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Dementia What Is Dementia ? Dementia Is An Organic Brain Syndrome Whic

h results in global cognitive impairments. Dementia can occur as a result of a variety of neurological diseases. Some of the more well known dementing diseases include Alzheimer’s disease (AD), multi-infarct dementia (MID), and Huntington’s disease (HD). Throughout this essay the emphasis will be placed on AD (also known as dementia of the Alzheimer’s type, and primary degenerative dementia), because statistically it is the most significant dementing disease occurring in over 50% of demented patients (see epidemiology). The clinical picture in dementia is very similar to delirium, except for the course. Delirium is an acute transitory disorder. By contrast Dementia is a long term progressive disorder (with the exception of the reversible dementias). The course of AD can range anywhere from 1.5 to 15 years with an average of about 8.1 years (Terry , 1988). AD is usually divided into three stages mild, moderate, and severe. Throughout these stages a specific sequence of cognitive deterioration is observed (Lezak, 1993). The mild stage begins with memory, attention, speed dependent activities, and abstract reasoning dysfunction. Also mild language impairments begin to surface. In the moderate stage, language deficits such as aphasia and apraxia become prominent. Dysfluency, paraphasias, and bizzare word combinations are common midstage speech defects. In the severe stage the patient is gradually reduced to a vegetative state. Speech becomes nonfluent, repetitive, and largely non-communicative. Auditory comprehension is exceedingly limited, with many patients displaying partial or complete mutism. Late in the course of the disease many neuropsychological functions can no longer be measured. Also primitive reflexes such as grasp and suck emerge. Death usually results from a disease such as pneumonia which overwhelms the limited vegetative functions of the patient. Dementia is commonly differentiated along two dimensions: age and cortical level. The first dimension, age, distinguishes between senile and presenile dementia. Senile dementia is used to describe patients who become demented after the age of 65, whereas presenile dementia applies to patients who become demented prior to that age. Late onset AD (LOAD) also known as senile dementia Alzheimer’s type (SDAT) is the predominant cause of senile dementia. Early onset AD (EOAD) is the most frequent cause of presenile dementia, but HD, Pick’s disease and Creutzfeldt-Jakob disease though not as frequent are also important causes in presenile dementia. The second dimension, cortical level, differentiates between cortical and subcortical dementia. Cortical dementia is used to describe dementia which results from brain lesions at the cortical level, whereas subcortical dementia describes dementia resulting from subcortical brain lesions. AD and Pick’s disease are the best known examples of cortical dementia; whereas HD, Parkinson’s disease (PD), and progressive supranuclear palsy (PSP) are good examples of subcortical dementia (Mayke, 1994). Dementia with both cortical and subcortical features is also possible, in that case the term mixed dementia is used. MID is a common example of mixed dementia. Historical developments in dementia Pre-Modern Developments The use of the term dementia dates back to Roman times. The Latin word demens did not originally have the specific connotation that it does today. It meant ‘being out of one’s mind’ and, as such, was a general term for insanity (Pitt, 1987). It was the encylopedist Celsus who first used the word dementia in his De re medicina, published around AD 30. A century later the Cappadocian physician Aretaeus first described senile dementia with the word dotage (i.e., “The dotage which is the calamity of old age…dotage commencing with old age never intermits, but accompanies the patient until death.”). Curiously, dementia was mentioned in most systems of psychiatric classification throughout pre-modern times, though the precise meaning of the word is often unclear (Pitt, 1987). Nineteenth Century It can be argued that the origins of the scientific study of dementia date back to the early nineteenth century. The initial steps were undertaken by the great French psychiatrist Pinel at the beginning of that century. Pinel’s observations led him to the conclusion that the term dementia should be applied in relation to the “progressive mental changes seen in some idiots” (Pitt,3). Furthermore, Pinel thought that dementia was a distinct abnormal entity, and thus he used the term dementia to designate one of the five classes of mental derangement. However, by applying the term dementia to ‘idiots’, Pinel failed to differentiate between dementia and mental subnormality. This was accomplished by Pinel’s student Esquirol in his 1838 textbook Mental maladies-A treatise on insanity. Esquirol summed up the difference between the demented and the mentally handicapped in the following epigram: “The dement is a man deprived of the possessions he once enjoyed, he is a rich man who has become poor. But the defective has been penniless and wretched all his life” (Mahendra, 10). Furthermore, Esquirol was also instrumental in the popularization of the term senile dementia. Remarkably, his description of senile dementia is very similar to our present day definition. Interestingly, in 1845 Griesinger proposed that senile dementia was due to a disease of the cerebral arteries, a faulty view which persisted until Alzheimer’s time. Much of today’s basic knowledge about dementia was accumulated throughout the second half of the nineteenth century, and the first decade of the twentieth century. 1872 saw Huntington present a paper called “On chorea”, in which he discussed a typical case of what is now known as Huntington’s disease. Twenty years later in 1892 two significant events occurred. First Pick in a paper called “On the relation between aphasia and senile brain atrophy” described the case of August H. a 71 year old patient with senile dementia. Although the case is not typical of our present day conception of the disease Pick was given credit for discovering a new disease. The other more significant event in 1892 was Blocq and Mariensco’s description of scattered silver staining plaques in the cortex of senile patients. These plaques were subsequently named senile plaques (SP) by Simchowitz in 1911. The year 1894 saw Alzheimer’s first major contribution , a differentiation between senile and vascular (arteriosclerotic)dementia. Alzheimer described the specific changes observed in arteriosclerotic atrophy of the brain, which resemble what we might call vascular dementia. In 1898 another milestone occurred when Binswanger introduced the term presenile dementia. Thus by the twentieth century significant changes were taking place in our understanding of dementia. The nineteenth century view that there was only one mental disease-insanity-and that dementia was its terminal stage was dispelled by Kraepelin in the 6th edition of his textbook Psychiatrie, published in 1899 (Pitt, 4). Kraepelin separated dementia praecox (a concept he proposed in 1898 in relation to Schizophrenia) from the other dementias (paralytica and organic), and Senile dementia was included under another category called involution psychosis (Pitt, 4). Twentieth Century In 1907 Alzheimer published his landmark case “A unique illness involving the cerebral cortex” in which he described a fifty-five year old demented woman. The case was very unusual for two reasons its clinical course, and the discovery of a striking microscopic lesion in the woman’s brain (Beach, 1987). The clinical course was unusual because of the young age of the patient and the rapidity of degeneration (the patient died within four and a half years of symptom onset). At autopsy neuropathological findings were even more unusual. One quarter to one third of cerebral cortical neurons had disappeared, and many of the remaining neurons contained thick, coiled masses of fibers within their cytoplasm (Beach, 1987). Alzheimer speculated that a chemical change had occurred in the neurofibrils. Thus Alzheimer described for the first time neurofibrillary tangles (NFT), which togther with SP are considered to be the neuropathologocal halmarks of AD (See Appendix 1 for Alzheimer’s original drawing of NFT). Alzheimer concluded that he discovered a unique entity separate from senile dementia as it was known at that time. However, it was not until 1910 when Kraepelin discussed the condition in the 8th edition of his textbook Psychiatrie that AD gained official recognition. The second decade of the twentieth century witnessed the end of the golden period in dementia research (this only lasted until the 1960’s when a renaissance occurred). U’Ren cites two reasons as the principal causes (Pitt, 6). First the rise of Freud’s Psychodynamic theory caused American psychiatry to swerve in the direction of psychological explanations. Second Kraepelin’s descriptions and classifications seemed to leave little room for therapeutic efforts or optimism. Notwithstanding, several key contributions have been made in the ‘Dark Ages’ of dementia research. In 1920 Creutzfeldt, and in 1921 Jakob, described cases of dementia with pyramidal and extrapyramidal signs. Although it is now thought that only Jakob’s case was typical of the disease the Creutzfeldt-Jakob disease (CJD) was given to the world. The year 1936 saw an important change with regards to the diagnosis of AD. Before 1936 it was common practice to provide a diagnosis based on both clinical and pathological characteristics. However, when it became clear that many non-demented people had some senile plaques and neurofibrillary tangles, Jervis and Soltz advised that only clinical criteria would suffice for a diagnosis of AD (Mahendra, 14). In 1948 Jervis published his landmark paper called “Early senile dementia in Mongoloid idiocy.” Jervis described three individuals with Down’s syndrome (DS), aged 37, 42 and 47 years, each of whom had shown a profound emotional and intellectual deterioration in the last few years of life. At autopsy, all were found to have SP and two also displayed NFT (Beach, 39). This was the first demonstration of NFT in DS and the first full clinical and pathological correlation supporting an Alzheimer- like syndrome in DS (Beach, 39). Research in dementia began to revive in the early sixties. New causes of the dementia syndrome have been recognized including, depression, which in the form of psuedodementia may mimic dementia (Kiloh, 1961), progressive supranuclear palsy (Steele et al, 1964) and normal pressure hydrocephalus (Adams et al, 1965) , (cited in Pitt, 6). Prior to the 1960’s dementia was still viewed as a chronic, irreversible and untreatable condition (Mahendra, 14). Accordingly, in the 1960s, several writers in Europe called for a revision of the concept and emphasized that irreversibility should not be viewed as an essential feature of dementia. Another important change that took place in the 1960’s concerned epidemiology. Prior to the sixties arteriosclerosis was thought to be the predominant cause of dementia, whereas AD was thought to be rare (Pitt, 12). However, arteriosclerosis was decisively challenged as the prime cause of dementia by several reports between 1960 and 1970 (i.e.,Tomlinson, Blessed, and Roth, 1968 and 1970). These reports demonstrated that arteriosclerosis was greatly overestimated as a cause of dementia, and that the majority of patients dying with dementia in fact showed the characteristic plaques and tangles of AD. Furthermore, Katzman, in 1976 argued that because of similarity in the clinical picture and the identical nature of the histopatholgy, distinctions between AD and senile dementia were arbitrary and no longer useful (Pitt, 12). Thus when it was understood that AD and senile dementia are similar, it was clear that AD is a common illness. In the mid-1970’s two important contributions were made. First, Butler in his 1975 book Why survive? Being old in America criticized the widespread notion that senility was a normal part of aging. Butler argued that, senility, was a result of brain disease or depression and was potentially treatable. The extension of this view was that senility was abnormal, and that its usual causes were diseases, not just aging (Pitt, 1987). Second, three different labs (Bowen et al, 1976; Davies & Maloney, 1976; and Perry et al, reported low levels of choline acetyltransferase, the marker enzyme for acetylcholine 1977) (ACh), in the brains of patients who died from AD. ACh deficiency has since been the target of most therapeutic efforts in AD (see treatment). Throughout the 1980’s and 1990’s two trends emerged. First, with regards to diagnosis, criteria have been made stricter. Classification systems like the Diagnostic and Statistical Manual have evolved towards a more precise and comprehensive definition of dementia. Moreover, neuoroimaging techniques are becoming more and more standard, allowing in some cases for a more accurate diagnosis. Second, the past fifteen years have witnessed a substantial growth in genetically based research. For instance one of the genes involved in AD, the amyloid precursor protein (APP), has been localized to a specific segment of chromosome 21 (see risk factors). Epidemiology Dementia is known as the quiet epidemic, but it affects a significant proportion of our population. In 1989 the Canadian consensus conference on the assessment of dementia reported that Canada had about 250,000 cases of dementia (which at the time comprised about 1% of the population), with 25,000 new cases occurring annually (Clarfield, 1989). Jorm et al. (1988) project that until the year 2025 Canada will experience a growth in the prevalence of dementia, more rapid than the rise if the number of elderly aged over 65. The majority of dementia cases are attributable to AD, vascular dementias, or a combination of these (Table 1). In the past there were hopes that up to 40% of dementias had reversible causes. However, recent reports (Clarfield, 1988; Barry and Moskowitz, 1988) suggest that the true incidence of reversible dementias is at the most 11% and is probably far lower, with drugs, metabolic causes and depression accounting for about two thirds of the cases (Clarfield, 1989). Overall, there are no significant gender differences in prevalence and incidence rates for dementia as a whole. However, for AD, there is an increased prevalnce in females. Jorm et al. (1987) estimate a female to male AD prevalence ratio of 1.6. Ethnically there seem to be important differences in both prevalence and subtype of dementia. Prevalence wise, Heyman et al. (1991) found that out of a random sample of 4116 16% of African Americans had dementia compared to only 3.1% of Caucasians. The same study also found that mixed and MID were more likely to occur in African Americans (26% of dementias in African Americans compared to 14% in Caucasians). Moreover, in both Europe and North America most studies point to AD as the most common dementing illness; whereas in Asia (especially Japan) MID predominates (Morris, 1994). The observed high rate of stroke in Japan is consistent with a high MID rate. Possibly the higher level of stress in Japan leads to more strokes and therefore a higher incidence of MID. Table 1. Etiology of Progressive Dementia and Approximate Incidence senile dementia of the Alzheimer type 50% Multi-infract dementia 10-15% Mixed SDAT and MID 10-15% Alcoholic-nutritional dementia 5-10% Normal pressure hydrocephalus 5% Miscellaneous: Huntington’s disease, neoplasms, chronic subdural hematomas, Parkinson’s disease, Cruetzfeldt-Jakob disease, AIDS, unknown cause 5-20% Life Expectancy and Mortality Estimates The following summary is based on Terry’s (1988) review of the Wang (1978) and Barclay et al. (1985) studies. The Wang study examined senile dementia (mean age of onset 71.3 years) and presenile dementia (mean age of onset 53.8 years) survival rates during the 1960s. Senile dementia patients survived on the average 6.0 years, close to half of the expected survival rate (11.1 years) of similarly aged non demented people. Presenile demented patients survived slightly longer an average of 6.9 years, against an expected survival of 22.3 years. The Barclay et al. Studies examined survival rates in AD and MID patients in the 1980s. The mean survival rates for AD and multi-infarct dementia were 8.1 and 6.7 years respectively. Interestingly, the survival rate of demented women on the whole is significantly higher than that of men. Terry (1988) suggests that the lower survival rate of demented men is due to a higher incidence of MID in men. Risk Factors Age Age is the biggest risk factor for developing dementia. According to a model proposed by Jorm et al. (1987) a doubling of the prevalence rate occurs every 5.1 years. (1987) For the elderly population aged 65 and above the prevalence of dementia is estimated at about 10%. Whereas in the very elderly it can reach up to 40% (Clarfield, 1989). Genetics Genetic factors are important in some dementing diseases. In HD an autosomal dominant gene on chromosome 4 is directly responsible for the disease. The genetic evidence in AD is less conclusive. On the one hand there are studies (i.e., Breitner et al. , 1988) which have reported a cumulative risk of AD among relatives of patients approaching 50%, thus implying an autosomal dominant mode of transmission (Morris, 1994). But, on the other hand, genetically transmitted diseases should be concordant in monozygotic twins, this does not appear to be the case in AD. For instance both Creasey et al. (1989) and Kumar et al. (1991) have reported three pairs of monozygotic twins who were discordant. Whereas Nee et al. (1987) only found a 41% concordance rate for AD in 17 monozygotic twins. Farrer et al. (1990) suggest that AD appears as an autosomal dominant in families in which the average age of onset among kindreds is under 58. Supporting evidence for this comes from studies which have linked EOAD with DS (Lezak, 1993). Individuals who are afflicted with Down syndrome and who survive to age 40 almost invariably develop Alzheimer like dementia. During the intermediate and terminal stages of DS the individual suffers from recent memory loss, apraxia, temporal disorientation, and mutism, all of which are also common in AD (Morris, 1994). Thus it is not surprising that four studies have found an increased risk for AD with late maternal age (Morris, 1994). The increased risk of AD to patients born to mothers over 40 is consistent with Down syndrome risk curve (Rocca et al. , 1991). Both EOAD and DS have been localized to chromosome 21. However, chromosome 21 does not appear to be a very good genetic marker for EOAD (Green book, 104). Recent studies have shown that a defect in chromosome 14 is more likely to be associated with EOAD, but the specific gene(s) have not yet been isolated (Green book, 104). Evidence for genetic predisposition to LOAD has only emerged over the last two years. It is now known that a gene which codes for a lipoprotein called ApolipoproteinE (APOE) in chromosome 19 is involved (Green book, 101). APOE is linked to the type 4 allele (e4). It has now been proven that an increase risk for dementia is dependent on a strong chemical binding between the main ingredient of SP, the Beta amyloid protein, and the APOE-e4 (Green book, 102). Table 2 summarizes the genetic findings that have been made thus far in EOAD and in LOAD. Table 2. Alzheimer’s Disease Genetics Chromosome 21 Chromosome 14 Chromosome 19 Onset EOAD EOAD LOAD Risk factor for developing AD Low Higher Highest Specific gene(s) APP Not yet isolated Not yet identified Marker APOE-e4 ________________________________________________________________________________ Note: Reproduced from Berger & Finkel, 1995, Treating Alzheimer’s and other dementias , New York: Springer publishing Other Risk Factors Corsellis and Brierly (1959) [as cited by Graves ; Kukull, 1994] have shown that dementia similar to that seen in AD may occur following a single head injury. In addition, dementia puglistica, (the so called ‘punch-drunk syndrome’) develops in some boxers. Lower education has also been associated with dementia. Animal studies demonstrate a positive relation between environmental stimulation and dendritic growth. It is also known that dendritic growth in humans continues throughout life. Possibly lower education is related to a lack of mental exercise, which could delay the onset of significant cognitive decline (Graves ; Kukull, 1994). Aluminum (Al) has been implicated as a possible neurotoxin, but the evidence is inconclusive (Carson ; Butcher, 1992)). Proponents of the Al neurotoxin hypothesis argue that Al has been shown to accumulate in neurons with neurofibrillary degeneration, and that aluminosilicates accumulate in senile plaques. Critics argue that the abnormal accumulation of Al is an effect, not a cause, of brain degeneration. Another controversial risk factor is depression. Four studies have reported a statistically significant association between a history of depression and AD (Graves ; Kukull, 1994). The controversy revolves around the idea that depression is possibly an early manifestation of AD. There is some research suggesting that individuals with a weakened immune system may be more susceptible to develop AD. Heyman et al. (1984) [as cited by Graves ; Kukull, 1994] have found an increased risk of AD associated with thyroid disease in women. However, their findings have not been replicated. Interestingly, there is some evidence to suggest that smoking can have a protective effect from AD. For instance, Duijn and Hofman (1991) [as cited by Graves ; Kukull, 1994] have found a negative correlation between smoking and AD in a study involving 198 individuals. Neuropathology For each dementing disease a specific neuropathological pattern is observed. However, due to the limited scope of this essay the discussion will be limited to the most important dementing disease, AD. Gross Features Several changes are observed at the gross neuropathological level in AD (Mirra ; Gearing, 1994). Cortical atrophy is generally observed in the frontal, temporal, and parietal cortex. Sectioning of the brain reveals variable enlargement of the lateral and third ventricles. Disproportionate enlargement of the temporal horn of the lateral ventricle is commonly encountered, with concomitant atrophy of the entorhinal cortex, amygdala, and hippocampus. Microscopic Features At the microscopic level the two most distinguishing neuropathological features are senile plaques (SP) and Neurofibrillary tangles (NFT). There are two types of SP, neuritic and diffuse, both plaques share antigenic determinants with the Beta amyloid 4 protein. Neuritic plaques can be distinguished by their abnormally thickened neurites ( i.e., axons or dendrites) arranged around a central core of amyloid (Mirra ; Gearing, 1994). By contrast the diffuse plaques lack the thickened neurites and the amyloid core seen in the neuritic plaques (Mirra ; Gearing, 1994). Plaques of both types are found in varying degrees in the neocortex, entorhinal cortex, hippocampus, and in the amygdala. SP also occur in the brains of healthy people. It is only when they exceed a certain critical number that AD emerges. NFT are intraneuronal structures which occupy the cell body of the neuron. Usually NFT coexist with SP in the neocortex, but they may be absent there in up to 30% of AD patients (Mirra ; Gearing, 1994). However, NFT are consistently found in the entorhinal cortex, hippocampus, amygdala, nucleus basalis of Meynert, and dorsal raphe nucleus (Mirra ; Gearing, 1994). It is thought that the major antigenic component in NFT is the protein tau. Neuronal Loss Neuronal loss is directly related to the degree of synaptic density, which has been found to be crucial in determining the severity of cognitive decline. It is greatest in the temporal lobes, but is also significant in the frontal and parietal lobes (Lezak, 1995). The strongest correlation with a global measure of dementia is the loss of functional synapses in the midfrontal and lower parietal areas which surround the temporal lobes (Lezak, 1995). The effect of this pattern of neuronal cortical loss is twofold. First it disconnects the temporal lobe structures from the rest of the cerebral cortex. This accounts for the prominence of memory impairments (Lezak, 1995). Second this pattern also disconnects the prefrontal structures from the parietal ones. This accounts for the compromised capacity for attentional tasks (Lezak, 1995). It is thought that besides the effects of SP and NFT, neuronal loss is chiefly related to the depletion of the neurotransmitter acetylcholine (see treatment). Overall Picture In a study conducted by Brun and Gustafson (1978) [as cited by Cummings, 1988], the regional distribution of SP, NFT, and neuronal loss, was examined in AD patients. The results indicated that the most severely affected areas were the medial temporal and the temporo-parieto-occipital junction region (see figure 1). Two positron emission tomography (PET) studies by Benson et al. (1983) and Foster et al. (1984) [as cited by Cummings, 1988] have confirmed this pattern. [A1] Cognitive Deficits General Intelligence A profile of declining IQ scores reliably discriminates normals from AD patients. However, the utility of IQ scores in other dementing diseases is unknown. In the early stages of the disease performance IQ tends to decline at a faster rate than Verbal IQ which remains relatively unimpaired. Subsequently, as the disease progresses the decline is evident in both performance and verbal IQ (Schmitt ; Sano, 1994). Memory Memory dysfunction is often considered to be the distinguishing clinical feature of AD. Therefore, it is unlikely that a diagnosis of AD will be assigned unless a memory deficit is present. Hom’s (1992) study [as cited by Schmitt & Sano, 1994] compared the verbal and visual memory of elderly demented patients with similarly aged normals, under two conditions, immediate and delayed recall. Memory performance in the immediate recall condition was 29% for verbal memory and 31% for visual memory, of the average performance of the normals. The deficit was even more pronounced in the delayed recall condition, where the figures were 11% for verbal recall and 6% for visual recall. Common examples of memory dysfunction in mild dementia include misplacement of items without independent retrieval, failure to recall details of re cent conversations or events, and frequent repetition of questions. At a more advanced stage recent events are forgotten, and even knowledge of highly learned material erodes (Morris, 1994). It is thought that in AD, memory failure occurs as a result of improper encoding rather than due to retention failure (Schmitt & Sano, 1994). Orientation dysfunction usually co-occurs with a memory deficit. There are difficulties with dates, temporal sequencing, day/night distinction, and navigating through familiar places (Morris, 1994). With regards to the last deficit it seems that an underlying visuospatial impairment is the critical causal factor (see other cognitive impairments). Language The most common language impairment in AD patients is dysnomia, the inability to name common objects. Dysnomia emerges early in the course of AD, later on expressive and receptive aphasia are often present (Schmitt & Sano, 1994). Table 3 illustrates the linguistic impairments seen in each of the three AD stages (mild, moderate, and severe dementia). Table 3. Progressive Changes in Linguistic abilities in AD Stage I 1. Dysnomia 2. Empty, fluent speech 3. Poor word list generation 4. Mild anomia 5. Lack of spontaneously initiated conversation Stage II 1. Anomia 2. Paraphasia with increasingly little relation to target word 3. Impaired auditory comprehension 4. Impaired comprehension of written language 5. Aphasic agraphia 6. Relative preservation of repetition and reading aloud 7. Poor engagement in conversation Stage III 1. Incoherent verbal output 2. Echolalia, palilalia, logoclonia 3. Diminished articulatory agility 4. Terminal mutism 5. Mechanical agraphia ____________________________________________________________________________________ Note: Modified from Cummings & Benson, 1983, Dementia: A clinical approach, Boston: Butterworths The typical AD linguistic impairment pattern includes poor auditory comprehension, poor naming with paraphasia, writing impairment, and poor reading comprehension (Cummings, 1988). According to Benson (1979) [as cited by Cummings, 1988] the pattern of verbal output seen in AD resembles transcortical sensory aphasia (which is associated with focal posterior left hemisphere damage). The difference is that in AD there is less paraphsia, echolalia, and the completion phenomenon, and more impairment of automatic speech production. Other Cognitive impairments Several other cognitive impairments are commonly seen in AD patients. Constructional dyspraxia (impairment in constructional tasks) is often present. Additionally, many patients suffer from basic visuospatial impairment. It is quite common for patients to find themselves lost in familiar neighborhoods, or drive in the wrong direction on a one way road (Cummings, 1988). Also common are attentional deficits, and disturbances of abstraction, calculation, problem solving and judgment. The latter cluster of deficits points to an underlying frontal lobe dysfunction (Morris, 1994). Model for Overall Cognitive Deficit Picture Cummings (1988) has proposed a model to explain the above deficit picture observed in AD. The following discussion summarizes the main points. The combination of all of the cognitive deficits in AD is greater than the sum of the individual losses. For instance a focal lesion which results in a memory defect has a small impact on verbal output, and an aphasic disorder does not effect memory . By contrast, the dysfunction seen in AD results from multiple defects which interact to produce additive abnormalities. In AD a memory deficit directly contributes to impoverished linguistic output and the aphasia in turn magnifies the memory problems. Furthermore, other abnormalities such as visuospatial and calculation deficits are superimposed on these, and together they disable various integrative abilities such as insight, strategy formulation, and anticipatory planning. Taking into account these considerations, Cummings (1988) proposes a three-tired model of human intellectual activity which applies to AD. The most basic activities (i.e., arousal, attention, motivation) are mediated by subcortical structures. These fundamental functions are largely intact in AD. However, two other aspects of intellectual activity are damaged in AD. First instrumental functions which are specific neuropsychological abilities (i.e., memory, language, calculation) mediated by the cerebral cortex are damaged. More importantly, the distinguishing feature of AD involves damage to supraordinant functions (integrative abilities). These functions are dependent upon a proper interaction between the fundamental and instrumental functions. Behavioral Problems and Psychopathology The gradual destruction of various brain structures, causes several maladaptive behavioral changes. Typically dementia is viewed as a collection of negative symptoms, but positive symptoms are present as well. Tariot and Blazina (1994) suggest that these behavioral changes may be collectively present up to 90% of the time during the course of a given dementing illness. Furthermore, they have determined that certain behaviors occur at a particularly high rate. Table 4 shows the eight different categories which include these behaviors. During the early stages of the illness when the patient is only mildly impaired it is very common for individuals to avoid active participation in life. Patients tend to withdraw from social engagements, lack initiative, and overall behave in an indifferent and apathetic manner. A possible explanation for this behavior is that these patients may be embarrassed by their cognitive deficits, and so they avoid interacting. As the illness progresses and the cognitive deficits increase patients may become more anxious and agitated. Patients with preexisting psychological problems are prone to experiencing hallucinations and delusions. In particular these patients exhibit paranoid delusions, for instance accusing the elderly spouse of being unfaithful. Misperceptions, such as the inability to distinguish real people from television images, are also common at this stage (Tariot & Blazina, 1994). Aggression, in particular verbal hostility tends to increase as accurate perception declines. According to Cohen-Mansfield et al. (1986) [as cited by Tariot & Blazina, 1994, P. 470] agitated and aggressive behaviors may represent “adaptive efforts to obtain stimulation and certain verbal behaviors may be frustrated efforts to communicate or obtain assistance.” Table 4. Schematic Summary of Reported Frequencies of Behavioral disturbances Associated with Dementia (% of patients) Behavioral Disturbance Range Median 1. Disturbed affect/mood 0-86 19 2. Disturbed ideation (Delusions) 10-73 33.5 3. Altered perception Hallucinations 21-49 28 Misperceptions 1-49 23 4. Agitation Global 10-90 44 Wandering 1-49 23 5. Aggression Verbal 11-51 24 Physical 0-46 14.3 Resistive/uncooperative 27-65 14 6. Anxiety 0-50 31.8 7. Withdrawn/passive behavior 21-88 61 8. Vegetative behaviors Sleep 0-47 27 Diet/appetite 12.5-77 34 _________________________________________________________________________________ Note: Reproduced from Morris, 1994, Handbook of Dementing Illnesses, New York, Marcel Dekker Assessment Interview The initial diagnostic procedure used in the assessment of dementia is the interview. The purpose of the interview is twofold. First it is important for the clinician to gain an accurate picture of the case history. It is important to interview at least one significant other person, and if possible more, to gain an objective view. Information should be collected about premorbid functioning, and about the nature, onset, and course of the symptoms. Second during the interview the clinician evaluates whether the individual’s presenting complaints match the clinical profile for dementia. It is important to rule out other disorders that may mimic dementia. For instance self reported memory complaints correlate better with the presence of depression than with dementia ( Morris, 1994). Brief Mental Status Examination Alongside the interview, a brief mental status examination is often used. The exam’s purpose is to indicate whether any gross cognitive deficits are present. According to Schmitt & Sano (1994, P. 94) the strengths of such an exam are: “(1) the ability to rapidly screen a large number of people, and (2) the ability to measure progression in those who have been identified with dementia”. The problem with these exams is that they are insensitive to mild dementia, particularly in highly educated individuals. Furthermore, they lack the ability to assess specific neuropsychological functions, and thus are of little value in specifying the type of dementia (Schmitt & Sano, 1994). Nevertheless, these brief exams can be very useful. In practice many primary care physicians do not routinely administer these tests. For instance in a study by McCartney and Palmateer (1985) [as cited by Katzman et al. , 1988] it was found that these exams were carried out in only 4 out of 165 patients in the United States. As a result 50 patients with cognitive impairments were missed. The two mental status tests which are in widest use are the information-concentration-orientation test of Blessed et al. and the mini-mental state exam of Folstein et al. The Blessed test is the most sensitive, and thus is used the most in very early cases. The mini-mental test is broader in that it also tests language, writing, and drawing. Both tests are inappropriate to use with mentally retarded individuals or those with a poor educational background. Also the tests should be adjusted for individuals who are not fluent in English or for those who have a different cultural background (Katzman et al. , 1988). Another useful brief item is the dementia rating scale. It is utilized to estimate the severity of dementia. Neuropsychological Testing According to Morris (1994, P. 79) neuropsychological testing in demented patients serves three functions: “(1) to provide objective documentation of impaired cognition and therefore support the clinical diagnosis of dementia (2) to assess cognitive changes longitudinally, and (3) to identify selective patterns of cognitive deficits for correlation with neuroimaging and postmortem findings”. The shortest battery for discriminating dementia patients from normals is the Iowa screening battery for mental decline. It consists of three neuropsychological tests, Temporal Orientation, Benton Visual Retention Test and the Controlled Oral Word Association Test. This battery is used to determine if further evaluation is necessary. If further evaluation is necessary usually the Consortium to Establish a Registry for Alzheimer’s disease (CERAD) battery is used. The battery consists of seven tests, some of which are slightly modified from their original form (Lezak, 1995). These tests include the Word List Memory Test and the Boston Naming Test, which test for memory and language respectively. The word List Memory Test tests for memory by verifying how well a person can recall three lists of ten words. Whereas the Boston Naming Test tests for language by verifying how well the person can duplicate three lists of five words (Lezak, 1995). Sometimes it is useful to test for specific cognitive abilities. For instance the Wechsler Memory Scale-Revised is often used to see if a memory impairment is present. Table 5 illustrates some of the more common neuropsychological tests utilized in the assessment of dementia. Table 5. Assessment of Neuropsychological Functions for Dementia Diagnosis Function(s) assessed Examples of useful clinical tests Global mental status Mini Mental State, Mattis Dementia Rating Scale, Information-Memory Concentration Test, Syndrome Kurtz Test Premorbid functioning National Adult Reading Test, Wide-Range Achievement Test-Reading General intellectual functioning Wechseler Adult Intelligence Scale-Revised, Ravens Progressive Matrices, Test of Nonverbal Intelligence Memory Wechsler Memory Scale Revised, Benton Visual Retention Test, Rey-Osterreith Complex Figure, Rey Auditory Verbal Learning Test, Selective Reminding Test, California Verbal Learning Test, Rivermade Behavioral Memory Test Language (naming and fluency) Boston Diagnostic Aphasia Examination, Western Aphasia Battery, Holland Communicative Abilities in Daily Living, Halstead-Wepman Aphasia Screening Test, Boston Naming Test, Controlled Oral Word Association, Semantic Category Naming Problem solving (and executive functioning) Halstead-Reitan Category Test, Wisconsin Card Sorting Test, Trailmaking A ; B, Stroop Praxis and constructional ability Rosen Drawing Test, Rey-Osterreith Complex Figure (copy), Benton 3-Dimensional Blocks, Beery Test of Visual Motor Integration, WAIS-R Block Design, BDAE Stick Test Motor Finger Oscillation, Grooved and Purdue Pegboards, Diadokinesis Attention/concentration WAIS-R Digit Span, Reaction Time Tests, Cancellation Tasks, Syndrome Kurtz Test ______________________________________________________________________________________ Note: Reproduced from Morris, 1994, Handbook of Dementing Illnesses, New York: Marcel Dekker Clinical Diagnosis and Related Problems A definitive diagnosis of AD and many other dementing diseases can only be made either through cerebral biopsy, the surgical removal of a small piece of the cerebral cortex, or when the patient dies and an autopsy is performed. The two most widely used criteria for the diagnosis of dementia are the Diagnostic and Statistical Manual Third Edition-Revised (DSM-IIIR) and the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS/ADRDA). DSM-IIIR is more often used for research purposes and the NINCDS/ADRDA for clinical purposes. There are several problems in diagnosing dementia, most notably differentiating dementia from normal aging and from depression. In general, the cerebral processing resources needed for attention demanding tasks and secondary memory functions are adversely affected by age (Morris, 1994). Clinically, these impairments result in limited attentional capacity and diminished speed of information processing and retrieval. But unlike in dementia these symptoms are largely nonprogressive, and do not interfere substantially with everyday life (Morris, 1994). In patients with mild cognitive changes it is almost impossible to make an exact diagnosis even with the best neuropsychological tests. Only the likelihood of developing dementia can be estimated. There can be a great deal of symptom overlap between dementia and depression especially in the early stages of dementia. Depression presenting as dementia is often called pseudodementia. The term pseudodementia implies that the dementia is reversible, and is not caused by an organic disorder but rather it is caused by a psychiatric disorder (Clarfield, 1989). Currently there are no definitive tests to differentiate between dementia and depression. Clinical Subgroups of Alzheimer’s Disease Blenow, Wallin ; Gttfries (1994) have proposed a model for clinical subgroups in AD based upon differential clinical symptomatology and neuropathology. Their findings indicate that there are two distinct subtypes which they have termed Alzheimer’s disease type I and type II. Alzheimer’s disease type I is characterized by dominant temporoparietal symptoms, low frequency of vascular factors, normal blood-brain barrier function, low frequency of CT indicated leukoaraiosis (white matter lesions), and relatively younger age of onset. These characteristics correspond to the classic description of AD. Therefore AD type I appears to constitute classical or pure AD (Blenow et al. , 1994). Alzheimer’s disease type II is characterized by general cognitive symptoms, absence of or mild temporo- parietal symptoms, high frequency of confusional symptoms, relatively high frequency of vascular factors, mildly impaired blood-brain barrier function, high frequency of CT indicated leukoaraiosis, and relatively late age of onset. These characteristics suggest that vascular changes are responsible for the production of dementia symptoms in AD type II (Blenow et al. , 1994). Markers Markers Reflecting Brain Changes Markers which belong to this category utilize cerebral spinal fluid (CSF) changes to reflect altered neurotransmitter levels or abnormal proteins (Katzman et al. , 1988). The enzyme Acetylcholinesterase (which regulates the neurotransmitter Achetylocholine, see treatment) is known to be decreased in the cerebral cortex of demented patients. Several investigators have found it decreased in the CSF, while others have failed to confirm this. According to Thal (1985) [as cited by Katzman et al. , 1988] the apparent decrease in some studies may be a dilutional effect secondary to ventricular enlargement. Similarly Somatosatin and Norepinephrine are also reduced in the cerebral cortex of demented patients. However, in the CSF Somatosatin is only decreased in some patients, whereas Norepinephrine is actually increased in the CSF. A good area for future research is to investigate whether any of the abnormal proteins associated with AD can be found in the CSF (Katzman et al. , 1988). Peripheral Markers Peripheral markers are markers which reflect changes in the skin or blood cells (Katzman et al. , 1988). Most of the findings in this category are either inconclusive or have not been replicated. For instance Diamond et al. (1983) [as cited by Katzman et al. , 1988] have found that the sodium-lithium counter- transport rates in red blood cells were elevated in AD patients, but this finding has not been replicated. Olfactory deficit Markers Several investigators have found that AD patients have olfactory recognition and threshold deficits. Peabody and Tinklenberg (1985) [as cited by Katzman et al. , 1988] have found that 8 out of 18 AD patients had these deficits compared to only 1 out of 26 normals. Katzman et al. (1988) discuss increased carbon dioxide production, increased superoxide dismutase, and decreased calcium uptake as possible causes for these deficits in AD patients. Pharmacological Treatment Cholinergic Drugs There is no known cure for AD or many other dementing diseases. Several medications are available but their effectiveness is limited. The most promising group of drugs work by potentiating the cholinergic systems in the brain. During the 1970’s several studies have shown that demented patients have low levels of the neurotransmitter Acetylocholine (ACh). This has led to the development of the cholinergic hypothesis for dementia. It has since been established that the enzyme from which ACh is synthesized, Choline Acetyltransfearse (ChAT), is severely decreased in AD patients. There are three mechanisms by which these drugs work (1) precursor loading , (2) preventing the breakdown of ACh , and (3) the direct stimulation of the postsynaptic receptors. Precursor loading in AD is similar to Parkinson’s disease (PD). The difference is that instead of using the precursor L-dopa for dopamine in PD, the precursors choline and lecithin are used in AD to synthesize ACh. Generally this treatment when used alone fails to improve cognitive performance (Schneider, 1994). Preventing the breakdown of ACh involves inhibiting the enzyme Acetylocholinesterase (AChE). The principal drugs which utilize this mechanism are Physostigmine, Tacrine, and Valancrine. The problem with Physostigmine is that the duration of its therapeutic effect is very short, usually about one to two hours, whereas Tacrine and Valancrine have serious side effects (Schneider, 1994). A second generation of cholinesterase inhibitors which are longer acting and more selective are currently being developed, and the initial results are encouraging. In AD the postsynaptic M-1 cholinergic receptors are relatively intact. It is the presynaptic M-2 cholinergic receptors which regulate ACh release that are damaged. Therefore, it makes sense to try to directly stimulate the postsynaptic receptors (Schneider, 1994). These cholinergic agonists include Bethanechol, Oxotremorine, Pilocrapine, RS-86, and Arecholine. When these drugs are given orally they are not very effective. They are more effective when administered through an implant of an intracereroventricular pump. But the risks of such an implant are not insignificant. For instance in one trial out of 68 implants 16 resulted in surgical complications, including one death, two hemorrhages, and seven seizures (Schneider, 1994). Other Drugs There are several other drugs used in the treatment of dementia, although their therapeutic mechanisms are not understood very well. Hydergine is the longest used and most extensively studied antidementia drug. Hydergine is an ergoloid derivative which effects the alpha-adrenergic, dopaminergic, and sertoninergic receptors. There have been conflicting reports about its efficacy, but overall it seems that it is only slightly better than a placebo in relieving symptoms (Schneider, 1994). Nootropics are a group of drugs derived from the neurotransmitter GABA. But instead of having GABA effects they have a neuroprotective effect on the central nervous system, and they may stimulate central cholinergic activity. Still, the specific mechanism of action relevant for dementia has not been established for these drugs. Overall results with Nootropics such as Piracetam, and Oxiracetam have not been very encouraging (Schneider, 1994). Summary As the human race marches forward into the new millennia, one of the challenges that will remained to be solved is the dementia epidemic. The continuous increase in life span means that the number of people which are afflicted with dementia will continue to grow. Notwithstanding, we have come along way in our understanding of the dementia syndrome since the days of Pinel or even since the days of Alzheimer. We now know that dementia (senility) is not the natural outcome of aging, rather it is the result of a variety of possible abnormal brain processes. For instance in AD (the most important dementing disease) the formation of SP and NFT in the brain have been proven to be the main causal factors of the disease. Furthermore, in AD these processes have been shown to occur mainly in the cerebral cortex, and in particularly in the temporal lobes. The effects of these brain lesions are mainly manifested in various cognitive and behavioral impairments. With regards to cognition, memory and language dysfunction are the most commonly encountered deficits in AD. In fact memory impairment is so crucial, that a diagnosis of AD will almost never be made unless it is present. With respect to behavior, anxiety disturbances tend to predominate in the earlier stages of AD, whereas aggression is encountered in the latter stages. Significant progress has also been made in the assessment of dementia. Standard interviewing methods are now used alongside brief mental status examinations. Although the mental status exams have a limited diagnostic usefulness (they are only used as initial screening devices), they are nevertheless important because of their relative low cost and quick administration time. When further confirmation is required or more detail is desired neuropsychological testing is performed. Neuropsychological testing allows for the assessment of specific cognitive functions (i.e. memory, language, attention) thus discovering which brain areas are affected. This is useful because not only is it possible to judge if the person suffers from dementia, but with a high degree of accuracy it is possible to say which dementing disease is responsible. Notwithstanding, even the best neuropsychological tests may run into difficulties at times. For instance differentiating dementia from depression is extremely difficult since people who are depressed may display many of the clinical symptoms observed in dementia. As our understanding of dementia grows it is conceivable that an effective treatment will be found within the next century. Genetically several important breakthroughs have occurred recently in AD. Abnormalities in chromosomes 14 and 19 have been added to chromosome 21 as causal factors. Furthermore, investigators are now close to localizing the specific genes involved in these chromosomes (it is already known that in chromosome 21 the specific gene involved is the APP gene). With regards to pharmacological treatment the ACh hypothesis for dementia has led to the development of three groups of cholinergic drugs, some of which show great promise. Other drugs are also available but their effectiveness is questionable. 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Finkel (Eds.), Treating Alzheimer’s and other dementias. New York: Springer Publishing. Mirra, Suzanne S., & Gearing, Marla. (1994). The neuropathology of dementia. In John C. Morris (Ed.), Handbook of dementing illnesses. New York: Marcel Dekker Inc. Morris, John C. (1994). Evaluation of the demented patient. In John C. Morris (Ed.), Handbook of dementing illnesses. New York: Marcel Dekker Inc. Plum, Fred. (1987). Dementia. In George Adelman (Ed.), Encyclopedia of Neuroscience (Volume 1). Boston: Birkhauser. Schmitt, Frederick A. and Sano, Mary C. (1994). Neuropsychological approaches to the study of dementia. In John C. Morris (Ed.), Handbook of dementing illnesses. New York: Marcel Dekker Inc. Schneider, Lon S. (1994). Experimental pharmacotherapy of primary symptoms of dementia. In John C. Morris (Ed.), Handbook of dementing illnesses. New York: Marcel Dekker Inc. [A1]


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