Search PubMed⌕ Search

Biomedical subjects

W A Kukull

Publications and source records attributed to W A Kukull.

At least 37 records · Page 2Linked to original sources
PubMed1998

Accelerated decline in apolipoprotein E-epsilon4 homozygotes with Alzheimer's disease.

BACKGROUND: The apolipoprotein E-epsilon4 (APOE-epsilon4) allele is a powerful genetic risk factor for the development of Alzheimer's disease (AD). AD patients who are APOE-epsilon4 homozygotes have an earlier age at onset, increased amyloid burden, and decreased acetylcholine levels--findings that suggest differences in disease severity or rate of progression. Studies of genotype differences in rate of decline, however, have produced negative results that may be due to methodologic biases. The current study examined rate of decline in the largest sample of APOE-genotyped AD patients for whom longitudinal cognitive data have been reported. METHODS: Newly diagnosed patients with probable AD (n = 201) comprised four genotype groups: epsilon2/3 (n = 14), epsilon3/3 (n = 75), epsilon3/4 (n = 82), and epsilon4/4 (n = 30). The Dementia Rating Scale (DRS) was administered at baseline and then annually for 1 to 6 years (mean, 2.5 years). For each subject, a DRS slope was calculated reflecting annual rate of decline. Rate of decline as measured by DRS slope differed according to genotype, with the effect modified by DRS score (p < 0.014). At the mean DRS score observed in our sample (DRS = 105), the epsilon4/4 group had an increased rate of decline (11.9 points per year) relative to the epsilon2/3 (5.8 points per year; p < 0.003), epsilon3/3 (9.3 points per year; p < 0.076), and epsilon3/4 (9.6 points per year; p < 0.055) groups. At a lower DRS score (DRS = 80), even larger differences were observed among genotypes; the epsilon4/4 group had a increased rate of decline (22.2 points per year) relative to the epsilon2/3 (9.7 points per year; p < 0.0006), epsilon3/4 (15.8 points per year; p < 0.020), and epsilon3/3 (18.2 points per year; p < 0.173) groups. The epsilon2/3 group had a significantly slower rate of decline than all other groups at DRS scores of 80 or 105. CONCLUSIONS: APOE-epsilon4 homozygosity is associated with a faster rate of cognitive decline, whereas the epsilon2 allele slows disease progression. These findings suggest that APOE plays a mechanistic role in the progression of AD, and is not simply related to disease onset.

Age of Onset↗
PubMed1998

Progression of Alzheimer's disease in black and white patients: the CERAD experience, part XVI. Consortium to Establish a Registry for Alzheimer's Disease.

We compared the progression of Alzheimer's disease (AD) in CERAD-enrolled black and white patients, as indicated by changes in selected clinical and neuropsychology measures, over a 1-year time interval. Of 225 black and 935 white AD patients who were enrolled, 148 (66%) black and 770 (82%) white patients remained in the study. Of these, 82 black and 532 white patients provided complete in-person information on first annual re-evaluation. Overall, with age, education, initial level of performance on each measure, and stage of disease at entry controlled, race had a very mild effect on change in disease (8 df multivariate analysis of variance [MANOVA], p < 0.047). Black patients showed less decline than white patients, most notably for the CERAD Boston Naming test (p < 0.02) and the third and final trial of the 10-item Word List Learning task (p < 0.003). Although unadjusted data indicate that black and white patients appear to differ notably at entry, our findings indicated that differences in progression of the dementing process are minor, suggesting that course of AD is comparable in these racial groups. Examination over a longer period is difficult because of the high attrition rate of black patients.

Aged↗
PubMed1998

Exercise and activity level in Alzheimer's disease: a potential treatment focus.

This article provides information on the baseline health and physical function of 30 individuals with Alzheimer's disease (AD); describes a community-based program designed to increase balance, flexibility, strength, and endurance in these persons by the training of caregivers to facilitate and supervise exercise activity; and documents the adherence of these subjects and their caregivers to this intervention. Subjects were recruited from an ongoing, community-based Alzheimer's Disease Patient Registry, and met NINCDS-ADRDA criteria for probable or possible AD. Caregivers were family members living with the demented individuals in the community. Physical performance was measured using walking speed, functional reach, and standing balance. Health status was measured with the Medical Outcomes Study Short Form, the Sickness Impact Profile, and caregiver reports of subject's restricted activity days, bed disability days, falls, and exercise participation. Baseline data indicated that persons with AD were impaired on measures of physical performance and function, compared to published data on nondemented older adults. During a 12-wk treatment period, caregivers were taught to guide their demented charges in an individualized program of endurance activities (primarily walking), strength training, and balance and flexibility exercises. Adherence data indicated that 100% of the subjects were compliant with some exercise recommendations, and one-third completed all assigned exercises during the training period. Caregivers were able to learn and direct subjects during scheduled exercise activities. These findings indicate that the integration of exercise training into the care of persons with AD is both needed and feasible. Further research is currently underway to determine the efficacy of this approach for reducing additional physical disability in these individuals.

Activities of Daily Living↗
PubMed1997

Head injury and risk of Alzheimer's disease by apolipoprotein E genotype.

Head injury and apolipoprotein E (APOE)-epsilon 4 (e4) genotype have each been associated with increased risk of Alzheimer's disease. If APOE-e4 affects neuronal viability and branching, and if response to head injury differs in e4 patients, then the association between head injury and Alzheimer's disease may vary with the presence of the e4 allele. The authors examined this association in a case-control study conducted between 1987 and 1995 among enrollees of the Group Health Cooperative of Puget Sound, a health maintenance organization in Seattle, Washington. Proxy informants reported prior head injury with loss of consciousness for 32 of 349 patients with probable Alzheimer's disease and for 16 of 342 control subjects of similar age and sex who had been randomly selected from the same population (odds ratio (OR) = 2.1, 95% confidence interval (CI) 1.1-3.8). Elevated risk was observed among men (OR = 4.2, 95% CI 1.5-11.5) but not among women (OR = 1.1, 95% CI 0.5-2.6). No significant variation in the head injury-Alzheimer's disease risk relation by APOE-e4 genotype was found among 230 cases and 309 controls (OR = 3.1 (95% CI 0.7-14.6) for persons with at least one e4 allele and OR = 2.0 (95% CI 0.8-5.2) for those without e4). Neither age, education, race, type of proxy informant, nor duration of relationship with the proxy confounded the association. Head injury with loss of consciousness, although uncommon in this sample, was associated with increased risk of Alzheimer's disease. APOE-e4 was an independent risk factor which neither modified nor confounded the association. Susceptibility to Alzheimer's disease as conferred by APOE-e4 does not appear to increase the risk associated with head injury.

Aged↗
PubMed1997

Alzheimer's disease and history of blood transfusion by apolipoprotein-E genotype.

Some dementias, such as Creutzfeldt-Jakob disease, may result from transmissible agents. To assess the possibility of a blood-borne transmissible agent in Alzheimer's disease (AD), we compared informant-reported history of blood transfusions among 326 newly recognized probable AD cases and 330 control subjects of similar age and sex, randomly selected from the same health maintenance organization population. Since risk of AD is increased in persons with apolipoprotein E epsilon 4 (APOE-e4) alleles, we examined whether the transfusion-AD relationship varies by APOE genotype. Transfusion was more frequent among controls (17.9%) than cases (12.0%) in the overall group (crude odds ratio = 0.62; 95% confidence interval = 0.40, 0.97). Similar risks were seen for transfusions occurring < or = or > 10 years before the reference year. Stratified analysis by APOE-e4 genotype showed no effect modification. Logistic regression adjusting for age, sex, education, and presence of e4 did not change the transfusion-AD association. We conclude that a history of blood transfusion is not associated with increased risk of AD, nor does consideration of APOE-e4 status modify that conclusion.

Aged↗
PubMed1996

Apolipoprotein E in Alzheimer's disease risk and case detection: a case-control study.

The objective of this study was to describe the association between the epsilon 4 allele of the apolipoprotein E gene (APOE E4) and Alzheimer's disease (AD) and to evaluate APOE E4 genotyping as a test for AD. The study base of this case-control study included about 23,000 persons 60 year of age or greater (a large health maintenance organization); the demographic characteristics of this group are similar to those of the surrounding area. Analysis focused on 234 Caucasian probable AD patients first identified between 1987 and 1993; and 304 cognitively intact controls of similar age, sex, and race who were randomly selected from the same study base. All cases were examined and diagnosed by study physicians using standard protocols. All subjects participate in continuing annual follow-up testing to verify their cognitive status. APOE genotypes were determined from blood samples using standard laboratory methods. Subject characteristics and diagnoses were obtained from interviews, diagnostic examination, or medical record review. Heterozygous E4 individuals had a crude odds ratio of 3.1 (2.1-4.5) for AD compared to those with no E4, while homozygous E4 subjects had an odds ratio of 34.3 (8.0-146.3) for AD. As an indicator of AD, having one E4 allele showed a sensitivity of 0.52 and a specificity of 0.74. Homozygous E4 genotype had a sensitivity of 0.23 and a specificity of 0.99 (when compared to non-E4 genotypes). Cardiovascular disease differed in cases and controls, but did not confound or modify the APOE E4-AI) association. In this study base, the APOE E4 allele was a significant risk factor. However, considering either homozygous or heterozygous E4 genotype as a screen or diagnostic marker for AD would miss many true cases and could misclassify many normals as AD.

Aged↗
PubMed1996

Prevention of Alzheimer disease: a perspective based on successes in the prevention of other chronic diseases.

Alzheimer disease, like other common chronic diseases, likely has genetic and environmental risk factors. Prevention of arteriosclerotic vascular disease has occurred based on efforts to reduce risk factors demonstrated in epidemiologic and more basic science research. At present, there are no known risk factors for Alzheimer disease which could form the basis of a preventive strategy. To make progress in the prevention of Alzheimer disease, new findings from epidemiology and basic science will be needed. The current state of the art of epidemiologic studies of dementia is well enough developed to test credible hypotheses. The availability of reliable biomarkers along with cooperative efforts between molecular biologists and clinical epidemiologists should allow us to pursue promising fields in clinical research.

Alzheimer Disease↗
PubMed1996

Risk of dementia among relatives of Alzheimer's disease patients in the MIRAGE study: What is in store for the oldest old?

Despite recent advances in the molecular genetics of Alzheimer's disease (AD), several fundamental questions concerning risk of illness are unresolved, namely, if Mendelian factors account for the incidence of the disease, and if AD is an inevitable consequence of the aging process. This study was designed to address these issues and other aspects of familial aggregation of the disorder. A consecutive sample of 1,694 patients who met criteria for a diagnosis of probable or definite AD were ascertained in 13 centers participating in the Multi-Institutional Research in Alzheimer Genetic Epidemiology (MIRAGE) project. Lifetime risk and age at onset of AD among various strata of 12,971 first-degree relatives was estimated using survival analysis procedures. The lifetime risk of AD in first-degree relatives was 39.0% +/- 2.1% by age 96 years. Age-specific risk of AD declined after age 90 and the data set included 61 apparently unaffected persons who survived to age 96 without becoming demented. Female relatives had a higher risk of AD than male relatives at all ages. By age 80, children of conjugal AD couples had a cumulative risk of 54%, 1.5 times greater than the sum of the risks to children having affected mothers or fathers, and nearly 5 times greater than the risk to children having normal parents. Children of affected fathers had a cumulative risk that was 1.4 times the corresponding risk to children of affected mothers. Risk assessment in early-onset and late-onset families, using various strategies for determining the age cut-off, yielded contradictory results. These data suggest the following: (1) the lifetime risk among relatives does not support a simple autosomal dominant inheritance pattern of disease; (2) women are innately more susceptible to AD than men; (3) the proportion of hereditary cases may be higher in men than women; (4) distinction between early- onset and late-onset forms of AD has little meaning in the absence of a biological marker; (5) the risk of AD decreases after age 90; and (6) AD therefore may not be an inevitable concomitant of the aging process, a conclusion that has profound implications for basic and applied AD research. The age- and sex-specific lifetime risks derived from this study are sufficiently robust to be a reliable source of information for counseling relatives of AD patients.

Age Factors↗
PubMed1996

Predictors of mortality in patients diagnosed with probable Alzheimer's disease.

OBJECTIVE: We sought to identify factors associated with mortality in persons recently diagnosed with probable Alzheimer's disease (AD). BACKGROUND: Predicting mortality in AD in needed both in patient care and public health planning. Previous studies have identified several factors which contribute to mortality in AD, but few longitudinal studies of population-based cohorts exist. METHODS: In a longitudinal follow-up study 327 patients with newly diagnosed probable AD (mean Mini-Mental State Examination [MMSE] score of 20) from a large, stable health maintenance organization were identified. Demographic characteristics, dementia severity, and comorbid conditions were identified at enrollment. Patients were followed longitudinally (median 3.3 years, total 898 person-years). Baseline characteristics were used to predict survival in univariate and multivariate models. RESULTS: Increased mortality was seen in patients with probable AD (9.0 deaths per 100 person-years) compared with the community population adjusted for age and gender (4.3 deaths per 100 person-years). On univariate analysis we found increased age, male gender, impairment on MMSE or Blessed dementia rating scale (DRS), rate of MMSE decline, wandering or agitation, vascular disease, and sensory impairment affecting the ability to read or hear to be moderately associated with decreased survival. After adjusting for age and gender in a multivariate model, Blessed DRS score and sensory impairment affecting the ability to read were independently associated with decreased survival. CONCLUSIONS: Short-term mortality is increased in patients newly diagnosed with probable AD. Measures of dementia severity, measures of general debility, and vascular disease are associated with increased mortality. Of these, general debility and sensory impairment were more strongly associated with shortened survival.

Aged↗
PubMed1995

Solvent exposure as a risk factor for Alzheimer's disease: a case-control study.

This case-control study investigates whether history of organic solvent exposure is associated with increased risk of Alzheimer's disease. The study base includes about 23,000 persons aged 60 years or more from the local membership of a health maintenance organization in Seattle, Washington, who entered the study between 1987 and 1992. Probable Alzheimer's disease cases (n = 193) who had presented with new dementia symptoms were identified, enrolled, and diagnosed by our Alzheimer's Disease Patient Registry following standardized criteria. Control subjects (n = 243), free of dementia and neurologic disease causing dementia, were selected randomly from the study base and frequency matched to cases for age and sex. Proxy informants provided specific solvent exposure history as well as job descriptions likely to involve solvent use as part of a comprehensive risk factor interview. Kappa statistics indicated substantial agreement for control-control proxy solvent responses. History of exposure to one or more solvent groups (benzene and toluene; phenols and alcohols; ketones; other solvents) yielded an adjusted Alzheimer's disease odds ratio of 2.3 (95 percent confidence interval 1.1-4.7); among males only, it increased to 6.0 (95% confidence interval 2.1-17.2). Thus, past exposure to organic solvents may be associated with onset of Alzheimer's disease.

Age Factors↗
PubMed1995

The effect of diagnosing Alzheimer's disease on frequency of physician visits: a case-control study.

OBJECTIVE: Two groups of elderly subjects were studied to see whether patterns of visits to physicians changed after one group received the diagnosis of Alzheimer's disease. DESIGN: Case-control study. SETTING: Health maintenance organization (HMO). PATIENTS/PARTICIPANTS: Two groups of ambulatory subjects (mean age 77 years) were enrolled from an HMO population for this case-control study: 120 cases had probable Alzheimer's disease diagnosed at enrollment, and another 120 cognitively intact controls with similar comorbidity were enrolled after being frequency-matched for age and gender. Exclusion criteria were nursing home admission and death during the study period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Medical records were examined for a four-year period: two years prior to and two years following enrollment and diagnosis. Physician visits declined slightly after enrollment for the persons receiving the diagnosis of Alzheimer's disease [17.5/2 years prior vs 16.5/2 years after (NS)], whereas visits increased over time for the controls [13.7/2 vs 16.3/2 (p < 0.05)], hence the rates were similar after enrollment [16.5 vs 16.3 (NS)]. The proportion of subjects with fewer visits during the period after enrollment was higher among the cases than it was among the controls [54% vs 37%; odds ratio = 2.0 (95% confidence interval = 1.6, 3.1)]. Hospitalizations and emergency department use did not change significantly after enrollment. CONCLUSIONS: Physician visit frequency was high before, then decreased after, demented patients received their diagnosis, approaching the frequency in a control population without dementia. This phenomenon cannot be accounted for by nursing home placement, comorbidity, or mortality. Increased hospitalization and emergency department use did not ensue after diagnosis.

Aged↗
PubMed1995

Cognitive decline in Alzheimer's disease: a longitudinal investigation of risk factors for accelerated decline.

BACKGROUND: --Although Alzheimer's disease (AD) is a progressive degenerative condition, there is great intra- and inter-individual variability in rates of cognitive decline. Thus far, little data exist to explain such variability. Studies that have attempted to explain it have often been based on cross-sectional designs, small sample sizes, and clinical population data. They have also failed to correct for level of cognitive function, despite clinical evidence that rate of decline varies among patients with varying levels of cognitive ability. METHODS: This study presents longitudinal data on a community-based sample of 156 patients diagnosed with probable AD, followed annually for one to five years (average age at entry = 79, range 54-91 years). The effect of level of cognitive impairment (as measured by the MMSE and Mattis DRS), demographic characteristics (e.g., education and age), behavioral problems (e.g., agitation), and co-existent health problems (e.g., vascular disease) on rate of decline was investigated via multivariate regression analysis. RESULTS: Study results indicate that the average rate of decline in cognitive function, as measured by the MMSE and mDRS, becomes more rapid as the disease progresses. Higher education, younger age, and agitation at intake were also significantly related to increased rates of cognitive decline.

Aged↗
PubMed1995

History of depression as a risk factor for Alzheimer's disease.

Research regarding the possible association between Alzheimer's disease and a history of depression has been inconclusive. Using a case-control design, we assessed the strength of the association between reported history of depression and onset of Alzheimer's disease. We enrolled probable Alzheimer's disease cases (N = 294), who were ascertained and diagnosed by our Alzheimer's Disease Patient Registry, and randomly selected nondemented controls (N = 300) of similar age and gender from the same base population. The mean age (for cases) was 78.5 years. Informants provided data regarding history of depression. "Treated depression" was defined as depression for which a physician/psychologist consultation, medication, or hospitalization had occurred. Restricting treated depression to exclude primary loss or grief reactions, we found a modest association with Alzheimer's disease [odds ratio (OR) = 1.8; 95% confidence interval (CI) = 0.9-3.5] after adjusting for gender, age, education, and type of informant. When these data were stratified by depression onset year, we observed an odds ratio of 2.0 (95% CI = 0.9-4.6) for depression occurring more than 10 years before the onset of dementia symptoms, and an OR of 0.9 (95% CI = 0.2-3.0) for depression onset within 10 years of the onset of dementia symptoms. Thus, depressive episodes occurring well before dementia symptom onset appear to increase the risk of Alzheimer's disease.

Age Distribution↗
PubMed1995

Interactions of apolipoprotein E genotype, total cholesterol level, age, and sex in prediction of Alzheimer's disease: a case-control study.

OBJECTIVE: The joint effects of total cholesterol (TC) levels and the APOE genotype in Alzheimer's disease (AD) were evaluated because of previous reports that the APOE locus epsilon 4 allele was associated with both late-onset AD and elevated TC. DESIGN: Logistic regression was used to determine the effects of the APOE genotype, TC, age, and sex on prediction of AD in a community-based study of 206 cases and 276 controls. RESULTS: The relationship of the APOE genotype and AD was dependent on TC, age, and sex. However, current TC level does not fully explain the epsilon 4-Alzheimer's disease association. Affected men with higher TC and age under 80 years had the highest epsilon 4 allele frequencies. The epsilon 4 frequency declined significantly with age. SIGNIFICANCE: A pathologic role of higher TC or cholesterol-based differential survival of epsilon 4-carrying individuals may be involved in the relationship of the epsilon 4 allele with AD. The observed association of the APOE genotype and AD is expected to depend on the age, sex, and TC distributions of a given sample.

Aged↗
PubMed1994

Postmenopausal estrogen replacement therapy and the risk of Alzheimer's disease: a population-based case-control study.

Preliminary animal and human data suggest that estrogens may be protective against Alzheimer's disease in women. In a population-based case-control study at Group Health Cooperative of Puget Sound, Seattle, Washington, the authors compared the exposure of estrogen replacement therapy of 107 female Alzheimer's disease cases with 120 age- and sex-matched controls by using computerized pharmacy data. The cases were obtained from the Alzheimer's Disease Patient Registry of the University of Washington, Seattle, Washington, which is based on the enumerated health plan population from 1987 to 1992. Newly recognized cases of probable Alzheimer's disease according to standardized diagnostic criteria were ascertained, evaluated, and enrolled in the Registry. The controls were selected from the same defined population by stratified random sampling. When the authors applied logistic regression, ever use of estrogens did not show an association with Alzheimer's disease (adjusted odds ratio = 1.1, 95 percent confidence interval 0.6-1.8). Oral and vaginal estrogens yielded similar results. In conclusion, this study provides no evidence that estrogen replacement therapy has an impact on the risk of Alzheimer's disease in women.

Administration, Intravaginal↗
PubMed1994

The Mini-Mental State Examination score and the clinical diagnosis of dementia.

To set a working cutoff score for the referral to diagnostic examination, we evaluated 150 consecutive patients with complaints potentially related to dementia, using the Mini-Mental State Examination (MMSE). All patients were later given a complete, standardized work-up and diagnosis as part of our Alzheimer's Disease Patient Registry protocol. Dementia diagnosis was made, consistent with accepted criteria, by consensus of the physicians and psychologist. Diagnosis was reaffirmed after 1-year follow-up exam; 133 of the 150 original patients completed follow-up (80 dementia, 53 no dementia). We evaluated the initial MMSE score compared with the follow-up diagnosis. Sensitivity, specificity, and predictive values were calculated for MMSE scores ranging from 22 through 29. The conventional cutoff score of < 24 shows a sensitivity of 0.63 and a specificity of 0.96; sensitivity increased at higher cutoff scores. Multivariate analysis showed that educational level added significant prediction only at scores of > or = 27. We conclude that an MMSE score of 26 or 27 should be used as a cutoff score in symptomatic populations with similar educational and socioeconomic backgrounds when the goal is to miss few true cases. Population surveys where the expected prevalence is low may require a different cutoff score to indicate the need for further diagnostic evaluation.

Aged↗