G. W. Ross

Frequency of bowel movements and the future risk of Parkinson’s disease

Background: Constipation is frequent in PD, although its onset in relation to clinical PD has not been well described. Demonstration that constipation can precede clinical PD could provide important clues to understanding disease progression and etiology. The purpose of this report is to examine the association between the frequency of bowel movements and the future risk of PD. Methods: Information on the frequency of bowel movements was collected from 1971 to 1974 in 6790 men aged 51 to 75 years without PD in the Honolulu Heart Program. Follow-up for incident PD occurred over a 24-year period. Results: Ninety-six men developed PD an average of 12 years into follow-up. Age-adjusted incidence declined consistently from 18.9/10,000 person-years in men with <1 bowel movement/day to 3.8/10,000 person-years in those with >2/day (p = 0.005). After adjustment for age, pack-years of cigarette smoking, coffee consumption, laxative use, jogging, and the intake of fruits, vegetables, and grains, men with <1 bowel movement/day had a 2.7-fold excess risk of PD versus men with 1/day (95% CI: 1.3, 5.5; p = 0.007). The risk of PD in men with <1 bowel movement/day increased to a 4.1-fold excess when compared with men with 2/day (95% CI: 1.7, 9.6; p = 0.001) and to a 4.5-fold excess versus men with >2/day (95% CI: 1.2, 16.9; p = 0.025). Conclusions: Findings indicate that infrequent bowel movements are associated with an elevated risk of future PD. Further study is needed to determine whether constipation is part of early PD processes or is a marker of susceptibility or environmental factors that may cause PD.

Association of vitamin E and C supplement use with cognitive function and dementia in elderly men.

Objective: To determine whether use of vitamin E and C supplements protects against subsequent development of dementia and poor cognitive functioning. Methods: The Honolulu–Asia Aging Study is a longitudinal study of Japanese-American men living in Hawaii. Data for this study were obtained from a subsample of the cohort interviewed in 1982, and from the entire cohort from a mailed questionnaire in 1988 and the dementia prevalence survey in 1991 to 1993. The subjects included 3,385 men, age 71 to 93 years, whose use of vitamin E and C supplements had been ascertained previously. Cognitive performance was assessed with the Cognitive Abilities Screening Instrument, and subjects were stratified into four groups: low, low normal, mid normal, and high normal. For the dementia analyses, subjects were divided into five mutually exclusive groups: AD (n = 47), vascular dementia (n = 35), mixed/other types of dementia (n = 50), low cognitive test scorers without diagnosed dementia (n = 254), and cognitively intact (n = 2,999; reference). Results: In a multivariate model controlling for other factors, a significant protective effect was found for vascular dementia in men who had reported taking both vitamin E and C supplements in 1988 (odds ratio [OR], 0.12; 95% CI, 0.02 to 0.88). They were also protected against mixed/other dementia (OR, 0.31; 95% CI, 0.11 to 0.89). No protective effect was found for Alzheimer’s dementia (OR, 1.81; 95% CI, 0.91 to 3.62). Among those without dementia, use of either vitamin E or C supplements alone in 1988 was associated significantly with better cognitive test performance at the 1991 to 1993 examination (OR, 1.25; 95% CI, 1.04 to 1.50), and use of both vitamin E and C together had borderline significance (OR, 1.18; 95% CI, 0.995 to 1.39). Conclusions: These results suggest that vitamin E and C supplements may protect against vascular dementia and may improve cognitive function in late life.

Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS <

Midlife hypertension is associated with later development of cognitive impairment, vascular dementia (VsD), and possibly Alzheimers disease (AD). Neuropathic cerebrovascular lesions and brain atrophy have been associated with elevated blood pressure (BP), however, to our knowledge there have been no prospective investigations of an association of blood pressure levels measured in midlife with the microscopic lesions of AD. We investigated the relationship of BP level in midlife to development of neurofibrillary tangles (NFT), neuritic plaques (NP), and low brain weight at autopsy among Japanese-American men who were members of the Honolulu Heart Program/Honolulu-Asia aging Study (HHP/HAAS) cohort. The HHP/HAAS is a population-based, longitudinal study of cognitive function and dementia with 36 years of follow-up. Neocortical and hippocampal NFT and NP were counted per mm(2), and fixed brain weight was measured for 243 decedents. Elevated systolic BP, (> or =160 mm Hg) in midlife was associated with low brain weight and greater numbers of NP in both neocortex and hippocampus. Diastolic BP elevation, (> or =95 mm Hg) was associated with greater numbers of NFT in hippocampus. Results indicate that in addition to the accepted association of high BP with neuropathic cerebrovascular lesions, there is a direct relationship with brain atrophy, NP and NFT.

Excessive daytime sleepiness and subsequent development of Parkinson disease

Objective: To determine if excessive daytime sleepiness (EDS) can predate future Parkinson disease (PD). Methods: EDS was assessed in 3,078 men aged 71 to 93 years in the Honolulu-Asia Aging Study from 1991 to 1993. All were free of prevalent PD and dementia. Follow-up for incident PD was based on three repeat neurologic assessments from 1994 to 2001. Results: During the course of follow-up, 43 men developed PD (19.9/10,000 person-years). After age adjustment, there was more than a threefold excess in the risk of PD in men with EDS vs men without EDS (55.3 vs 17.0/10,000 person-years; odds ratio [OR] = 3.3; 95% CI = 1.4 to 7.0; p = 0.004). Additional adjustment for insomnia, cognitive function, depressed mood, midlife cigarette smoking and coffee drinking, and other factors failed to alter the association between EDS and PD (OR = 2.8; 95% CI = 1.1 to 6.4; p = 0.014). Other sleep related features such as insomnia, daytime napping, early morning grogginess, and frequent nocturnal awakening showed little relation with the risk of PD. Conclusions: Excessive daytime sleepiness may be associated with an increased risk of developing Parkinson disease.

Cerebral amyloid angiopathy and cognitive function: the HAAS autopsy study.

Objective To investigate the relationship between cerebral amyloid angiopathy (CAA), dementia, and cognitive function in an autopsy sample of 211 Japanese-American men from the population-based Honolulu–Asia Aging Study. Methods Starting in 1991, participants were assessed with the Cognitive Abilities Screening Instrument (CASI) and diagnosed with dementia (including subtype) based on published criteria. At autopsy, neuropathologists blinded to clinical data examined brains for neurofibrillary tangles (NFT), neuritic plaques (NP), and a number of vascular pathologies, including CAA. CAA was detected by immunostaining for &bgr;A4 amyloid in parenchymal vessels in the neocortex and semiquantitatively rated. Linear regression models were used to examine the association of CASI score, dementia subtype, and CAA controlling for age at death, time between CASI administration and death, education, NP and NFT counts, infarcts, hemorrhage, and APOE genotype. Results A total of 44.1% of subjects had CAA in at least one neocortical area. The presence of CAA was associated with higher mean NFT and NP counts and having at least one APOE-&egr;4 allele. The interaction between CAA and AD on the adjusted mean CASI score was significant; compared with nondemented men without CAA, the CASI score was 16.6% lower in men with AD and no CAA and 45.9% lower in men with AD plus CAA. Conclusions CAA may contribute to the clinical presentation of dementia by interacting with other neuronal pathologies, leading to more severe cognitive impairment in men with both CAA and AD compared with men with only AD or CAA.

Longitudinal association of vascular and Alzheimer's dementias, diabetes, and glucose tolerance.

Objective: To assess the relationship between impaired glucose tolerance and both vascular dementia and AD. Background: Diabetes and abnormalities of glucose metabolism have been associated with stroke and poor cognitive function. In addition, glycoproteins and glycosylation have been postulated to be associated with the development of neuritic plaques characteristic of AD. Methods: A historical prospective cohort study of Japanese-American men (n = 3,774), who were examined at ages 45 to 68 (1965 through 1968) and again at ages 71 to 93 (1991 through 1993). Measurements were obtained by clinical and home examinations: assessment of glucose intolerance (nonfasting 1 hour after glucose load) from 1965 through 1968 and history of diabetes diagnosed by a physician at examinations given from 1965 through 1968 and from 1976 through 1978. At the 1991 through 1993 examinations, the Cognitive Assessment Screening Instrument (CASI)—an instrument designed for use in cross-cultural settings combining features of the Folstein Mini-Mental State Examination, the Modified Mini-Mental State Examination, and the Hasegawa Dementia Screening Scale—was used. Diagnosis and classification of AD and vascular dementia were made by a consensus panel using neuropsychologic assessment data, a neurologist’s evaluation, and information from a family informant. Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised criteria were used to establish dementia, and subclassification by cause was based on other published criteria. Results: No association between AD and diabetes, present either 25 or 15 years previously, was found after adjustment for age and education in a multiple regression model. A significant association was found between impaired glucose tolerance at baseline and vascular dementia (p < 0.01). Conclusions: These findings confirm expected relationships between impaired glucose tolerance and stroke-related dementia but do not support an association of disordered glucose metabolism with AD.

Brain Aging and Midlife Tofu Consumption

Objective: To examine associations of midlife tofu consumption with brain function and structural changes in late life. Methods: The design utilized surviving participants of a longitudinal study established in 1965 for research on heart disease, stroke, and cancer. Information on consumption of selected foods was available from standardized interviews conducted 1965–1967 and 1971–1974. A 4-level composite intake index defined “low-low” consumption as fewer than two servings of tofu per week in 1965 and no tofu in the prior week in 1971. Men who reported two or more servings per week at both interviews were defined as “high-high” consumers. Intermediate or less consistent “low” and “high” consumption levels were also defined. Cognitive functioning was tested at the 1991–1993 examination, when participants were aged 71 to 93 years (n=3734). Brain atrophy was assessed using neuroimage (n=574) and autopsy (n=290) information. Cognitive function data were also analyzed for wives of a sample of study participants (n=502) who had been living with the participants at the time of their dietary interviews. Results: Poor cognitive test performance, enlargement of ventricles and low brain weight were each significantly and independently associated with higher midlife tofu consumption. A similar association of midlife tofu intake with poor late life cognitive test scores was also observed among wives of cohort members, using the husband’s answers to food frequency questions as proxy for the wife’s consumption. Statistically significant associations were consistently demonstrated in linear and logistic multivariate regression models. Odds ratios comparing endpoints among “high-high” with “low-low” consumers were mostly in the range of 1.6 to 2.0. Conclusions: In this population, higher midlife tofu consumption was independently associated with indicators of cognitive impairment and brain atrophy in late life.

Cholesterol and neuropathologic markers of AD: A population-based autopsy study

Objective: To examine the association of plasma cholesterol (total and high-density [HDL] and low-density lipoprotein) levels with neuritic plaques (NP) and neurofibrillary tangles (NFT) in a population-based autopsy series of 218 Japanese American men followed as a part of the Honolulu–Asia Aging Study. Methods: Cholesterol levels were measured in late life (average age at death 84.6 years) in all subjects (n = 218) and in midlife (20 years before late life) in a subsample (n = 89); for the analyses, levels were categorized into quintiles, with the lowest quintile serving as the reference. Tissue from four areas of neocortex and two areas of hippocampus was prepared with Bielschowsky silver-stained sections and evaluated by one of three neuropathologists who were blinded to clinical information. Diffuse and neuritic plaques and NFT were counted in field areas standardized to 1 mm2. Fields were selected from areas with the highest numbers of lesions, and the field with the highest count was taken to represent the brain area. Results: After adjusting for age at death, education, APOE allele, dementia, neuropathologic infarction, and blood pressure, a strong linear association was found for increasing late-life HDL cholesterol (HDL-C) levels and an increasing number of neocortical NP (5th versus 1st quintile: count ratio [95% CI] 2.30 [1.05 to 5.06]) and hippocampal (2.63 [1.25 to 5.50]) and neocortical (4.20 [1.73 to 10.16]) NFT. Trends were similar for the midlife HDL-C levels. Conclusions: The constituents of HDL-C may play a role in the formation of AD pathology, and these processes are reflected in peripheral measures.

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.

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/mm2 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.