THIRD INTERNATIONAL CONFERENCE ON ALZHEIMER’S DISEASE Sl19

A large variability has been reported for the age at onset in Familial Alzheimer's Disease (FAD) (Bird et al, 1989; St. George Hyslop et al, 1990). Similar variability was described in Huntington Disease (HD), in which, moreover, the sex of the affected parent influences the onset of the disease. Decreased paternal age increases the risk for HD (Ridley et al, 1988; Reik W. 1988).

The age at onset was studied in two FAD families: Family N (Foncln et al, 1985) and Family To (Bergamini et al, 1989); for them a founder effect is a likely explanation of their similarl- ties (Bruni et al, 1991). The age at onset distribution is iden- tlcal in both families and fits well with a log normal distri- bution. Although differences in age at onset were found between affected males and females, children of affected fathers develop the illness later (ptO.05) compared with children of affected mothers. Pairwise correlation was significant. only between affect- ed fathers and their children. Sex ratlo is 1:l in both families and the number and gender of children, affected or not, is the same regardless of the sex of the affected parent. A sort of protection seems to derive from the paternal transmission of the disease. These results are in contrast with those obtained by Farrer et al, 1990 in late onset AD.

469 EDUCATION LEVEL AND DEMENTIA: A REVIEh' OF THE SCIENTIFIC LITERATURE ON THIS SUBJECT., G. Neroni-Mercati, M. Mele, B. Giannandrea and S. Bonaiuto. I.N.R.C.A.; 62010 Appignano (MC), Italy.

Many recent studies suggest that socio-cultural factors, and education level in particular, deeply influence the diagnosis of dementia. The open question is whether education level must be considered as a factor influencing the onset and the progression of dementia, or only 88 a variable influencing cognitive teat performances.

Usinn the Medline. we sorted out all scientific works published during 1990 and 1991, concerning the relation between education and Alzheimer’s disease or other types of dementia; then, following the references of each article, we were able to select and examine works published from 1979 onwards.

We found 25 worka investigating the association between education and dementia: 15 examined the relation between low education level and dementia, 10 the association between low education and low tests preformance. Most authors agree about the influence of education level on brief cognitive tests usually adopted in population screening for dementia. while the association between low education and dementia is still debated. It is important to observe that 7 of the 8 studies which give evidence of the association between low education and dementia are prevalence studies. While studies not sharing this conclusion are often not population based, the sampling methods adopted are quite heterogeneous, and the population under investigation usually derives from subjects referring to health-structures.

We au&&test that the reliability of results obtained through studies adopting a sampling method not population based are quite doubtful because of the self-selection of subjects included in the sample. I” fact, demented subjects with low education usually have also economic problems, and there is little probability of their referring to hospitals. or outpatient structures. We think that only po~lation based studies, with a sample duly stratified and randomized, are able to investigate properly the real degree of influence of education level on dementia.

470 EPIDEMIOLOGY OF SENILE DEMENTIA: PROTECTIVE EFFECT OF EDUCATION E. Kahana, Y. Galper, A.D. Korczyn (Ashkelon and Tel-Aviv, Israel)

Obiective: We studied the prevalence of dementia in the elderly (>7Syr)

population of Ashkelon.

Backaround: Data on effects of ethnicity, gender and education on

dementia are meager and conflicting. Ashkelo” is a town with ethnic

diversity and good neurological. services.

Methods: Screening for dementia of the total population of the elderly

in Ashkelon (age >75yr) was performed. The population consisted of

2,424 subjects, and we used both family assessment, and a structured

questionnaire for cognitive assessment.

Results: Age-dependent increase in the prevalence of dementia was

seen, with significantly higher rate among women, Sephardic Jews, and

those with poor education. Poor education “explained” the differences in

gender and ethnicity.

Conclusion: Education seems to be the most significant factor, beyond

age, which is related to the prevalence of dementia.

471 Methodological Issues in Studier of the NaturaI History of Alzheimer’s Disease: C Sigler; C Wolfron, S Van de Carr.

Longitudinal studies of the clinical course of AD are aimed at elucidating the natural history of the disease and ultimately providing prognostic information to patients and their families. For such purposes, the outcomes of interest are multidimensional and include rates of cognitive and functional decline, occurrence of co-morbidities, and reduced life expectency.

Although much research has already been published, there is a need to further refine estimates of the strength of covariates as potential predictors of outcome. These covariates include a) patient characteristics (gender, age, age at onset, etc.) b) disease characteristics (presence or absence of symptoms and time of onset and duration of symptoms) and c) external factors (institutionalization, social support, etc.) as potential predictors of outcomes for AD patients.

The lack of consensus about predictors of disease course in AD is likely a consequence of the wide variety of methodological approaches taken in existing studies. Only through following widely accepted principles of study design will the maximum benefits which come from combining and comparing results be achieved.

We present guidelines for the design of future observational studies of AD patients and for the interpretation of published results. Topics include: case definition; case ascertainment; exclusion criteria; comparison groups; baseline data; outcome measures; follow-up strategies; and statistical analysis.

472 ABSENCE OF HEALTH-RELATED FACTORS AS PROTECTIVE FACTOR OF DEMENTIA, P. Houx, F. Vreeling, J. Jolles. Depts. of Neuropsychology and Psychobiology, Neurology; University of Limburg, P.O. Box 616,620O MD Maastricht, The Netherlands. Most studies on human aging show a genera1 decline of functioning, both cognitive and physical. Recently, however evidence is being obtained that functional decline is not a result of calender age as such. Several factors - biological as well as psychological and soclal- appear to interact with the aging process. Thus, an average decline with age, observed in normal subjects of different ages, may well be an artifact of the procedure of subject selection en health screening.

We performed a cross-sectional study into cognitive aging with 247 normal, healthy subjects, with ages ranging from 20 to 80 years. Each subject was thoroughly screened for health-related factors that were known to be associated with less optimal brain functioning

s120 THIRD INTERNATIONAL CONFERENCE ON ALZHEIMER’S DISEASE

such as mild head injury or general anesthesia (Biological Life Events; BLE). It appeared that -even within normal, healthy subjeck- there was a performance gap between subjects who had experienced one or more BLE, and those who had not. Moreover, this gap widened significantly with the subject’s age. It was hypothesized that the absence of BLE constitutes an important determinant for successful cognitive aging. Conversely, elderly subjects who had experienced BLE showed poor performance on almost every aspect of cognition tested, thus resembling mildly demented patients. It was inferred from this that presence of BLE might be a predictor of dementia and other age-related pathology.

These hypotheses are currently being tested in a longitudinal follow-up of the above-mentioned study. Preliminary results will be presented at the conference. It is anticipated that subjects with BLE will have deteriorated more and show a higher incidence of dementia than subjects without. Lately, important theories have arisen on usual versus successful aging. Presence of BLE is probably more frequent in the elderly than absence. Therefore, BLE may be a predictor of less than successful aging. We intend to re-test all participants in the study every five years. Furthermore, a much larger, cross-sequential study into cognitive aging is being planned in Maastricht.

473 lwE‘vB YEAR SUCCESS IN AECRUIT”ENT POR PROSPECTIVE CI,INICOPATHOI,GGICAL STVDIES OF AGING AND DEMENTIA, H. Harks-Nelson, P. Antis, H. Crystal, D. Dickson, Departments Of Neurology and Pathology, Albert Einstein College of Medicine.

Clinicopathologic etudiee have bee” a foundatlo” of medical science for over 150 years. Theee studles are now more difficult to do becauee autopsy rates have declined to leea than 5%. For the past 12 years, we have been conducting longitudinal clinlcopathologic etudies of normal aging end dementia in separate cohorts of 390 demented and nondemented subjects and 488 initially nondemented subjects. All subject9 were followed with yearly neurological and neuropeychological tests. coneent for autopsy was not a criteria for participating In the study. Over the 12 years of the etudles, 271 subjects have died and 90 autopales (a,*) have been performed. Pending autopsy consents are available from a” additional 79 subjecte.

When a subject in enrolled in the longitudinal study, consent for autopsy Le broached by the study “urees after raooort has been established. Ill case* of coa”itlve im;;irme”t, consent is obtained both from the-subject and hie or her next of kin. They can rescind their consent at any pime.

Ten autopsies were not obtained despite premortem consent. This may have been due to the families not remembering the autopsy arrangements during the strew of their loved one’s death. streamlinlna of arranaemente and wrlodic review of autopsy plans by the &udy “ur& with subjbcts’ families resulted in a 90% yield. Autopsies were performed within 6.929.7 hours of death eve” though many subjecte dled at home.

Autopsy coneente were obtained from 50 men (17%) and 128 women (23%). Well-educated subjecte were more likely to give consent than subjects with limited educatlo”. Protestant subjects were more likely to give consent than Jowlsh or Catholic eubjecta. Coneent was obtained from 32\ of demented eub+ects. and 14% of nondemented eubiecta.

- The high percentage of autop&e obtained may be due to e combination Of tactore: 1) subjects are participants I” oroewctive. lonaltudinal research studlest 21 close raooort k&n etuby n&sea and femiliea develope~du;l”g the co;ree of the etudy and the lesue of autopey Le reintroduced for dlscuseion perlodlcally~ 3) subjecte are made aware of the imoortance of their oarticloatina bv revlewina reeearch findlnge with them) i) the ;eaulfe bf the autopsy are dlecussed with the famlllee and couneelllng Le provided) and 5) etreamlining and perlodlc revlaw-of autopsy procedures with families eneures a hLgh rate of LIUCC~SB.

474

CONTROL BRAINS: A GROWING PROBLEM IN ALZHEIMER’S DISEASE RESEARCH. J. Falitico, L. Km&y, T. Wheelock, J.P. Vonsattel, E.D. Bird and E.G. Stopa. Dept. of Pathology, SUNY, HSC, Symcuse, NV and Brain Tissue Resource Cenler, McLean Hospital, Belmont, MA, USA.

A shoriage of suitable control brains may be threatening the progress of Alzheimer’s disease (AD) research. This reduction is, in pat, related to the continuing decline in the number of autopsies performed each year. Another complicating factor, however, is that although more families affected by Alzheimer’s disease are willing to participate in the brain donation process, control brain donacioos have “ot been increasing at a rate. comparable to those affected by AD.

Statistic from the McLean Hospital Brain Tissue Resource Center during the past WO years indicate that only 10% of the total brains received were suitable cootrol brains, whereas 2Q% had pathologic evidence of Alzheimer’s disease. Five years ago, these figure were 12% and 10% respectively. A similar trend has been observed by the Alzheimer’s brain donation program at the SUNY-HSC ia Syracuse, NY. In the past hvo years approximately 40% of the total brains received were control cases, and approximately 26% had pathologic evidence of Alzheimer’s disease. This is in contrast to the rate ten years ago when 42% of brains received were control cases, but only 4% were diagnosed as having Alzheimer’s disease. The problem is further magnified if one limits the comparison to age matched controls since the preceding figures include all age groups.

A recent Boston shldy has indicated that the prevalence. of Alzheimer’s disease in tbe elderly may be significantly greater than previous estimates have suggested (Evans, DA, et al, JAMA 262:25X2556, 1989). In addition, the recent establishment of standardized criterion for the pathologic diagnosis of Alzheimer’s disease (Khachaturiao, ZS, Arch. Neural. 42:1097-1105, 1985) has resulted in the exclusion of some brains which may have been utilized as coo&ok with “age-related” plaques and tangles, and no clinical history of dementia. Such observations suggest that age matched controls may be increasingly more difficult to fiod in the future.

Acquisition of brains is directly related lo public awareness which frequently requires an active campaign aimed at educating the public in the area of AD research. A noticeable increase in donations has bee” consistently observed following media exposure. The public must be made aware of the growing need for suitable age matched controls in addition to AD cases. This can perhaps be best accomplished through already established donation programs for other organs, such as those sponsored by the American Red Cross. (Supported by: AG:l0682 and Brain Bank Grant MH:31862.)

PHARMACOLOGY, CLINICAL TRIALS AND THERAPEUTIC STRATEGIES

475 PHARMACOTHERAPY OF ALZHEIMER DISEASE. NEW DRUGS AND NOVEL STRATEGIES. Ezio Giacobini. Dept. Pharmacology, Southern Illinois Univ. Sch. Med., P.O. Box 19230, Springfield, IL 62794-9230 USA

The major symptoms of Alzheimer disease. result from massive destruction of synaptic terminals in cortical and subcortical stru~ures. Neuronal loss is also significant and heterogeneous but never total. The pmcess is continuous but different neuronal systems deteriorate to various degrees as the decrease progxsses. The result is a complex clinical picture with high patient to patient variability. Several new drugs (choline&erase inhibitors, cholinergic agonists, nerve growth factor, etc.) are being tested in clinical trials. The first results indicate that not all patients are responders. We propose a therapeutical scheme based on three basic approaches (trophic, functional and symptomatic) to be applied at different stages of the disease:

Clinical Stage Early Inlemxdiate

Goal of Partial Replacement Therapy Trophic-Regenerative of Function

Cholinestearse Inhibitors Drug Nerve Growth Nicotinic and Treatment Factors Muscarinic Agents

< - Anti-beta amyloid agent - >

Advanced

Functional Maintenance

Symptomatic

Effect of Prevent cell death Replace Attenuate Therapy Improve regeneration NT-function symptoms

The goal is to use a combination of therapeutical approaches in order Io shift the curve of progressive deterioration and delay the labor-intensive and high cost care for a number of years in as many patients as possible. Supported in part by National Institute of Aging Alzheimer Disease Center Core Grant #P3OAGO8014.

476 HETHODOLOGIC ISSUES IN CLINICAL TRIALS IN AD, B. Reieberg, S .G. SCh”, S. Auer, and S.H. Ferris. Aging and Dementia Research Center; NYU Medical Center, New York, NY 10016, U.S.A. Recent investigations on the phenomenology and symptometology of AD have demonstrated that two major symptomatic domains are identifiable: (I) cognitive and (II) behavioral.’ Cognitive symptoms include progressive changes in concentration end