence [98]. Increasing longevity in many populations has also increased the importance and burden of vascularrelated memory deficits. A long-term survey demonstrated that the incidence of post-stroke

but clinicians should be aware of the risk of epilepsy in people with MS [88].

activity [85].

72 Senescence - Physiology or Pathology

**3.3. Aging and dementia**

ers on caregivers [90].

*3.3.1. Vascular dementia*

dementia between 1984 and 2001 had doubled [99].

AD is the most common form of dementia in older adults [132]. AD is a progressive incurable neurodegenerative disease where aging is the primary risk factor. AD may be divided into two main clinical subtypes: familial AD (FAD) characterized by early onset (before 65 years of age) and, frequently, the presence of mutations in the *APP*, *PSEN1*, and *PSEN2* genes. This genetic triad is responsible for nearly half of the FAD cases seen [133]. However, mutations in these genes occur very rarely in the human population. Subsequently, the majority (90%) of AD cases are sporadic (SAD) and manifest mostly in patients over 65 years of age. The multifactorial character of the disease makes it extremely difficult to determine a causative factor for SAD [134]. To date, nearly 700 genes have been associated with AD, although the most investigated risk factor for SAD remains the E4 allele of the *APOE* gene [90, 135, 136].

The diagnosis of probable AD is based on clinical criteria [137], however, the disease may be diagnosed with certainty only after death, by histopathologic study of the brain, revealing characteristic lesions: Aβ plaques and neurofibrillary tangles (NFTs) formed by hyperphosphorylated protein tau. Aβ is formed via pathologic cleavage of (amyloid precursor protein (APP), encoded by the *APP* gene) by β- and γ-secretases (encoded by the *BACE* and *PSEN* genes, respectively). The appearance of Aβ plaques and NFTs seems to be one of the causes for neurodegeneration: the morphological and functional loss of neurons and synapses, as well as excessive neuroinflammatory processes occurring in AD brains. Martin et al. [138] showed that aging and Aβ pathology may activate similar receptors on microglia and monocyte-derived macrophages. Moreover, carriers of the *APOE* E4 allele and rare variants in other genes, such as *HLA-DRB5/DRB1*, *INPP5D*, *MEF2C*, *CR1*, *CLU,* and *TREM2*, may exhibit an even stronger activation of microglia than noncarriers [139]. This explains why older patients with unfavorable genetic variants are more prone to excessive neuroinflammatory responses leading to neuronal loss and dementia.

The neurons mostly affected by AD are cells expressing acetylcholine (ACh) receptors, also called "cholinergic neurons" (AChN). Loss and degeneration of this type of cells is another hallmark of dementia and occurs gradually with age and the course of the disease [140]. The age-related degeneration of AChN leads to decreasing levels of ACh in the brain. ACh has been proven to be the neurotransmitter that is most reduced in the majority of AD patients [141]. It seems that genetic factors, such as the presence of the pathogenic *APOE* E4 allele, may also significantly influence the production and release of ACh. The study on transgenic mice expressing human *APOE* indicated that age-related decrease in ACh levels released by the hippocampus was more prominent in mice with human *APOE* E4/E4 than in mice with *APOE* E3/E3 variants [142] (**Figure 1**).

The main cholinergic structure of the brain is the basal forebrain (BF), the underlying neurodegeneration of which may be observed in advanced aging as well as in the early phase of AD and other dementias [143]. BF degeneration occurs due to a decrease in cholinergic neurotransmission and a reduction in the amount of ACh in synaptic clefts, followed by a loss of cholinergic receptors, finally resulting in AChN death. This process, according to the "cholinergic deficit hypothesis," results in behavioral and cognitive impairment, especially learning difficulties, which advance rapidly with age [144].

It is worth noting that in AD, similarly to VaD and stroke, the concentration of Hcy may be increased and so may inflict damage to the vasculature, thereby leading to decreased blood flow and inefficient nutrient delivery to neurons. Subsequently, the starving cells become more prone to ROS and apoptosis. HHcy is also associated with a decrease of the glutathione pool, the deficiency of which results in the deterioration of protection mechanisms from free radicals, further contributing to neuronal loss and neurodegeneration [145].

#### **3.4. Parkinson's disease and aging**

PD is an age-related neurodegenerative disease characterized by resting tremor, rigidity, and bradykinesia. The number of PD patients increases over the years due to population aging. The exact pathomechanism of PD remains unclear, but it is known that the degeneration process starts many years before the occurrence of clinical symptoms. The hallmark of PD is dopaminergic (DA) neuron death in the substantia nigra (SN), which is a result of Lewy body (LB) formation due to impairment of the ubiquitin-proteasome system and disturbances in the proteins alpha-synuclein (ASN) and Parkin [146, 147]. Molecular characteristic of PD include increased ROS production due to mitochondrial dysfunction and accompanied by decreased mitophagy [148], neuroinflammation and loss of neurotrophic factors [149, 150], exposure to (1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP)) or paraquat [151], exposure to trichloroethylene or polychlorinated biphenyls [152], iron (the level of which increase in the SN with age), copper, manganese [153, 154], or mutations in *PARK* genes [155]. Mitochondrial dysfunction is associated with aggregation of ASN, apoptosis, accumulation of damaged mitochondria, and changes in the activity of complex 1 [156]. A decline in mitochondrial function as well as inflammation and changes in DA metabolism are linked with the aging process.

Advancing age is the most important risk factor of developing PD. PD affects about 1% of the population over the age of 60 and 5% over the age of 85 [157]. It has been since 1987 that the loss of DA neurons progresses with aging, but the rate of the physiological process is slower than that seen in PD [158]. Moreover, LB may be present in elderly individuals without PD [159]. The aging brain is also more prone to stressor stimuli and generation of ROS, which results in the injury and eventual death of SN neurons. On the other hand, a decreased level or even loss of ROS scavengers, e.g. neuromelanin, in the PD brain may be a cause of DA neuron damage rather than an effect of this damage [157].

Many epigenetic mechanisms, such as changes in DNA methylation profile and histone modification, play an important role in aging and contribute to PD. The epigenetic clock can be characterized just by measuring the DNA methylation pattern. Interestingly, PD patients represent an increased acceleration in aging when compared to controls of the same age [160]. Hypomethylation of *SNCA*, the gene encoding ASN, leads to an increased expression of ASN and has been observed in the SN of PD patients [161]. ASN can also influence histone acetylation (a feature of transcriptionally active genes) and enhance ASN fibrillation [162].

During normal aging, the functional decline of the BBB can cause neuroinflammation and the development of neurodegenerative diseases [163]. Disturbances in BBB permeability observed in the senescence process may be involved in the genesis of WM lesions, which may also affect the efficacy of treatment. In the course of aggregation of ASN in PD, elevated ROS production and increased levels of proinflammatory cytokines or toxic agents may intensify disruptions of the BBB [164].

HHcy observed in PD may be involved in the disease pathogenesis; however, the exact mechanism of interaction remains unrecognized. Both HHcy and age are risk factors for developing dementia in PD patients [165]. Treatment with L-dopa may be responsible for HHcy in individuals with PD [166]. In those patients, Hcy is formed in the methylation of L-dopa via catechol-O-methyltransferase (COMT) [167]. Other side effects of L-dopa at the molecular level include increased oxidative stress, as well as altered concentrations of catecholamines and apoptotic proteins [147]. Damage of DA neurons due to oxidative stress may be enhanced by elevated Hcy (**Figure 1**). A study performed on mice has shown that elevated Hcy increases the sensitivity to MPTP and developing PD-like dysfunction [168].

#### **3.5. Brain tumors in the elderly**

The neurons mostly affected by AD are cells expressing acetylcholine (ACh) receptors, also called "cholinergic neurons" (AChN). Loss and degeneration of this type of cells is another hallmark of dementia and occurs gradually with age and the course of the disease [140]. The age-related degeneration of AChN leads to decreasing levels of ACh in the brain. ACh has been proven to be the neurotransmitter that is most reduced in the majority of AD patients [141]. It seems that genetic factors, such as the presence of the pathogenic *APOE* E4 allele, may also significantly influence the production and release of ACh. The study on transgenic mice expressing human *APOE* indicated that age-related decrease in ACh levels released by the hippocampus was more prominent in mice with human *APOE* E4/E4 than in mice with *APOE*

The main cholinergic structure of the brain is the basal forebrain (BF), the underlying neurodegeneration of which may be observed in advanced aging as well as in the early phase of AD and other dementias [143]. BF degeneration occurs due to a decrease in cholinergic neurotransmission and a reduction in the amount of ACh in synaptic clefts, followed by a loss of cholinergic receptors, finally resulting in AChN death. This process, according to the "cholinergic deficit hypothesis," results in behavioral and cognitive impairment, especially

It is worth noting that in AD, similarly to VaD and stroke, the concentration of Hcy may be increased and so may inflict damage to the vasculature, thereby leading to decreased blood flow and inefficient nutrient delivery to neurons. Subsequently, the starving cells become more prone to ROS and apoptosis. HHcy is also associated with a decrease of the glutathione pool, the deficiency of which results in the deterioration of protection mechanisms from free

PD is an age-related neurodegenerative disease characterized by resting tremor, rigidity, and bradykinesia. The number of PD patients increases over the years due to population aging. The exact pathomechanism of PD remains unclear, but it is known that the degeneration process starts many years before the occurrence of clinical symptoms. The hallmark of PD is dopaminergic (DA) neuron death in the substantia nigra (SN), which is a result of Lewy body (LB) formation due to impairment of the ubiquitin-proteasome system and disturbances in the proteins alpha-synuclein (ASN) and Parkin [146, 147]. Molecular characteristic of PD include increased ROS production due to mitochondrial dysfunction and accompanied by decreased mitophagy [148], neuroinflammation and loss of neurotrophic factors [149, 150], exposure to (1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP)) or paraquat [151], exposure to trichloroethylene or polychlorinated biphenyls [152], iron (the level of which increase in the SN with age), copper, manganese [153, 154], or mutations in *PARK* genes [155]. Mitochondrial dysfunction is associated with aggregation of ASN, apoptosis, accumulation of damaged mitochondria, and changes in the activity of complex 1 [156]. A decline in mitochondrial function as well as inflammation and changes in DA metabolism are linked with

radicals, further contributing to neuronal loss and neurodegeneration [145].

E3/E3 variants [142] (**Figure 1**).

74 Senescence - Physiology or Pathology

**3.4. Parkinson's disease and aging**

the aging process.

learning difficulties, which advance rapidly with age [144].

Another type of CNS disease, manifesting particularly in the elderly, are brain tumors, classified according to WHO criteria to four grades, with grade IV considered most malignant [169]. In adults, the most prevalent type of primary brain tumor is malignant glioma (MGs), with the highest incidence between 40 and 65 years of age. The majority of MGs are sporadic, with ionizing radiation as the only known risk factor. The most common type of glioma is glioblastoma multiforme (GBM), qualified as a WHO grade IV astrocytic tumor, and constituting about half of all MGs with the highest incidence in the elderly, between 70 and 90 years of age [170–172]. Old age is a negative prognostic factor in GBM [173]. One of the most significant characteristics of GBM is an increasing prevalence with age; thus, due to an increasing median length of life, the number of patients is expected to grow in the coming decades. Other types of brain tumors common in the elderly are primary CNS lymphomas (PCNSLs) and meningiomas [174].

GBM comprise a rather heterogenic group of neoplasms, with two major types: primary glioblastomas (85–90%) and secondary GBMs that arise from low-grade astrocytomas (10–15%) [175]. Although both types are indistinguishable under the microscope, they appear to differ genetically. Genetically, primary GBMs exhibit by amplification and mutation of the *EGFR* gene, a lack of heterozygosity on chromosome 10q, inactivation of the *PTEN* homolog gene, and only rare occurrence of mutations in the *IDH* and *TP53* genes. Conversely, the genetics of secondary GBM are characterized by mutations in the *IDH* and/or *TP53* genes, as well as platelet-derived growth factor receptor activation [176]. A gene expression-based GBM classification was established by The Cancer Genome Atlas (TCGA) Research Network in 2010. The authors distinguished four subtypes of GBM. Characteristics that differentiate the subtypes at most were indicated as follows: proneural GBM has alterations of the *PDGFRA* gene and point mutations of *IDH1*, classical GBM has *EGFR* aberrations, and mesenchymal demonstrates GBM aberrations in *NF1*. The fourth subtype, neural GBM, is characterized by the expression of neuron markers such as *NEFL, GABRA1, SYT1*, and *SLC12A5*. Each subtype of GBM differs in its sensitivity to radiotherapy and chemotherapy, thus determining the genetic type of a surgically removed or biopsied lesion could protect patients against unnecessary ineffective therapy [177].

Unfortunately, GBMs are mostly incurable in the elderly, with most of these patients surviving less than 6 months [171]. Diagnosis of primary brain tumors in old age can be further complicated and delayed due to nonspecific symptoms that can be masked by physical and cognitive changes observed in the normal aging process [178]. Moreover, elderly patients are an underrepresented group in many clinical trials [179]. The literature data indicate that, at the close of the twentieth century, the chances of receiving a treatment, be that surgery and/ or radiotherapy, were decreasing as the patient got older. Treatment mostly took place for 82% of patients younger than 65 years of age, whereas only 47% of people older than 65 years and merely 25% of patients older than 75 were subjected to any kind of therapy. Additionally, patients treated with radiotherapy and/or surgery had a significantly lower survival rate as they crossed the age border of 60 years [180].

Although pathological processes differ depending on the glioma subtype, there is a common core of molecular events. Growth factor receptor tyrosine kinases cause downstream signaling by activation of extracellular signal-regulated kinases (ERK) or protein kinase B (Akt) pathways. Lack of p53 activation is followed by the loss of the ability to activate DNA repair processes and cell death by apoptosis. An additional adverse characteristic occurring in GBM is that the cells provoke the secretion of vascular endothelial growth factor (VEGF), which is responsible for angiogenesis. The secretion of VEGF by GBM results in vascularization of the tumor, elevation of capillary permeability of the BBB, and creation of extracellular edema [181]. Finally, due to vasculature growth, there is progression of tumor invasion [182].

Although these brain tumors are very invasive, it is important to note that, depending on the tumor subtype, they may be effectively treated in elderly patients by maximally safe surgical resection, radiotherapy, and/or chemotherapy with Temozolomide, a drug which is especially preferable as first-line treatment in patients with the *MGMT* promoter [179, 183]. In addition to radiotherapy and/or Temozolomide, Bevacizumab (BV, Avastin®) is being studied for the treatment of brain tumors. BV is a humanized IgG1 monoclonal antibody targeting VEGF with high affinity and inactivating the growth factor. Thus, BV promotes tumor regression and helps to decrease the risk of cerebral edema [184]. Interestingly, it has been demonstrated that, although old age is a negative prognostic factor, BV was more effective in older patients (≥55 years of age); those treated with BV remained in better health longer and used lower doses of steroids. These findings were in line with the study published by Nghiemphu et al. [185], who demonstrated that expression of VEGF was 1.4-fold higher in older patients than in younger subjects, and so inhibition of VEGF could give a more positive outcome in these patients.

The increased incidence of brain tumors in the elderly may also be due to decreased efficiency of repair mechanisms. Inactivation of genes involved in DNA repair, such as the above-mentioned *TP53* and *MGMT*, may advance with age. This may lead to increased accumulation of DNA damage, in turn resulting in further activation of proto-oncogenes and silencing of tumor suppressor genes. Such changes, inflicted either by mutation or epigenetic changes, may cause additional destabilization of cellular repair mechanisms, increasing the susceptibility to ROS and spontaneous mutagenesis, and triggering the positive feedback loop of neoplasia [186] (**Figure 1**).
