Total and differential white blood cell counts in late life predict 8-year incident stroke: the Honolulu Heart Program.

OBJECTIVES: To study the association between total and differential white blood cell (WBC) count and incident stroke in an older Asian population. DESIGN: Prospective population-based study with 8 years of follow-up. SETTING: The Honolulu Heart Program, Oahu, Hawaii. PARTICIPANTS: Japanese-American men aged 71 to 93 who were free of stroke and had baseline WBC counts measured in 1991-93 (N=3,342). MEASUREMENTS: Participants were divided into quartiles of total and differential WBC count for analysis and were followed for incident stroke (thromboembolic and hemorrhagic (hemorrhagic)) for 8 years using data from a comprehensive hospital surveillance system. RESULTS: Age-adjusted incident stroke rates increased significantly with increasing WBC quartile (Q1, 7.68; Q2, 9.04; Q3, 9.26; Q4, 14.10 per 1,000 person-years of follow-up, P=.001). Hazard ratios (HRs) for stroke for each quartile of total and differential WBC count were obtained using Cox regression analysis, with the lowest quartile as the reference group. After full adjustment, including age; cardiovascular risk factors; fibrinogen; prevalent coronary heart disease, cancer, or chronic obstructive pulmonary disease, and nonsteroidal anti-inflammatory drug use, HRs were 1.62 (95% confidence interval (CI)=1.04-2.52, P=.03) in the highest quartile of total WBC and 2.19 (95% CI=1.41-3.39, P<.001) in the highest quartile of neutrophil counts. Significant associations were also seen for thromboembolic but not for hemorrhagic strokes. No significant associations were found between lymphocyte or monocyte counts and incident stroke or subtypes. CONCLUSION: In elderly Japanese-American men, higher total WBC and neutrophil counts were independent predictors of overall stroke, as well as thromboembolic stroke.

Shorter men live longer: association of height with longevity and FOXO3 genotype in American men of Japanese ancestry.

OBJECTIVES: To determine the relation between height, FOXO3 genotype and age of death in humans. METHODS: Observational study of 8,003 American men of Japanese ancestry from the Honolulu Heart Program/Honolulu-Asia Aging Study (HHP/HAAS), a genetically and culturally homogeneous cohort followed for over 40 years. A Cox regression model with age as the time scale, stratified by year of birth, was used to estimate the effect of baseline height on mortality during follow-up. An analysis of height and longevity-associated variants of the key regulatory gene in the insulin/IGF-1 signaling (IIS) pathway, FOXO3, was performed in a HHP-HAAS subpopulation. A study of fasting insulin level and height was conducted in another HHP-HAAS subpopulation. RESULTS: A positive association was found between baseline height and all-cause mortality (RR = 1.007; 95% CI 1.003-1.011; P = 0.002) over the follow-up period. Adjustments for possible confounding variables reduced this association only slightly (RR = 1.006; 95% CI 1.002-1.010; P = 0.007). In addition, height was positively associated with all cancer mortality and mortality from cancer unrelated to smoking. A Cox regression model with time-dependent covariates showed that relative risk for baseline height on mortality increased as the population aged. Comparison of genotypes of a longevity-associated single nucleotide polymorphism in FOXO3 showed that the longevity allele was inversely associated with height. This finding was consistent with prior findings in model organisms of aging. Height was also positively associated with fasting blood insulin level, a risk factor for mortality. Regression analysis of fasting insulin level (mIU/L) on height (cm) adjusting for the age both data were collected yielded a regression coefficient of 0.26 (95% CI 0.10-0.42; P = 0.001). CONCLUSION: Height in mid-life is positively associated with mortality, with shorter stature predicting longer lifespan. Height was, moreover, associated with fasting insulin level and the longevity genotype of FOXO3, consistent with a mechanistic role for the IIS pathway.

Brain organochlorines and Lewy pathology: the Honolulu-Asia Aging Study.

Although organochlorines have been reported more frequently in Parkinson's disease (PD) brains than in controls, the association with brain Lewy pathology is unknown. Honolulu-Asia Aging Study (HAAS) participants, exposed to organochlorines from a variety of sources during midlife, represent a population well suited to determining the relationship of brain organochlorines with Lewy pathology in decedents from the longitudinal HAAS. The study design included the measurement of 21 organochlorine levels in frozen occipital lobe samples from HAAS decedents. Alpha-synuclein immunostaining performed on 225 brains was used to identify Lewy bodies and Lewy neurites. With the potential for spurious associations to appear between Lewy pathology and 17 organochlorine compounds found in at least 1 brain, initial assessments identified heptachlor epoxide isomer b, methoxychlor, and benzene hexachloride b as being most important. The prevalence of Lewy pathology was 75% (6 of 8) among brains with any 2 of the 3 compounds, 48.8% (79 of 162) among those with 1, and 32.7% (18 of 55) for those with neither (P = .007 test for trend). Although findings persisted after removing cases with PD and dementia with Lewy bodies and after adjustment for age at death, body mass index, pack-years of cigarette smoking, and coffee intake (P = .013), the results were insignificant when correcting for multiple testing. Although consistent with earlier accounts of an association between organochlorines and clinical PD, associations with Lewy pathology warrant further study.

Serum selenium, genetic variation in selenoenzymes, and risk of colorectal cancer: primary analysis from the Women's Health Initiative Observational Study and meta-analysis.

BACKGROUND: Selenium may prevent colorectal cancer. However, several previous studies are small and few investigated the association between selenium and colorectal cancer among women whose selenium metabolism may differ from men. Furthermore, genetic variants in selenoenzymes may be associated with colorectal cancer risk. METHODS: This nested case-control study investigated whether serum selenium concentration and genetic variants in five selenoenzymes (glutathione peroxidase 1-4 and selenoprotein P) were associated with colorectal cancer risk in 804 colorectal cancer cases and 805 matched controls from the Women's Health Initiative (WHI) Observational Study. A meta-analysis was conducted to compare the WHI result with previous studies including 12 observational studies and two clinical trials on selenium. RESULTS: Within the WHI, selenium concentrations were relatively high (mean = 135.6 µg/L) and were not associated with colorectal cancer risk (P(trend) = 0.10); the adjusted OR comparing the fifth with first quintile was 1.26 (95% CI, 0.91-1.73). Moreover, genetic variants in selenoenzymes were not significantly associated with colorectal cancer risk. Consistent with the finding in WHI, our meta-analysis showed no association between selenium and colorectal tumor risk in women (OR = 0.97; 95% CI, 0.79-1.18) comparing the highest quantile with the lowest); however, in men, there was a significant inverse association (OR = 0.68; 95% CI, 0.57-0.82) (P = 0.01). CONCLUSION: Consistent with previous studies, we observed no protective effect of selenium on colorectal cancer among women. IMPACT: Our analyses suggest that a population with relatively high selenium concentrations, especially women, would not benefit from increasing selenium intake.

Occupational exposure to pesticides, metals, and solvents: the impact on mortality rates in the Honolulu Heart Program.

OBJECTIVE: To investigate the impact of occupational exposure to pesticides, metals, and solvents on mortality. PARTICIPANTS: Middle-aged Japanese-American men (n = 7,540) who had participated in the Honolulu Heart Program during 1965-1968. METHODS: Industrial hygienists assessed participants' potential for exposure based on their primary job. Cumulative exposure scores were categorized as none, low, medium, and high. The underlying cause of death was ascertained by a physician panel. All associations were assessed using Cox proportional hazards models. RESULTS: A total of 4, 485 deaths occurred. Compared to no exposure, pesticide exposure was significantly associated with mortality from all causes, circulatory diseases, stroke, and all cancers. Results for all-cause mortality at the 0-yr lag after risk-factor adjustment were: Low, hazard ratio (HR) = 0.85, 95% confidence interval (CI)=0.68-1.08; medium, HR = 1.18, 95% CI = 1.01-1.37; and high, HR = 1.29, 95% CI = 1.06-1.57; trend, p=0.002. Exposure to metals and solvents was significantly associated with mortality from all causes, cancer, and respiratory disease, and exposure to solvents was additionally associated with mortality from circulatory disease. Associations were strongest at the 15-yr lag. CONCLUSIONS: Results show that occupational exposures to pesticides, metals, and solvents during mid-life are independently associated with increased mortality, and indicate potential importance of exposures that occurred approximately 15 years prior to death.

Effect of walking distance on 8-year incident depressive symptoms in elderly men with and without chronic disease: the Honolulu-Asia Aging Study.

OBJECTIVES: To determine the effect of walking on incident depressive symptoms in elderly Japanese-American men with and without chronic disease. DESIGN: Prospective cohort study. SETTING: The Honolulu-Asia Aging Study. PARTICIPANTS: Japanese-American men aged 71 to 93 at baseline. MEASUREMENTS: Physical activity was assessed according to self-reported distance walked per day. Depressive symptoms were measured using an 11-question version of the Centers for Epidemiologic Studies Depression Scale (CES-D 11) at the fourth examination (n=3,196) and at the seventh examination 8 years later (1999/00, n=1,417). Presence of incident depressive symptoms was defined as a CES-D 11 score of 9 or greater or taking antidepressants at Examination 7. Subjects with prevalent depressive symptoms at baseline were excluded. RESULTS: Age-adjusted 8-year incident depressive symptoms were 13.6%, 7.6%, and 8.5% for low (<0.25 miles/day), intermediate (0.25-1.5 miles/day), and high (>1.5 miles/day) walking groups at baseline (P=0.008). Multiple logistic regression analyses, adjusted for age, education, marital status, cardiovascular risk factors, prevalent diseases, and functional impairment, showed that those in the intermediate and highest walking groups had significantly lower odds of developing 8-year incident depressive symptoms (odds ratio (OR)=0.52, 95% confidence interval (CI)=0.32-0.83, P=.006 and OR=0.61, 95% CI= 0.39-0.97, P=.04, respectively). Analysis found that this association was significant only in participants without chronic diseases (coronary heart disease, cerebrovascular accident, cancer, Parkinson's disease, dementia, or cognitive impairment) at baseline. CONCLUSION: Daily physical activity (≥0.25 mile/day) is significantly associated with lower risk of 8-year incident depressive symptoms in elderly Japanese-American men without chronic disease at baseline.

Low LDL cholesterol and increased risk of Parkinson's disease: prospective results from Honolulu-Asia Aging Study.

Low-density lipoprotein cholesterol (LDL-C) levels are suggested to be associated inversely with Parkinson's disease (PD). To test the hypothesis that LDL-C levels may increase PD risk, we studied a prospective cohort of 3,233 men (Honolulu-Asia Aging Study) for whom the LDL-C from fasting lipid profiles was obtained during 1991 to 1993. The cohort was followed longitudinally until 2001 for incident Parkinson's cases. During follow-up, 41 men developed PD (18.4/10,000 person-years). Although the incidence of PD increased with decreasing LDL-C in a dose-dependent manner, the association was only significant for men aged 71 to 75 years. In the latter group, risk of PD declined from 38.5/10,000 person-years in men with LDL-C levels <80 mg/dl to less than 9/10,000 person-years for concentrations that were > or =140 mg/dl. After adjustment for age, smoking, coffee intake, and other factors, the relative odds of PD for men at the 80th versus the 20th percentile of LDL-C (135 vs. 85 mg/dl) was 0.4 (95% confidence interval: 0.2, 0.9). This prospective study supports the hypothesis that low LDL-C is associated with an increased risk of PD. Although confirmation is required, the underlying mechanisms may be useful in understanding key aspects of PD.

Association of olfactory dysfunction with risk for future Parkinson's disease.

OBJECTIVE: Although olfactory dysfunction is commonly associated with Parkinson's disease (PD), it is not known whether such dysfunction can predate the onset of clinical PD in a community-based population. This study examines the association of olfactory dysfunction with future development of PD in Honolulu-Asia Aging Study cohort members METHODS: Olfaction was assessed from 1991 to 1996 in 2,267 men in the Honolulu-Asia Aging Study aged 71 to 95 years who were free of clinical PD and dementia at the time of olfaction testing. Participants were followed for up to 8 years for incident PD RESULTS: In the course of follow-up, 35 men were diagnosed with PD (24.6/10,000 person-years). The average age at the time of diagnosis was 82.9 +/- 3.8 (range, 76-93) years, and the average time to a diagnosis was 4.0 +/- 1.9 (range, 1-8) years. During the first 4 years of follow-up, age-adjusted incidence of PD declined from 54.5/10,000 person-years in the lowest quartile of odor identification to 26.6, 8.2, and 8.4/10,000 person-years in the second, third, and fourth quartiles, respectively (p < 0.001 for trend). After adjustment for age and other potential confounders, the odds ratios for PD in the lowest quartile was 5.2 (95% confidence interval, 1.5-25.6) compared with the top two quartiles. This relation was not evident beyond 4 years of follow-up. INTERPRETATION: Impaired olfaction can predate clinical PD in men by at least 4 years and may be a useful screening tool to detect those at high risk for development of PD in later life.

Bowel movement frequency in late-life and incidental Lewy bodies.

It is not known if constipation is associated with the preclinical phase of Parkinson's disease (PD), often characterized by the presence of incidental Lewy bodies (ILB). Such an association could provide evidence that constipation is an early symptom of PD. The purpose of this report is to examine the association between late-life bowel movement frequency and ILB. Bowel movement frequency was assessed from 1991 to 1993 in 245 men aged 71 to 93 years in the Honolulu-Asia Aging Study who later received postmortem examinations. All were without clinical PD and dementia. Brains were examined for ILB in the substantia nigra and locus ceruleus. Among the decedents, 30 men had ILB (12.2%). After age-adjustment, the percent of brains with ILB declined with increasing bowel movement frequency (P=0.013). For men with <1, 1, and >1 bowel movement/day, corresponding percents were 24.1, 13.5, and 6.5%. Findings persisted after additional adjustment for time to death, mid-life pack-years of smoking and coffee intake, physical activity, and cognitive function. Infrequent bowel movements are associated with ILB. Findings provide evidence that constipation can predate the extrapyramidal signs of PD. Constipation could be one of the earliest markers of the beginning of PD processes.

Sex hormones and neuropathology in elderly men: the HAAS.

Experimental studies suggest 17-beta estradiol (E2) and testosterone (T) may have neuroprotective properties that are associated with Alzheimer's and vascular pathology. However, there are limited studies correlating steroid hormones with autopsy findings in humans. In this community-based autopsy study of elderly men (n=232) participating in the Honolulu Asia Aging Study, we found a significant decrease of neurofibrillary tangles in the highest tertile of free serum estradiol [IRR=0.43 (0.3-0.7)] after controlling for age at blood draw, interval from blood draw until death, ApoE allele, and socio-demographic health factors. Higher Free-T levels were associated with a two-fold increased risk for micro infarcts [IRR=2.2; 95% CI (1.2-4.1)]. There was no association between sex hormones and amyloid plaques or cerebral amyloid angiopathy. This community-based autopsy study suggests that peripheral levels of sex hormones are associated with neurofibrillary tangles and micro-infarcts, but not with other neuropathologic markers of brain disease in elderly men.

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.

High density lipoprotein cholesterol and the risk of stroke in elderly men: the Honolulu heart program.

High density lipoprotein (HDL) cholesterol has been inversely associated with coronary heart disease. Associations with stroke are less clear, particularly among the elderly. In this study, the authors examined the relation between HDL cholesterol levels and the risk of stroke in elderly men. Levels of HDL cholesterol were measured in 2,444 Honolulu Heart Program men aged 71-93 years at the 1991-1993 examinations. The participants, who were free of prevalent stroke, coronary heart disease, and cancer at baseline, were followed to the end of 1998 for thromboembolic and hemorrhagic stroke. While HDL cholesterol was unrelated to hemorrhagic events, incidence of thromboembolic stroke declined consistently with increasing HDL cholesterol level (p = 0.003). There was a nearly threefold excess of thromboembolic stroke in men with low HDL cholesterol levels (<1.0 mmol/liter (<40 mg/dl)) compared with men with high levels (> or =1.6 mmol/liter (> or =60 mg/dl)) (10.6/1,000 person-years vs. 3.6/1,000 person-years; p = 0.001). Adjustment for other risk factors had little effect on these findings, although associations appeared strongest in elderly men with "desirable" total cholesterol levels, hypertension, or diabetes mellitus. These findings suggest that HDL cholesterol level is inversely related to the risk of thromboembolic stroke in elderly men. Whether HDL cholesterol alters the effect of other factors on stroke risk in elderly men warrants further study.

Environmental, life-style, and physical precursors of clinical Parkinson's disease: recent findings from the Honolulu-Asia Aging Study.

BACKGROUND: Increased westernization with Japanese migration to the U. S. in the early 20(th) century is thought to have altered the risk of cardiovascular disease. Whether similar effects include changes in the risk of Parkinson's disease (PD) is not clear. This report describes the relations between environmental, life-style, and physical attributes and the incidence of PD that have been observed in the Honolulu-Asia Aging Study. METHODS: Beginning in 1965, environmental, life-style, and physical attributes were recorded at selected examinations in a cohort of 8,006 Japanese-American men. Subjects were followed for clinical PD. FINDINGS: During 30 years of follow- up, PD was observed in 137 men. Overall incidence (7.1/10,000 person-years) was generally higher than in Asia and similar to rates observed in Europe and the U. S. Precursors of PD included constipation, adiposity, years worked on a sugar or pineapple plantation, years of exposure to pesticides, and exposure to sugar cane processing. Factors showing an inverse association with PD included coffee intake and cigarette smoking. Among dietary factors, carbohydrates increased the risk of PD while the intake of polyunsaturated fats appeared protective. Total caloric intake, saturated and monounsaturated fats, protein, niacin, riboflavin, beta-carotene, vitamins A, B, and C, dietary cholesterol, cobalamin, alpha-tocopherol, and pantothenic acid showed no clear relation with clinical PD. INTERPRETATION: Findings suggest that several environmental, life-style, and physical attributes appear to be precursors of PD. Whether patterns of precursors can be used to identify individuals at high risk of future PD or can broaden the scope of early interventions or recruitment into neuroprotective trials warrants further study.

Benefits of off-pump bypass on neurologic and clinical morbidity: a prospective randomized trial.

BACKGROUND: Neurologic and clinical morbidity after coronary artery bypass grafting (CABG) can be significant. By avoiding cardiopulmonary bypass, off-pump CABG (OPCAB) may reduce morbidity. METHODS: Sixty patients (30 CABG and 30 OPCAB) were prospectively randomized. Neurocognitive testing was performed before the operation and 2 weeks and 1 year after the operation. Neurologic testing to detect stroke and (99m)Tc-HMPAO whole-brain single photon emission computed tomography scanning to assess cerebral perfusion were performed before the operation and 3 days afterward. Bilateral middle cerebral artery transcranial Doppler scanning was performed intraoperatively to detect cerebral microemboli. All examiners were blinded to treatment group. Clinical morbidity and costs were compared. RESULTS: Coronary artery bypass grafting was associated with more cerebral microemboli (575 +/- 278.5 CABG versus 16.0 +/- 19.5 OPCAB (median +/- semiinterquartile range) and significantly reduced cerebral perfusion after the operation to the bilateral occipital, cerebellar, precunei, thalami, and left temporal lobes (p < or = 0.01). Cerebral perfusion with OPCAB was unchanged. Compared with base line, OPCAB patients performed better on the Rey Auditory Verbal Learning Test (total and recognition scores) at both 2 weeks and at 1 year (p < or = 0.05), whereas CABG performance was statistically unchanged for all cognitive measures. Patients who underwent CABG had more chest tube drainage (1389 +/- 1256 mL CABG versus 789 +/- 586 mL OPCAB, p = 0.02) and required more blood (3.9 +/- 5.8 U CABG versus 1.2 +/- 2.2 U OPCAB, p = 0.02), fresh frozen plasma (3.0 +/- 6.0 U CABG versus 0.5 +/- 2.2 U OPCAB, p = 0.03), and hours of postoperative use of dopamine (16.3 +/- 21.2 hours CABG versus 7.3 +/- 9.7 hours OPCAB, p = 0.04). These differences culminated in higher costs for CABG ($23,053 +/- $5,320 CABG versus $17,780 +/- $4,390 OPCAB, p < 0.0001). One stroke occurred with CABG, compared with none with OPCAB (p = NS). One OPCAB patient died because of a pulmonary embolus (p = NS). CONCLUSIONS: Compared with CABG, OPCAB may reduce neurologic and clinical morbidity as well as cost.

Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial.

CONTEXT: The Women's Health Initiative trial of combined estrogen plus progestin was stopped early when overall health risks, including invasive breast cancer, exceeded benefits. Outstanding issues not previously addressed include characteristics of breast cancers observed among women using hormones and whether diagnosis may be influenced by hormone effects on mammography. OBJECTIVE: To determine the relationship among estrogen plus progestin use, breast cancer characteristics, and mammography recommendations. DESIGN, SETTING, AND PARTICIPANTS: Following a comprehensive breast cancer risk assessment, 16 608 postmenopausal women aged 50 to 79 years with an intact uterus were randomly assigned to receive combined conjugated equine estrogens (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) or placebo from 1993 to 1998 at 40 clinical centers. Screening mammography and clinical breast examinations were performed at baseline and yearly thereafter. MAIN OUTCOME MEASURES: Breast cancer number and characteristics, and frequency of abnormal mammograms by estrogen plus progestin exposure. RESULTS: In intent-to-treat analyses, estrogen plus progestin increased total (245 vs 185 cases; hazard ratio [HR], 1.24; weighted P<.001) and invasive (199 vs 150 cases; HR, 1.24; weighted P =.003) breast cancers compared with placebo. The invasive breast cancers diagnosed in the estrogen plus progestin group were similar in histology and grade but were larger (mean [SD], 1.7 cm [1.1] vs 1.5 cm [0.9], respectively; P =.04) and were at more advanced stage (regional/metastatic 25.4% vs 16.0%, respectively; P =.04) compared with those diagnosed in the placebo group. After 1 year, the percentage of women with abnormal mammograms was substantially greater in the estrogen plus progestin group (716 [9.4%] of 7656) compared with placebo group (398 [5.4%] of 7310; P<.001), a pattern which continued for the study duration. CONCLUSIONS: Relatively short-term combined estrogen plus progestin use increases incident breast cancers, which are diagnosed at a more advanced stage compared with placebo use, and also substantially increases the percentage of women with abnormal mammograms. These results suggest estrogen plus progestin may stimulate breast cancer growth and hinder breast cancer diagnosis.

Age-related changes in risk factor effects on the incidence of thromboembolic and hemorrhagic stroke.

We examined the changes in risk factor effects on the incidence of thromboembolic and hemorrhagic stroke as they may occur with age. Findings were based on repeated risk factor measurements at four examinations over a 26-year period in 7589 men in the Honolulu Heart Program. After each examination, 6 years of follow-up were available to assess risk factor effects on the incidence of stroke over a broad range of ages (45-93 years). As compared with normotensive men, the risk of thromboembolic stroke in the presence of hypertension declined from a 7-fold excess in men aged 45 to 54 years to a 1.4-fold excess in men aged > or =75 (P<.001). Adverse effects of diabetes and atrial fibrillation seemed to be equally important across all ages, whereas a protective effect of physical activity increased with age. Except for men with atrial fibrillation, the incidence of thromboembolic stroke increased significantly with age regardless of risk factor status, including men with normal blood pressure (P<.001). Although hemorrhagic events were less common, positive relations with cigarette smoking seemed to strengthen with age, whereas those with hypertension tended to decline. Our findings suggest that strategies for the prevention of stroke may need to account for changes in risk factor effects as they occur with age. Control of diabetes and the encouragement of active lifestyles in the elderly seem to be especially important.

Mid-life smoking and late-life dementia: the Honolulu-Asia Aging Study.

We studied the association between mid-life smoking and late-life dementia in the Honolulu Heart Program (1965-1971) and follow-up assessment for dementia (1991-1996) of 3734 Japanese-American men (80% of survivors). Neuropathologic data were available for 218 men. Adjusting for age, education and apolipoprotein E (APOE) genotype, the risk of Alzheimer's disease (AD) in smokers increased with pack-years of smoking at medium (odds ratio (OR)=2.18, 95% confidence interval (CI)=1.07-4.69) and heavy (OR=2.40; 95% CI=1.16-5.17) smoking levels. Very heavy smoking was not associated with AD (OR=1.08; 95% CI=0.43-2.63). Findings were similar when AD cases included those with cerebrovascular disease and for all dementias combined. Adjustment for cardiovascular and respiratory factors or stratification by apolipoprotein E genotype did not change these associations. In an autopsied subsample, the number of neuritic plaques increased with amount smoked. This study suggests that amount smoked is associated with an increasing risk of AD and Alzheimer-type neuropathology up to heavy smoking levels. The lack of association in very heavy smokers may be due to a hardy survivor effect.

Are depressive symptoms a risk factor for mortality in elderly Japanese American men?: the Honolulu-Asia Aging Study.

OBJECTIVE: This study determined the influence of depressive symptoms on subsequent mortality of all causes. METHOD: The Honolulu Heart Program, established in 1965, is a prospective, community-based cohort of Japanese American men living in Hawaii. The analysis was based on 3,196 Japanese American men aged 71-93 at the time of the fourth examination in 1991-1993. Depressive symptoms were measured by use of an 11-question version of the Centers for Epidemiologic Studies Depression Scale questionnaire. All-cause mortality data were available for 6 years of follow up. Data were analyzed on the basis of presence or absence of chronic diseases. RESULTS: The overall prevalence of frequent depressive symptoms was 9.9%. Age-adjusted mortality rates at 3 years were 48.0 and 30.3 per 1,000 person-years for the depressed and nondepressed groups, respectively. At 6 years, the rates were 54.1 (depressed) and 41.5 (nondepressed) per 1,000 person-years. After adjustment for age, marital status, and antidepressant use, the relative risk for all-cause mortality associated with depressive symptoms was 1.53 for 3-year and 1.27 for 6-year mortality. Among participants who were healthy (without cognitive impairment, coronary heart disease, stroke, diabetes, or cancer), the association between depressive symptoms and mortality was greater (relative risk of 2.30 and 1.57 for 3- and 6-year mortality, respectively). Among participants with chronic disease, there were no significant associations between depressive symptoms and mortality. CONCLUSIONS: Depressive symptoms are a risk factor for mortality in elderly people, particularly in physically healthy individuals.

Age-related changes in risk factor effects on the incidence of coronary heart disease.

PURPOSE: The purpose of this report is to examine the potential for risk factor effects on the incidence of CHD to change over a broad range of ages from middle adulthood to late-life. METHODS: Findings are based on repeated risk factor measurements at four examinations over a 26-year period in men enrolled in the Honolulu Heart Program. After each examination, six years of follow-up were available to assess risk factor effects as the cohort aged from 45 to 93 years. RESULTS: Based on 18,456 person intervals of follow-up, 677 men developed CHD (3.7%). After risk factor adjustment, a positive relation between hypertension and CHD declined significantly with age (p = 0.013), primarily due to a large increase in the risk of CHD in elderly men (75 to 93) without hypertension. Effects of total cholesterol on CHD also seemed to decline with advancing age, although changes were not statistically significant. In contrast, men with diabetes had a consistent 2-fold excess risk of CHD across all age groups, while a positive association with body mass index in younger men (45 to 54) became negative in those who were the oldest (75 to 93). Due to infrequent smoking in the elderly, associations between smoking and CHD weakened with age. In the oldest men (75 to 93), alcohol intake was unrelated to CHD, while effects of sedentary life-styles on promoting CHD appeared stronger than in those who were younger. CONCLUSION: Findings suggest that changes in risk factor effects on the incidence of CHD with advancing age may require updated strategies for CHD prevention as aging occurs.