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1.  Shorter Men Live Longer: Association of Height with Longevity and FOXO3 Genotype in American Men of Japanese Ancestry 
PLoS ONE  2014;9(5):e94385.
To determine the relation between height, FOXO3 genotype and age of death in humans.
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.
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).
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.
PMCID: PMC4013008  PMID: 24804734
2.  Long-chain n-3 polyunsaturated fatty acids and incidence rate of coronary artery calcification in Japanese in Japan and United States whites – population-based prospective cohort study 
Heart (British Cardiac Society)  2013;100(7):569-573.
To determine whether serum levels of long-chain n-3 polyunsaturated fatty acids (LCn3PUFAs) contribute to the difference in incidence rate of coronary artery calcification (CAC) between Japanese in Japan and U.S. whites.
In a population-based prospective-cohort study, 214 Japanese and 152 white men aged 40–49 years at baseline (2002–2006) with coronary calcium score (CCS) = 0 were reexamined for CAC in 2007–2010. Among these, 175 Japanese and 113 whites participated in the follow-up exam. Incident cases were defined as participants with CCS ≥ 10 at follow-up. A relative risk regression analysis was used to model incidence rate ratio between Japanese and whites. The incidence rate ratio was first adjusted for potential confounders at baseline and then further adjusted for serum LCn3PUFAs at baseline.
Mean (standard deviation) serum percentage of LCn3PUFA was > 100% higher in Japanese than in whites (9.08 (2.49) versus 3.84 (1.79), respectively, p<0.01). Japanese had a significantly lower incidence rate of CAC compared to whites (0.9 versus 2.9/100 person-years, respectively, p < 0.01). Incidence rate ratio of CAC taking follow-up time into account between Japanese and white men was 0.321 (95% confidence interval (CI) 0.150, 0.690: p<0.01). After adjusting for age, systolic-blood pressure, low-density-lipoprotein cholesterol, diabetes, and other potential confounders, the ratio remained significant: 0.262 (95% CI: 0.094, 0.731, p=0.01). After further adjusting for LCn3PUFAs, however, the ratio was attenuated and became non-significant (0.376 (95% CI: 0.090, 1.572, p=0.18).
LCn3PUFAs significantly contributed to the difference in CAC incidence between Japanese and white men.
PMCID: PMC3949146  PMID: 24352736
long-chain n-3 fatty acids; coronary artery calcification; prospective cohort study; incidence; risk factors
3.  Regional pulse wave velocities and their cardiovascular risk factors among healthy middle-aged men: a cross-sectional population-based study 
Both carotid-femoral (cf) pulse wave velocity (PWV) and brachial-ankle (ba) PWV employ arterial sites that are not consistent with the path of blood flow. Few previous studies have reported the differential characteristics between cfPWV and baPWV by simultaneously comparing these with measures of pure central (aorta) and peripheral (leg) arterial stiffness, i.e., heart-femoral (hf) PWV and femoral-ankle (fa) PWV in healthy populations. We aimed to identify the degree to which these commonly used measures of cfPWV and baPWV correlate with hfPWV and faPWV, respectively, and to evaluate whether both cfPWV and baPWV are consistent with either hfPWV or faPWV in their associations with cardiovascular (CV) risk factors.
A population-based sample of healthy 784 men aged 40–49 (202 white Americans, 68 African Americans, 202 Japanese-Americans, and 282 Koreans) was examined in this cross-sectional study. Four regional PWVs were simultaneously measured by an automated tonometry/plethysmography system.
cfPWV correlated strongly with hfPWV (r = .81, P < .001), but weakly with faPWV (r = .12, P = .001). baPWV correlated moderately with both hfPWV (r = .47, P < .001) and faPWV (r = .62, P < .001). After stepwise regression analyses with adjustments for race, cfPWV shared common significant correlates with both hfPWV and faPWV: systolic blood pressure (BP) and body mass index (BMI). However, BMI was positively associated with hfPWV and cfPWV, and negatively associated with faPWV. baPWV shared common significant correlates with hfPWV: age and systolic BP. baPWV also shared the following correlates with faPWV: systolic BP, triglycerides, and current smoking.
Among healthy men aged 40 – 49, cfPWV correlated strongly with central PWV, and baPWV correlated with both central and peripheral PWVs. Of the CV risk factors, systolic BP was uniformly associated with all the regional PWVs. In the associations with factors other than systolic BP, cfPWV was consistent with central PWV, while baPWV was consistent with both central and peripheral PWVs.
PMCID: PMC3893368  PMID: 24410766
Arterial stiffness; Aorta; Carotid arteries; Brachial artery; Femoral artery
4.  Influence of Type 2 Diabetes on Brain Volumes and Changes in Brain Volumes 
Diabetes Care  2012;36(1):90-97.
To study how type 2 diabetes adversely affects brain volumes, changes in volume, and cognitive function.
Regional brain volumes and ischemic lesion volumes in 1,366 women, aged 72–89 years, were measured with structural brain magnetic resonance imaging (MRI). Repeat scans were collected an average of 4.7 years later in 698 women. Cross-sectional differences and changes with time between women with and without diabetes were compared. Relationships that cognitive function test scores had with these measures and diabetes were examined.
The 145 women with diabetes (10.6%) at the first MRI had smaller total brain volumes (0.6% less; P = 0.05) and smaller gray matter volumes (1.5% less; P = 0.01) but not white matter volumes, both overall and within major lobes. They also had larger ischemic lesion volumes (21.8% greater; P = 0.02), both overall and in gray matter (27.5% greater; P = 0.06), in white matter (18.8% greater; P = 0.02), and across major lobes. Overall, women with diabetes had slightly (nonsignificant) greater loss of total brain volumes (3.02 cc; P = 0.11) and significant increases in total ischemic lesion volumes (9.7% more; P = 0.05) with time relative to those without diabetes. Diabetes was associated with lower scores in global cognitive function and its subdomains. These relative deficits were only partially accounted for by brain volumes and risk factors for cognitive deficits.
Diabetes is associated with smaller brain volumes in gray but not white matter and increasing ischemic lesion volumes throughout the brain. These markers are associated with but do not fully account for diabetes-related deficits in cognitive function.
PMCID: PMC3526228  PMID: 22933440
5.  Calcium and Vitamin D Supplementation and Cognitive Impairment in the Women’s Health Initiative 
Calcium and vitamin D are thought to play important roles in neuronal functioning. Studies have found associations between low serum vitamin D levels and reduced cognitive functioning, as well as high serum calcium levels and reduced cognitive functioning.
To examine the effects of vitamin D and calcium on cognitive outcomes in elderly women.
Post-hoc analysis of a randomized double-blinded placebo-controlled trial.
40 Women’s Health Initiative clinical centers across the U.S.
4143 women aged 65 years and older without probable dementia at baseline who participated in the WHI Calcium and Vitamin D trial and the Women’s Health Initiative Memory Study.
2034 women were randomized to 1000 mg of calcium carbonate combined with 400 IU of vitamin D3; 2109 women were randomized to placebo.
Primary: classifications of probable dementia or mild cognitive impairment via a 4-phase protocol that included central adjudication. Secondary: global cognitive function and individual cognitive subtests.
Mean age of participants was 71 years. During mean follow-up of 7.8 years, there were 39 cases of incident dementia among calcium plus vitamin D subjects compared to 37 cases among placebo subjects (hazard ratio=1.11, 95% CI: 0.71–1.74, p=0.64). Likewise, there were 98 cases of incident mild cognitive impairment among calcium plus vitamin D subjects compared to 108 cases among placebo subjects (hazard ratio=0.95, 95% CI: 0.72–1.25, p=0.72). There were no significant differences in incident dementia or mild cognitive impairment, or in global or domain-specific cognitive function between groups.
There was no association between treatment assignment and incident cognitive impairment. Further studies are needed to investigate the effects of vitamin D and calcium separately, on men and in other age and ethnic groups, and with other doses.
PMCID: PMC3521077  PMID: 23176129
Vitamin D; Calcium; Dementia; Cognition; Mild Cognitive Impairment
6.  Relation of Serum Leptin and Adiponectin Level to Serum C-Reactive Protein: The INTERLIPID Study 
Objective. Despite considerable study, the relevance of leptin and adiponectin for atherosclerosis development is still unsettled. We investigated relations of serum leptin and adiponectin to serum C-reactive protein (CRP), using the INTERLIPID dataset on Japanese emigrants living in Hawaii and Japanese in Japan. Design and Methods. Serum leptin, adiponectin, and CRP were measured by standardized methods in men and women of ages 40 to 59 years from two population samples, one Japanese-American in Hawaii (83 men, 89 women) and the other Japanese in central Japan (111 men, 104 women). Participants with CRP >10 mg/L were excluded. Results. Sex-specific multiple linear regression analyses, with log-transformed leptin and adiponectin (log-leptin, log-adipo), site (Hawaii = 1, Japan = 0), SBP, HbA1c, smoking (cigarettes/day), and physical activity index score of the Framingham Offspring Study as covariates, showed that log-leptin directly related and log-adipo inversely related to log-CRP for both sexes (Ps < 0.05 to <0.01). Addition to the model of BMI and interaction terms (BMI × log-leptin, BMI × log-adipo, SITE × log-leptin, SITE × log-adipo) resulted in disappearance of statistical significance except for direct relation of log-leptin to log-CRP in men (P = 0.006). Conclusions. Leptin directly related to CRP independent of BMI and other confounding factors in men but not in women.
PMCID: PMC3859203  PMID: 24371525
7.  Correlation of a Self-Report and Direct Measure of Physical Activity Level in the Electron-Beam Tomography and Risk Assessment Among Japanese and US Men in the Post World War II Birth Cohort (ERA JUMP) Study 
Journal of Epidemiology  2013;23(6):411-417.
Physical activity (PA) is complex and a difficult behavior to assess as there is no ideal assessment tool(s) that can capture all contexts of PA. Therefore, it is important to understand how different assessment tools rank individuals. We examined the extent to which self-report and direct assessment PA tools yielded the same ranking of PA levels.
PA levels were measured by the Modifiable Activity Questionnaire (MAQ) and pedometer at baseline among 855 white (W), African-American (AA), Japanese-American (JA), and Korean (K) men (mean age 45.3 years) in 3 geographic locations in the ERA JUMP study.
Korean men were more active than W, AA, and JA men, according to both the MAQ and pedometer (MAQ total PA [mean ± SD]: 41.6 ± 17.8, 20.9 ± 9.9, 20.0 ± 9.1, and 29.4 ± 10.3 metabolic equivalent [MET] hours/week, respectively; pedometer: 9584.4 ± 449.4, 8363.8 ± 368.6, 8930.3 ± 285.6, 8335.7 ± 368.6 steps/day, respectively). Higher levels of total PA in Korean men, as shown by MAQ, were due to higher occupational PA. Spearman correlations between PA levels reported on the MAQ and pedometer indicated positive associations ranging from rho = 0.29 to 0.42 for total activity, rho = 0.13 to 0.35 for leisure activity, and rho = 0.10 to 0.26 for occupational activity.
The 2 assessment methods correlated and were complementary rather than interchangeable. The MAQ revealed why Korean men were more active. In some subpopulations it may be necessary to assess PA domains other than leisure and to use more than 1 assessment tool to obtain a more representative picture of PA levels.
PMCID: PMC3834277  PMID: 24064592
ethnic groups; exercise; pedometry; self-report; occupational activity
8.  Reducing Cost by Reducing Polypharmacy: The Polypharmacy Outcomes Project 
PMCID: PMC3489959  PMID: 22959733
Polypharmacy; Long-term care; Nursing homes
9.  FOXO3 Gene Variants and Human Aging: Coding Variants May Not Be Key Players 
FOXO3 is generally recognized as a “master” gene in aging since its association with longevity has been replicated in multiple organisms and human populations. A group of single nucleotide polymorphisms in linkage disequilibrium with a coding region has been associated with human longevity, but the actual functional variant is unidentified. Therefore, we sequenced the coding region in our long-lived Japanese American population in order to enhance resources for fine mapping this region. We demonstrate that of 38 published variants, 6 are misalignments with homologous nonallelic sequences from FOXO3B (ZNF286B), a pseudogene on a different chromosome; 2 are attributable to ZNF286B only, and the remaining 30 were unconfirmed, indicating that they are very rare and not likely involved in longevity. Furthermore, we identified a novel, unique, nonsynonymous coding variant in exon 3 (Gly566Ala; rs138174682) that is prevalent in multiple ethnic groups but appeared too rare for major longevity effects in our study populations.
PMCID: PMC3668389  PMID: 22459618
Aging; FOXO3; Genetic; Human longevity
10.  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
11.  Association of Vitamin D Deficiency with Functional Disability and Chronic Diseases Among Veterans Entering a Nursing Home 
Nursing home residents are at high risk of vitamin D deficiency. There has been only one previous study about vitamin D status on admission to the nursing home, and limited data are available about associations with functional disability and chronic diseases.
Data were collected by retrospective chart review of electronic medical records and Minimum Data Set (MDS) for all veterans admitted to a VA nursing home in Honolulu, Hawai‘i, between January 2011 and June 2012. All veterans had a comprehensive geriatric assessment and measurement of serum 25-hydroxyvitamin D level within 7 days of admission. Females, hospice patients, vitamin D supplement users, and those transferred from other nursing homes were excluded, leaving a final analytic sample of 104 patients. Vitamin D deficiency was defined as serum 25-hydroxyvitamin D level <20 ng/mL. Baseline data collected included age, ethnicity, BMI, functional disability (mobility, bathing, dressing, toileting, continence, and feeding) and prevalent chronic diseases to study cross-sectional associations of vitamin D deficiency using logistic regression.
Prevalence of vitamin D deficiency on admission to the nursing home was 49.0% (51/104) among male veterans not taking supplements. The mean age was 70.6 years (range 35–95), with ethnicity as follows: 51 (49.0%) White, 34 (32.7%) Asian, and 6 (5.8%) Black. In multiple logistic regression models adjusted for age, ethnicity and BMI, vitamin D deficiency was significantly associated with number of ADL disabilities (OR = 1.36 for each increase in ADL disability, 95%CI = 1.03–1.78, P = .03) and prevalent diabetes (OR = 2.99, 95%CI = 1.12–7.99, P = .03). When all six ADL disabilities were entered separately into the multivariate logistic regression model instead of total number of ADL disabilities, only the disability in feeding (OR = 4.74, 95%CI = 0.97–23.23, P = .05) and prevalent diabetes (OR = 2.92, 95%CI = 1.03–8.24, P = .04) remained significant. There were no significant associations between vitamin D deficiency and prevalent hypertension, hypercholesterolemia, coronary artery disease, stroke, cancer, depression or dementia.
Almost half the male patients entering a nursing home in Hawai‘i had vitamin D deficiency. A high number of ADL disabilities, disability in feeding, and prevalent diabetes were independently associated with vitamin D deficiency. Future studies should focus on targeting these patients for screening and intervention with supplementation to possibly prevent adverse health outcomes of vitamin D deficiency.
PMCID: PMC3764550
12.  Prevalence and Factors Associated with Percutaneous Endoscopic Gastrostomy (PEG) Tube Feeding Among Nursing Home Patients 
Unnecessary percutaneous endoscopic gastrostomy (PEG) tube feeding in nursing homes (NH) is a growing concern and an important area of research. Hawaii has one of the highest rates of PEG tube feeding in NH patients in the US, yet has lower rates than many NHs in Asian countries. We examined prevalence and factors associated with PEG tube feeding in NH patients in Hawaii.
We conducted an observational cohort study of all patients admitted between 2003 and 2006 to an urban 180-bed hospital-affiliated NH in Honolulu, Hawaii. Data were collected from time of admission until discharge or death through 6/30/2011, from electronic and paper medical records and Minimum Data Set (MDS). Data included demographic characteristics, baseline medical conditions, functional status, cognitive status and code status. We created a Charlson Comorbidity Index (CCI) score based on baseline medical conditions on admission, and a disability score (ADL score) and Cognitive Performance Score (CPS) using baseline MDS data. Multivariable logistic regression was used to analyze factors associated with PEG tube feeding.
Of 238 NH patients aged 45–104 years (mean 83 years), 35 (14.7%) had PEG tube feeding. Of the NH cohort, 130 (54.6%) were female, 218 (92.3%) were Asian, 123 (51.9%) had a prior stroke and 163 (72%) had dementia based on CPS score. Among the 35 PEG tube fed patients, 23 (66%) had PEG placement prior to NH admission, 12 (34%) had PEG placement after NH admission, and 26 (74%) patients had PEG tube feeding until death or the end of follow-up (61 days to 8.4 years, mean 2.4 years). Prior stroke was associated with increased likelihood of PEG tube feeding (aOR = 2.52, 95%CI = 1.03–6.17, P = .04); with borderline increased likelihood for high comorbidity index (aOR = 2.21, 95%CI = 0.89–5.52, P = .09) and high ADL disability score (aOR = 2.03, 95%CI = 0.87–4.73, P = .10). DNR status was inversely associated with PEG tube feeding (aOR = 0.31, 95%CI = 0.11–0.85, P = .02). Age, dementia, Medicaid status, previous speech or physical therapy, and weight loss were not significantly associated with PEG tube feeding.
In this predominantly Asian-American NH cohort with high prevalence of PEG tube feeding, prior stroke was strongly associated with PEG tube feeding, while dementia was not. Further study is needed to examine ways to identify and reduce unnecessary tube feeding in this population.
PMCID: PMC3764570
13.  Factors Associated with 30-Day Hospital Readmission Among Nursing Home Residents 
Hospital readmissions within 30 days are increasingly targeted as a quality parameter. Frail nursing home patients are at high risk for hospitalization. The purpose of this study was to examine baseline prevalent chronic diseases associated with hospital readmission within 30 days.
We collected data on demographics and prevalent diseases for all patients admitted to one hospital-affiliated nursing home between January 2003 and December 2006, with follow-up data on pneumonia episodes and hospitalizations through June 2011. Multivariable logistic regression models identified baseline prevalent chronic diseases associated with hospital readmission within 30 days of nursing home admission.
Of 238 patients (mean age 83.4, range 45-103) admitted to the nursing home, 156 (65.5%) originally came from hospitals, 54.6% were female, 92.4% were Asian, 43.6% were on Medicaid, and 76.5% were first admitted for intermediate care and 23.5% for skilled nursing care. Although recent pneumonia was the factor most strongly associated with hospital readmission (OR = 14.5, P <.0001), in the model without pneumonia, chronic diseases associated with 30-day hospital readmission included pulmonary disease (OR = 2.2, 95%CI = 1.1–4.3, P = .019) and congestive heart failure (OR = 1.8, 95%CI = 1.0–3.4, P = .055). There were no significant associations between hospital readmission and myocardial infarction, stroke, cancer, diabetes, and dementia.
Among nursing home patients, although recent pneumonia was the strongest risk factor for 30-day hospital readmission, those with baseline chronic pulmonary disease and congestive heart failure were at especially high risk for hospital readmission within 30 days of nursing home admission. These patients may benefit from care focused on preventing hospital readmissions.
PMCID: PMC3764574
14.  Low Dietary Vitamin D Predicts 34-Year Incident Stroke: The Honolulu Heart Program 
Background and Purpose
Vitamin D deficiency has been reported to contribute to the risk of cardiovascular disease, especially stroke. We examined the relationship between dietary vitamin D intake and 34-year incident stroke.
The Honolulu Heart Program is a prospective population-based cohort study of 8,006 Japanese-American men in Hawaii who were 45-68 years old at the baseline examination in 1965-68. Dietary vitamin D intake was calculated using the Nutritionist IV v3 software from a 24-hour dietary recall. Subjects with prevalent stroke were excluded, leaving 7,385 men followed through 1999 for incident stroke. Subjects were divided into quartiles of dietary vitamin D for analyses.
During 34 years of follow-up, 960 subjects developed stroke. Age-adjusted rates of incident stroke were significantly higher in the lowest dietary vitamin D quartile compared to the highest (all stroke: 6.38 vs. 5.14 per 1,000 person-years follow-up, p=0.030; thromboembolic stroke: 4.36 vs. 3.30, p=0.033). Using Cox regression, adjusting for age, total kilocalories, BMI, hypertension, diabetes mellitus, pack-years smoking, physical activity index, serum cholesterol, and alcohol intake, those in the lowest quartile had a significantly increased risk of incident stroke (all stroke HR=1.22, 95% CI=1.01-1.47, p=0.038; thromboembolic stroke HR=1.27, 95% CI=1.01-1.59, p=0.044), with the highest as reference. We found no significant associations between dietary vitamin D and hemorrhagic stroke.
Low dietary vitamin D intake was an independent risk factor for 34-year incidence of all stroke and thromboembolic stroke in Japanese-American men. Additional research is needed on vitamin D supplementation to prevent stroke.
PMCID: PMC3404239  PMID: 22627988
dietary vitamin D intake; incident stroke; Japanese-American men; longitudinal cohort study
15.  Ethnic difference in liver fat content: A cross-sectional observation among Japanese American in Hawaii, Japanese in Japan, and non-Hispanic whites in United States 
We recently reported that Japanese had higher liver fat at a lower level of BMI compared with non-Hispanic whites (NHW).
We hypothesize that ethnic difference in fat storage capacity contributes to this ethnic difference in liver fat.
To examine this, we assessed liver fat among 244 Japanese-American aged 40-49, using regional computed-tomography images, along with metabolic variables.
Despite the similar BMI between Japanese-Americans and NHW men, Japanese-Americans had more liver fat (liver to spleen attenuation ratio: 1.03 ± 0.22 for Japanese-Americans, and 1.07 ± 0.15 for NHW men; p<0.05) and tended to have a greater disposition for fatty liver with an increase in BMI than NHW, indicating a clear difference between the two groups. In addition, liver fat is less in Japanese-Americans compared with Japanese men (1.03 ± 0.22 vs. 1.01 ± 0.16; p<0.05), despite of a much higher BMI. These ethnic differences support the hypothesis that higher fat storage capacity indeed seems to be associated with less liver fat. In all the groups, liver fat content strongly correlated with triglycerides, homeostasis model assessment-insulin resistance, and C-reactive protein (CRP). Nevertheless, these metabolic variables were worse in Japanese-Americans, despite of less liver fat, compared with Japanese. Moreover, CRP levels were least among Japanese with highest liver fat, and highest among NHW men with least liver fat, despite of a strong positive association between CRP and fatty liver within each population.
Fat content in the liver is intermediate for Japanese-Americans compared with Japanese and NHW men, which supports the hypothesis of less fat storage capacity among Japanese, closely linked to ethnic difference in predisposition to fatty liver.
PMCID: PMC3664948  PMID: 23697588
Ethnicity; Fatty liver; Genetic; Environmental; CRP
16.  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
17.  Serum levels of marine-derived n-3 fatty acids in Icelanders, Japanese, Koreans, and Americans - A descriptive epidemiologic study 
In the 1990’s Iceland and Japan were known as countries with high fish consumption whereas coronary heart disease (CHD) mortality in Iceland was high and that in Japan was low among developed countries. We described recent data fish consumption and CHD mortality from publicly available data. We also measured CHD risk factors and serum levels of marine-derived n-3 and other fatty acids from population-based samples of 1,324 men in Iceland, Japan, South Korea, and the US. CHD mortality in men in Iceland was almost 3 times as high as that in Japan and South Korea. Generally a profile of CHD risk factors in Icelanders compared to Japanese was more favorable. Serum marine-derived n-3 fatty acids in Iceland were significantly lower than in Japan and South Korea but significantly higher than in the US.
PMCID: PMC3404187  PMID: 22658580
n-3 fatty acids; eicosapentaenoic acid; docosaehexaenoic acid; coronary heart disease; descriptive epidemiologic study
18.  Aortic stiffness and calcification in men in a population-based international study 
Atherosclerosis  2012;222(2):473-477.
Aortic stiffness, a hallmark of vascular aging, is an independent risk factor of cardiovascular disease and all-cause mortality. The association of aortic stiffness with aortic calcification in middle-aged general population remains unknown although studies in patients with end-stage renal disease or elderly subjects suggest that aortic calcification is an important determinant of aortic stiffness. The goal of this study was to examine the association of aortic calcification and stiffness in multi-ethnic population-based samples of relatively young men.
We examined the association in 906 men aged 40–49 (81 Black Americans, 276 Japanese Americans, 258 White Americans and 291 Koreans). Aortic stiffness was measured as carotid-femoral pulse wave velocity (cfPWV) using an automated waveform analyzer. Aortic calcification from aortic arch to iliac bifurcation was evaluated using electron-beam computed tomography.
Aortic calcium score was calculated and was categorized into four groups: zero (n=303), 1–100 (n=411), 101–300 (n=110), and 401+ (n=82). Aortic calcification category had a significant positive association with cfPWV after adjusting for age, race, and mean arterial pressure (mean (standard error) of cfPWV (cm/second) from the lowest to highest categories: 836 (10), 850 (9), 877 (17) and 941 (19), p for trend <0.001). The significant positive association remained after further adjusting for other cardiovascular risk factors. The significant positive association was also observed in each race group.
The results suggest that aortic calcification can be one mechanism for aortic stiffness and that the association of aortic calcification with stiffness starts as early as the 40’s.
PMCID: PMC3361615  PMID: 22537531
aortic stiffness; aortic calcification; international multi-ethnic study
19.  Coronary Artery Calcification in Japanese Men in Japan and Hawaii 
American journal of epidemiology  2007;166(11):1280-1287.
Explanations for the low prevalence of atherosclerosis in Japan versus United States are often confounded with genetic variation. To help remove such confounding, coronary artery calcification (CAC), a marker of subclinical atherosclerosis, was compared between Japanese men in Japan and Japanese men in Hawaii. Findings are based on risk factor and CAC measurements that were made from 2001 to 2005 in 311 men in Japan and 300 men in Hawaii. Men were aged 40 to 50 years and without cardiovascular disease. After age-adjustment, there was a 3-fold excess in the odds of prevalent CAC scores ≥10 in Hawaii versus Japan (relative odds [RO] = 3.2; 95% confidence interval [CI] = 2.1,4.9). While men in Hawaii had a generally poorer risk factor profile, men in Japan were 4-times more likely to smoke cigarettes (49.5 vs. 12.7%, p<0.001). In spite of marked risk factor differences between the samples, none of the risk factors provided an explanation for the low amounts of CAC in Japan. After risk factor adjustment, the RO of CAC scores ≥10 in Hawaii versus Japan was 4.0 (95% CI = 2.2,7.4). Further studies are needed to identify factors that offer protection against atherosclerosis in Japanese men in Japan.
PMCID: PMC3660555  PMID: 17728270
Atherosclerosis; cohort studies; coronary disease; Japan; men; risk factors
20.  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
21.  Does cultural assimilation influence prevalence and presentation of depressive symptoms in older Japanese-American men? The Honolulu-Asia Aging Study 
Sociocultural factors have been implicated in affecting prevalence, incidence, and diagnosis of depression but previous studies have included heterogeneous ethnic populations. We studied the influence of cultural assimilation on the prevalence and presentation of depressive symptoms in elderly Japanese-American men.
This analysis was based on 3,139 Japanese-American men aged 71–93 years who were participants in the Honolulu-Asia Aging Study between 1991 and 1993. We created a Cultural Assimilation Scale (CAS) using 8 questions assessing the degree of Japanese identity and lifestyle compared to a Western one. Subjects were divided into tertiles of CAS score for analysis. Prevalence of depressive symptoms was measured using an 11-question version of the Centers for Epidemiologic Studies Depression Scale questionnaire (CESD-11), and presence of depressive symptoms was defined as score ≥ 9.
Prevalent depressive symptoms did not reach a statistically significant association with CAS tertiles (Western 10.8%, Mixed 9.6%, Japanese 8.5%). However after adjusting for demographic, functional and disease factors, the most culturally Japanese group had significantly lower odds for prevalent depressive symptoms, compared to the most Western group. Among the subset of subjects with a high CESD-11 score, there were no significant differences in both mean psychological scores and mean somatic scores between the three Cultural Assimilation Scale groups.
Prevalent depressive symptoms were significantly lower among elderly Japanese-American men who were most culturally Japanese, compared to more Westernized men. Improving knowledge and understanding about the pathogenesis of depression will have important public health implications.
PMCID: PMC3116068  PMID: 21358388
22.  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
23.  Creutzfeldt-Jakob Disease: A Case Report and Differential Diagnoses 
Sporadic Creutzfeldt-Jakob disease is a rare neurodegenerative disorder of unknown etiology that causes rapidly progressive dementia. This disease is uniformly fatal and most patients die within 12 months. Clinical findings include myoclonus, visual disturbances, and cerebellar and pyramidal/extrapyramidal signs in addition to rapidly progressive cognitive and functional impairment. These findings are all non-specific and it is often difficult and challenging to diagnose premortem because of low awareness and clinical suspicion.
We present a 66-year-old woman with a 5-month history of rapidly progressive dementia. After a series of extensive diagnostic examinations and continuous follow-up, she was diagnosed with probable sporadic Creutzfeldt-Jakob disease based on Centers for Disease Control and Prevention (CDC) criteria, with key findings of rapidly progressive dementia, blurry vision, extrapyramidal signs (cogwheel rigidity), and abnormal hyperintensity signals on diffusion-weighted MRI. Her symptoms progressively worsened and she died 7 months after the onset. The postmortem brain autopsy demonstrated the presence of abnormal protease-resistant prion protein by Western Blot analysis.
A literature review was performed on differential diagnoses that present with rapidly progressive dementia and thereby mimic sporadic Creutzfeldt-Jakob disease. These include Alzheimer's disease, dementia with Lewy Bodies, frontotemporal dementia, meningoencephalitis, corticobasal degeneration, progressive supranuclear palsy, CADASIL, and paraneoplastic encephalomyelitis.
PMCID: PMC3689509  PMID: 23795314
sporadic Creutzfeldt-Jakob disease; prion disease; rapidly progressing dementia
24.  Risk factors for fractures among Japanese-American men: the Honolulu Heart Program and Honolulu-Asia Aging Study 
Archives of osteoporosis  2011;6(1-2):197-207.
The objective of this study was to identify risk factors ascertained at baseline that were associated with prevalence and incidence of fractures at advanced age among Japanese-American men.
The present study used data from Honolulu Heart Program (HHP) and Honolulu-Asia Aging Study (HAAS). The HHP was a prospective study with primary focus on risk factors for cardiovascular diseases and stroke. A cohort of 8,006 men of Japanese ancestry aged 45–68 residing on Oahu was recruited in 1965, and followed through 1999. The HAAS started in 1991 in conjunction with the HHP with a focus on age-related health conditions. Self-reported cumulative prevalence of hip, spine and forearm fractures was ascertained in 1991–1993 among 3,845 men aged 71–93. Incidence was obtained during the follow-up period (1994–1999) among 2,737 men aged 74–98. Poisson regression models were used to determine multi-variable adjusted prevalence and incidence ratios for fracture.
Baseline age was directly and inversely associated with cumulative incident spine and prevalent forearm fracture, respectively. Education was inversely and directly associated with prevalent spine and forearm fracture, respectively. Body mass index (BMI) was independently and directly, and upper arm girth was inversely associated with incident hip fracture. Height and diabetic medication were directly associated with prevalent spine fracture. Physical activity and pack-years of smoking were independently and directly associated with incident and prevalent hip fracture, respectively.
These results indicated that multiple baseline demographic lifestyle and anthropometric characteristics predict fracture risk at advanced age. In addition, associations varied by fracture location.
PMCID: PMC3565433  PMID: 22886106
fracture; incidence ratio; men; prevalence ratio; risk factors
25.  Influence of cigarette smoking on coronary artery and aortic calcium among random samples from populations of middle-age Japanese and Korean men 
Cigarette smoking is a risk factor of coronary heart disease (CHD). Vascular calcification such as coronary artery calcium (CAC) and aortic calcium (AC) is associated with CHD. We hypothesized that cigarette smoking is associated with coronary artery and aortic calcifications in Japanese and Koreans with high smoking prevalence.
Random samples from populations of 313 Japanese and 302 Korean men aged 40 to 49 were examined for calcification of the coronary artery and aorta using electron beam computed tomography. Coronary artery calcium (CAC) and aortic calcium (AC) were quantified using the Agatston score. We examined the associations of cigarette smoking with CAC and AC after adjusting for conventional risk factors and alcohol consumption. Current and past smokers were combined and categorized into two groups using median pack-years as a cutoff point in each of Japanese and Koreans. The never smoker group was used as a reference for the multiple logistic regression analyses.
The odds ratios of CAC (score ≥10) for smokers with higher pack-years were 2.9 in Japanese (P<0.05) and 1.3 in Koreans (non-significant) compared to never smokers. The odds ratios of AC (score ≥100) for smokers with higher pack-years were 10.4 in Japanese (P<0.05) and 3.6 in Koreans (P<0.05).
Cigarette smoking with higher pack-years is significantly associated with CAC and AC in Japanese men, while cigarette smoking with higher pack-years is significantly associated with AC but not significantly with CAC in Korean men.
PMCID: PMC3521870  PMID: 22844083
atherosclerosis; cigarette smoking; coronary calcium; aortic calcium; Japanese; Koreans

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