In-home assessment of dementia by nurses: experience using the CERAD evaluations. Consortium to Establish a Registry for Alzheimer's Disease.

PURPOSE OF STUDY: To maximize respondent participation in a study of the prevalence, incidence, and natural history of dementia. DESIGN AND METHODS: Clinical research nurses were trained to carry out evaluations for dementia in the home. We describe the assessment and training procedures used and note the advantages and drawbacks of this approach. RESULTS: Nurse identification of the presence of dementia agreed well with that of medical specialists (kappa = 0.84), but was slightly poorer regarding type of dementia (kappa = 0.71). IMPLICATIONS: Use of nurses for such activity need not be limited to epidemiological studies, but is relevant also in clinical practice.

Performance of elderly African American and White community residents on the CERAD Neuropsychological Battery.

The CERAD Neuropsychological Battery, includes 7 measures: Verbal Fluency; Modified Boston Naming; Mini-Mental State: Word List Learning, Recall and Recognition; Constructional Praxis. It was originally developed to evaluate patients with a clinical diagnosis of Alzheimer's disease, but is increasingly used in epidemiological studies of the incidence and prevalence of dementia in the elderly. The current study reports norms for African American and White representative community residents 71 years of age and older in North Carolina, and compares performance with that of African Americans in Indianapolis and with Whites in the Monongahela Valley, Pennsylvania. For all 3 studies, increased education and younger age was related to better performance on each of the 7 measures. Sex differences, when present, tended to favor women. Although on average African Americans performed more poorly than Whites, with demographic characteristics controlled, no significant racial differences were found in the North Carolina sample. Both African American and White participants in North Carolina performed more poorly than their racial counterparts in the other 2 studies, possibly because of selection-induced differences in health and educational status. Nevertheless, the use of an identical evaluation battery, such as the CERAD neuropsychologic instrument, facilitates comparisons not otherwise possible, and should be encouraged.

Use and cost of outpatient visits of AD patients: CERAD XXII.

OBJECTIVE: To determine the probability, frequency, and cost of outpatient visits of patients with AD in the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) as a function of stage of dementia and institutional status. METHODS: Clinical information on 388 patients with AD enrolled in CERAD who had no serious comorbidities at baseline and for whom the stage of disease and institutional status were known, were linked to Health Care Financing Administration Physician/Supplier and Outpatient Standard Analytic (institutional outpatient) files for 1991 through 1995. None was registered in a health maintenance organization. Repeated measures regression models were used to examine the relationship of stage of disease to probability, frequency, and cost of outpatient visits for institutionalized and noninstitutionalized patients, with demographic characteristics and calendar time controlled. RESULTS: The annual proportion of patients with AD and a Medicare-reimbursed outpatient visit ranged from 81% to 95% and was not related to stage of dementia or institutional status. Among those with at least one outpatient visit, however, those living at home had fewer visits than did those in institutions, but their number of visits increased as dementia worsened. Those in institutions had a larger number of outpatient visits, but these did not vary significantly by stage of dementia. Neither location of residence nor stage affected the cost of outpatient visits. CONCLUSION: Among those with an outpatient visit, the frequency of visits and their relationship to stage of disease depends on institutional status.

Use and cost of hospitalization of patients with AD by stage and living arrangement: CERAD XXI.

OBJECTIVE: To determine the probability, frequency, length of stay, and Medicare costs of hospitalization of institutionalized and noninstitutionalized patients with AD at various stages of dementia. METHODS: The authors analyzed the 1991 to 1995 Medicare records of 420 CERAD patients with AD, a group which, at entry, had no serious comorbidities. They were geographically distributed across the United States and observed for a median of 2.5 years. Repeated measures logistic regression and generalized estimating equations were used to model the probability of hospitalization. Among those hospitalized, the general linear mixed model was used to determine number of admissions, length of stay, and Medicare cost. Demographic characteristics and calendar date were controlled in all analyses. RESULTS: As dementia worsened, the probability of hospitalization increased among patients living at home, but decreased among those who were institutionalized. Number of admissions, length of stay, and cost also decreased significantly as stage worsened among the institutionalized patients, but the stage of dementia had no effect in non-institutionalized patients. CONCLUSION: The hospitalization experience of patients with AD living at home differs from that of patients with AD living in institutions. Residential setting appears to be an important determinant of hospitalization in patients with AD.

Ectopic white matter neurons, a developmental abnormality that may be caused by the PSEN1 S169L mutation in a case of familial AD with myoclonus and seizures.

We report clinical, neuropathologic and molecular genetic data from an individual affected by a familial Alzheimer disease (AD) variant. The proband had an onset of dementia at age 29 followed by generalized seizures a year later. He died at age 40. Neuropathologically, he had severe brain atrophy and characteristic histopathologic lesions of AD. Three additional neuropathologic features need to be emphasized: 1) severe deposition of Abeta in the form of diffuse deposits in the cerebral and cerebellar cortices, 2) numerous Abeta deposits in the subcortical white matter and in the centrum semiovale, and 3) numerous ectopic neurons, often containing tau-immunopositive neurofibrillary tangles, in the white maner of the frontal and temporal lobes. A molecular genetic analysis of DNA extracted from brain tissue of the proband revealed a S169L mutation in the Presenilin 1 (PSEN1) gene. The importance of this case lies in the presence of ectopic neurons in the white matter, early-onset seizures, and a PSEN1 mutation. We hypothesize that the PSEN1 mutation may have a causal relationship with an abnormality in neuronal development.

Frequency and duration of hospitalization of patients with AD based on Medicare data: CERAD XX.

Medicare records on 477 Consortium to Establish a Registry for Alzheimer's Disease patients with AD for 1991 through 1995 showed a hospitalization rate of 0.37/person-year with a length of stay of 3.7 days/ person-year (average of 10 days/hospitalization). Unmarried and less-educated patients with AD were admitted to the hospital more frequently, and, along with black patients, had a longer length of stay. Frequency and duration of hospitalization were greater in the patients with AD than in Medicare beneficiaries in general, but the rate of diagnostic/therapeutic procedures was lower.

Variability in annual Mini-Mental State Examination score in patients with probable Alzheimer disease: a clinical perspective of data from the Consortium to Establish a Registry for Alzheimer's Disease.

OBJECTIVE: To determine the variability in annual Mini-Mental State Examination scores of patients with Alzheimer disease enrolled in the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). PATIENTS: A total of 372 patients with probable Alzheimer disease with 1 or more years of follow-up. SETTING: Twenty-one CERAD clinical sites throughout the United States. RESULTS: An average annual decline of 3.4 points in CERAD patients returning for longitudinal reassessments was close to the SD of the measurement error of 2.8 points for the Mini-Mental State Examination. There was wide variability in individual rates of decline. Even with 4 years of follow-up, 15.8% of the patients had no clinically meaningful decline in Mini-Mental State Examination score (defined as a change in initial score >3, ie, 1 SD of measurement error). Validity of measurements of the rate of change in Mini-Mental State Examination scores improved with longer observation intervals and was reliable for most patients when observations were separated by 3 or more years. CONCLUSIONS: Although the Mini-Mental State Examination is a useful screening instrument to assess level of cognitive function, it has limited value in measuring the progression of Alzheimer disease in individual patients for periods less than 3 years because of a large measurement error and substantial variation in change in annual score.

Comparison of Lewy body variant of Alzheimer's disease with pure Alzheimer's disease: Consortium to Establish a Registry for Alzheimer's Disease, Part XIX.

OBJECTIVE: To compare the clinical, neuropsychological, and neuropathologic findings in patients with AD alone with those in patients with the Lewy body variant of AD (LBV). BACKGROUND: Prior studies indicate that patients with LBV not only have distinct clinical and neuropsychological differences from those with AD alone, but have a poorer prognosis with shorter survival time. METHODS: The authors evaluated 74 patients with autopsy-confirmed AD alone and 27 patients with LBV, and compared demographic characteristics and clinical, neuropsychological, and neuropathologic findings. RESULTS: The two groups of patients were equivalent with respect to age at time of entry into the study, years of education, and sex. Two or more extrapyramidal clinical manifestations were found in 44% of patients with LBV, compared with 16% of patients with AD alone (p = 0.02). Duration of survival after entry into the study was similar in both groups, with a mean survival of 3.6 (+/-2.1) years for AD alone versus 3.8 (+/-1.9) years for LBV. Of the various neuropsychological tests administered at the last Consortium to Establish a Registry for Alzheimer's Disease evaluation, only delayed recall of a learned word list was significantly different in the two groups, with 32% of patients with LBV versus 15% of patients with AD alone recalling any items (p = 0.04). Neuropathologic findings confirmed those of previous studies and showed that neurofibrillary tangles were significantly less frequent in the neocortex of patients with LBV than in those with AD alone. CONCLUSION: Compared with patients with AD alone, those with LBV had a greater frequency of extrapyramidal manifestations, somewhat better recall on a selected memory task at their final evaluation, and a significantly lower frequency of neocortical neurofibrillary tangles at autopsy. There were no differences between the two groups, however, in survival time from entry into the study.

Cross-sectional versus longitudinal estimates of cognitive change in nondemented older people: a CERAD study. Consortium to Establish a Registry for Alzheimer's Disease.

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.

The prevalence and 3-year incidence of dementia in older Black and White community residents.

OBJECTIVE: To determine the prevalence and 3-year incidence of dementia in Blacks and Whites age 65 and older in a five-county Piedmont area of North Carolina. DESIGN: Stratified random sample of members of the Duke Established Populations for Epidemiologic Studies of the Elderly (EPESE) (baseline n = 4,136; 55% Black; weighted n = 28,000). Prevalence study members were differentially selected on the basis of score on the Short Portable Mental Status Questionnaire at the second in-person Duke EPESE wave. Incidence study members included all persons with obvious cognitive decline over a 3-year period, and a 10% sample of the remainder. MEASUREMENTS: Self- and informant report on health history, functional status, and memory. Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Neuropsychology Battery administered to all subjects, and CERAD Clinical Battery to those with impaired memory. Clinical consensus to determine presence and type of dementia. RESULTS: Prevalence of dementia for persons > or =68 years old was 0.070 (95% confidence interval = 0.021-0.119) for Blacks and 0.072 (0.022-0.122) for Whites. Rates for Black men (0.078, 0.001-0.155) exceeded those for Black women (0.066, 0.003-0.129), but gender rates for Whites were reversed (men: 0.044, 0.000-0.103), (women: 0.087, 0.015-0.160). Neither race nor gender differences were significant. Prevalence of dementia increased through age 84 and tapered off thereafter. Three-year incidence of dementia was 0.058 (0.026-0.090) for Blacks and 0.062 (0.027-0.097) for Whites. Neither race nor gender differences were significant. Incidence increased through age 84, but moderated thereafter for all but Black men. The proportional representation of different types of dementia varied little by race. CONCLUSION: Prevalence, 3-year incidence, and types of dementia are comparable in Black and White elderly in the Piedmont area of North Carolina.

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.

Cerebral infarcts in patients with autopsy-proven Alzheimer's disease: CERAD, part XVIII. Consortium to Establish a Registry for Alzheimer's Disease.

OBJECTIVE: To study the relation between cerebral infarction and clinical and neuropsychologic manifestations in patients with autopsy-proven Alzheimer's disease (AD) enrolled in the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). BACKGROUND: Prior studies report that subjects with neuropathologic evidence of AD and concomitant brain infarcts had poorer cognitive function and higher frequency of dementia than those with AD alone. METHODS: Clinical and neuropsychologic manifestations of dementia were studied in 74 subjects with neuropathologic findings of AD alone and 32 with AD and concomitant cerebral infarcts or lacunar lesions. RESULTS: The 32 patients with both AD and vascular lesions were significantly older at time of death (median age, 81 years) than the 74 patients with AD alone (76 years; p = 0.02). At the final follow-up visit, the severity of the dementia was greater in AD patients with vascular lesions (median Clinical Dementia Rating [CDR] = 3) than in those with AD alone (CDR = 2; p = 0.03). Patients with AD and vascular lesions performed significantly worse on verbal fluency, Boston Naming, and Mini-Mental State Examination (MMSE) tests. No differences between the groups were observed, however, in the semiquantitative measures of frequency of neuritic plaques or neurofibrillary tangles. CONCLUSIONS: The clinical-neuropathologic correlations in CERAD patients generally confirm those in prior studies, indicating that the presence of cerebral infarction in patients with AD is associated with greater overall severity of clinical dementia and poorer performance on specific tests of language and cognitive function.

The relationship between extrapyramidal signs and cognitive performance in patients with Alzheimer's disease enrolled in the CERAD Study. Consortium to Establish a Registry for Alzheimer's Disease.

The objective of this study was to determine the relationship between the presence of extrapyramidal signs and the severity of cognitive and functional impairment in patients with Alzheimer's disease (AD). Eleven university medical centers in the United States and France participated in the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) study of extrapyramidal signs in AD. Forty-seven patients with probable AD who had extrapyramidal signs were matched by sex, race, education, and age with 132 probable AD patients without extrapyramidal signs. The main outcome measures were the Clinical Dementia Rating, Blessed Dementia Scale, and the CERAD Neuropsychology Battery (verbal fluency, naming, Mini-Mental State Examination, word list learning, word list recall, savings ratio, word list recognition, and constructional praxis). AD patients with extrapyramidal signs performed more poorly than AD patients without parkinsonism on various neuropsychological tests, even after controlling for the Clinical Dementia Rating and reported duration of cognitive impairment. The severity of the extrapyramidal manifestations was related to the degree of cognitive and functional impairment. Muscular rigidity and bradykinesia were the most frequent extrapyramidal signs associated with AD. Patients with AD associated with extrapyramidal signs have greater cognitive and functional impairment than AD patients without clinical evidence of parkinsonism.

Consortium to establish a registry for Alzheimer's disease: development, database structure, and selected findings.

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) was funded in 1986 by the National Institute on Aging to develop standardized assessments for patients with Alzheimer's disease (AD). Since that time, CERAD has developed and evaluated clinical and neuropsychological test batteries, a neuroimaging protocol, and an assessment of the neuropathological findings of the brains of these patients at autopsy. Approximately 1,200 carefully screened patients with AD and 450 control subjects were evaluated using these instruments at 24 major medical centers around the United States. Annual follow-up observations of these subjects were made for up to eight years. Autopsy examinations of the brain were done in over half of the deceased cases and the clinical diagnosis of AD was confirmed in 85 percent of them. This article outlines the procedures used for identifying the clinical sites, the entry and annual evaluations of patients and control subjects, the collection and analysis of data at a central Methodology and Data Management Center, and evaluation of the CERAD measures. We also present selected data from the 50 or so peer-reviewed papers published to date, with particular emphasis on findings from African-American patients with AD, and related policy implications.

Predictors of time to institutionalization of patients with Alzheimer's disease: the CERAD experience, part XVII.

We studied the time to institutionalization (or death as the first event) in 727 white patients with Alzheimer's disease (AD) enrolled in the Consortium to Establish a Registry for Alzheimer's disease (CERAD). At the time of analysis, 417 patients had been admitted to nursing homes and 32 others had died without previous institutionalization. The major predictors of time to first event were sex, age, marital status (men only), and severity of dementia at entry into the study, as measured by activities of daily living, the Mini-Mental State Examination, and the Clinical Dementia Rating scale. The overall median time from enrollment in the study to first event was 3.1 years. For unmarried men, the median time was significantly less (2.1 years) than for either married men or for married or unmarried women, all of whom had medians greater than 3 years. In an analysis of survival time following institutionalization, we found that men survived a median of 2.1 years, compared with 4.5 years for women. This nationwide study of AD largely confirms earlier studies that reported on smaller numbers of cases from local catchment areas and included patients with various types of dementia.

Clinical-neuropathologic findings in multi-infarct dementia: a report of six autopsied cases.

To clarify the neuropathologic criteria for the diagnosis of vascular dementia principally caused by large-vessel cerebral infarction, we solicited autopsy cases of vascular dementia from 10 university neuropathology laboratories. We included only those cases with progressive dementia clinically diagnosed as Alzheimer's disease (AD) or multi-infarct dementia, in whom autopsy revealed only cerebral infarction, without significant neuropathologic features of AD or other neurodegenerative disorders. Only six cases, all men, met these criteria. Each of them had, for a year or longer, gradually increasing cognitive impairment sufficient to interfere with daily activities, without clear evidence of "stepwise" progression. The age of onset of dementia was 66 years or less in five of the six patients. The duration of dementia ranged from 2 to 14 years. Five of the six cases had a history of either cerebral ischemia or acute stroke with residual focal neurologic deficits. Only two were known to have hypertension. At autopsy severe atherosclerosis of the cerebral arteries was present in three cases; two of these had a thrombotic occlusion of one internal carotid artery and one had partial obstruction of other cerebral arteries. In five of six brains, gross infarctions were present involving the thalamus, caudate, putamen, or large portions of the frontal, parietal, and temporal lobes of one or both hemispheres. Vascular amyloid was absent in all but one of these five brains. In four cases, the dementia was clinically indistinguishable from AD except for a history of focal neurologic deficits. The difficulty encountered in finding large numbers of cases of VaD without coexisting neuropathologic evidence of AD suggests that "pure" vascular dementia is very uncommon.

Measurement choices in multi-site studies of outcomes in dementia.

This paper summarizes the measurement choices made by selected current or recently completed multi-site projects with a common emphasis on measuring outcomes in dementia. Information on number of items and scoring, reason(s) for selecting the measure, and reliability and validity of the measure (either citations providing this information or a report of pertinent unpublished findings) is presented for eight domains: cognition, behavioral symptoms, physical health status, physical functioning and self-care abilities, quality of life, family/staff caregiver outcomes, service use, and cost. We found considerable reliance on the published literature as a guide to measurement choice, motivated largely by measures' superior psychometric properties, their ubiquity in the literature, and/or their brevity or ease of use. There is still evidence of "starting from scratch" in some domains, however. To the extent that these projects reflect the state of the art in dementia-relevant outcomes research, we conclude that comparison of outcomes across studies will continue to be problematic. However, as long as dissemination of methodological as well as substantive findings continues to characterize outcome studies in dementia, there is hope that a more congruent view of how to assess key outcomes in dementia will emerge.

Cerebral amyloid angiopathy in the brains of patients with Alzheimer's disease: the CERAD experience, Part XV.

We studied the frequency, severity, and clinical correlations of cerebral amyloid angiopathy (CAA) in 117 CERAD subjects with autopsy-confirmed AD. Eighty-three percent showed at least a mild degree of amyloid angiopathy. Thirty of 117 brains (25.6%) showed moderate to severe CAA affecting the cerebral vessels in one or more cortical regions. These brains also showed a significantly higher frequency of hemorrhages or ischemic lesions than those of subjects with little or no amyloid angiopathy (43.3% versus 23.0%; odds ratio = 2.6, 95% CI = 1.1 to 6.2) High CAA scores also correlated with the presence of cerebral arteriosclerosis and with older age at onset of dementia. Our findings suggest that factors contributing to non-AD-related vascular pathology (e.g., atherosclerosis) may play a role in amyloid deposition in cerebral vessels in AD.