Alzheimer Disease: van Belle G

Stockbridge HL, Lewis D, Eisenberg B, Lee M, Schacher S, van Belle G, Keifer M, Brodkin CA, Buchwald D. · Washington State Department of Labor and Industries, Seattle, USA. · Nucl Med Commun. · Pubmed #12029208 No free full text.

Abstract: A detailed assessment of intra- and inter-reader variation in the interpretation of brain SPECT scans has been performed. A random sample was selected from scans performed at a community/teaching hospital in Seattle. Scans were interpreted independently by three experienced readers who were blinded to all patient information. Forty-eight scans were interpreted twice by each reader, for a total of 288 readings. Readers recorded detailed assessments of individual lesions and overall impressions using a standardized reporting form. Intra-observer agreement as reflected in per cent agreement for severity scores ranged from 65% to 100%. Intra-observer agreement on the 'overall impression' was very good for Alzheimer's pattern (kappa=0.73-1.00), and fair to good for the 'heterogeneous pattern' (kappa=0.30-0.63). Inter-observer agreement, as reflected in per cent agreement, ranged from 29% to 100%. Inter-observer agreement about the 'overall impression' was fair to moderate for Alzheimer's pattern (kappa=0.24-0.54) and was poor for the descriptors 'heterogeneous' and 'normal'. It is concluded that brain SPECT has great potential value in many important conditions. This study demonstrates a need for further work in the areas of pattern definition and reduction of observer variation.

Fillenbaum GG, van Belle G, Morris JC, Mohs RC, Mirra SS, Davis PC, Tariot PN, Silverman JM, Clark CM, Welsh-Bohmer KA, Heyman A. · Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, NC, USA. · Alzheimers Dement. · Pubmed #18631955 No free full text.

Abstract: The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) was funded by the National Institute on Aging in 1986 to develop standardized, validated measures for the assessment of Alzheimer's disease (AD). The present report describes the measures that CERAD developed during its first decade and their continued use in their original and translated forms. These measures include clinical, neuropsychological, neuropathologic, and behavioral assessments of AD and also assessment of family history and parkinsonism in AD. An approach to evaluating neuroimages did not meet the standards desired. Further evaluations that could not be completed because of lack of funding (but where some materials are available) include evaluation of very severe AD and of service use and need by patient and caregiver. The information that was developed in the U.S. and abroad permits standardized assessment of AD in clinical practice, facilitates epidemiologic studies, and provides information valuable for individual and public health planning. CERAD materials and data remain available for those wishing to use them.

Xiong C, Tang Y, van Belle G, Miller JP, Launer LJ, Morris JC. · Division of Biostatistics, Washington University, St. Louis, MO 63110, USA. · Neuroepidemiology. · Pubmed #18334827 No free full text.

Abstract: BACKGROUND/AIMS: To evaluate the quality of longitudinal statistical applications in published studies on Alzheimer's disease (AD). METHODS: A 21-item instrument, the Quality of Longitudinal AD Studies (QLADS), was developed by the research team (4 biostatisticians, 1 neuroepidemiologist, and 1 neurologist). All items were extensively discussed within the team for content validity. After pilot testing on 5 publications, the instrument was revised and tested for reliability with a sample of 40 published longitudinal AD studies randomly sampled from MEDLINE. RESULTS: Item-specific test-retest reliability coefficients for QLADS ranged from 0.53 to 1.00 with the associated standard error (SE) ranging from 0.02 to 0.13. The test-retest reliability for the overall score over the 21 items was high (intraclass correlation coefficient (ICC) = 0.94, 95% CI 0.90, 0.97). Item-specific inter-rater reliability coefficients for QLADS ranged from 0.46 to 1.00 with the associated SE ranging from 0.07 to 0.18. The inter-rater reliability for the overall score was also high (ICC = 0.87, 95% CI 0.77, 0.93). CONCLUSIONS: This study indicates that the quality of longitudinal statistical applications in AD publications can be reliably assessed.

Xiong C, Tang Y, van Belle G, Miller JP, Launer LJ, Bergmann KR, Morris JC. · Division of Biostatistics, Washington University, St. Louis, MO 63110, USA. · Neuroepidemiology. · Pubmed #17878738 No free full text.

Abstract: BACKGROUND/AIMS: To evaluate statistical applications in publications on Alzheimer's disease (AD). METHODS: Three instruments/checklists were developed: Assessment of Statistical Reporting (ASR; 44 items), Survey of Statistical Designs (SSD; 10 items), and Survey of Statistical Methods (SSM; 7 items). After a pilot testing on 5 AD publications, the instruments/checklists were revised and tested for reliability with a sample of 30 AD articles and for validity with another sample of 10 AD articles from MEDLINE. RESULTS: Item-specific test-retest and interrater reliability for ASR ranged from 0.29 to 1.0 with the associated standard errors (SEs) ranging from 0.01 to 0.31. The test-retest reliability (intraclass correlation coefficient = 0.94, 95% CI: 0.88-0.97) and the interrater reliability (intraclass correlation coefficient = 0.84, 95% CI: 0.69-0.92) for the overall score of ASR were high. The correlational validity of the ASR with a published checklist was also high (r = 0.74, SE = 0.24). The item-specific test-retest reliability in SSD and SSM ranged from 0.58 to 1.00 with the associated SEs ranging from 0.01 to 0.32. The item-specific interrater reliability in SSD and SSM ranged from 0.17 to 1.00 with the associated SEs ranging from 0.01 to 0.22. CONCLUSIONS: This study suggested that it was feasible to assess statistical applications in AD publications.

Wang L, Larson EB, Bowen JD, van Belle G. · Health Services Research and Development Center of Excellence, VA Puget Sound Health Care System, Seattle, USA. · Arch Intern Med. · Pubmed #16717174 links to  free full text

Abstract: BACKGROUND: The association of physical function with progression to dementia has not been well investigated. We aimed to determine whether physical function is associated with incident dementia and Alzheimer disease (AD). METHODS: We performed a prospective cohort study of 2288 persons 65 years and older without dementia. Patients were enrolled from 1994 to 1996 and followed up through October 2003. Main outcome measures included incident dementia and AD. RESULTS: During follow-up 319 participants developed dementia (221 had AD). The age-specific incidence rate of dementia was 53.1 per 1000 person-years for participants who scored lower on a performance-based physical function test at baseline (< or = 10 points) compared with 17.4 per 1000 person-years for those who scored higher (> 10 points). A 1-point lower performance-based physical function score was associated with an increased risk of dementia (hazard ratio, 1.08; 95% confidence interval, 1.03-1.13; P < .001), an increased risk of AD (hazard ratio, 1.06; 95% confidence interval, 1.01-1.12; P = .01), and an increased rate of decline in the Cognitive Ability Screening Instrument scores (0.11 point per year; 95% confidence interval, 0.08-0.14; P < .001) after adjusting for age, sex, years of education, baseline cognitive function, APOE epsilon4 allele, family history of AD, depression, coronary heart disease, and cerebrovascular disease. CONCLUSIONS: Lower levels of physical performance were associated with an increased risk of dementia and AD. The study suggests that poor physical function may precede the onset of dementia and AD and higher levels of physical function may be associated with a delayed onset.

Crane PK, Gibbons LE, Jolley L, van Belle G, Selleri R, Dalmonte E, De Ronchi D. · Department of Internal Medicine, Harborview Medical Center, University of Washington, Seattle, WA 98104, USA. · Int Psychogeriatr. · Pubmed #16478571 No free full text.

Abstract: BACKGROUND: Differential item functioning (DIF) exists when test item responses by members of different demographic groups are statistically different when controlling for ability. DIF may indicate item bias. Our objective was to determine whether items from the Italian Mini-mental State Examination (MMSE) had DIF related to educational attainment, age, gender and occupation. We were also interested in exploring the significance of DIF in screening tests. METHODS: In a two-stage study from Granarolo, Italy, residents over age 61 (n = 495) were evaluated with the Italian MMSE. Those with MMSE scores of 28 or lower were further evaluated for dementia. MMSE results were coded in 10 item bundles. We used ordinal logistic regression to determine whether item bundles had DIF. RESULTS: Six of the 10 MMSE item bundles had DIF in educational attainment subgroups. Four of these six bundles also had DIF related to age. Items that required literacy were much harder for those with lower educational attainment. CONCLUSIONS: DIF related to education appeared at as few as 3 years of formal schooling. These findings suggest cautious interpretation of data from studies using the Italian MMSE in populations with heterogeneous educational backgrounds. DIF is especially troublesome for two-stage studies that use screening tests.

Xiong C, van Belle G, Miller JP, Morris JC. · Division of Biostatistics, Washington University in St. Louis, St. Louis, MO 63110, USA. · Stat Med. · Pubmed #16345029 No free full text.

Abstract: This article studies the problem of measuring and estimating the diagnostic accuracy when there are three ordinal diagnostic groups. We use a receiver operating characteristic (ROC) surface to describe the probabilities of correct classifications into three diagnostic groups based on various sets of diagnostic thresholds of a test and propose to use the entire and the partial volume under the surface to measure the diagnostic accuracy. Mathematical properties and probabilistic interpretations of the proposed measure of diagnostic accuracy are discussed. Under the assumption of normal distributions of the diagnostic test from three diagnostic groups, we present the maximum likelihood estimate to the volume under the ROC surface and give the asymptotic variance to the estimate. We further propose several asymptotic confidence interval estimates to the volume under the ROC surface. The performance of these confidence interval estimates is evaluated in terms of attaining the nominal coverage probability based on a simulation study. In addition, we develop a method of sample size determination to achieve an adequate accuracy of the confidence interval estimate. Finally, we demonstrate the proposed methodology by applying it to the clinical diagnosis of early stage Alzheimer's disease based on the neuropsychological database of the Washington University Alzheimer's Disease Research Center.

Clark CM, DeCarli C, Mungas D, Chui HI, Higdon R, Nuñez J, Fernandez H, Negrón M, Manly J, Ferris S, Perez A, Torres M, Ewbank D, Glosser G, van Belle G. · Department of Neurology, Alzheimer's Disease Center, University of Pennsylvania, Philadelphia 19104, USA. · Arch Neurol. · Pubmed #15883265 links to  free full text

Abstract: BACKGROUND: Latino individuals are the largest minority group and the fastest growing population group in the United States, yet there are few studies comparing the clinical features of Alzheimer disease (AD) in this population with those found in Anglo (white non-Latino) patients. OBJECTIVE: To compare the age at AD symptom onset in Latino and Anglo individuals. DESIGN: Cross-sectional assessment using standardized methods to collect and compare age at AD symptom onset, demographic variables, and medical variables. SETTING: Five National Institute on Aging-sponsored Alzheimer's Disease Centers with experience evaluating Spanish-speaking individuals. PATIENTS: We evaluated 119 Latino and 55 Anglo patients who had a diagnosis of AD. MAIN OUTCOME MEASURE: Age at symptom onset. RESULTS: After adjusting for center, sex, and years of education, Latino patients had a mean age at symptom onset 6.8 years earlier (95% confidence interval, 3.5-10.3 years earlier) than Anglo patients. CONCLUSIONS: An earlier age at symptom onset suggests that US mainland Latino individuals may experience an increased burden of AD compared with Anglo individuals. The basis for the younger age at symptom onset remains obscure.

Beekly DL, Ramos EM, van Belle G, Deitrich W, Clark AD, Jacka ME, Kukull WA, Anonymous00017. · National Alzheimer's Coordinating Center, Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, Washington 98105, USA. · Alzheimer Dis Assoc Disord. · Pubmed #15592144 No free full text.

Abstract: The National Alzheimer's Coordinating Center (NACC) is responsible for developing and maintaining a database of patient information collected from the 29 Alzheimer disease centers (ADCs) funded by the National Institute on Aging. Each of the centers collects center-determined data elements on patients enrolled into its center and transmits a minimum dataset to NACC. Data are managed differently at each center depending on that center's research needs. The centers' data systems vary from a single personal computer running spreadsheet software to a network of servers running an advanced data management system such as Oracle. The challenge for NACC is to expand and adjust previously collected data elements into an integrated database that could be used for administrative as well as research purposes. In addition, NACC sought to allow the centers to have the flexibility they needed for data submission. To accomplish this task, NACC designed a database that contained separate specific datasets each with individual data elements. NACC also designed a data management system to easily collect and manage these data. The NACC web site (www.alz.washington.edu) was created to allow access to the data.

Li G, Higdon R, Kukull WA, Peskind E, Van Valen Moore K, Tsuang D, van Belle G, McCormick W, Bowen JD, Teri L, Schellenberg GD, Larson EB. · Department of Psychiatry and Behavioral Science, University of Washington, Seattle, USA. · Neurology. · Pubmed #15534246 No free full text.

Abstract: OBJECTIVE: To assess the association between statin therapy and risk of Alzheimer disease (AD) in a prospective cohort study with documented statin exposure and incident dementia. METHODS: This is a prospective, cohort study of statin use and incident dementia and probable AD. A cohort of 2,356 cognitively intact persons, aged 65 and older, were randomly selected from a health maintenance organization (HMO), and were assessed biennially for dementia. Statin use was identified using the HMO pharmacy database. A proportional hazards model with statin use as a time-dependent covariate was used to assess the statin-dementia/AD association. RESULTS: Among 312 participants with incident dementia, 168 had probable AD. The unadjusted hazard ratios (HRs) with statin use were 1.33 (95% CI 0.95 to 1.85) for all-cause dementia and 0.90 (CI 0.54 to 1.51) for probable AD. Adjusted corresponding HRs were 1.19 (CI 0.82 to 1.75) and 0.82 (CI 0.46 to 1.46). A subgroup analysis of participants with at least one APOE-epsilon4 allele who entered the study before age 80 produced an adjusted HR of 0.33 (CI 0.10 to 1.04). CONCLUSION: Employing time-dependent proportional hazards modeling, the authors found no significant association between statin use and incident dementia or probable AD. In contrast, when the data were analyzed, inappropriately, as a case-control study, the authors found an OR of 0.55 for probable AD, falsely indicating a protective effect of statins. Study design and analytic methods may explain the discrepancy between the current null findings and earlier findings.

Kukull WA, Higdon R, Bowen JD, McCormick WC, Teri L, Schellenberg GD, van Belle G, Jolley L, Larson EB. · National Alzheimer Coordinating Center, Department of Epidemiology, Box 357236, School of Public Health and Community Medicine, University of Washington, Seattle, WA 98195-7236, USA. · Arch Neurol. · Pubmed #12433261 links to  free full text

Abstract: CONTEXT: Age-specific incidence rates for dementia and Alzheimer disease (AD) are important for research and clinical practice. Incidence estimates for the United States are few and vary with the population sampled and study design; we present data that will contribute to a consensus of these rates. OBJECTIVES: To provide age-specific incidence estimates for dementia and AD and to estimate the association of sex, educational level, and apolipoprotein E genotype with onset. DESIGN: Prospective cohort study; begun in 1994 with follow-up interviews every 2 years. SETTING: Members of community-based, large health maintenance organization with demographics consistent with the surrounding base population; diagnostic evaluation by university-based study clinicians. SUBJECTS: Random sample of subjects aged 65 years or older from the base population; dementia free, nonnursing home residents. Of 5422 who were eligible, 2581 were enrolled, and 2356 had at least 1 follow-up evaluation (10 591 person-years of observation). MAIN OUTCOME MEASURE: Dementia and Alzheimer disease diagnoses were based on standard criteria. Age-specific incidence rates were calculated using a person-years approach with Poisson distribution confidence intervals. Cox proportional hazards model analysis was used to examine other factors. RESULTS: Two hundred fifteen cases of dementia and 151 cases of AD were diagnosed. Incidence rates for dementia and AD increase across the 5-year age groups; AD rates rise from 2.8 per 1000 person-years (age group, 65-69 years) to 56.1 per 1000 person-years in the older than 90-year age group. The rates nearly triple from the 75-to-79-year and 80-to-84-year age groups, but the relative increase is much less thereafter. Sex was not associated with AD onset. Educational level (>15 years vs <12 years) was associated with a decreased risk of AD; however, the association was also dependent on the baseline cognitive screening test score. CONCLUSIONS: Our dementia and AD incidence rates are consistent with recent US and European cohort studies, providing clinicians and researchers new information concerning the reproducibility of incidence estimates across settings. Increased risk was associated with age and the apolipoprotein E genotype; also with a low baseline cognitive screening test score. Educational level was inversely associated with the risk of dementia and positively associated with the baseline cognitive test score; thus, detection of AD by the screening test could also be influenced by educational level.

Gibbons LE, van Belle G, Yang M, Gill C, Brayne C, Huppert FA, Paykel E, Larson E. · Department of Psychosocial and Community Health, University of Washington, Seattle, Washington 98195, USA. · Int J Geriatr Psychiatry. · Pubmed #12211121 No free full text.

Abstract: OBJECTIVES: the relative difficulties of items on the Mini-Mental State Examination (MMSE) were compared in English-speaking Alzheimer's disease (AD) patients in the United States (US) and United Kingdom (UK). METHODS: participants were aged 75 and over, with a clinical diagnosis of AD according to standardized methods. Initial MMSE scores from an AD patient registry in the US (n = 401), and a field survey in the UK (n = 139) were compared. Item Characteristic Curve analysis (ICC) was used to calculate the relative difficulty of individual MMSE items, adjusted for the remaining MMSE items. Age, gender, education, and severity of disease were evaluated as possible confounders. RESULTS: UK participants found it relatively more difficult to name their county than US participants did to name their state. The relative difficulties of registration and recall, repeating a phrase, and following verbal directions also were significantly higher for the UK participants, even after adjustment for other factors. CONCLUSIONS: differences between the cohorts could be explained by translation artifacts in the test items or by cultural differences in the manifestation of AD. In this study, most, if not all differences can be explained by the former. ICC analysis can be used to develop tests that are functionally equivalent, a prerequisite for comparing dementia in different populations.

Moceri VM, Kukull WA, Emanual I, van Belle G, Starr JR, Schellenberg GD, McCormick WC, Bowen JD, Teri L, Larson EB. · Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, WA 98195-7236, USA. · Epidemiology. · Pubmed #11416775 No free full text.

Abstract: The early-life environment and its effect on growth and maturation of children and adolescents are associated with several adult chronic diseases, including Alzheimer's disease. Because it is not feasible to collect information prospectively over the average life span, methods to reconstruct the early-life environment of the aged are necessary to evaluate these associations. In a community-based case-control study conducted in the United States, we collected U.S. census records and birth certificates to reconstruct the early-life socioeconomic environment of each elderly subject. Information was found on 82% of the available Alzheimer's disease cases (239 of 292) and 87% of the available controls (245 of 282). We investigated risk of Alzheimer's disease associated with father's occupation, parental age, household size, sibship size, and birth order. Subjects whose fathers were unskilled manual workers or laborers were at higher risk for Alzheimer's disease (odds ratio = 1.80, 95% confidence interval = 1.19--2.73). The risk of Alzheimer's disease was increased with increasing number of people in the household. We also evaluated whether subjects with the apolipoprotein epsilon 4 allele (APOE epsilon 4), a strong genetic risk factor that is not a necessary cause or a sufficient cause by itself for the development of Alzheimer's disease, were at higher risk than subjects who did not carry this allele. Among subjects with the APOE epsilon 4 allele whose fathers held lower-socioeconomic level occupations, the odds of developing Alzheimer's disease were higher (odds ratio = 2.35, 95% confidence interval = 1.07--5.16) compared with subjects without the allele (odds ratio = 1.40, 95% confidence interval = 0.78--2.52). Subjects carrying the APOE epsilon 4 allele alone have a threefold increased risk of Alzheimer's disease (odds ratio = 3.17, 95% confidence interval = 1.99--5.04). Compared with subjects with neither risk factor, subjects with both the genetic and the environmental risk factors (household size of seven or more and father's occupation being manual) had a relatively high risk of Alzheimer's disease (odds ratio = 14.8, 95% confidence interval = 4.9--46). The data suggest that APOE epsilon 4 may modify the associations between father's occupation, other early-life environmental factors, and development of Alzheimer's disease in late life.

van Belle G, Arnold A. · Department of Environmental Health, Box 354691, University of Washington, Seattle, WA 98195-4691, USA. · Stat Med. · Pubmed #10844706 No free full text.

Abstract: Assessment of cognitive status is a key component of monitoring Alzheimer's patients during the course of their illness. The reliability of a cognitive test is a measure of its reproducibility under replicate conditions. In the classical setting, reliability is defined in three ways: the ratio of the variance of the true scores to the variance of the observed scores; the correlation of observed scores on two parallel forms of the test, and the square of the correlation between the observed score and the true score. In the classical case of independence of true scores and measurement errors, the three definitions are equivalent. Estimation of reliability through analysis of variance techniques and construction of confidence intervals is accomplished when the true scores and errors are normally distributed. This paper examines a non-parametric, probabilistic estimate of reliability as the probability that, given a parallel test, the second set of scores has the same ranking as the first set. In the classical case there is a monotonic relationship between this measure and the reliability. This measure is also linked to Kendall's tau. The performance of the probabilistic measure is compared with the traditional measures in a variety of models, including those with bounded scales, and those with skewed distributions. The ideas are extended to the case of the reliability of change scores and to biased estimators of true scores. In this context truncation models and Bayes estimates of true scores are considered.

Moceri VM, Kukull WA, Emanuel I, van Belle G, Larson EB. · Department of Epidemiology, University of Washington, Seattle 98195-7236, USA. · Neurology. · Pubmed #10668705 No free full text.

Abstract: OBJECTIVE: To investigate the association of early-life factors with AD. BACKGROUND: The early-life environment and its effect on growth and maturation of children and adolescents are linked to many adult chronic diseases (heart disease, stroke, hypertension, and diabetes mellitus), and these effects are also linked to maternal reproduction. AD may have an early-life link. The areas of the brain that show the earliest signs of AD are the same areas of the brain that take the longest to mature during childhood and adolescence. A poor-quality childhood or adolescent environment could prevent the brain from reaching complete levels of maturation. Lower levels of brain maturation may put people at higher risk for AD. METHODS: In a community-based case-control study (393 cases, 377 controls), we investigated the association of early-life factors and AD. Early-life variables include mother's age at patient's birth, birth order, number of siblings, and area of residence before age 18 years. Patient education level and apolipoprotein E (APOE) genotypes were also included in the analysis. Results: Area of residence before age 18 years and number of siblings are associated with subsequent development of AD. For each additional child in the family the risk of AD increases by 8% (OR = 1.08, 95% CI = 1.01 to 1.15). More controls compared with cases grew up in the suburbs (OR = 0.45, 95% CI = 0.25 to 0.82). APOE epsilon 4 and the patient's education level did not confound or modify the associations. CONCLUSIONS: The early-life childhood and adolescent environment is associated with the risk of AD.

Unger JM, van Belle G, Heyman A. · Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA. · J Am Geriatr Soc. · Pubmed #10323649 No free full text.

Abstract: OBJECTIVES: To investigate the effect of increasing age on cognition in nondemented older people. DESIGN: A cross-sectional and longitudinal analysis. PARTICIPANTS: A total of 454 control subjects for Alzheimer's cases from the cohort assembled by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). MEASUREMENT: The Mini-Mental State Examination (MMSE) to assess cognitive function. RESULTS: Cross-sectional estimates were derived by generalized linear models and longitudinal estimates by generalized estimating equations. The cross-sectional model indicated a small but significant decline in MMSE of -.4 points per 10 years. The longitudinal model indicated a small but significant increase in MMSE of about +.6 points per 10 years. Evidence of an early learning effect and nonrandom dropout exists. CONCLUSIONS: The question of "normal" aging can be approached by considering cross-sectional information and, usually separately, longitudinal information. This study does both using recently developed statistical methods. We conclude that there is a small but significant decline in scores on the MMSE with increasing population age. The effect can be masked in longitudinal cohorts by a learning effect (especially early in follow-up) and other factors associated with repeated testing.