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1.  Antihypertensive medication use and risk of cognitive impairment 
Neurology  2013;81(10):888-895.
To determine the associations between classes of antihypertensive medication use and the risk of cognitive impairment among elderly hypertensive men.
The Honolulu-Asia Aging Study is a prospective, community-based cohort study of Japanese American men conducted in Honolulu, Hawaii. We examined 2,197 participants (mean age 77 years at cohort entry, 1991–1993, followed through September 2010) with hypertension and without dementia or cognitive impairment at baseline, who provided information on medication use. Cognitive function was assessed at 7 standardized examinations using the Cognitive Abilities Screening Instrument (CASI). Cognitive impairment was defined as a CASI score <74.
A total of 854 men developed cognitive impairment (median follow-up, 5.8 years). β-Blocker use as the sole antihypertensive drug at baseline was consistently associated with a lower risk of cognitive impairment (incidence rate ratio [IRR] 0.69; 95% confidence interval [CI] 0.50–0.94), as compared with men not taking any antihypertensive medications, adjusting for multiple potential confounders. The use of diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors, or vasodilators alone was not significantly associated with cognitive impairment. Results were similar excluding those with cardiovascular disease or <1 year of follow-up, and additionally adjusting for pulse pressure, heart rate, baseline and midlife systolic blood pressure, and midlife antihypertensive treatment (IRR 0.65; 95% CI 0.45–0.94). The association between β-blocker use and cognitive impairment was stronger among men with diabetes, men aged >75 years, and those with pulse pressure ≥70 mm Hg.
β-blocker use is associated with a lower risk of developing cognitive impairment in elderly Japanese American men.
PMCID: PMC3885214  PMID: 23911753
2.  Lewy pathology is not the first sign of degeneration in vulnerable neurons in Parkinson disease 
Neurology  2012;79(24):2307-2314.
To determine whether evidence of neuronal dysfunction or demise preceded deposition of Lewy pathology in vulnerable neurons in Parkinson disease (PD).
We examined the extent of nigral dysfunction and degeneration among 63 normal, incidental Lewy body disease (ILBD), and PD cases based on tyrosine hydroxylase (TH) immunoreactivity and neuron densities, respectively. The relationship between these markers and Lewy pathology (LP) burden in the substantia nigra (SN) and Braak PD stage was assessed.
Compared with normal subjects, ILBD cases displayed a significantly higher percentage of TH-negative cells and lower neuronal densities in the SN as early as Braak PD stages 1 and 2, before LP deposition in the nigrostriatal system. ILBD nigral neuron densities were intermediate between normal subjects and PD cases, and TH-negative percentages were higher in ILBD than either normal or PD cases. Furthermore, neuron density and neuronal dysfunction levels remained relatively constant across Braak PD stages in ILBD.
These results suggest that significant neurodegeneration and cellular dysfunction precede LP in the SN, challenging the pathogenic role of LP in PD and the assumption that ILBD always represents preclinical PD.
PMCID: PMC3578379  PMID: 23152586
NeuroImage  2007;40(3):1003-1015.
Understanding the variability of the hippocampus in human brain research is essential. The effect of age on the hippocampus has been explored in several studies that have been focused on either normal aging or neural degeneration. Shape analysis of magnetic resonance imaging (MRI) provides morphological measures for brain structures. This study further investigates the age effects on hippocampal morphology in three groups (104 normal controls, 24 Alzheimer’s disease (AD) and 14 vascular dementia (VaD) patients). By utilizing a parametric shape analysis of hippocampal MRI scans, each individual distance map is generated and analyzed statistically. Specifically, after eliminating similarity parameters (rotation, translation, and scaling) effects for each hippocampus, an individual distance map is generated from parametric hippocampal surfaces and medial axes. Then statistical methods, including regression, and permutation tests, are applied to detect the differences in hippocampal distance maps and volumes under the effect of age in each group. Statistical analyses reveal that the loss of hippocampal volume and changes in shape are more significantly related to aging in the control group than in AD/VaD. The results also show that the asymmetry of hippocampus in healthy subjects is greater than that in either of the disease groups. Our study shows that 3D statistical shape analysis could enhance the understanding of age effects on local areas of hippocampi. However, the sample sizes of disease groups are relatively low; further studies with more AD/VaD data are needed.
PMCID: PMC3785795  PMID: 18280181
Statistical shape analysis; age; hippocampus; Alzheimer’s disease; vascular dementia
4.  Brain Organochlorines and Lewy Pathology: The Honolulu-Asia Aging Study 
Although organochlorines have been reported more frequently in Parkinson’s disease (PD) brains than controls, the association with brain Lewy pathology is unknown. Honolulu-Asia Aging Study (HAAS) participants, exposed to organochlorines from a variety of sources during mid-life, represent a population well suited to determine the relationship of brain organochlorines with Lewy pathology in decedents from the longitudinal HAAS.
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 to be present in at least one brain, initial assessments identified heptachlor epoxide isomer b, methoxychlor, and benzene hexachloride b as being most important. Prevalence of Lewy pathology was 75% (6/8) among brains with any 2 of the 3 compounds, 48.8% (79/162) among those with 1, and 32.7% (18/55) for those with neither (P=0.007 test for trend). While findings persisted after removing cases with PD and dementia with Lewy bodies, and when adjustments were made for age at death, body mass index, pack-years of cigarette smoking, and coffee intake (p=0.013), results were insignificant when correcting for multiple testing.
While consistent with earlier accounts of an association between organochlorines and clinical PD, associations with Lewy pathology warrant further study.
PMCID: PMC3474594  PMID: 22976848
Parkinson’s disease; epidemiology; Lewy body; organochlorines; pesticides
5.  Coffee Intake in Midlife and Risk of Dementia and its Neuropathologic Correlates 
While animal data suggest a protective effect of caffeine on cognition, studies in humans remain inconsistent. We examined associations of coffee and caffeine intake in midlife with risk of dementia, its neuropathologic correlates, and cognitive impairment among 3494 men in the Honolulu-Asia Aging Study (mean age 52 at cohort entry, 1965–1968) examined for dementia in 1991–1993, including 418 decedents (1992–2004) who underwent brain autopsy. Caffeine intake was determined according to self-reported coffee, tea, and cola consumption at baseline. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for overall dementia, Alzheimer's disease (AD), vascular dementia (VaD), cognitive impairment (Cognitive Abilities Screening Instrument score <74), and neuropathologic lesions at death (Alzheimer lesions, microvascular ischemic lesions, cortical Lewy bodies, hippocampal sclerosis, generalized atrophy), according to coffee and caffeine intake. Dementia was diagnosed in 226 men (including 118 AD, 80 VaD), and cognitive impairment in 347. There were no significant associations between coffee or caffeine intake and risk of cognitive impairment, overall dementia, AD, VaD, or moderate/high levels of the individual neuropathologic lesion types. However, men in the highest quartile of caffeine intake (≥411.0 mg/d) were less likely than men in the lowest quartile (≤137.0 mg) to have any of the lesion types (adjusted-OR, 0.45; 95% CI, 0.23–0.89; p, trend = 0.04). Coffee and caffeine intake in midlife were not associated with cognitive impairment, dementia, or individual neuropathologic lesions, although higher caffeine intake was associated with a lower odds of having any of the lesion types at autopsy.
PMCID: PMC3731132  PMID: 21157028
Caffeine; coffee; cohort studies; dementia
6.  Rapid Growth from 12 to 23 Months of Life Predicts Obesity in a Population of Pacific Island Children 
Ethnicity & disease  2012;22(4):439-444.
Rapid growth (RG) in early childhood has been associated with increased risk of obesity. The specific intervals when risk is highest have not been well examined and may help identify modifiable risk factors.
To determine the correlation between RG in consecutive time intervals during the first 2 years of life with obesity at 4–5 years.
This was a retrospective study of children attending the largest community health center in Hawaii. Children, aged 4–5 years, with a pre-kindergarten (PreK) well-child physical examination were included; data were abstracted from medical charts.
Children were classified as overweight (BMI for age/sex 85–94%) or obese (BMI for age/sex ≥ 95%). Moderate and severe rapid growth was defined as an increase in weight-for-height z-score of .67–1.0 SD and ≥1.0, respectively. Relationship between RG and PreK obesity was assessed using logistic regression analyses.
389 children were included: 66% Hawaiian, 21.6% Samoan and 12.3% Filipino. At the PreK 19.6% were obese, and 20.9% were overweight. Severe RG from 12 to 23 months was strongly associated with PreK obesity (OR 4.36, 95% CI 1.85–10.27). Of children with severe RG from 12–23 months, 48% were obese at PreK compared with 16.7% of children with moderate RG and 19.3% of children without RG.
Rapid growth between 12 and 23 months, a key period of nutritional transition in toddlers, was strongly associated with obesity at 4 to 5 years of age in this high-risk population of Pacific Island minority subgroups.
PMCID: PMC3726535  PMID: 23140074
Obesity; Overweight; Child; Growth; Pacific Islander; Hawaii
7.  Late-life Hemoglobin and the Incidence of Parkinson’s Disease 
Neurobiology of Aging  2010;33(5):914-920.
Brain iron promotes neurodegeneration in Parkinson’s disease (PD). While hemoglobin (Hb) is the most abundant source of peripheral iron in humans, its relationship with PD is uncertain. This report examines the association between Hb in late-life and PD incidence.
From 1991-1993, Hb was measured in 3,507 men in the Honolulu-Asia Aging Study. Men were aged 71-93 years and without PD. Participants were followed until 2001 for incident PD.
Hb levels declined markedly with age. For men aged 71-75 years, 14.8% had levels <14 g/dL versus 53.6% in those aged 86 and older (p<0.001). During follow-up, 47 men developed PD (19.8/10,000 person-years). After age-adjustment, PD incidence rose significantly from 10.3 to 34.9/10,000 person-years as Hb increased from <14 to ≥16 g/dL (p=0.024, relative hazard 3.2, 95% CI 1.2-8.9). Associations persisted after accounting for early mortality and adjustments for concomitant risk factors.
While Hb declines with advancing age, evidence suggests that Hb that remains high in elderly men is associated with an increased risk of PD.
PMCID: PMC3006667  PMID: 20709430
Hemoglobin; iron; Parkinson’s disease; epidemiology
8.  Midlife blood pressure, plasma β amyloid and the risk for Alzheimer’s disease: the Honolulu Asia Aging Study 
Hypertension  2012;59(4):780-786.
Beta-amyloid (Aβ), a vasoactive protein, and elevated blood pressure (BP) levels are associated with Alzheimer’s disease (AD) and possibly vascular dementia (VaD). We investigated the joint association of mid-life BP and Aβ peptide levels with the risk for late-life AD and VaD. Subjects were 667 Japanese-American men (including 73 with a brain autopsy), from the prospective Honolulu Heart Program/Honolulu Asia Aging Study (1965 – 2000). Mid-life BP was measured starting in 1971 participants mean age 58 years, Aβ was measured in specimens collected1980/82, and assessment of dementia and autopsy collection started in 1991/93. The outcome measures were prevalent (present in 1991/3) and incident AD (n= 53, including 38 with no contributing cardiovascular disease), and VaD (n=24). Cerebral amyloid angiopathy (CAA), β-amyloid neuritic plaques, and neurofibrillary tangles were evaluated in post-mortem tissue. The risk for AD significantly increased with lower levels of plasma Aβ (Aβ1-40 hazard ratio (HR) 2.1, 95% confidence interval (CI) 1.4 – 3.1; Aβ1-42 HR 1.6, 95% CI 1.1 – 2.3). Evidence of interaction between diastolic BP and plasma Aβ (1-40 pinteraction <0.05; 1-42 pinteraction <0.07) levels, indicated the Aβ-related risk for AD was higher when BP was higher. Low plasma Aβ was associated with the presence of CAA (ptrend<0.05), but not the other neuropathologies. Aβ plasma levels start decreasing at least 15 years before AD is diagnosed, and the association of Aβ to AD is modulated by mid-life diastolic BP. Elevated BP may compromise vascular integrity leading to CAA and impaired Aβ clearance from the brain.
PMCID: PMC3319436  PMID: 22392902
Amyloid; blood pressure; brain; aging; dementia
9.  Lifestyle and the Risk of Dementia Among Japanese American Men 
To determine whether adhering to a healthy lifestyle in midlife may reduce the risk of dementia.
Case-control study nested in a prospective cohort.
The Honolulu-Asia Aging Study on Oahu, Hawaii.
3468 Japanese American men (mean age 52, 1965–1968) examined for dementia after 25 years.
Men at low risk were defined as those with the following midlife characteristics: nonsmoking, body mass index <25.0 kg/m2, physically active, and having a healthy diet (based on alcohol, dairy, meat, fish, fruit, vegetables, cereals, and monounsaturated-to-saturated fat). Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for developing overall dementia, Alzheimer’s disease (AD), and vascular dementia (VaD), adjusting for potential confounders.
Dementia was diagnosed in 6.4% of men (52.5% with AD, 35.0% with VaD). Examining the risk factors individually, BMI was most strongly associated with increased risk of overall dementia (OR, 1.87; 95% CI, 1.26–2.77; BMI >25.0 vs. <22.6 kg/m2). All of the individual risk factors except diet score were significantly associated with VaD, whereas none were significantly associated with AD alone. Men with all four low-risk characteristics (7.2% of cohort) had the lowest OR for overall dementia (OR, 0.36; 95% CI, 0.15–0.84), as compared to other men. There were no significant associations between the combined low-risk characteristics and the risk of AD alone.
Having a healthy lifestyle in midlife is associated with a lower risk of dementia in late life among Japanese American men.
PMCID: PMC3258374  PMID: 22211390
dementia; lifestyle; risk
10.  Changes in Selenoprotein P in Substantia Nigra and Putamen in Parkinson’s Disease 
Journal of Parkinson's disease  2012;2(2):115-126.
Oxidative stress and oxidized dopamine contribute to the degeneration of the nigrostriatal pathway in Parkinson’s disease (PD). Selenoproteins are a family of proteins containing the element selenium in the form of the amino acid selenocysteine, and many of these proteins have antioxidant functions. We recently reported changes in expression of the selenoprotein, phospholipid hydroperoxide glutathione peroxidase GPX4 and its co-localization with neuromelanin in PD brain. To further understand the changes in GPX4 in PD, we examine here the expression of the selenium transport protein selenoprotein P (Sepp1) in postmortem Parkinson’s brain tissue. Sepp1 in midbrain was expressed in neurons of the substantia nigra (SN), and expression was concentrated within the centers of Lewy bodies, the pathological hallmark of PD. As with GPX4, Sepp1 expression was significantly reduced in SN from PD subjects compared with controls, but increased relative to cell density. In putamen, Sepp1 was found in cell bodies and in dopaminergic axons and terminals, although levels of Sepp1 were not altered in PD subjects compared to controls. Expression levels of Sepp1 and GPX4 correlated strongly in the putamen of control subjects but not in the putamen of PD subjects. These findings indicate a role for Sepp1 in the nigrostriatal pathway, and suggest that local release of Sepp1 in striatum may be important for signaling and/or synthesis of other selenoproteins such as GPX4.
PMCID: PMC3527083  PMID: 23268326
Selenium; selenoproteins; selenoprotein P; GPX4; glutathione peroxidase; Parkinson’s disease; Lewy bodies; dopamine; substantia nigra; striatum; putamen; presynaptic terminals
11.  Microinfarcts, brain atrophy, and cognitive function: the HAAS autopsy study 
Annals of neurology  2011;70(5):774-780.
To study the association of microinfarcts (MBI) to ante-mortem global cognitive function (CF), and to investigate whether brain weight (BW), Alzheimer’s lesions (neurofibrillary tangles (NFT) or neuritic plaques (NP) mediate the association.
Subjects are 437 well-characterized male decedents from the Honolulu Asia Aging Autopsy Study. Brain pathology was ascertained with standardized methods, CF was measured by the Cognitive Abilities Screening Instrument (CASI)and data were analyzed using formal mediation analyses, adjusted for age at death, time between last CF measure and death, education, and head size. Based on ante-mortem diagnoses, demented and non-demented subjects were examined together and separately.
In those with no dementia, MBI were strongly associated with the last ante-mortem CF score; this was significantly mediated by BW, and not NFT or NP. In contrast, among those with an ante-mortem diagnosis of dementia, NFT had the strongest associations with BW and with CF, and MIB were modestly associated with CF.
This suggests microinfarct pathology is a significant and independent factor contributing to brain atrophy and cognitive impairment, particularly before dementia is clinically evident. The role of vascular damage as initiator, stimulator, or additive contributor to neurodegeneration may differ depending on when in the trajectory towards dementia the lesions develop.
PMCID: PMC3241005  PMID: 22162060
12.  AD brain pathology: Vascular origins? Results from the HAAS Autopsy Study 
Neurobiology of aging  2007;29(10):1587-1590.
An increasing number of studies suggest a vascular contribution to Alzheimer’s disease [AD]. One major question these findings raise is whether vascular disease enhances the formation of AD-like lesions, or whether vascular disease just adds to clinical severity. We examined this question in a fully characterized autopsy sample based on the Honolulu Asia Aging Study. We found that AD markers of neurodegeneration [amyloid plaques, cerebral amyloid angiopathy and neurofibrillary tangles] were no more prevalent in those with neuropathologically defined vascular lesions compared to those without lesions. Our study suggests the burden of vascular and AD type lesions are independent of each other, and are consistent with an additive effect of the two types of lesions on cognitive impairment.
PMCID: PMC3437222  PMID: 17466414
13.  Ecology of aging human brain 
Archives of neurology  2011;68(8):1049-1056.
Alzheimer’s disease (AD), cerebral vascular brain injury (VBI), and isocortical Lewy body (LB) disease (LBD) are the major contributors to dementia in community- or population-based studies: Adult Changes in Thought (ACT) study, Honolulu-Asia Aging Study (HAAS), Nun Study (NS), and Oregon Brain Aging Study (OBAS). However, the prevalence of clinically silent forms of these diseases in cognitively normal (CN) adults is less clear.
We evaluated 1672 brain autopsies from ACT, HAAS, NS, and OBAS of which 424 met criteria for CN.
Of these, 336 cases had a comprehensive neuropathologic examination of neuritic plaque (NP) density, Braak stage for neurofibrillary tangles (NFTs), Lewy body (LB) distribution, and number of cerebral microinfarcts (CMIs).
47% of CN cases had moderate or frequent NP density; of these 6% also had Braak stage V or VI for NFTs. 15% of CN cases had medullary LBD; 8% also had nigral and 4% isocortical LBD. The presence of any CMIs was identified in 33% and high level CMIs in 10% of CN individuals. Overall burden of lesions in each individual and their co-morbidity varied widely within each study but were similar among studies.
These data show an individually varying complex convergence of subclinical diseases in the brain of older CN adults. Appreciating this ecology should help guide future biomarker or neuroimaging studies as well as clinical trials that focus on community- or population-based cohorts.
PMCID: PMC3218566  PMID: 21825242
Alzheimer’s disease; vascular brain injury; Lewy body disease; cognitive aging
14.  Hippocampal morphometry in population-based incident Alzheimer’s disease and vascular dementia: the HAAS 
Hippocampal changes may be a useful biomarker for Alzheimer’s disease if they are specific to dementia sub-type. We compare hippocampal volume and shape in population-based incident cases of Alzheimer’s disease and vascular dementia (VaD).
Participants are Japanese-American men from the Honolulu Asia Aging Study. The following analysis is based on a sub-group of men with mild incident Alzheimer’s disease (n=24: age=82.5±4.6) or incident VaD (n=14: age=80.5±4.5). To estimate hippocampal volume, one reader, blinded to dementia diagnosis, manually outlined the left and right formation of the hippocampus using published criteria. We used 3-D mapping methods developed at the Laboratory of Neuro Imaging (LONI) to compare regional variation in hippocampal width between dementia groups.
Hippocampal volume was about 5% smaller in the Alzheimer’s disease group compared to the VaD group, but the difference was not significant. Hippocampal shape differed between the two case groups for the left (p<0.04) but not right (p<0.21) hippocampus. The specific region of the hippocampus that most consistently differed between the Alzheimer’s disease and VaD cases was in the lateral portion of the left hippocampus. Our interpretation of this region is that it intersects the CA1 sub-region to a great extent but also includes the dentate gyrus (and hilar region) and subiculum.
As indicated by shape analysis, there are some differences in atrophy localisation between the Alzheimer’s disease and VaD cases, despite the finding that volume of the hippocampi did not differ. These findings suggest hippocampal atrophy in Alzheimer’s disease may be more focal than in VaD.
PMCID: PMC3192810  PMID: 20826877
15.  Bowel Movement Frequency in Late-Life and Substantia Nigra Neuron Density at Death 
Movement Disorders  2009;24(3):371-376.
Constipation is associated with future risk of Parkinson’s disease (PD) and with incidental Lewy bodies (LB) in the locus ceruleus or substantia nigra (SN). Our purpose is to examine the independent association between bowel movement frequency in late-life and post mortem SN neuron density. Bowel movement frequency was assessed in the Honolulu-Asia Aging Study from 1991 to 1993 in 414 men aged 71 to 93 years with later postmortem evaluations. Brains were examined for LB in the SN and locus ceruleus and neurons were counted in four quadrants from a transverse section of SN. In non-smokers, neuron densities (counts/mm2) for men with >1, 1, and <1 bowel movement daily were 18.5, 18.8, 10.1 (p<0.001) for dorsomedial; 15.3, 16.4, 10.2 (p<0.03) for ventromedial; and 18.6, 18.3, 10.9 (p=0.011) for ventrolateral quadrants. Relationships were not significant in the dorsolateral quadrant or in any quadrant among smokers. After adjustment for age, time to death, coffee drinking, tricep skinfold thickness, excessive daytime sleepiness, cognitive function, PD, and incidental LB, density ratios in nonsmokers with 1 or more bowel movement(s) daily were significantly higher compared to those with <1 daily. Constipation is associated with low SN neuron density independent of the presence of LB.
PMCID: PMC3272050  PMID: 19006191
Parkinson’s disease; constipation; Lewy body; substantia nigra; neuron density
16.  Trends in the incidence and prevalence of Alzheimer’s disease, dementia, and cognitive impairment in the United States* 
Declines in heart disease and stroke mortality rates are conventionally attributed to reductions in cigarette smoking, recognition and treatment of hypertension and diabetes, effective medications to improve serum lipid levels and to reduce clot formation, and general lifestyle improvements. Recent evidence implicates these and other cerebrovascular factors in the development of a substantial proportion of dementia cases. Analyses were undertaken to determine if corresponding declines in age-specific prevalence and incidence rates for dementia and cognitive impairment have occurred in recent years. Data spanning 1 or 2 decades were examined from community-based epidemiologic studies in Minnesota, Illinois, and Indiana, and from the Health and Retirement Study, a national survey. Although a marginal decline was observed in the Minnesota cohort, no clinically significant trends were apparent in the community studies. A significant reduction in cognitive impairment measured by neuropsychological testing was identified in the national survey. Cautious optimism appears justified.
PMCID: PMC3026476  PMID: 21255746
17.  Lowering mid-life levels of systolic blood pressure as a public health strategy to reduce late-life dementia 
Hypertension  2010;55(6):1352-1359.
To estimate the potential benefits towards preventing late-life dementia, of lowering systolic blood pressure [SBP] we estimated the population attributable risk (PAR) of elevated SBP on dementia. Analyses are based on the cohort of 8006 Japanese American men (b. 1900 – 1919) followed since 1965 as a part of the Honolulu Heart Program, continued as the Honolulu Asia Aging Study. Mid-life cardiovascular risk factors and late-life brain function are well described. We estimated the PAR of dementia cases attributed to mid-life SBP, grouped by JCN-7 criteria [<120, 120 – < 140, and ≥ 140 mmHG], taking into account treatment history, confounding factors, and competitive risk for death. The analysis is based on 7878 subjects, including 491 cases of dementia, with a mean interval of 25 years between measurement of BP and dementia diagnosis. Compared to those with SBP <120 mmHG, untreated and <50 years at baseline, 17.7% (95% CI 4.6% – 29.1%) of the cases are attributable to prehypertensive levels (SBP 120 – <140 mmHG) of SBP, translating into 11 excess cases per 1000. Among those who did not report taking anti-hypertensive medication in mid-life, 27% [95%CI 8.9%, 42.1%] of dementia cases can be attributed to systolic BP >120 mmHG, translating into 17 excess cases per 1000. Although PAR estimates for population sub –groups may differ by relative risk for dementia or prevalence of elevated levels of BP, these data suggest reducing mid-life systolic BP is an effective prevention strategy to reduce risk for late-life dementia.
PMCID: PMC3241740  PMID: 20404223
Dementia; population attributable risk; hypertension; older persons; cohort study; epidemiology
18.  Use of Spoken and Written Japanese Did Not Protect Japanese-American Men From Cognitive Decline in Late Life 
Spoken bilingualism may be associated with cognitive reserve. Mastering a complicated written language may be associated with additional reserve. We sought to determine if midlife use of spoken and written Japanese was associated with lower rates of late life cognitive decline.
Participants were second-generation Japanese-American men from the Hawaiian island of Oahu, born 1900–1919, free of dementia in 1991, and categorized based on midlife self-reported use of spoken and written Japanese (total n included in primary analysis = 2,520). Cognitive functioning was measured with the Cognitive Abilities Screening Instrument scored using item response theory. We used mixed effects models, controlling for age, income, education, smoking status, apolipoprotein E e4 alleles, and number of study visits.
Rates of cognitive decline were not related to use of spoken or written Japanese. This finding was consistent across numerous sensitivity analyses.
We did not find evidence to support the hypothesis that multilingualism is associated with cognitive reserve.
PMCID: PMC2954325  PMID: 20639282
Aging; Bilingualism; Cognitive decline; Cognitive reserve; Japanese language; Psychometrics
19.  Effect of Walking Distance on 8-Year Incident Depressive Symptoms in Elderly Men With and Without Chronic Disease: The Honolulu-Asia Aging Study 
To determine the effect of walking on incident depressive symptoms in elderly Japanese-American men with and without chronic disease
Prospective cohort study
The Honolulu-Asia Aging Study
Japanese-American men aged 71 to 93 years at baseline
Physical activity was assessed by self-reported distance walked per day. Depressive symptoms were measured with an 11-question version of the Centers for Epidemiologic Studies Depression Scale (CES-D) at the 4th exam (n=3196) and again at the 7th exam 8 years later (1999-2000, n=1417). Presence of incident depressive symptoms was defined as CESD-11 score ≥ 9 or taking anti-depressants at Exam 7. Subjects with prevalent depressive symptoms at baseline were excluded.
Age adjusted 8-year incident depressive symptoms were 13.6%, 7.6% and 8.5% for low (< ¼ miles/day), intermediate (¼ to 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 found that those in the intermediate and highest walking groups had significantly lower odds for developing 8-year incident depressive symptoms (OR=0.52; 95% CI=0.32-0.83, p=0.006; and OR=0.61; 95% CI=0.39-0.97, p=0.04 respectively). Analysis found that this association was only significant in those without chronic diseases (CHD, CVA, Cancer, PD, Dementia or cognitive impairment) at baseline.
Daily physical activity (≥¼ mile/day) is significantly associated with a lower risk for 8-year incident depressive symptoms in elderly Japanese-American men who do not have chronic disease at baseline.
PMCID: PMC2955160  PMID: 20670378
Physical activity; aged; depressive symptoms; chronic disease
20.  Educational attainment and mid-life stress as risk factors for dementia in late life 
Brain  2010;133(8):2180-2182.
PMCID: PMC3139940  PMID: 20639546
21.  Thyroid function, the risk of dementia and neuropathologic changes: The Honolulu-Asia Aging Study 
Neurobiology of aging  2007;30(4):600-606.
Thyroid dysfunction is associated with cognitive impairment and dementia, including Alzheimer disease (AD). It remains unclear whether thyroid dysfunction results from, or contributes to, Alzheimer pathology. We determined whether thyroid function is associated with dementia, specifically AD, and Alzheimer-type neuropathology in a prospective population-based cohort of Japanese-American men. Thyrotropin, total and free thyroxine were available in 665 men aged 71–93 years and dementia-free at baseline (1991), including 143 men who participated in an autopsy sub-study. During a mean follow-up of 4.7 (SD: 1.8) years, 106 men developed dementia of whom 74 had AD. Higher total and free thyroxine levels were associated with an increased risk of dementia and AD (age and sex adjusted hazard ratio (95% confidence interval) per SD increase in free thyroxine: 1.21 (1.04; 1.40) and 1.31 (1.14; 1.51) respectively). In the autopsied sub-sample, higher total thyroxine was associated with higher number of neocortical neuritic plaques and neurofibrillary tangles. No associations were found for thyrotropin. Our findings suggest that higher thyroxine levels are present with Alzheimer clinical disease and neuropathology.
PMCID: PMC3147246  PMID: 17870208
Epidemiology; thyroid hormones; thyrotropin; total thyroxine; free thyroxine; dementia; Alzheimer disease; neuropathology; neuritic plaques; neurofibrillary tangles
22.  Change in blood pressure and incident dementia: a 32-year prospective study 
Hypertension  2009;54(2):233-240.
Studies of the association of high blood pressure [BP] to dementia are not consistent. Understanding long term trajectories in blood pressure of those who do and do not develop dementia can help clarify the issue. The Honolulu Heart Program/Honolulu-Asia Aging Study followed a cohort of Japanese American men for an average of 32 years, with systolic and diastolic BP measured at six examinations and dementia assessed at the final three. In an analysis of 1890 men who completed all six exams, 112 diagnosed with incident dementia at exam 6 were compared to the 1778 survivors without dementia. Trajectories in systolic and diastolic BP up to and including the sixth examination were estimated with a repeated measures analysis using 3 splines. From mid- to late-life, men who went on to develop dementia had an additional age-adjusted increase in systolic BP of 0.26 (95% CI 0.01-0.51) mmHg per year compared to survivors without dementia. Over the late-life examinations this group had an additional age-adjusted decline in systolic BP of 1.36 (0.64-2.07) mmHg per year. These associations were strongest for vascular dementia, and were reduced substantially in men who were previously taking antihypertensive medication. Similar changes in diastolic BP were observed but only for vascular dementia and the findings were not modified by antihypertensive treatment. Over a 32-year period, compared to men who did not, those who did develop dementia have had a greater increase, followed by a greater decrease in systolic BP. Both these trends are modified by antihypertensive therapy.
PMCID: PMC3136040  PMID: 19564551
blood pressure; hypertension; hypotension; dementia; Alzheimer’s disease; vascular dementia
23.  Midlife muscle strength and human longevity up to age 100 years: a 44-year prospective study among a decedent cohort 
Age  2011;34(3):563-570.
We studied prospectively the midlife handgrip strength, living habits, and parents’ longevity as predictors of length of life up to becoming a centenarian. The participants were 2,239 men from the Honolulu Heart Program/Honolulu–Asia Aging Study who were born before the end of June 1909 and who took part in baseline physical assessment in 1965–1968, when they were 56–68 years old. Deaths were followed until the end of June 2009 for 44 years with complete ascertainment. Longevity was categorized as centenarian (≥100 years, n = 47), nonagenarian (90–99 years, n = 545), octogenarian (80–89 years, n = 847), and ≤79 years (n = 801, reference). The average survival after baseline was 20.8 years (SD = 9.62). Compared with people who died at the age of ≤79 years, centenarians belonged 2.5 times (odds ratio (OR) = 2.52, 95% confidence interval (CI) = 1.23–5.10) more often to the highest third of grip strength in midlife, were never smokers (OR = 5.75 95% CI = 3.06–10.80), had participated in physical activity outside work (OR = 1.13 per daily hour, 95% CI = 1.02–1.25), and had a long-lived mother (≥80 vs. ≤60 years, OR = 2.3, 95% CI = 1.06–5.01). Associations for nonagenarians and octogenarians were parallel, but weaker. Multivariate modeling showed that mother’s longevity and offspring’s grip strength operated through the same or overlapping pathway to longevity. High midlife grip strength and long-lived mother may indicate resilience to aging, which, combined with healthy lifestyle, increases the probability of extreme longevity.
PMCID: PMC3337929  PMID: 21541735
Aging; Longevity; Inter-generational; Grip strength; Mortality; Human; Life Sciences; Molecular Medicine; Geriatrics/Gerontology; Cell Biology
24.  Midlife use of written Japanese and protection from late life dementia 
Epidemiology (Cambridge, Mass.)  2009;20(5):766-774.
The cognitive reserve hypothesis would predict that use of written Japanese should confer protection against dementia because of the complexity of its ideograms compared with written English. We sought to test this hypothesis in analyses from a longitudinal study of Japanese-American men.
Participants were second-generation Japanese-American men (Nisei) on the island of Oahu, Hawaii, who were seen in 1965 and in subsequent examinations to detect dementia beginning in 1991-1993. Use of spoken and written Japanese was self-reported in 1965 (Analyses 1 and 2), and mid-life use of written Japanese and written English was self-reported in 1994-1996 (Analysis 3). We analyzed prevalent dementia outcomes in 1991-1993 (Analysis 1, n=3,139) using logistic regression, and incident dementia outcomes in 1994-2002 (Analysis 2, n=2,299) and in 1997-2002 (Analysis 3, n=1,655) using Cox proportional hazards regression. Dementia outcomes included all-cause dementia, probable and possible Alzheimer disease, and probable vascular dementia. We adjusted models for probable and possible confounders.
Participants who reported proficiency with written Japanese were older and had lower incomes. For Analysis 1, there were 154 prevalent cases of dementia, 74 of Alzheimer disease, and 43 of vascular dementia; for Analysis 2, 236 incident cases of dementia, 138 of Alzheimer disease, and 45 of vascular dementia; and for Analysis 3, 125 incident cases of dementia, 80 of Alzheimer disease, and 20 of vascular dementia. There was no relationship in adjusted models between self-reported proficiency with written Japanese and any dementia outcomes.
Proficiency with written Japanese does not appear to be protective for dementia.
PMCID: PMC3044600  PMID: 19593152
25.  Glutathione Peroxidase 4 is associated with Neuromelanin in Substantia Nigra and Dystrophic Axons in Putamen of Parkinson's brain 
Parkinson's disease is a neurodegenerative disorder characterized pathologically by the loss of nigrostriatal dopamine neurons that project from the substantia nigra in the midbrain to the putamen and caudate nuclei, leading to the clinical features of bradykinesia, rigidity, and rest tremor. Oxidative stress from oxidized dopamine and related compounds may contribute to the degeneration characteristic of this disease.
To investigate a possible role of the phospholipid hydroperoxidase glutathione peroxidase 4 (GPX4) in protection from oxidative stress, we investigated GPX4 expression in postmortem human brain tissue from individuals with and without Parkinson's disease. In both control and Parkinson's samples, GPX4 was found in dopaminergic nigral neurons colocalized with neuromelanin. Overall GPX4 was significantly reduced in substantia nigra in Parkinson's vs. control subjects, but was increased relative to the cell density of surviving nigral cells. In putamen, GPX4 was concentrated within dystrophic dopaminergic axons in Parkinson's subjects, although overall levels of GPX4 were not significantly different compared to control putamen.
This study demonstrates an up-regulation of GPX4 in neurons of substantia nigra and association of this protein with dystrophic axons in striatum of Parkinson's brain, indicating a possible neuroprotective role. Additionally, our findings suggest this enzyme may contribute to the production of neuromelanin.
PMCID: PMC3037910  PMID: 21255396

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