[show abstract][hide abstract] ABSTRACT: Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance. Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (epsilon 4) in the gene encoding apolipoprotein E (APOE ) is a risk factor for more typical late-onset (>60 years) AD. A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease. We performed a 9 cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade. Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE. Twelve additional locations-on 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22-met criteria for 'suggestive' linkage [i.e. two-point lod score (TLS) >/=1.9 and/or multipoint lod score (MLS) >/=2.2] in at least one of our analyses. Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD.
Human Molecular Genetics 01/2003; 12(1):23-32. · 7.69 Impact Factor
[show abstract][hide abstract] ABSTRACT: Accumulating biologic evidence suggests that estrogen is related to cognitive function. Several epidemiologic investigations have reported that hormone therapy may reduce the risk of Alzheimer's disease. However, fewer studies have examined the relation of postmenopausal hormone use to general cognitive function in nondemented older women. Thus, we examined the association of hormone therapy to performance on four cognitive tests among healthy participants of the Nurses' Health Study.
The Nurses' Health Study, an ongoing prospective cohort study begun in 1976.
From the Nurses' Health Study, 2138 women aged 70-78 years.
From 1995-1999 we administered four cognitive tests (Telephone Interview for Cognitive Status (TICS), immediate and delayed recall of the East Boston Memory Test (EBMT), and verbal fluency) by telephone. Hormone use was ascertained from biennial questionnaires beginning in 1976. Linear and logistic regression models were used to calculate multivariate-adjusted differences in scores and relative risks of a low score for never users compared to current and past hormone users.
After adjustment for confounders, neither current nor long-term hormone users demonstrated better performance on an overall measure of cognition (TICS), or on three tests of verbal memory (immediate and delayed recall of the EBMT, immediate recall of the TICS 10-word list) than never users. On the test of verbal fluency, current hormone users scored significantly better than never users (linear regression estimate of the difference in score = 0.78 points, 95% confidence interval (CI) 0.19-0.38, P = .01 for any current use; and 0.91 points, 95% CI 0.28-1.54, P = .005 for > or = 5 years current use). Current hormone users also had a 30% decrease (RR = 0.70, 95% CI 0.45-1.09) in their risk of a low score on the test of verbal fluency. These results were similar for women taking estrogen alone and estrogen combined with a progestin.
Verbal fluency may be enhanced among women taking postmenopausal hormones, however, there is little support for better overall cognitive function in hormone users than nonusers.
Journal of the American Geriatrics Society 08/2000; 48(7):746-52. · 3.98 Impact Factor
[show abstract][hide abstract] ABSTRACT: Examined the association of hormone therapy to performance on 4 cognitive tests among 2,138 healthy female participants (aged 70–78 yrs) of the Nurses' Health Study. From 1995 to 1999 the authors administered 4 cognitive tests (Telephone Interview for Cognitive Status [TICS], immediate and delayed recall of the East Boston Memory Test [EBMT], and verbal fluency) by telephone. Hormone use was ascertained from biennial questionnaires beginning in 1976. Linear and logistic regression models were used to calculate multivariate-adjusted differences in scores and relative risks of a low score for never users compared to current and past hormone users. After adjustment for confounders, neither current nor long-term hormone users demonstrated better performance on an overall measure of cognition (TICS), or on 3 tests of verbal memory (immediate and delayed recall of the EBMT, immediate recall of the TICS 10-word list) than never users. On the test of verbal fluency, current hormone users scored significantly better than never users. Current hormone users also had a 30% decrease in their risk of a low score on the test of verbal fluency. These results were similar for women taking estrogen alone and estrogen combined with a progestin. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Journal of the American Geriatrics Society 06/2000; · 3.98 Impact Factor
[show abstract][hide abstract] ABSTRACT: The purpose of this pilot study was to gain information about attitudes of individuals with bipolar disorder and their spouses toward some of the ethical and social issues arising from rapidly advancing genetic research on bipolar disorder.
Patients with bipolar disorder and their unaffected spouses were asked to answer questionnaires assessing their knowledge and attitudes about treatment response rates for bipolar disorder, probability of inheritance, genetic testing, disclosure of genetic information, abortion, marriage, and child-bearing.
The overwhelming majority of the patients and spouses said that they would take advantage of genetic tests for bipolar disorder if such tests were to become available. Most patients and spouses agreed that the benefits of knowing whether one carries a gene for bipolar disorder would outweigh the risks. The decisive majority of respondents also felt that they would not abort a fetus that carried a gene for bipolar disorder. Furthermore, most patients and spouses agreed that the knowledge that one of them carried a gene for bipolar disorder would not have deterred them from marriage or childbearing.
The results of this study suggest that most individuals believe that they would benefit from the use of genetic testing for bipolar disorder if it were to become available. Follow-up studies using a broader patient sample and nonclinical control groups would be useful in further evaluating the issues addressed in this pilot study.
American Journal of Psychiatry 08/1998; 155(7):899-904. · 14.72 Impact Factor
[show abstract][hide abstract] ABSTRACT: The purpose of this analysis was to examine: (1) the prevalence of psychiatric disorders among disabled people, using seven different measures of disability; (2) variation in disability between and within psychiatric diagnostic categories; and (3) relationship of diagnosis and disability to health service utilization.
Data were drawn from Phase I and Phase II of the Eastern Baltimore Mental Health Survey, part of the Epidemiologic Catchment Area Program (ECA) conducted in 1980-1 to survey mental morbidity within the adult population. A total of 810 individuals received both a household interview and a standardized clinical psychiatric evaluation. Estimated prevalence rates were computed using appropriate survey sampling weights.
Prevalence of disability ranged from 2.5 to 19.5%, varying with specific disability measure. Among those classified as disabled by any of the measures examined, 56 to 92% had a psychiatric disorder and serious chronic medical conditions were present in the majority of these cases (54 to 78%). Disability was expressed differently among the various diagnostic groups. Diagnostic category and disability were significant independent predictors of medical service utilization and receipt of disability payments.
The majority of disabled adults living in the community have diagnosable psychiatric disorders, with the majority of these individuals suffering from significant chronic medical conditions as well, thus making co-morbidity the norm.
Psychological Medicine 06/1998; 28(3):509-17. · 5.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: As part of the NIMH Genetics Initiative Alzheimer's Disease (AD) Study Group, a brief structured telephone interview to distinguish individuals with normal cognitive functioning from those with changes in cognition and daily functioning suggestive of early AD was developed. The Structured Telephone Interview for Dementia Assessment (STIDA), yields a dementia score between 0 and 81 (higher scores indicating greater impairment). Subscales corresponding to the subscales of the Clinical Dementia Rating Scale (CDR) can be derived. The STIDA performed well as a screening instrument for mildly demented individuals. When a score of 10 or more (based on informant interview and subject testing) was used to identify mildly impaired individuals, the STIDA had a sensitivity of .93 and a specificity of .92 for a clinician-derived CDR of 0.5 or more. The STIDA was also capable of accurately assessing the level of dementia. STIDA-derived CDR ratings agreed with clinician-derived CDR scores in 23 of 28 cases, corresponding to an unweighted kappa of.71 and a weighted kappa of.81. A much-abbreviated short STIDA that could be administered directly to the subject was able to detect possible impairment with a sensitivity of .93 and a specificity of.77. These results suggest that the short STIDA provides a sensitive and fairly specific telephone screen for dementia, and that the full STIDA, consisting of an interview with a knowledgeable informant and subject testing, approximates the success of a face-to-face clinical interview, and provides reliable and valid screening and staging of dementia over the telephone.
Journal of Geriatric Psychiatry and Neurology 11/1997; 10(4):161-7. · 3.53 Impact Factor
[show abstract][hide abstract] ABSTRACT: One hundred patients with clinically diagnosed Huntington's disease (HD) were randomized to either idebenone, an antioxidant and enhancer of oxidative metabolism, or placebo, in a 1-year, double-blind, parallel-group study aimed at slowing the rate of progression of the disease. Ninety-one patients completed the study. There were no significant differences between groups on the primary outcome measures of the Huntington's Disease Activities of Daily Living Scale (ADL-an index of functional status) and the Quantified Neurologic Examination (QNE). Sample size calculations based on progression of the ADL and QNE in this study group revealed that a larger study group is necessary to detect any differences less than an almost complete halting of the disease. This argues for multicenter efforts for future therapeutic trials in HD.
Movement Disorders 10/1996; 11(5):549-54. · 4.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: We explored the inter-rater agreement and validity of diagnoses of Alzheimer's disease (AD) and other dementias made in an epidemiological study. A previously described protocol for cognitive screening and clinical assessment was applied to a large registry of twins. An expert panel then reviewed results from the assessment of 41 subjects whose screening results suggested the presence of AD. After review of the information at each of four stages of data collection, we assessed inter-rater agreement among the experts as well as their individual agreement with the final consensus diagnosis. We investigated these measures to assess the amount and quality, respectively, of new and diagnostically useful information that was revealed at each stage. A new scheme of weighted differences among the available diagnostic categories was developed for these analyses. As expected, incremental information from successive stages of data collection enabled the panel to increase their diagnostic agreement and rates of "correct" diagnoses. Over half of the total information was available, however, after review of only the initial telephone screening results (stage 1). A brief standardized videotape segment of the mental status and neurologic examinations provided substantial additional information. We were able to compare the final consensus diagnoses with autopsy results from seven individuals who had consensus clinical diagnoses of Probable or Possible AD (n = 6) or "demented, questionable etiology" (n = 1). All these subjects had Definite AD.
(C) Lippincott-Raven Publishers.
Cognitive and Behavioral Neurology 03/1996; 9(2). · 1.19 Impact Factor
[show abstract][hide abstract] ABSTRACT: Previous studies reveal significant relationships between some quantitative computed tomography (CT) measures and level of cognitive functioning in patients with Alzheimer's disease (AD). This study was designed to determine whether measurements from CT scans of AD patients could predict future rates of decline in cognitive function. Subjects were 8 men and 19 women diagnosed with probable AD. CT measures included bifrontal ratio, bicaudate ratio, and areas of lateral ventricles, third ventricle, and suprasellar cistern (SSC). Measures of cognitive and adaptive functioning were obtained at the time of the scan and on follow-up. Of the CT measures, the SSCR (SSC corrected for intracranial area) was the most highly correlated with Mini-Mental State Exam (MMSE) score and other cognitive measures at the time of the scan. Follow-up data were obtained for those 20 individuals who were mildly to moderately demented at the time of the scan (MMSE > or = 10). Rate of change was calculated for each neuropsychological measure. The SSCR correlated significantly with rate of change for MMSE and other measures of cognitive and adaptive functioning. This study demonstrates that CT measurement of the SSC can predict the subsequent rate of neurocognitive decline in AD patients.
Journal of the International Neuropsychological Society 03/1996; 2(2):89-95. · 2.70 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: We determined the apolipoprotein E4 (apoE) genotype in 12 cases of autopsy-confirmed hippocampal sclerosis dementia (HSD), a disorder characterized pathologically by neuronal degeneration, predominantly of temporal lobe structures, without senile plaques or neurofibrillary tangles. The frequency of the apoE4 allele in HSD was 12.5%, similar to that of a control population and significantly different from the approximately 40% found in Alzheimer's disease (AD) (P < 0.001). These observations suggest that apoE4 is not a risk factor for HSD.
[show abstract][hide abstract] ABSTRACT: 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.
American Journal of Psychiatry 01/1996; 152(12):1771-5. · 14.72 Impact Factor
[show abstract][hide abstract] ABSTRACT: To evaluate the efficacy of a dementia care program to reduce behavior disorders in nursing home patients with dementia.
Randomized controlled clinical trial with 6-month follow-up.
A 250-bed community nursing home.
The nursing home was screened to identify patients with dementia and behavior disorders. A total of 118 patients were eligible for randomization. Of these, 89 (75.4%) were randomized, and 81 of these (91.0%) completed the trial.
The A.G.E. dementia care program consisted of Activities, Guidelines for psychotropic medications, and Educational rounds. The control treatment was usual nursing home care.
Behavior disorders, antipsychotic drug and physical restraint use, patient activity levels, and cognitive and functional status.
After 6 months, 12 of 42 (28.6%) intervention patients exhibited behavior disorders compared with 20 of 39 (51.3%) controls (OR = 0.38; 95% CI [0.15, 0.95]; P = .037). Controls were more than twice as likely to receive antipsychotics (OR = 2.55, 95% CI [0.96, 6.76]; P < .056), to be restrained during activity times (OR = 2.98, 95% CI [1.10, 8.04]; P < .028), and to be restrained on nursing units (OR = 2.14, 95% CI [0.9, 5.3]; P < .10). Intervention patients were much more likely to participate in activities (OR = 13.71; 95% CI [4.51, 41.73]; P = .001).
The A.G.E. program reduces the prevalence of behavior disorders and the use of antipsychotic drugs and restraints. It is practical, feasible, and appears to improve the lives of patients with dementia in nursing homes.
Journal of the American Geriatrics Society 01/1996; 44(1):7-13. · 3.98 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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).
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.
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: To determine whether patients with Alzheimer's disease (AD) who do not have historical or clinical evidence of stroke but who do have computed tomographic or magnetic resonance imaging evidence of noncortical lesions smaller than 2 cm or periventricular "caps" differ from other patients with AD.
The computed tomographic or magnetic resonance imaging scans of 158 patients meeting criteria of the National Institute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association for probable AD were reviewed by one neuroradiologist. Two measures of disease severity--the Modified Mini-Mental State examination and the Blessed Dementia Rating Scale (Part I)--were subjected to two-way analysis of variance with scan type (computed tomography or magnetic resonance imaging) and lesion number as between-group factors and age and disease duration as covariates.
No relationship was seen between lesion number or periventricular caps and disease severity.
In this cross-sectional analysis using these clinical measures, patients with AD who have well-defined radiographic abnormalities cannot be differentiated from patients with AD who do not have them.
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: To assess interrater reliability and validity of NINCDS-ADRDA (National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association) criteria for Alzheimer's disease (AD).
A multisite reliability and validity study in which clinicians from each site diagnosed 60 case summaries yielding a preconsensus estimate of reliability and validity. A consensus conference was conducted for each disagreement, leading to a postconsensus estimate of validity. The criterion standard was a diagnosis of AD by autopsy.
Three academic medical centers.
A convenience sample of 60 detailed case summaries, 40 with AD and 20 with other dementing disorders.
The kappa coefficient, sensitivity, and specificity.
The kappa coefficient for preconsensus agreement on a diagnosis of probable or possible AD vs non-AD was 0.51; the sensitivity of a diagnosis of probable or possible AD for a pathological diagnosis of AD was 0.81, and the specificity was 0.73. The postconsensus sensitivity was 0.83, and the specificity was 0.84.
The results support the reliability and validity of NINCDS-ADRDA criteria and show that the consensus process may improve diagnostic accuracy. The cases are reviewed with a focus on the sources of diagnostic disagreements and errors and possible changes that might improve the accuracy of the criteria.
[show abstract][hide abstract] ABSTRACT: Developed the Dementia Signs and Symptoms (DSS) Scale and tested its reliability and validity. 56 patients with Alzheimer's disease (AD) were administered the DSS, the BEHAVE-AD by B. Reisberg et al (1987), the Cornell Scale for Depression in Dementia by G. S. Alexopoulos (see record
1989-03545-001), the Young Mania Rating Scales by R. C. Young et al (see record
1980-08727-001), the Hamilton Rating Scale for Depression, the Hamilton Rating Scale for Anxiety, and the Psychogeriatric Dependency Rating Scale. The DSS subscale scores correlated with corresponding scale scores, confirming construct validity. The DSS subscales were internally consistent, and the interrater reliability was high. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
American Journal of Geriatric Psychiatry 10/1994; · 4.13 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.