**7. Wernicke-Korsakoff syndrome and alcohol-related dementia**

behavior, and/or speech and language disorder. FTD is less common than the before-mentioned dementias. Among these clinical presentations, Pick's disease is the most common type of presentation due to damage on the frontal and temporal lobes characterized by behavior and personality (apathy) disorders, which usually precede memory loss and dysarthria.

Sometimes, clinical manifestations such as behavioral and personality changes, psychomotor slowness, and decline in executive functions can be seen in both iNPH and behavioral FTD (BvFTD) at the same time and indistinctly [110], and other neuropsychiatric symptoms are frequently detected in both diseases [111, 112] including mania, aggression, disturbances of impulse control, obsessive-compulsive disorder, and psychosis, including paranoia and hallucinations [113–115]. It is well known that personality changes, impulsive behavior, apathy, decreased social interest, and executive dysfunctions, including impairment in solving problems and inhibitory control, are typical manifestations of BvFTD [116]. Almost one-half of patients with frontotemporal lobe degeneration (FTLD) have a familial component, and some authors have found mutations in microtubule-associated protein tau, progranulin, and expanded hexanucleotide repeat in a noncoding region of the chromosome 9 open reading frame 72 (C9ORF72) as a common cause of the problem [117]. The expansion of C9ORF72 as a major genetic cause of FTLD has been confirmed by others [118]. On the other hand, Majounie et al. [119] reported that the C9ORF72 repeat expansion is the highest in Finland and is pres-

Amyotrophic lateral sclerosis (ALS) is the most common motor presentation associated with the *C9ORF72* expansion, but extrapyramidal symptoms have also been documented [120–122]. Fifty percent of patients with ALS exhibit frontal executive deficits during the course of their

To distinguish BvFTD from iNPH can be a very difficult task considering that both have similar clinical manifestations. Extrapyramidal clinical manifestations of parkinsonism are predominant in patients with BvFTD [117]. Apart from disorder of gait, other remarkable symptoms of iNPH are balance disturbances and psychomotor slowing [123]. Deficits in

Some authors have confirmed in large studies that the prevalence on FTD is 15 to 22/100,000 individuals [124, 125]. *The most prevalent age is among 60–69 years old with roughly 13% having onset when younger than age 50. Heavy genetic loading for FTD is the main cause of younger onset, with up to half of cases being familial and up to 40% autosomal dominant in nature* [99]*. Survival partially depends on the variant of FTD and ranges from 2 to 3 years after symptom onset when motor* 

A new of variant of FTD named phenocopy frontotemporal dementia (phFTD) has been described by Meijboom et al. recently [127]. It is an uncommon and poorly understood clinical syndrome characterized by similar clinical manifestations of BvFTD without abnormalities on MRI of the brain and without associated cognitive disorder. In contrast to phFTD, functional connectivity and white matter (WM) microstructural abnormalities have been observed in bvFTD. Some authors concluded that phFTD and bvFTD may belong to the same disease

disease representing the comorbidity of FTD-ALS and associated delusional disorder.

executive functions are core cognitive changes in both iNPH and BvFTD [116, 123].

*neuron symptoms are prominent and up to 12 years for the semantic dementia variant* [126].

ent in about 48% of familial FTLD.

204 Cognitive Disorders

spectrum.

Wernicke encephalopathy and Korsakoff syndrome [Wernicke-Korsakoff syndrome (WKS)] and alcohol-related dementia (ARD) are preventable, life-threatening neuropsychiatric syndromes resulting from thiamine deficiency mainly in patients with chronic alcoholism, anorexia nervosa or patients who have undergone bariatric surgery for obesity, chronic hepatic disease, immunodeficiency syndromes, nutritional deficiencies of any cause, metastatic carcinomas, hyperthyroidism, prolonged parenteral nutrition, hyperemesis gravidarum, longterm dialysis and diuretic therapy, among other causes, and clinically, patients' complaints about short-term memory, confusional states, and neuropsychiatry manifestations.

In most of our patients, WKS is an acute nutritional disorder characterized by the clinical triad of ophthalmoplegia, cerebellar disorder, and altered mental state secondary to neuronal loss and hemorrhagic lesions in the periaqueductal gray matter of the midbrain, the anterior thalamus, and hypothalamus.

Altered mental state includes abulia, inattentiveness, and progressive memory disturbance with progressive deterioration of level of consciousness until comatose state if no treatment is received.

Before ophthalmoplegia is established, the eye movement abnormalities begin with limitations of abduction or horizontal gaze, and gait ataxia progresses to inability to stand.

All patients presenting thiamine deficiency improve their symptoms rapidly when thiamine is replaced in a timely fashion. Sometimes, patients do not improve completely, and nystagmus, broad-based gait, and cognitive dysfunction including a selective amnestic disorder (Korsakoff syndrome) remain present.

Some authors said that during the acute symptomatic stage of Wernicke encephalopathy, there is an impairment of the glucose and oxidative cellular energy metabolism, leading to an imbalance of the ionic gradients across the cell membrane causing cytotoxic edema (intracellular water shift and cell injury) and vasogenic edema because of breakdown of the blood-brain barrier permeability with intravascular fluids penetrating into cerebral parenchymal [102]. Currently, it is well known that the MRI findings of cytotoxic or vasogenic edema are a remarkable information to detect WE in clinical settings and the presence of bilateral symmetrical signal hyperintensities in the periventricular region of the third ventricle, periaqueductal area, and hypothalamus confirms clinical impressions of WE [129, 130].

is, thiamine deficiency) or multiple factors (for example, neurotoxicity in combination with nutritional deficiencies). Attempts to clarify this have been hindered by confounding factors that often accompany the lifestyles of alcohol abusers, such as head injury, psychiatric and

Updated Information on Some Cognitive Disorders http://dx.doi.org/10.5772/intechopen.81826 207

According to neuroimaging and neuropathological findings, the main damage on the brain (in ethanol abuser) is prominent white matter loss (most remarkable in the prefrontal cortex, corpus callosum, and cerebellum) and neuronal loss in the hypothalamus, superior frontal association cortex, and cerebellum [154]. Nevertheless, the most susceptible region is the frontal lobe with documented evidence of markedly decreased neuron density, volume shrinkage, and abnormal glucose metabolism and perfusion [155]. Cholinergic neurotransmission in the basal forebrain, which plays a key role in attention, learning, and memory, also appears

Thiamine deficiency as a main cause for the development of ARD is another hypothesis, and ethanol abusers are at particularly high risk of thiamine deficiency due to poor dietary nutri-

Apart from deficient in thiamine, nicotinic acid, other B vitamins, and folate, alcoholics frequently develop neurological disorders associated with malnutrition, including cerebellar degeneration, amblyopia, polyneuropathy, and disorders affecting cognition. In pellagra, nicotinic acid deficiency results in skin, gastrointestinal, and mental abnormalities, which can progress to memory impairment, delusions, hallucinations, dementia, or delirium; hypertonus and startle myoclonus may be present. Symptoms usually improve following treatment

Some authors documented that ARD and WKS are different pathological process with overlapping clinical symptoms and both can be associated with ataxia and polyneuropathies [159]. One of the problems that we afford is the variety of available definitions for "standard drink" and its different meanings from country to country. While a standard drink in the United Kingdom contains 8 g of alcohol, a standard drink in Australia contains 10 g and in America and Japan contains 14 and 19.7 g, respectively [160], which affect the best comprehension of

As it was mentioned before, in the review made by Parson and Nixon in 1989, they found that consumption of five to six drinks per day (which, by US standards, equates to 70–84 g) over extended periods results in "cognitive inefficiencies," while consumption of 10 or more standard drinks a day manifests as moderate cognitive deficits equivalent to that found in individuals with diagnosed alcoholism [144], and studies conducted by Oslin and colleagues [161] suggested that consuming 35 standard drinks a week for men and 28 for women for 5-year history constitutes a sufficient level of neurotoxic burden to risk the development of ARD. However, other studies found that light to moderate ethanol intake *reduced* the likeli-

Damage of the brain seen on MRI is the biggest in female's alcoholic patients compared with the male's ones. Therefore, it seems to be that females are more susceptible than males to

adverse ethanol's effect, but their recovery after abstinence is better [171].

tion and also because of the direct effect of ethanol on thiamine metabolism [130].

other substance abuse comorbidities, and a higher rate of vascular risk factors [153].

to be damaged by prolonged ethanol intake [156, 157].

with nicotinic acid or nicotinamide [158].

the information delivered in the medical literature.

hood of dementia [162–170].

Dry beriberi happens when thiamine (vitamin B1) deficiency affects the central and peripheral nervous system, and wet beriberi happens when it damages the cardiovascular system. Ophthalmoplegia and nystagmus are present in 85% of patients with dry beriberi [131].

In developing countries, Wernicke syndrome is more likely to occur in nutritionally deficient alcoholics than in comparably deficient nonalcoholics, and thiamine deficiency in a nonalcoholic is more likely to produce wet beriberi with polyneuropathy than Wernicke syndrome [132]. However, several of Korsakoff's original patients had not been heavy drinkers [133].

Neuropathological report and MRI studies have confirmed that excessive and prolonged use of alcohol may lead to structural and functional damage that is permanent in nature [134].

Chronic and excessive drinking of alcohol can affect mentation in a different way, the commonest affected mechanism are systems of neurotransmitter by inhibition of excitatory glutamate receptors and by inhibition of γ-aminobutyric acid receptors [135]. In conclusion, alcohol intoxication has some mechanism to produce nervous system damage, including glutamate excitotoxicity and oxidative stress, which is increased by thiamine deficiency, hyperhomocysteinemia, and folate deficiency. Homocysteine functions as an agonist at glutamate NMDA receptors, increasing NMDA receptor transmission and the potential for excitotoxicity [136–138].

By neuropsychological investigations, Goldstein and Shelly [139] documented brain pathology in about 78% of patients with chronic alcoholism. However, there is debate about the relative contributions of the direct toxic effect of alcohol (ARD), and the impact of thiamine deficiency, to lasting damage [140]. The two main syndromes about alcohol-associated cognitive disorders are WKS and ARD. The last one has enjoyed little recognition as a discrete clinical entity because of lack of a distinct pathophysiological profile [141, 142].

Currently, it is well known that low-to-moderate ethanol consumption can reduce the risk of coronary syndrome and ischemic stroke due to the inhibitory effect of alcohol on platelet aggregation and the reduction of inflammatory markers and also by changing the lipid profile [143], while attempts to define a safe dose threshold for ethanol have been inconsistent. Parson and Nixon [144] reviewed 19 published studies addressing this issue and concluded that 5 or 6 "standard drinks" per day over extended periods resulted in "cognitive inefficiencies", that 7–9 drinks per day resulted in "mild cognitive deficits," and that 10 or more drinks per day caused impaired cognition of a degree encountered in frank alcoholics.

The neurotoxic effect of ethanol on memory and learning has been confirmed in animal studies [145, 146], and the abnormalities are found on the dentate granule cells, loss of hippocampal CA1 and CA3 pyramidal neurons, mossy fiber-CA3 synapses, pathological changes in neurons of cerebral cortex, hypothalamus, brainstem, loss of cholinergic neurons in the basal forebrain, and impaired pruning of redundant cortical synapses during early development [147–152].

Much of the debate surrounding ARD encompasses whether it is possible to have a dementia that is the direct result of ethanol neurotoxicity—a primary alcoholic dementia—or whether the clinical presentation of dementia represents another underlying pathology (that is, thiamine deficiency) or multiple factors (for example, neurotoxicity in combination with nutritional deficiencies). Attempts to clarify this have been hindered by confounding factors that often accompany the lifestyles of alcohol abusers, such as head injury, psychiatric and other substance abuse comorbidities, and a higher rate of vascular risk factors [153].

symmetrical signal hyperintensities in the periventricular region of the third ventricle, periaq-

Dry beriberi happens when thiamine (vitamin B1) deficiency affects the central and peripheral nervous system, and wet beriberi happens when it damages the cardiovascular system. Ophthalmoplegia and nystagmus are present in 85% of patients with dry beriberi [131].

In developing countries, Wernicke syndrome is more likely to occur in nutritionally deficient alcoholics than in comparably deficient nonalcoholics, and thiamine deficiency in a nonalcoholic is more likely to produce wet beriberi with polyneuropathy than Wernicke syndrome [132]. However, several of Korsakoff's original patients had not been heavy drinkers [133].

Neuropathological report and MRI studies have confirmed that excessive and prolonged use of alcohol may lead to structural and functional damage that is permanent in nature [134].

Chronic and excessive drinking of alcohol can affect mentation in a different way, the commonest affected mechanism are systems of neurotransmitter by inhibition of excitatory glutamate receptors and by inhibition of γ-aminobutyric acid receptors [135]. In conclusion, alcohol intoxication has some mechanism to produce nervous system damage, including glutamate excitotoxicity and oxidative stress, which is increased by thiamine deficiency, hyperhomocysteinemia, and folate deficiency. Homocysteine functions as an agonist at glutamate NMDA receptors, increasing NMDA receptor transmission and the potential for excitotoxicity [136–138].

By neuropsychological investigations, Goldstein and Shelly [139] documented brain pathology in about 78% of patients with chronic alcoholism. However, there is debate about the relative contributions of the direct toxic effect of alcohol (ARD), and the impact of thiamine deficiency, to lasting damage [140]. The two main syndromes about alcohol-associated cognitive disorders are WKS and ARD. The last one has enjoyed little recognition as a discrete

Currently, it is well known that low-to-moderate ethanol consumption can reduce the risk of coronary syndrome and ischemic stroke due to the inhibitory effect of alcohol on platelet aggregation and the reduction of inflammatory markers and also by changing the lipid profile [143], while attempts to define a safe dose threshold for ethanol have been inconsistent. Parson and Nixon [144] reviewed 19 published studies addressing this issue and concluded that 5 or 6 "standard drinks" per day over extended periods resulted in "cognitive inefficiencies", that 7–9 drinks per day resulted in "mild cognitive deficits," and that 10 or more drinks

The neurotoxic effect of ethanol on memory and learning has been confirmed in animal studies [145, 146], and the abnormalities are found on the dentate granule cells, loss of hippocampal CA1 and CA3 pyramidal neurons, mossy fiber-CA3 synapses, pathological changes in neurons of cerebral cortex, hypothalamus, brainstem, loss of cholinergic neurons in the basal forebrain, and impaired pruning of redundant cortical synapses during early development [147–152].

Much of the debate surrounding ARD encompasses whether it is possible to have a dementia that is the direct result of ethanol neurotoxicity—a primary alcoholic dementia—or whether the clinical presentation of dementia represents another underlying pathology (that

clinical entity because of lack of a distinct pathophysiological profile [141, 142].

per day caused impaired cognition of a degree encountered in frank alcoholics.

ueductal area, and hypothalamus confirms clinical impressions of WE [129, 130].

206 Cognitive Disorders

According to neuroimaging and neuropathological findings, the main damage on the brain (in ethanol abuser) is prominent white matter loss (most remarkable in the prefrontal cortex, corpus callosum, and cerebellum) and neuronal loss in the hypothalamus, superior frontal association cortex, and cerebellum [154]. Nevertheless, the most susceptible region is the frontal lobe with documented evidence of markedly decreased neuron density, volume shrinkage, and abnormal glucose metabolism and perfusion [155]. Cholinergic neurotransmission in the basal forebrain, which plays a key role in attention, learning, and memory, also appears to be damaged by prolonged ethanol intake [156, 157].

Thiamine deficiency as a main cause for the development of ARD is another hypothesis, and ethanol abusers are at particularly high risk of thiamine deficiency due to poor dietary nutrition and also because of the direct effect of ethanol on thiamine metabolism [130].

Apart from deficient in thiamine, nicotinic acid, other B vitamins, and folate, alcoholics frequently develop neurological disorders associated with malnutrition, including cerebellar degeneration, amblyopia, polyneuropathy, and disorders affecting cognition. In pellagra, nicotinic acid deficiency results in skin, gastrointestinal, and mental abnormalities, which can progress to memory impairment, delusions, hallucinations, dementia, or delirium; hypertonus and startle myoclonus may be present. Symptoms usually improve following treatment with nicotinic acid or nicotinamide [158].

Some authors documented that ARD and WKS are different pathological process with overlapping clinical symptoms and both can be associated with ataxia and polyneuropathies [159].

One of the problems that we afford is the variety of available definitions for "standard drink" and its different meanings from country to country. While a standard drink in the United Kingdom contains 8 g of alcohol, a standard drink in Australia contains 10 g and in America and Japan contains 14 and 19.7 g, respectively [160], which affect the best comprehension of the information delivered in the medical literature.

As it was mentioned before, in the review made by Parson and Nixon in 1989, they found that consumption of five to six drinks per day (which, by US standards, equates to 70–84 g) over extended periods results in "cognitive inefficiencies," while consumption of 10 or more standard drinks a day manifests as moderate cognitive deficits equivalent to that found in individuals with diagnosed alcoholism [144], and studies conducted by Oslin and colleagues [161] suggested that consuming 35 standard drinks a week for men and 28 for women for 5-year history constitutes a sufficient level of neurotoxic burden to risk the development of ARD. However, other studies found that light to moderate ethanol intake *reduced* the likelihood of dementia [162–170].

Damage of the brain seen on MRI is the biggest in female's alcoholic patients compared with the male's ones. Therefore, it seems to be that females are more susceptible than males to adverse ethanol's effect, but their recovery after abstinence is better [171].

Because of the introduction of thiamine supplementation programs in some countries, as well as general dietary habits, there is no direct correlation between the prevalence of WE and per capita consumption of standard drinks, but all patients under suspicion of having WE should be treated immediately with parenteral thiamine [130]. Thiamine given orally does not work because it reaches poor concentration in plasma; therefore, a dosage of 200 mg IV three times a day (1 g may be required in the first 24 hours) for 5–7 days followed by oral thiamine in doses of 100 mg eight hourly for 1–2 weeks is strongly recommended. At this point, it is very important to highlight that other electrolyte deficiencies such as magnesium and niacin should also be corrected. Apart from parenteral thiamine, to eat food with a high content of vitamins such as peas, lentils, brown rice, pork, organ meats, milk, eggs, nuts, fruits, and vegetables is suggested. Alcohol interferes with thiamine uptake [172]. This treatment should be continued until no further improvement in signs and symptoms is evident [173].

Because not all ARD patients recover from abstinence, around 20% of them need long-term admissions and the amount of ARD patients will increase gradually due to the growing pro-

Updated Information on Some Cognitive Disorders http://dx.doi.org/10.5772/intechopen.81826 209

*Physicians should be aware of preventable vitamin deficiency-related neuropsychiatric syndromes and should consider new signs and symptoms in patients with known psychiatric disorders as potential harbingers of reversible WE and irreversible WKS* [185, 186]. Indirectly, ethanol abuse can cause intoxication, brain injury, withdrawal, hypoglycemia, chronic liver disease, Marchiafava-Bignami disease, and cognitive disorders, and nutritional deficit causes WKS and pellagra.

*Marchiafava-Bignami disease, a rare disorder nearly always diagnosed in alcoholics, causes mania, depression, paranoia, and dementia, plus seizures, paresis, and ataxia and often progresses to coma and death within a few months; symptoms are not readily explained by the prominent corpus callosum demyelination that is the pathological hallmark of this poorly understood disease* [187]. For the other

Results of neuroimaging studies have corroborated postmortem neuropathological studies and have expanded the understanding of the neuropsychological deficits resulting from thia-

First of all, it is very important to highlight the importance of clinical assessment on any type of dementia followed by imagenology and other investigations. The best assessment can be done by the well-skilled health-care professional knowing the clinical features of all dementia, duration, frequency, and rate of progression. This professional must guarantee an adequate comfortableness of the patients, while the process of diagnosis is finished. Therefore, the patient's fears regarding type of dementia and condition should be well managed including a full review of the patient's health care, family history and treatment history, proper evaluation for depression, toxic substance abuse and nutrition, and other conditions that can cause memory dysfunction such as infections, chronic anemia, vitamin deficiency, diabetes mellitus type 2, chronic kidney or liver disease, thyroid gland disease, cardiopulmonary disorders, and other risk factors for dementia including hearing loss. Currently, there is no single test that confirms Alzheimer's disease, although to achieve 90% accuracy is certain. Nevertheless,

Findings from physical examination are crucial, and some laboratory tests such as CFS levels of total tau protein results are of relevant importance for identifying type of dementia and way of management. One of the most recent investigations has documented the results from evaluation of cerebrospinal fluid phosphorylated tau231 as a biomarker in the differential diagnosis of Alzheimer's disease and vascular dementia by assessing whether the use of sensitive and specific biomarkers such as phosphorylated tau proteins could contribute to an earlier and more accurate diagnosis of AD and VD, as well as to their differentiation, and the authors found that FS (p-tau231 and MMSE) has a strong potential to provide an early distinc-

portion of aging population and rise in per capita ethanol consumption [174, 183].

hand, low dosage decreases the risk for dementia and AD is included [156].

mine deficiency, alcohol neurotoxicity, and their combined effect [188].

to identify the true underlying cause of the problem can be very difficult.

tion between AD and VD [189, 190].

**8. Brief information about how to diagnose dementia**

Some patients with ARD and WKS have shown cognitive improvement following treatment with memantine, although these findings require replication [174, 175].

As we also mentioned before, ARD and WKS have some similarities. However, some neuropsychological studies have largely attempted to differentiate these syndromes by limiting individuals with more global cognitive impairment from WKS investigations and by excluding individuals with past symptoms of WKS from ARD studies, but the validity of this distinction is now being brought into question [140].

Ethanol concentration in blood raises blood levels of high-density lipoprotein cholesterol (HDL-C) in a dose-dependent fashion, and some studies suggest that this effect accounts for at least half of the protection against CAD [176]. Ethanol also increases insulin sensitivity [177], prevents platelet aggregation [178], increases fibrinolysis [179], opposes thrombin activity [180], and reduces inflammatory markers such as plasma C-reactive protein and fibrinogen levels [181].

*While "dementia" in current neurological settings is typically used to describe a progressive disease of the brain, it perhaps more accurately encompasses a deterioration of intellectual or cognitive function that may or may not be progressive in nature* [182]. Effect of ethanol on patients presenting ARD can be reversed if the diagnosis is made early enough (48–72 hours of the onset of symptoms) and adequately treated with parenteral thiamine [172]. Abovementioned foods are essential to replace the deficient vitamins/minerals, and faster recovery is usually seen in females than males as it was mentioned before as well. Support of family and friends is paramount in achieving abstinence [183]. The Wernicke's encephalopathy and WKS also may be reversed if diagnoses made at early stage (48–72 hours of the onset of symptoms) and adequately treated with parenteral thiamine [143]. In WE, if the administration of right doses of thiamine IV is not reached, then the mortality rate will be elevated up to 20% level [184] or patient will continue progressing up to Korsakoff syndrome or ARD.

In a prospective 12-week study done by Cheon et al. on patients with probable ARD, they found that memantine (a low-affinity NMDA receptor antagonist) improved global cognition, quality of life, and behavioral symptoms on their patients [174]. Another investigation reported that rivastigmine at the dose of 3–12 mg per day for 2 months improved clinical manifestations of ARD [185].

Because not all ARD patients recover from abstinence, around 20% of them need long-term admissions and the amount of ARD patients will increase gradually due to the growing proportion of aging population and rise in per capita ethanol consumption [174, 183].

*Physicians should be aware of preventable vitamin deficiency-related neuropsychiatric syndromes and should consider new signs and symptoms in patients with known psychiatric disorders as potential harbingers of reversible WE and irreversible WKS* [185, 186]. Indirectly, ethanol abuse can cause intoxication, brain injury, withdrawal, hypoglycemia, chronic liver disease, Marchiafava-Bignami disease, and cognitive disorders, and nutritional deficit causes WKS and pellagra.

*Marchiafava-Bignami disease, a rare disorder nearly always diagnosed in alcoholics, causes mania, depression, paranoia, and dementia, plus seizures, paresis, and ataxia and often progresses to coma and death within a few months; symptoms are not readily explained by the prominent corpus callosum demyelination that is the pathological hallmark of this poorly understood disease* [187]. For the other hand, low dosage decreases the risk for dementia and AD is included [156].

Results of neuroimaging studies have corroborated postmortem neuropathological studies and have expanded the understanding of the neuropsychological deficits resulting from thiamine deficiency, alcohol neurotoxicity, and their combined effect [188].
