M F Folstein’s research while affiliated with Johns Hopkins University and other places

Neuropathological examination confirmed the clinical diagnosis of possible or probable Alzheimer disease (AD) in 90 of the first 100 patients who came to autopsy at the Johns Hopkins Alzheimer's Disease Research Center. In 10 cases, postmortem brain examination did not confirm AD but revealed variable patterns of neuronal loss in neocortex and limbic structures without amyloid deposits. The most common pattern of degeneration was relatively isolated hippocampal sclerosis (HS). Despite the finding that the 10 patients with non-AD neuropathology were ill for less time and were less cognitively impaired at study entry than those patients with definite AD, they had shorter survival times and showed equal behavioral disturbance at study entry (on a standardized measure). The clinical case reports included here suggest early and progressive prominent behavioral disturbance and other indexes of rapid illness progression in three of the four HS patients and two other non-AD patients. We conclude that the criteria of the National Institute of Neurological Disorders and Stroke/Alzheimer Disease and Related Disorders Association for possible or probable AD are highly accurate and that misdiagnosis is most likely to occur early in the course of illness and in patients with prominent behavioral disturbance or other atypical features.

Evidence suggests that the neuropathology of Huntington's disease, a neuropsychiatric disorder due to a mutation on chromosome 4, results from excessive activation of glutamate-gated ion channels, which kills neurons by oxidative stress. Therefore, the authors hypothesized that alpha-tocopherol, which reduces oxyradical damage to cell membranes, might slow the course of Huntington's disease. A prospective, double-blind; placebo-controlled study of high-dose d-alpha-tocopherol treatment was carried out with a cohort of 73 patients with Huntington's disease who were randomly assigned to either d-alpha-tocopherol or placebo. Patients were monitored for changes in neurologic and neuropsychologic symptoms. Treatment with d-alpha-tocopherol had no effect on neurologic and neuropsychiatric symptoms in the treatment group overall. However, post hoc analysis revealed a significant selective therapeutic effect on neurologic symptoms for patients early in the course of the disorder. Antioxidant therapy may slow the rate of motor decline early in the course of Huntington's disease.

To detect cases of Alzheimer's disease (AD) in a large population of twins living throughout the United States and to examine concordance for AD in twins as a function of age and genotype for apolipoprotein E (APOE). Nationwide survey. Multistage screening and field evaluation beginning with two telephone interviews and culminating with laboratory tests, longitudinal neuropsychological measures, physician examination, and diagnostic consensus among experts. Membership in 1990-1991 of intact pairs in the National Academy of Sciences--National Research Council Registry of veteran twins, then aged 62 to 73 years. Completeness of case detection was examined in collateral studies. Zygosity and APOE genotypes were determined by restriction mapping. Concordance was calculated by the proband method. Ninety subjects who screened positively for AD were studied in person, and 60 whose differential diagnoses included AD were followed up, as were their co-twins. Sensitivity of screening was estimated at greater than 99%, but 24% of subjects refused participation after initial screening. Seven of 38 diagnoses of AD have been confirmed at autopsy, and 31 other subjects eventually met criteria for probable or possible AD (prevalence estimate, 0.42%, 95% confidence interval, 0.29% to 0.56%), with good interrater reliability (intraclass r = .86). Excluding one discordant pair with unknown zygosity, concordance rates were 21.1% (4/19) for monozygotic and 11.1% (2/18) for dizygotic probands. Concordance was 50% for twins sharing the epsilon 4/epsilon 4 genotype at APOE, but there were no affected co-twins of 15 probands with onset before age 70 years, no epsilon 4 allele, and no family history of AD. The mean (SD) period of discordance in the latter pairs was 11.3 (3.3) years. The multistage case-detection approach achieved reliable and valid diagnoses of AD with high apparent sensitivity but substantial attrition after initial screening. Genetic influences in AD at this age are limited, except among homozygotes for allele epsilon 4 at APOE. Subjects with early-onset AD who lack the epsilon 4 allele are not rare, and their condition appears to have little genetic influence. They should be ideal for studies on environmental cause of AD.

Several case-control studies have reported head injury to be more common among patients with Alzheimer's disease (AD) than healthy elderly controls. The present study sought to determine whether milder head injury is also a risk factor for AD. Furthermore, it was hypothesized that head injury would be more common among AD patients without a genetic risk for the disease. History of head injury in 68 consecutive cases of probable or definite AD and 34 non-demented control subjects was ascertained from their spouses. Head injury was reported in 20 of the AD patients (29%), and in only one control subject (2.9%) (odds ratio = 13.75). Twenty per cent of the familial and 43.5% of the sporadic AD cases reportedly had a premorbid head injury (odds ratio = 3.08). Head injury had no effect on age of dementia onset. The results indicate that head trauma may be a predisposing factor to AD, particularly in the absence of a clear genetic contribution.

We reviewed the records of 210 patients in the Johns Hopkins Alzheimer's Disease Research Center to evaluate the role of nonsteroidal anti-inflammatory drugs (NSAIDs) on clinical features and progression of the disease. We compared patients taking NSAIDs or aspirin on a daily basis (N = 32) to non-NSAID patients (N = 177) on clinical, cognitive, and psychiatric measures. The NSAID group had a significantly shorter duration of illness at study entry. Even after controlling for this difference, the NSAID group performed better on the Mini-Mental State Examination, Boston Naming Test, and the delayed condition of the Benton Visual Retention Test. Furthermore, analysis of longitudinal changes over 1 year revealed less decline among NSAID patients than among non-NSAID patients on measures of verbal fluency, spatial recognition, and orientation. These findings support other recent studies suggesting that NSAIDs may serve a protective role in Alzheimer's disease. NEUROLOGY 1995;45: 51-55

While cognitive and functional deficits are the hallmark of Alzheimer's disease (AD), loss of social function (and the dependence this implies) is also critical, especially in early stages of disease. Little attention has been directed to this facet of dementing disease. We describe a scale for assessing dependency in AD and present a baseline profile of dependency in a cohort of AD patients. In a study of the predictors of the course of AD, 233 patients in early stages of disease (modified MMS > or = 30) were assessed. Psychometric properties of the dependence scale were established. To validate the scale, dependence scores at baseline were correlated with a series of measures assessing cognition and function. The course of dependency over 18 months of follow-up was also analyzed. The scale shows adequate reliability (test-retest, intraclass correlation). Dependence stage was related to other measures of disease severity. Scalogram analysis shows that the dependence scale is consistent with the course of functional loss established for dementing disease. Prospective data indicate sensitivity of the scale to disease progression. Dependency is a distinct, measurable component of dementing disease and should be considered an important outcome in studies of AD.

The aims of this study were to estimate the prevalence and investigate the comorbidity and potential consequences of DSM-III personality disorders in the community. A total of 810 adults were examined in the second stage of the Eastern Baltimore Mental Health Survey in 1981, part of the National Institute of Mental Health Epidemiologic Catchment Area program. The subjects were directly examined by psychiatrists using a semi-structured method that allowed diagnosis of all DSM-III personality disorders as well as other DSM-III psychiatric disorders. The prevalence of personality disorders in these adults was 5.9% (9.3% when provisional cases were included). Men had higher rates than women, and subjects who were separated or divorced had the highest rates. There was little comorbidity among specific personality disorders. Subjects with personality disorders were significantly more likely to have a history of sexual dysfunctions, alcohol use disorders, and drug use disorders as well as suicidal thoughts and attempts. In addition, they reported significantly more life events in the past year. Among subjects with any axis I disorder, those with personality disorders were judged by the psychiatrists to be more in need of treatment; however, only 21% were receiving treatment. Personality disorders are relatively common in the community. They are associated with axis I disorders and life events. Only one-fifth of the individuals who qualify for diagnoses of personality disorders in the community are receiving treatment.

A total of 810 adults were examined by psychiatrists in the second stage of the Eastern Baltimore Mental Health Survey. A semistructured examination, the Standard Psychiatric Examination, was used. The relationships between obsessions and compulsions and personal characteristics, childhood behaviors, family history, and other psychopathology were evaluated. The estimated prevalence of obsessions and compulsions in this population was 1.5%. Cases were significantly more likely to report having had childhood fears, learning disabilities and a family history of alcoholism and suicidal behavior. There were significant positive relationships between scores on compulsive, borderline and histrionic personality disorder scales and the probability of obsessions and compulsions. These exploratory analyses in an epidemiologic sample may identify factors of etiologic importance in this condition.

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.

Quantitative power spectral analysis (PSA) was applied to frontal (F3, F4, F7, F8), temporal (T5, T6), and occipital (O1, O2) EEGs of 16 Huntington's disease (HD) patients and eight healthy control subjects. PSA revealed HD patients' EEGs to be abnormal: (i) raw and percent Alpha power were reduced; (ii) raw and percent Theta power were reduced at F3 and F4; (iii) percent Delta and percent Beta power were increased; (iii) Theta frequency was reduced by approximately 1.0 Hz. Frontal and temporal EEG power measures and decreased EEG amplitude correlated with severity of neurological and cognitive impairment.