G. van Belle

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease

The Neuropathology Task Force of the Consortium to Establish a Registry for Alzheimers Disease (CERAD) has developed a practical and standardized neuropathology protocol for the postmortem assessment of dementia and control subjects. The protocol provides neuropathologic definitions of such terms as “definite Alzheimers disease” (AD), “probable AD,” “possible AD,” and “normal brain” to indicate levels of diagnostic certainty, reduce subjective interpretation, and assure common language. To pretest the protocol, neuropathologists from 15 participating centers entered information on autopsy brains from 142 demented patients clinically diagnosed as probable AD and on eight nondemented patients. Eighty-four percent of the dementia cases fulfilled CERAD neuropathologic criteria for definite AD. As increasingly large numbers of prospectively studied dementia and control subjects are autopsied, the CERAD neuropathology protocol will help to refine diagnostic criteria, assess overlapping pathology, and lead to a better understanding of early subclinical changes of AD and normal aging.

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part I. Clinical and neuropsychological assesment of Alzheimer's disease

The Consortium to Establish a Registry for Alzheimers Disease (CERAD) has developed brief, comprehensive, and reliable batteries of clinical and neuropsychological tests for assessment of patients with the clinical diagnosis of Alzheimers disease (AD). We administered these batteries in a standardized manner to more than 350 subjects with a diagnosis of AD and 275 control subjects who were enrolled in a nationwide registry by a consortium of 16 university medical centers. The tests selected for this study measured the primary cognitive manifestations of AD across a range of severity of the disorder, and discriminated between normal subjects and those with mild and moderate dementia. The batteries also detected deterioration of language, memory, praxis, and general intellectual status in subjects returning for reassessment 1 year later. Interrater and testretest reliabilities were substantial. Long-term observations of this cohort are in progress in an effort to validate the clinical and neuropsychological assessments and to confirm the diagnosis by postmortem examinations. Although information on validation is limited thus far, the CERAD batteries appear to fill a need for a standardized, easily administered, and reliable instrument for evaluating persons with AD in multicenter research studies as well as in clinical practice.

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Part IV. Rates of cognitive change in the longitudinal assessment of probable Alzheimer's disease

Reliable information on rate of progression of cognitive impairment in probable Alzheimers disease (AD) is important for evaluating possible beneficial effects of therapeutic agents and in planning long-term care for patients with this chronic illness. However, wide variability exists in published rates of change for psychometric measures of the dementing process, and there is need for an accurate analysis of large numbers of persons with the disorder studied over long periods. Utilizing the large, well-characterized sample of the Consortium to Establish a Registry for Alzheimers Disease and employing a least squares regression method to adjust for different levels of impairment and periods of observation, we report rates of change on the Short Blessed Test, Mini-Mental State Examination, Blessed Dementia Scale, Clinical Dementia Rating, and other cognitive measures in 430 patients with probable AD (mean age at entry = 70.9 ± 8.0 SD years) studied for up to 4 years. We found that rate-of-change determinations are less reliable when the observation period is 1 year or less, that dementia progression may be nonlinear when described by certain measures, and that simple change scores do not accurately characterize the rate of decline. We also found that rate of progression in AD is determined by the severity of cognitive impairment: the less severe the dementia, the slower the rate of decline.

Prognosis in amyotrophic lateral sclerosis: A population-based study

Background: Accurate information on prognosis of ALS is useful to patients, families, and clinicians. Methods: In a population-based study of ALS in western Washington, the authors assembled a cohort of 180 patients with incident ALS between 1990 and 1994. Information on potential prognostic factors was collected during an in-person interview. Patients also completed the Medical Outcomes Study Short Form 36 (SF-36). Vital status through December 1999 was known for all patients. Results: Median survival was 32 months from onset of symptoms and 19 months from diagnosis. The 5-year survival after diagnosis was 7%. Older age and female sex were strongly associated with poor survival. In multivariable Cox proportional hazards regression models, factors significantly and independently associated with a worse prognosis included older age, any bulbar features at onset, shorter time from symptom onset to diagnosis, lack of a marital partner, and residence in King County. Recursive partitioning identified age, time from symptom onset to diagnosis, and marital status as the strongest predictors of survival. Good summary scores for physical health on the SF-36, but not for mental health, were significantly associated with longer survival than poor scores. Conclusion: These findings are consistent with other population-based studies of ALS and confirm its pernicious nature. Older age, female sex, any bulbar features at onset, short time from symptom onset to diagnosis, lack of a marital partner, and disease severity are key prognostic factors. Serial measurement of severity would likely improve predictions.

Progestagen supplementation of exogenous oestrogens and risk of endometrial cancer

The favourable effects of exogenous progestagen on the endometrium are well known, but have not been adequately quantified with respect to endometrial cancer. The benefits of progestagen need to be weighted against its possible untoward effects on the risk of breast cancer and cardiovascular disease. A population-based case-control study of endometrial cancer was undertaken to evaluate the benefits of progestagen use. 158 incident cases were identified between 1985 and 1987 among women aged 40-64 years who were residents of King County, Washington. Detailed interviews were conducted and the responses were compared with those of 182 controls selected by random telephone digit dialling. The risk of endometrial cancer among women who had used unopposed oestrogen for more than 3 years was over five times that of women who had used no hormones (relative risk [RR] 5.7, 95% confidence interval [Cl] 2.5-12.8), whereas those who had also used a progestagen for at least six months of that time had an RR of only 1.6 (95% Cl 0.6-3.9). The RR differed according to days per month that progestagen was used: 2.4 (0.6-9.3) for progestagen use of less than 10 days per month versus 1.1 (0.4-3.6) for use of 10 or more days per month. These results provide additional evidence that the use of progestagen for 10 or more days per cycle can reduce the excess risk of endometrial cancer associated with long-term postmenopausal oestrogen use.

Cigarette smoking, alcohol use, and subarachnoid hemorrhage.

Background and Purpose: Subarachnoid hemorrhage remains a devastating disease. Identification of etiologic risk factors would allow the possibility of prevention. Methods: We conducted a population-based case-control study in King County, Washington. Patients whose bleeds originated from a source other than an aneurysm were excluded. Two age- and gendermatched control subjects were identified for each case through random digit telephone dialing. A standardized in-person interview was conducted with the patient whenever possible, a proxy respondent for the case in all instances, the two control subjects, and their proxies. Analyses involved conditional logistic regression taking into account matching on age, gender and respondent type. Results: Over 2 years, 169 cases were identified, and 149 participated in the case-control study. Compared with those who never smoked, the odds ratio for current heavy smokers (>20 cigarettes/day) was 11.1 (95% confidence interval [CI], 5.0-24.9); for current light smokers (≤20 cigarettes/day), 4.1 (95% CI, 2.3-7.3); and for former smokers, 1.8 (95% CI, 1.0-3.2). The risk associated with smoking was greatest in the 3 hours after a cigarette (odds ratio [OR]=7.0; 95% CI, 3.7-13.1) and then fell, not reaching the risk in those who had never smoked until more than 10 years had passed since the last cigarette. Heavy alcohol use (>2 drinks/day) was also associated with bleeds (OR=2.2; 95% CI, 0.9-5.1, after adjusting for smoking status). These associations were not substantially altered after adjusting for several possible confounding factors, including a history of hypertension. Conclusions: Cigarette smoking and heavy alcohol use are associated with the occurrence of subarachnoid hemorrhage.

Statin therapy and risk of dementia in the elderly A community-based prospective cohort study

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-ε4 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.

Relationship between cigarette smoking and Alzheimer's disease in a population‐based case‐control study

We investigated whether cigarette smoking is negatively associated with Alzheimers disease (AD) in a population-based, frequency-matched, case-control study of 152 AD patients and 180 controls. Ever having smoked was associated with lower risk of AD (adjusted odds ratio = 0.61; 95% confidence interval: 0.37–0.99). Additional multivariate analyses demonstrated that education and history of hypertension modified this association. The direction of the modification was for higher education level and history of hypertension to further reduce the risk. The “dose response” pattern showed the greatest risk reduction among those who smoked least and suggests a biologic mechanism of a dose-dependent up-regulation of nicotinic (cholinergic) brain receptors. These data, although consistent with current opinion about pathophysiology of AD, do not suggest smoking should be used as a preventive strategy for AD.

Early-life risk factors and the development of Alzheimer's disease

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 ε4 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.

Dietary vitamin C and bone mineral density in postmenopausal women in Washington State, USA.

STUDY OBJECTIVE: To examine the relationship between dietary vitamin C and hip bone mineral density (BMD) in postmenopausal women. DESIGN: This was a cross sectional study using retrospective diet and vitamin supplement data. SETTING: The Seattle area of Washington State. PARTICIPANTS: Screenees for a clinical trial of a drug to prevent osteoporotic fractures; 1892 women aged 55-80 years who had hip bone densitometry and osteoporosis risk factor information. MAIN RESULTS: Mean energy adjusted dietary intake of vitamin C was 113 mg/day; including supplement use, mean intake was 407 mg/day. There were no differences in BMD according to diet-only vitamin C intake or combined dietary and supplemental vitamin C intake. Longer duration of vitamin C supplement use was associated with higher BMD in women who had not used oestrogen replacement therapy (trend p = 0.02) and among women aged 55-64 years (trend p = 0.01). Women aged 55-64 years who used vitamin C supplements for > or = 10 years had a higher BMD than non-users aged 55-64 years (multivariate adjusted mean BMD 0.699 (0.017) g/cm2 versus 0.655 (0.007) g/cm2, p = 0.02). Benefits were not evident in older age groups or in women who had used oestrogen in the past. Frequent intake of foods rich in vitamin C was not associated with BMD. CONCLUSION: There was no evidence that vitamin C from the diet was associated with BMD, although long term use of vitamin C supplements was associated with a higher BMD in the early postmenopausal years and among never users of oestrogen.