Biomedical subjects
Publications and source records attributed to M F Folstein.
The phenotype of Alzheimer's disease is variable. Age of onset, cognitive features, and neuropathology differ case to case. In some cases the differences are due to variable expression and others to genetic heterogeneity. Present evidence suggests four types of Alzheimer's disease: early and late onset autosomal dominant forms, trisomy 21, and phenocopies.
Epidemiologic studies of environmental factors associated with risk of Alzheimer's disease (AD) have produced inconsistent and disappointing results. By contrast, family/genetic studies and case control investigations suggest that genetic causes of AD are important. The investigation of such genetic causes remains an important aim in all forms of AD including typical, late-onset disease where linkage work is impractical. But the public health burden of AD creates an especially urgent need to identify environment risk factors, if these exist, since they will more likely be susceptible to intervention. Such environmental factors may interact with genetic susceptibility to accelerate or retard disease expression, and environmental interventions that delay onset may constitute an important strategy for prevention. All these issues may be addressed by twin studies of AD, but the few such studies to date have been limited by small samples and other methodologic difficulties. This paper reviews the rationale for twin studies of AD, and describes briefly the work in this area to date. It also discusses a number of suggestions for methodologic improvements. We conclude that the time is ripe for twin studies of AD, and that such work holds considerable potential for the investigation of etiology and, possibly, for the identification of strategies for prevention.
During a study of the effect of plasma exchange on glycosphingolipid metabolism, a patient with Fabry's disease noted a dramatic improvement in his painful acroparesthesia. A controlled study was therefore undertaken. Observations were made of nerve conduction times, graded exercise testing, and psychometric evaluations during and after two planned series of three plasma exchanges: one a true plasma exchange and the other a "sham' control in which the patient received his own plasma. All observers and the patient were blinded and unanimously attributed beneficial results to the sham procedure. This study demonstrates the need for controlled studies in diseases prone to unpredictable exacerbation or spontaneous remission and outlines one possible technique of controlling studies involving plasma exchange.
Over 3 years we followed 8 pairs of male twins one or both of whom had suspected Alzheimer's disease (AD) including 'mild/ambiguous' changes suggestive of incident AD. These pairs were screened in 1988 and 1989 from 339 pairs in the (US) National Academy of Sciences-National Research Council Registry (NASR) of aging veteran twins, then 61-72 years of age. Most of the suspected cases (10 of 12) had mild/ambiguous changes. Including these subjects, we had estimated the prevalence of AD in the NASR as about 2%. We now describe briefly the longitudinal evaluation of these 8 pairs. Only 1 of the 10 individuals with mild/ambiguous changes has progressed to show well-defined clinical symptoms of AD. Two others remain in their original research category, while 7 clearly do not have AD. Thus, we now estimate the 1988-1989 prevalence of AD in the NASR as 0.5%. These results contrast with other follow-up studies of mild cases from a university-based Alzheimer's clinic. We suggest that the contrasting findings reflect the nature of the samples studied, and we show that the present results are predicted by Bayesian reasoning.
The prevalence of psychiatric disorders and behavioral disturbances in nursing homes is high, but the relationship between the two is unknown. We studied 454 new admissions who were diagnosed by research psychiatrists using DSM-III-R criteria and compared patients who nursing staff designated as cooperative or uncooperative by psychiatric diagnosis and use of restraints and neuroleptics. Uncooperative patients (n = 79; 17.4%) had a variety of psychiatric disorders (total, 87.3%) but particularly had dementia syndromes complicated by delusions, depression, or delirium (44.3%). Uncooperative patients were more frequently restrained and prescribed neuroleptics. Determining the origins of behavior disorders in patients with psychiatric disorders in nursing homes may reduce behavior disturbances.
This study examined the prevalence of memory complaint and poor memory performance on brief screening measures within a community sample of 810 adults. All individuals received an extensive household interview and a clinical psychiatric evaluation. Overall, 22% indicated that they currently had trouble with their memory. This percentage increased with age, rising to 43% for those 65 to 74 years old, 51% for those 75 to 84 years old, and 88% for those 85 years of age and older; the percentage indicating memory problems decreased with educational attainment. The prevalence of poor memory performance was 11%, also increasing with less education and increased age, rising to 26% for those 65 to 74 years old and to 40% for those older then 75. Those who complained of memory trouble were twice as likely to show poor memory performance (29%) compared with those who did not complain (15%). Multivariate analysis found age, emotional distress, and physical illness to be independent predictors of memory complaint; age, functional disability, education, and physical illnesses proved to be independently associated with poor memory performance. A higher prevalence of complaints of memory trouble was found not only for those with affective disorders, as might be expected, but also among those with schizophrenic, cognitive, anxiety, and adjustment disorders. However, only individuals with cognitive disorders showed a higher prevalence of poor memory performance.
Individuals with Down syndrome develop neuropathologic and in some cases clinical evidence of Alzheimer disease after age 40. We compared CT scans of 18 Down syndrome subjects, 26-70 years old (seven of whom satisfied criteria for dementia), with 175 screened normal volunteer control subjects for evidence of cortical and subcortical atrophy. CT scans were analyzed as a function of age and cognitive status. The suprasellar cistern ratio, presumed to measure mesial temporal-lobe atrophy (or hypoplasia), was correlated with severity of cognitive impairment, even when age effects were removed. The suprasellar cistern ratio predicted dementia status with an accuracy of greater than 75%. Brain measurements on CT scans showed a distinct pattern of increased abnormality with age in patients with Down syndrome; this differed clearly from that seen in controls.
Clinical and laboratory methods were developed to detect motor abnormalities in patients with Huntington Disease. For clinical evaluation a quantitated neurological examination was used which factor analyzed into 2 scales: a chorea scale (a measure of involuntary movement) and a motor impairment scale (a measure of abnormalities of voluntary movement). Mechanized methods of measuring involuntary movement (accelerometer) and voluntary movement (reaction time, tapping speed, and movement time) were also developed. The motor abnormalities detected on the clinical and mechanical tests were not specific to HD but were also present in persons at 50% risk for HD and in patients with a variety of neurological disorders. The mechanized tests may be useful for screening for motor disorders in the population: they are non-specific, portable and do not require the services of an experienced clinician.
The clinical signs of Alzheimer Disease can be quantitated and correlated with neuropathological evidence of the disease. These clinical signs which include amnesia, aphasia and apraxia can be screened for using instruments such as the Mini-Mental State Exam. In addition, each of these cognitive functions can be quantitated using specific tests. Standardized scores are available for a mini mental state but further research is needed to develop normative data for more detailed psychological assessment tests of specific cognitive deficits. The fact that the cognitive impairment predicts the neuropathology and also the presence of a familial disorder, provides the basis for the validity of these characteristic cognitive signs and the rationale for developing more standardized versions of these tests.