Characterization of risk factors for vascular dementia: the Honolulu-Asia Aging Study.

BACKGROUND: The Honolulu Heart Program (HHP) is a prospective study of heart disease and stroke that has accumulated risk factor data on a cohort of 8,006 Japanese American men since the study began in 1965. A recent examination of the cohort identified all patients with vascular dementia (VaD) using the criteria of the California Alzheimer's Disease Diagnostic and Treatment Center. OBJECTIVE: To characterize patients with VaD by stroke subtype and to investigate risk factors for VaD in a cohort of Japanese American men, aged 71 to 93, living in Hawaii and participating in the HHP. METHODS: Sixty-eight men with VaD were compared with 3,335 men without dementia or stroke (NSND). Men with VaD were also compared with 106 men with stroke who were not demented (SND). Candidate risk factors were measured prospectively. RESULTS: Of the 68 men with VaD there were 34 (50%) whose VaD was attributed to small vessel infarcts, 16 (23%) whose VaD was related to large vessel infarcts, and 11 (16%) with both large and small vessel infarcts. The remainder could not be classified. In a multivariate logistic regression model for VaD compared with NSND containing variables found to be associated with VaD in a univariate analysis, age (odds ratio [OR] 1.19, 95% confidence interval [CI] 1.13 to 1.27), coronary heart disease (OR 2.50, 95% CI 1.35 to 4.62), and 1-hour postprandial glucose (OR 1.41, 95% CI 1.06 to 1.88) remained significantly predictive of VaD, whereas preference for a Western diet (OR 0.54, 95% CI 0.30 to 0.98) as opposed to an Oriental or mixed diet and use of supplementary vitamin E (OR 0.32, 95% CI 0.12 to 0.82) were protective. A similar model for the comparison of men with VaD and SND revealed age (OR 1.24, 95% CI 1.14 to 1.35) was predictive of VaD, whereas preference for a Western diet (OR 0.43, 95% CI 0.22 to 0.86) was protective. CONCLUSIONS: The most common stroke subtype associated with VaD was lacunar stroke. Age and traditional vascular risk factors are important contributors to the development of VaD in late life. The antioxidant vitamin E and presently unknown factors related to a Western diet as opposed to an Oriental diet may be protective against developing VaD.     

Twenty-six-year change in total cholesterol levels and incident dementia: the Honolulu-Asia Aging Study

BACKGROUND: The relationship between total cholesterol levels and dementia is unclear. OBJECTIVE: To compare the natural history of change in total cholesterol across 26 years between men who did and did not develop dementia 3 years after the last measurement. DESIGN, SETTING, AND PARTICIPANTS: In the Honolulu-Asia Aging Study, 1027 Japanese American men had total cholesterol levels assayed on 5 occasions between 1965 and 1993 and were screened for dementia on 2 occasions between 1991 and 1996. MAIN OUTCOME MEASURE: The slope of 26-year change in serum total cholesterol levels was estimated by a repeated-measures analysis and was compared between men with incident dementia (n = 56) and those without dementia (n = 971) at the end of the follow-up period. RESULTS: Cholesterol levels in men with dementia and, in particular, those with Alzheimer disease had declined at least 15 years before the diagnosis and remained lower than cholesterol levels in men without dementia throughout that period. The difference in slopes was robust to adjustment for potential confounding factors, including vascular risk factors, weight change, alcohol intake, and use of lipid-lowering agents. CONCLUSION: A decline in serum total cholesterol levels may be associated with early stages in the development of dementia.     

Early inflammation and dementia: a 25-year follow-up of the Honolulu-Asia Aging Study

Inflammatory responses are associated with cardiovascular disease and may be associated with dementing disease. We evaluated the long-term prospective association between dementia and high-sensitivity C-reactive protein, a nonspecific marker of inflammation. Data are from the cohort of Japanese American men who were seen in the second examination of the Honolulu Heart Program (1968-1970) and subsequently were reexamined 25 years later for dementia in the Honolulu-Asia Aging Study (1991-1996). In a random subsample of 1,050 Honolulu-Asia Aging Study cases and noncases, high-sensitivity C-reactive protein concentrations were measured from serum taken at the second examination; dementia was assessed in a clinical examination that included neuroimaging and neuropsychological testing and was evaluated using international criteria. Compared with men in the lowest quartile (<0.34mg/L) of high-sensitivity C-reactive protein, men in the upper three quartiles had a 3-fold significantly increased risk for all dementias combined, Alzheimer's disease, and vascular dementia. For vascular dementia, the risk increased with increasing quartile. These relations were independent of cardiovascular risk factors and disease. These data support the view that inflammatory markers may reflect not only peripheral disease, but also cerebral disease mechanisms related to dementia, and that these processes are measurable long before clinical symptoms appear.     

The Honolulu-Asia Aging Study: epidemiologic and neuropathologic research on cognitive impairment

The Honolulu-Asia Aging Study (HAAS) is a longitudinal epidemiologic investigation of rates, risk factors, and neuropathologic abnormalities associated with cognitive decline and dementia in aged Japanese-American men. The project was established in 1991 and will be brought to closure in 2012. Age-specific rates of total dementia and the major specific types of dementia in HAAS participants are generally similar to those reported from other geographic, cultural, and ethnic populations. Risk factors for dementia in the HAAS include midlife hypertension and other factors previously shown to influence cardiovascular disease. The autopsy component of the project has yielded novel findings, the most illuminating of which is the demonstration of 5 important lesion types linked independently to cognitive impairment. While one of these--generalized atrophy--is strongly associated with both Alzheimer lesions and microinfarcts, it also occurs in the absence of these lesions and is independently correlated with dementia. Each lesion type is viewed as representing a distinct underlying pathogenic process. Their summed influences is an especially robust correlate of dementia in the months and years prior to death.     

A 32-year prospective study of change in body weight and incident dementia: the Honolulu-Asia Aging Study

BACKGROUND: The course of weight loss associated with dementia is unclear, particularly prior to and around the onset of the clinical syndrome. OBJECTIVE: To compare the natural history of weight change from mid to late life in men with and without dementia in late life. DESIGN AND SETTING: The Honolulu-Asia Aging Study, a 32-year, prospective, population-based study of Japanese American men who had been weighed on 6 occasions between 1965 and 1999 and who had been screened for dementia 3 times between 1991 and 1999. PARTICIPANTS: Of 1890 men (aged 77-98 years), 112 with incident dementia were compared with 1778 without dementia at the sixth examination (1997-1999). MAIN OUTCOME MEASURE: Weight change up to and including the sixth examination was treated as the dependent variable and estimated using a repeated measures analysis. RESULTS: Groups with and without dementia did not differ with respect to baseline weight or change in weight from mid to late life (first 26 years' follow-up). In the late-life examinations (final 6 years), mean age- and education-adjusted weight loss was -0.22 kg/y (95% confidence intervals, -0.26 to -0.18) in participants without dementia. Men with incident dementia at the same examination had an additional yearly weight loss of -0.36 kg (95% confidence interval, -0.53 to -0.19). This was not changed substantially with adjustment for risk factors for vascular disease or functional impairment and was significant for both Alzheimer disease and vascular dementia subtypes. CONCLUSIONS: Dementia-associated weight loss begins before the onset of the clinical syndrome and accelerates by the time of diagnosis. The potential impact on prognosis should be considered in the case of elderly persons at risk for dementia.     

Pre-motor features of Parkinson's disease: the Honolulu-Asia Aging Study experience

The Honolulu-Asia Aging Study is a population based prospective study of neurodegenerative and cerebrovascular diseases in 8006 Japanese-American men, born 1900-1919. Beginning in 1965, environmental, life-style, and physical characteristics, including many features associated with pre-motor Parkinson's disease (PD), were ascertained at examinations over 40 years. Men with clinical PD were identified and final diagnosis was made by consensus of two neurologists. Additionally, brain autopsies have been sought since 1991 allowing use of incidental Lewy bodies and neuronal loss in the substantia nigra (SN) and locus coeruleus (LC) as additional endpoints for the PD process. Impaired olfaction, constipation, slow reaction time, excessive daytime sleepiness, and impaired executive function were all associated with future development of PD and/or with increased likelihood of either incidental Lewy bodies or neuronal loss in the SN or LC. Compared with persons without any, those with combinations of 2 or more of these pre-motor features had up to a 10-fold increase in risk for development of PD. While low specificity and positive predictive value limit the use of these clinical features alone to identify pre-motor PD, these methods may be useful for identifying a high risk group for participation in intervention trials aimed at preventing or slowing the progression of PD.     

Occupational exposures and movement abnormalities among Japanese-American men: the Honolulu-Asia Aging Study

OBJECTIVE: The authors analyzed data on 1,049 men aged 71-93 years (excluding those with prevalent Parkinson's disease and stroke) from the Honolulu Heart Program (1965-1968) and the Honolulu-Asia Aging Study (1991-1999) to determine whether occupational exposures to pesticides, solvents, metals, manganese, and mercury during middle age were associated with 14 movement abnormalities 25 years later. METHODS: Analyses of variance and multivariate logistic regression were used to assess associations of interest. RESULTS: After adjustment for age, BMI, cognitive functioning, smoking, alcohol drinking, education, and physical activity, there was a positive association between abnormal 'facial expression' and the highest exposure to metals [odds ratio (OR) = 2.62; 95% confidence interval (CI) = 1.35-5.11; trend, p = 0.02], and the highest exposure to mercury (OR = 1.91; 95% CI = 1.04-3.49; trend, p = 0.03). Age was positively associated with all movement abnormalities, and cognitive function, body mass index and physical activity were inversely associated with most movement abnormalities. CONCLUSION: Higher exposure to any metal, and specifically mercury, was associated with abnormal facial expression.     

Recent advances in dementia research in Japan: Alzheimer-type dementia

In a previous article, recent reports by Japanese researchers on non-Alzheimer-type degenerative dementias were reviewed. In the present article, recent Japanese reports on Alzheimer-type dementia (ATD) are reviewed. Alzheimer-type dementia has received great attention and has been studied from various viewpoints in Japan as well as in Europe and the Americas. In Japan, although it was believed that vascular dementia was the most frequent dementia in the elderly, ATD has recently been shown to be the most predominant type of dementia. Such a great number of papers on ATD have been reported in Japan that mainly the clinical, neuropathological, biochemical and molecular biological research papers alone are reviewed here.     

Accuracy of clinical criteria for AD in the Honolulu-Asia Aging Study, a population-based study

OBJECTIVE: To determine diagnostic accuracy for AD in a population-based study of Japanese-American men. AD is neuropathologically confirmed for more than 80% of cases at major referral centers (primarily Caucasians); however, information on diagnostic accuracy in population-based studies and studies of different ethnic groups is limited. METHODS: There were 3,734 men who participated in the Honolulu-Asia Aging Study 1991 through 1993 dementia examination and 2,603 in the 1994 through 1996 examination. Diagnoses were based on published criteria. Neuropathologists blinded to clinical data quantified neurofibrillary tangles (NFT) and neuritic plaques (NP). RESULTS: Of 220 autopsied subjects, clinical evaluation revealed 68 with normal cognition, 73 intermediate, and 79 with dementia: 20 AD, 27 vascular dementia, 19 AD + other, and 13 other dementia. Among 20 cases with pure AD, the median value for maximum neocortical NFT density was 6.9/mm(2) and for neocortical NP density was 8.0/mm2. Corresponding densities for other groups were <3.0/mm2. Using established neuropathologic criteria, 25% (5/20) of clinical AD cases had enough NP to meet definite AD criteria, whereas 65% (13/20) had sufficient NP to meet neuropathologic definite or probable AD criteria. Among nine AD cases with moderately severe dementia, only two (22%) had NP densities great enough to meet definite neuropathologic criteria, whereas seven (78%) met neuropathologic criteria for probable AD. CONCLUSIONS: Neuropathologic confirmation and NP density among decedents with clinical AD in this population-based study were lower than reported by referral centers and similar to reports from two other community studies. Ethnic differences in propensity for amyloid deposition as well as differences in clinical severity and representativeness of cases might contribute to these findings.     

Attention and executive control predict Alzheimer disease in late life: results from the Berlin Aging Study (BASE).

OBJECTIVE: Longitudinal studies of neuropsychological changes in the preclinical phase of Alzheimer disease (AD) have yielded mixed results. Although some studies report tests of episodic memory, others report tests of attention and executive functions as reliable predictors of subsequent AD. Following theoretical models of neuropsychological processes before AD onset, the authors examined the predictive value of attention and executive function in the preclinical phase of AD in old age. METHODS: Authors studied the cognitive performance of 187 initially normal participants of the Berlin Aging Study, a community-based representative sample of Berlin citizens age 70 to 103, over a period of 4 years. Tests of attention and executive function (Digit Letter Test, Trailmaking Part B Test, Digit Symbol Substitution Test, and Identical Pictures Test) and of learning and recall functions (Activity Recall, Memory for Text, and Paired-Associate Learning) were administered at baseline. Diagnosis of AD was made according to NINCDS-ADRDA criteria (probable AD). Receiver operating characteristics curve analyses and Cox regression analyses were used to assess the diagnostic accuracy and predictive value of the neuropsychological tests at baseline for incident AD after 4 years. RESULTS: After 4 years, 15 participants had developed AD. Tests of attention and executive function discriminated best between nonconverters and incident AD cases. A similar pattern was found in survival analyses; attention and executive function tests, together with tests of learning and recall, significantly predicted incident AD over and above age, gender, and education. CONCLUSION: These results support theoretical models of attention and executive function in the preclinical phase of AD in old age.     

Mental and behavioral disturbances in dementia: findings from the Cache County Study on Memory in Aging

OBJECTIVE: The authors report findings from a study of 5,092 community residents who constituted 90% of the elderly resident population of Cache County, Utah. METHOD: The 5,092 participants, who were 65 years old or older, were screened for dementia. Based on the results of this screen, 1,002 participants (329 with dementia and 673 without dementia) underwent comprehensive neuropsychiatric examinations and were rated on the Neuropsychiatric Inventory, a widely used method for ascertainment and classification of dementia-associated mental and behavioral disturbances. RESULTS: Of the 329 participants with dementia, 214 (65%) had Alzheimer's disease, 62 (19%) had vascular dementia, and 53 (16%) had another DSM-IV dementia diagnosis; 201 (61%) had exhibited one or more mental or behavioral disturbances in the past month. Apathy (27%), depression (24%), and agitation/aggression (24%) were the most common in participants with dementia. These disturbances were almost four times more common in participants with dementia than in those without. Only modest differences were observed in the prevalence of mental or behavioral disturbances in different types of dementia or at different stages of illness: participants with Alzheimer's disease were more likely to have delusions and less likely to have depression. Agitation/aggression and aberrant motor behavior were more common in participants with advanced dementia. CONCLUSIONS: On the basis of their findings in this large community population of elderly people, the authors conclude that a wide range of dementia-associated mental and behavioral disturbances afflict the majority of individuals with dementia. Because of their frequency and their adverse effects on patients and their caregivers, these disturbances should be ascertained and treated in all cases of dementia.     

Recent advances in dementia research in Japan: Non-Alzheimer-type degenerative dementias

In this article, we review recent reports by Japanese researchers on non-Alzheimer-type degenerative dementias. These dementias can be classified into the following subtypes: dementias with Lewy bodies, including diffuse Lewy body disease, dementias with neurofibrillary tangles, dementias with glial tangles, including progressive supranuclear palsy and corticobasal degeneration, argyrophilic grain dementia, frontotemporal dementias including Pick's disease, dementias with degeneration of subcortical nuclei, including Huntington's disease and, last, unclassified dementias. Recently, these various forms of dementia have received much attention in Japan, as elsewhere.     

Educational attainment and late life telomere length in the Health,Aging and Body Composition Study

Morbidity and mortality are greater among socially disadvantaged racial/ethnic groups and those of lower socioeconomic status (SES). Greater chronic stress exposure in disadvantaged groups may contribute to this by accelerating cellular aging, indexed by shorter age-adjusted telomere length. While studies consistently relate shorter leukocyte telomere length (LTL) to stress, the few studies, mostly from the UK, examining associations of LTL with SES have been mixed. The current study examined associations between educational attainment and LTL among 2599 high-functioning black and white adults age 70-79 from the Health, Aging and Body Composition Study. Multiple regression analyses tested associations of race/ethnicity, educational attainment and income with LTL, adjusting for potential confounders. Those with only a high school education had significantly shorter mean LTL (4806 basepairs) than those with post-high school education (4926 basepairs; B = 125, SE = 47.6, p = .009). A significant interaction of race and education (B = 207.8, SE = 98.7, p = .035) revealed more beneficial effects of post-high school education for blacks than for whites. Smokers had shorter LTL than non-smokers, but the association of education and LTL remained significant when smoking was covaried (B = 119.7, SE = 47.6, p = .012). While higher income was associated with longer LTL, the effect was not significant (p > .10). This study provides the first demonstration of an association between educational attainment and LTL in a US population where higher education appears to have a protective effect against telomere shortening, particularly in blacks.     

Anticholinergic drugs in late life: adverse effects on cognition but not on progress to dementia

Impaired cognitive function associated with use of anticholinergic drugs may be partly attributed to underlying physical illness and exposure to factors that increase the risk of some physical disorders such as low socioeconomic status (SES) and less education. To estimate the extent of cognitive impairment and risk of progress to dementia associated with anticholinergic drug use and to estimate confounding by gender, APOE, family history of dementia, lower SES, less education, and lower childhood mental ability, we recruited 281 volunteers at age 77-78 without overt dementia who had taken part in the Scottish Mental Survey of 1932. Clinical histories, use of medications, self reported frequency of emotional symptoms and standardized tests of cognitive function were obtained. With and without adjustment for age and childhood IQ, there were significant between-group differences in tests of non-verbal reasoning and spatial ability. During 10 year follow-up, progress to overt dementia was not associated with anticholinergic drugs use on recruitment but female gender and a history of dementia in parent or sibling were associated with dementia. We concluded that anticholinergic drug use in this narrow age range sample was linked to cognitive impairment but not to subsequent dementia.