Dementia

.. syndrome in DS (Beach, 1987). Later it was discovered that EOAD and DS share a common genetic pathology on chromosome 21 (see risk factors). Research in dementia began to revive in the early sixties. New causes of the dementia syndrome were recognized including progressive supranuclear palsy and normal pressure hydrocephalus. Prior to the 1960s dementia was still viewed as a chronic, irreversible and untreatable condition (Mahendra, 1984, P.

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 1960s concerned epidemiology. Before the sixties arteriosclerosis was thought to be the predominant cause of dementia, whereas AD was thought to be rare. However, arteriosclerosis was decisively challenged as the prime cause of dementia by several reports between 1960 and 1970. These reports demonstrated that arteriosclerosis was greatly overestimated as a cause of dementia, and that the majority of patients who were dying with dementia in fact showed the characteristic plaques and tangles of AD (URen, 1987).

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Furthermore, Katzman (1976) [as cited by URen] argued that because of the similarity in the clinical picture and the identical nature of the histopatholgy, distinctions between AD and senile dementia were arbitrary and no longer useful. Thus when it was understood that AD and senile dementia are similar, it was clear that AD is a common illness. In the 1970s 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 either the result of brain disease or depression, and that it was potentially treatable. The extension of this view was that senility was abnormal, and that its usual causes were diseases and not just aging (URen, 1987). Second, three different labs (Brown et al.

, 1976; Davies & Maloney, 1976; and Perry et al. , 1977) [as cited in URen, 1987], reported low levels of choline acetyltansferase, the marker enzyme for acetylcholine (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 1980s and 1990s 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, neuroimaging techniques are increasingly becoming more standard in assessment, 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) [as cited by Clarfield, 1989] project that by the year 2025 Canada will experience a growth in the prevalence of dementia, more rapid than the rise in the elderly population aged over 65. The majority of dementia cases are attributable to AD, Vascular dementias, or a combination of these (see Table 1).

In the past there were hopes that up to 40% of the 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 only 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 (Graves & Kukull, 1994). However, for AD, an increased prevalence rate is observed in females. Jorm et al.

(1987) [as cited by Graves & Kukull, 1994] estimate a female to male AD prevalence ratio of Ethnically there seem to be important differences in both prevalence rates and in the dementing diseases. With respect to prevalence, Heyman et al. (1991) [as cited by Graves & Kukull, 1994] found that out of a random sample of 4116 people 16% of African Americans had dementia compared to only 3.1% of Caucasians. The same study also found that MID and mixed dementia were more likely to occur in African Americans than in Caucasians (26% of all dementia cases in African Americans were of the MID and mixed type compared to only 14% in Caucasians). No clear explanation is given for these findings besides the mention that Blacks were more likely than whites to have a history of risk factors associated with MID (Graves & Kukull, 1994, P.

30). Interestingly, in both Europe and North America most studies point to AD as the most common dementing illness; whereas in Asia (especially Japan) MID predominates. The observed high rate of stroke in Japan is consistent with a high MID rate (Graves & Kukull, 1994). Possibly the higher level of stress in Japan leads to more strokes and therefore a higher prevalence of MID. Table 1. Etiology of Progressive Dementia and Approximate Incidence Senile dementia of the Alzheimer type (AD) 50% Multi-infarct dementia 10-15% Mixed SDAT and MID 10-15% Alcoholic-nutritional dementia 5-10% Normal pressure hydrocephalus 5% Miscellaneous: Huntingtons disease, neoplasms, chronic subdural hematomas, Parkinsons disease, Cruetzfeldt-Jakob disease, AIDS, Unknown causes 5-20% Note: Reproduced from Adelman, 1987, Encyclopedia of Neuroscience (Vol.

I), Boston: Birkhauser Life Expectancy and Mortality Estimates The following summary is based on Katzmans et al. (1988) review of the Wang (1978) and Barclay et al. 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 the expected survival rate of similarly aged non demented people which is 11.1 years.

Presenile demented patients survived a slightly longer average of 6.9 years against an expected survival rate of 22.3 years. The Barclay et al. (1985) study examined survival rates in AD and MID patients in the 1980s. The mean survival rates for these diseases were 8.1 and 6.7 years respectively. Interestingly, the survival rate of demented woman on the whole is significantly higher than that of men. Katzman et al.

(1988) suggest 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. [as cited by Graves & Kukull, 1994] a doubling of the prevalence rate occurs every 5.1 years. For the elderly population aged 65 and above the prevalence of dementia is estimated at about 10% (Clarfield, 1989). Whereas in the very elderly it can reach up to 40% (Evans et al.

, 1989) [as cited in 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, studies such as Breitner et al. (1988) [as cited by Graves & Kukull, 1994] have reported a cumulative risk of AD among relatives of patients approaching 50%, thus implying an autosomal dominant mode of transmission.

On the other hand, however, genetically transmitted diseases should be concordant in monozygotic twins, but this does not appear to be the case in AD. For instance both Creasey et al. (1989) and Kumar et al. (1989) [as cited by Graves & Kukull, 1994] have reported three pairs of monozygotic twins who were discordant for AD. Whereas Nee et al.

(1987) [as cited by Graves & Kukull , 1994] only found a 41% concordance rate for AD in 17 monozygotic twins. Farrer et al. (1990) [as cited by Lezak, 1995] 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. It has been shown that individuals who are afflicted with DS 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 (Graves & Kukull, 1994).

Thus it is not surprising that four studies have found an increased risk for AD with late maternal age. According to Rocca et al. (1991) [as cited in Graves & Kukull, 1994] the increased risk of AD to patients born to mothers over 40 is consistent with the DS risk curve. 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. 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 (Marco, 1995).

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. 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 (Marco, 1995). Table 2 summarizes the genetic findings that have been made thus far.

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