Differences Among Native Hawaiian, Asian, and White Patients with Progressive Supranuclear Palsy.

BACKGROUND: Most studies of progressive supranuclear palsy (PSP) have been conducted in White populations. OBJECTIVE: The objective of this study was to identify whether differences exist for patients with PSP among Whites, East Asians (EAs), and Native Hawaiians/Pacific Islanders (NHPIs) in Hawaii. METHODS: We conducted a single-center, retrospective study of patients meeting Movement Disorder Society probable PSP criteria (2006-2021). Data variables included age of onset and diagnosis, comorbidities, and survival rate. Variables were compared across groups using Fisher's exact test, Kruskal-Wallis rank sum test, and log-rank tests. RESULTS: A total of 94 (59 EAs, 9 NHPIs, 16 Whites, and 10 Others) patients were identified. Mean age ± standard deviation (in years) of symptom onset/diagnosis were both youngest in NHPIs (64.0 ± 7.2/66.3 ± 8.0) followed by Whites (70.8 ± 7.6/73.9 ± 7.8), then EAs (75.9 ± 8.2/79.2 ± 8.3) (P < 0.001). Median survival from diagnosis was significantly lower (P < 0.05) in NHPIs (2 years) compared with EAs (4 years) and Whites (6 years). CONCLUSIONS: There may be racial disparities for PSP, and studies are needed to identify genetic, environmental, and socioeconomic contributions. © 2023 International Parkinson and Movement Disorder Society.

Genome-wide epigenetic analyses in Japanese immigrant plantation workers with Parkinson's disease and exposure to organochlorines reveal possible involvement of glial genes and pathways involved in neurotoxicity.

BACKGROUND: Parkinson's disease (PD) is a disease of the central nervous system that progressively affects the motor system. Epidemiological studies have provided evidence that exposure to agriculture-related occupations or agrichemicals elevate a person's risk for PD. Here, we sought to examine the possible epigenetic changes associated with working on a plantation on Oahu, HI and/or exposure to organochlorines (OGC) in PD cases. RESULTS: We measured genome-wide DNA methylation using the Illumina Infinium HumanMethylation450K BeadChip array in matched peripheral blood and postmortem brain biospecimens in PD cases (n = 20) assessed for years of plantation work and presence of organochlorines in brain tissue. The comparison of 10+ to 0 years of plantation work exposure detected 7 and 123 differentially methylated loci (DML) in brain and blood DNA, respectively (p < 0.0001). The comparison of cases with 4+ to 0-2 detectable levels of OGCs, identified 8 and 18 DML in brain and blood DNA, respectively (p < 0.0001). Pathway analyses revealed links to key neurotoxic and neuropathologic pathways related to impaired immune and proinflammatory responses as well as impaired clearance of damaged proteins, as found in the predominantly glial cell population in these environmental exposure-related PD cases. CONCLUSIONS: These results suggest that distinct DNA methylation biomarker profiles related to environmental exposures in PD cases with previous exposure can be found in both brain and blood.

Concordance for Parkinson's disease in twins: A 20-year update.

During the 1990s, we estimated the genetic contribution to Parkinson's disease risk in a large, population-based twin registry. Because many unaffected twins were still alive, previous concordance estimates were based on incomplete information. Ninety-five percent of twins are now deceased. Here, we update concordance and heritability through 2015 using National Death Index data. In total, we identified 30 concordant and 193 discordant pairs. Proband-wise concordance was 0.20 in monozygotic and 0.13 in dizygotic pairs. Heritability was 0.27 overall, 0.83 in pairs diagnosed ≤50, and 0.19 in pairs diagnosed >50. High concordance in dizygotic twins suggests shared effects of early childhood environment. Ann Neurol 2019;85:600-605.

Association of brain heptachlor epoxide and other organochlorine compounds with lewy pathology.

BACKGROUND: Organochlorine pesticides are associated with an increased risk of Parkinson's disease. A preliminary analysis from the Honolulu-Asia Aging Study suggested that heptachlor epoxide, a metabolite from an organochlorine pesticide extensively used in Hawaii, may be especially important. This was a cross sectional analysis to evaluate the association of heptachlor epoxide and other organochlorine compounds with Lewy pathology in an expanded survey of brain organochlorine residues from the longitudinal Honolulu-Asia Aging Study. METHODS: Organochlorines were measured in frozen occipital or temporal lobes in 705 brains using gas chromatography with mass spectrometry. Lewy pathology was identified using hematoxylin and eosin- and α-synuclein immunochemistry-stained sections from multiple brain regions. RESULTS: The prevalence of Lewy pathology was nearly doubled in the presence versus the absence of heptachlor epoxide (30.1% versus 16.3%, P < 0.001). Although associations with other compounds were weaker, hexachlorobenzene (P = 0.003) and α-chlordane (P = 0.007) were also related to Lewy pathology. Most of the latter associations, however, were a result of confounding from heptachlor epoxide. Neither compound was significantly related to Lewy pathology after adjustment for heptachlor epoxide. In contrast, the association of heptachlor epoxide with Lewy pathology remained significant after adjustments for hexachlorobenzene (P = 0.013) or α-chlordane (P = 0.005). Findings were unchanged after removal of cases of PD and adjustment for age and other characteristics. CONCLUSIONS: Organochlorine pesticides are associated with the presence of Lewy pathology in the brain, even after exclusion of PD cases. Although most of the association is through heptachlor epoxide, the role of other organochlorine compounds is in need of clarification. © 2018 International Parkinson and Movement Disorder Society.

Mid-life proteinuria and late-life cognitive function and dementia in elderly men: the Honolulu-Asia Aging Study.

BACKGROUND: Impaired renal function has been linked to cognitive impairment. We assessed mid-life proteinuria and late-life cognitive function in elderly Asian men. METHODS: The Honolulu Heart Program is a prospective study that began in 1965 with 8006 Japanese-American men aged 45 to 68 years. Mid-life proteinuria was detected by urine dipstick in 1971 to 1974. The Honolulu-Asia Aging Study began 20 years later, with cognitive assessment by the Cognitive Abilities Screening Instrument (CASI) in 3734 men. Standard criteria were used to classify 8-year incident dementia and subtypes. RESULTS: The age-adjusted incidence of dementia increased significantly from 13.8, to 22.8, to 39.7 per 1000 person years follow-up, among those with no, trace, and positive mid-life proteinuria (P=0.004). Using linear regression adjusting for age, education, APOEε4, stroke, hypertension, systolic blood pressure, diabetes, fasting blood glucose, physical activity, and baseline CASI, those with positive proteinuria had significantly higher annual change in CASI over 8 years follow-up (-1.24, P=0.02) (reference=no proteinuria). Multivariate Cox regression found that positive proteinuria had a significant association with incident all-cause dementia (RR=2.66; 95%CI, 1.09-6.53; P=0.03), but no significant associations with incident Alzheimer disease or vascular dementia. CONCLUSION: Mid-life proteinuria was an independent predictor for late-life incident all-cause dementia and cognitive decline over 8 years.

Effect of creatine monohydrate on clinical progression in patients with Parkinson disease: a randomized clinical trial.

IMPORTANCE: There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies. OBJECTIVE: To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease. DESIGN, SETTING, AND PATIENTS: The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013. INTERVENTIONS: Participants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years). MAIN OUTCOMES AND MEASURES: The primary outcome measure was a difference in clinical decline from baseline to 5-year follow-up, compared between the 2 treatment groups using a global statistical test. Clinical status was defined by 5 outcome measures: Modified Rankin Scale, Symbol Digit Modalities Test, PDQ-39 Summary Index, Schwab and England Activities of Daily Living scale, and ambulatory capacity. All outcomes were coded such that higher scores indicated worse outcomes and were analyzed by a global statistical test. Higher summed ranks (range, 5-4775) indicate worse outcomes. RESULTS: The trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955). The median follow-up time was 4 years. Of the 955 participants, the mean of the summed ranks for placebo was 2360 (95% CI, 2249-2470) and for creatine was 2414 (95% CI, 2304-2524). The global statistical test yielded t1865.8 = -0.75 (2-sided P = .45). There were no detectable differences (P < .01 to partially adjust for multiple comparisons) in adverse and serious adverse events by body system. CONCLUSIONS AND RELEVANCE: Among patients with early and treated Parkinson disease, treatment with creatine monohydrate for at least 5 years, compared with placebo did not improve clinical outcomes. These findings do not support the use of creatine monohydrate in patients with Parkinson disease. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00449865.

Peptidoglycan recognition protein genes and risk of Parkinson's disease.

Increased gut permeability, inflammation, and colonic α-synuclein pathology are present in early Parkinson's disease (PD) and have been proposed to contribute to PD pathogenesis. Peptidoglycan is a structural component of the bacterial cell wall. Peptidoglycan recognition proteins (PGRPs) maintain healthy gut microbial flora by regulating the immune response to both commensal and harmful bacteria. We tested the hypothesis that variants in genes that encode PGRPs are associated with PD risk. Participants in two independent case-control studies were genotyped for 30 single-nucleotide polymorphisms (SNPs) in the four PGLYRP genes. Using logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for potential confounding variables, we conducted analyses in each study, separately and pooled. One SNP failed the assay, and three had little to no variation. The ORs were similar in both study populations. In pooled analyses, three of seven PGLYRP2 SNPs (rs3813135, rs733731, rs892145), one of five PGLYRP3 SNPs (rs2987763), and six of nine PGLYRP4 SNPs (rs10888557, rs12063091, rs3006440, rs3006448, rs3006458, and rs3014864) were significantly associated with PD risk. Association was strongest for PGLYRP4 5'untranslated region (UTR) SNP rs10888557 (GG reference, CG OR 0.6 [95%CI 0.4-0.9], CC OR 0.15 [95%CI 0.04-0.6]; log-additive P-trend, 0.0004). Common variants in PGLYRP genes are associated with PD risk in two independent studies. These results require replication, but they are consistent with hypotheses of a causative role for the gut microbiota and gastrointestinal immune response in PD.

Low dietary vitamin D in mid-life predicts total mortality in men with hypertension: the Honolulu heart program.

BACKGROUND: Vitamin D deficiency was associated with total mortality in previous epidemiological studies. Little is known about the effects of dietary vitamin D intake on mortality. We examined the association between mid-life dietary vitamin D intake and 45-year total mortality. METHODS: The Honolulu Heart Program is a longitudinal cohort study of 8006 Japanese American men in Hawaii aged 45 to 68 at baseline (1965-1968). Mid-life dietary vitamin D intake was calculated from 24-hour dietary recall using Nutritionist IV v3 software. We divided subjects into quartiles of dietary vitamin D. Total mortality data were available over 45 years through 2010. RESULTS: Age-adjusted total mortality rates were higher in the lower quartiles of dietary vitamin D intake compared to the highest (p for trend = 0.011). Using Cox regression, low dietary vitamin D was significantly associated with total mortality; quartile (Q) 1 hazard ratio (HR) = 1.14, 95% confidence interval (95% CI) = 1.07-1.22, p < 0.001; Q2 HR = 1.11, 95% CI = 1.04-1.18, p = 0.002; and Q3 HR = 1.08, 95% CI = 1.01-1.15, p = 0.027; Q4 = reference. After adjusting for age, kilocalories, cardiovascular risk factors, and prevalent chronic diseases, only Q2 remained significant (HR = 1.08, 95% CI = 1.00-1.15, p = 0.037). Among hypertensive subjects only, those in the lower 2 quartiles had higher total mortality; Q1 HR = 1.12, 95% CI = 1.01-1.25, p = 0.039, and Q2 HR = 1.13, 95% CI = 1.02-1.26, p = 0.025, compared to Q4. There was no significant relationship in subjects without hypertension. CONCLUSIONS: Low dietary vitamin D intake in mid-life was a weak predictor of total mortality over 45 years of follow-up. We found a significant association between low dietary vitamin D intake and higher total mortality only among hypertensive subjects. Vitamin D may have cardioprotective effects.

Prestroke weight loss is associated with poststroke mortality among men in the Honolulu-Asia Aging Study.

OBJECTIVE: To examine baseline prestroke weight loss and poststroke mortality among men. DESIGN: Longitudinal study of late-life prestroke body mass index (BMI), weight loss, and BMI change (midlife to late life) with up to 8-year incident stroke and mortality follow-up. SETTING: Community-based aging study data. PARTICIPANTS: Japanese-American men (N=3581; age range, 71-93y) who were stroke free at baseline. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Poststroke mortality: 30 days poststroke, analyzed with stepwise multivariable logistic regression; and long-term poststroke (up to 8y), analyzed with stepwise multivariable Cox regression. RESULTS: Weight loss (4.5kg decrements) was associated with increased 30-day poststroke mortality (adjusted odds ratio=1.48; 95% confidence interval [CI], 1.14-1.92), long-term mortality after incident stroke (all types, n=225; adjusted hazards ratio (aHR)=1.25; 95% CI, 1.09-1.44), and long-term mortality after incident thromboembolic stroke (n=153; aHR=1.19; 95% CI, 1.01 to 1.40). Men with overweight/obese late-life BMI (≥25kg/m(2), compared with healthy/underweight BMI) had increased long-term mortality after incident hemorrhagic stroke (n=54; aHR=2.27; 95% CI, 1.07-4.82). Neither desirable nor excessive BMI reductions (vs no change/increased BMI) were associated with poststroke mortality. In the overall sample (N=3581), nutrition factors associated with increased long-term mortality included the following: (1) weight loss (10lb decrements; aHR=1.15; 95% CI, 1.09-1.21), (2) underweight BMI (vs healthy BMI; aHR=1.76; 95% CI, 1.40-2.20), and (3) both desirable and excessive BMI reductions (vs no change or gain, separate model from weight loss and BMI; aHR range, 1.36-1.97; P<.001). CONCLUSIONS: Although obesity is a risk factor for stroke incidence, prestroke weight loss was associated with increased poststroke (all types and thromboembolic) mortality. Overweight/obese late-life BMI was associated with increased posthemorrhagic stroke mortality. Desirable and excessive BMI reductions were not associated with poststroke mortality. Weight loss, underweight late-life BMI, and any BMI reduction were all associated with increased long-term mortality in the overall sample.

The disease intersection of susceptibility and exposure: chemical exposures and neurodegenerative disease risk.

Alzheimer's disease, Parkinson's disease, and motor neuron disease, the most common of the late-life neurodegenerative disorders, are in most cases thought to have complex etiologies. Common features among these disorders include insidious onset, pathological findings of protein aggregates and selected neuronal degeneration, and resulting characteristic clinical syndromes. The number of elders in the United States, including aging veterans, is increasing. Investigation of causes and preventive interventions for neurodegenerative disorders is increasingly relevant. Recent epidemiological and laboratory studies suggest that exposures years or decades before diagnosis can trigger the processes that ultimately result in a neurodegenerative disease. If this is correct, preventive measures may be needed in midlife or earlier. This article will focus on putative risk factors relevant to military service.

The Prevalence of Hospitalized Parkinson's Disease Patients in All Case Hospitalization among Different Race/Ethnic Subgroups in Hawaii.

Background: Little is known about the epidemiology of Parkinson's disease (PD) patients in Native Hawaiian Or Other Pacific Islander (NHPI) and Asian American (AA) subgroups. Objective: To determine if the prevalence of hospitalized PD patients is different across age groups and racial/ethnic subgroups in Hawaii. Methods: We conducted a retrospective analysis of Hawaii statewide registry (2016-2020) hospitalization data for patients who were 50 years or older. PD patients were identified using an ICD 10 code: Parkinson's Disease (G20) as their primary/secondary hospitalization discharge diagnosis code. Demographic and clinical characteristics among racial/ethnic subgroups (White, Japanese, Filipino, Chinese, NHPI, or Other) were compared. Results: Of 146,844 total hospitalized patients (n = 429,879 records), 1.6% (n = 2,401) had a PD diagnosis. The prevalence of hospitalized PD patients was 2.3% among Japanese and Chinese, followed by 1.7% for Whites, 1.2% for Filipinos and was lowest for NHPI with 0.9% (p < 0.001). As patient's age increased, the prevalence of hospitalized PD patients increased, with 80-84 years old for the highest age range (3.4%). The prevalence of hospitalized PD patients at 80-84 years old varied across the race/ethnic subgroups (Chinese 4.3%, Japanese 4.0%, Whites 3.7%, Filipinos 2.5%, NHPI 2.3%). Conclusions: The prevalence of hospitalized PD patients among all case hospitalizations were lower for NHPI and Filipino compared to that of Japanese, Chinese, and Whites. As patients' age increased, the prevalence of hospitalized patients with PD increased, but less so in NHPI and Filipino groups. Further research is warranted to understand the reason for these observed differences among racial/ethnic subgroups.

FOXO3 longevity genotype attenuates the impact of hypertension on cerebral microinfarct risk.

OBJECTIVE: The G -allele of FOXO3 SNP rs2802292 , which is associated with human resilience and longevity, has been shown to attenuate the impact of hypertension on the risk of intracerebral hemorrhage (ICH). We sought to determine whether the FOXO3 G -allele similarly attenuates the impact of hypertension on the risk of cerebral microinfarcts (CMI). METHODS: From a prospective population-based cohort of American men of Japanese ancestry from the Kuakini Honolulu Heart Program (KHHP) and Kuakini Honolulu-Asia Aging Study (KHAAS) that had brain autopsy data, age-adjusted prevalence of any CMI on brain autopsy was assessed. Logistic regression models, adjusted for age at death, cardiovascular risk factors, FOXO3 and APOE-ε4 genotypes, were utilized to determine the predictors of any CMI. Interaction of FOXO3 genotype and hypertension was analyzed. RESULTS: Among 809 men with complete data, 511 (63.2%) participants had evidence of CMI. A full multivariable model demonstrated that BMI [odds ratio (OR) 1.07, 95% confidence interval (CI) 1.01-1.14, P  = 0.015) was the only predictor of CMI, while hypertension was a borderline predictor (OR 1.44, 95% CI 1.00-2.08, P  = 0.052). However, a significant interaction between FOXO3 G -allele carriage and hypertension was observed ( P  = 0.020). In the stratified analyses, among the participants without the longevity-associated FOXO3 G -allele, hypertension was a strong predictor of CMI (OR 2.25, 95% CI 1.34-3.77, P  = 0.002), while among those with the longevity-associated FOXO3 G -allele, hypertension was not a predictor of CMI (OR 0.88, 95% CI 0.51-1.54, P  = 0.66). CONCLUSION: The longevity-associated FOXO3 G -allele mitigates the impact of hypertension on the risk of CMI.

Racial disparities in hospitalization characteristics among Native Hawaiians, Pacific Islanders and Asian American subgroups with Parkinson's disease.

BACKGROUND: Differences among Native Hawaiians/Pacific Islanders (NHPI) and Asian American (AA) subgroups have not been adequately studied in Parkinson's disease (PD). OBJECTIVE: To determine differences in demographics, comorbidities, and healthcare utilization among NHPI, AA subgroups, and White hospitalized PD patients. METHODS: We conducted a retrospective cross-sectional analysis of Hawai'is statewide registry (2016-2020). Patients with PD were identified using ICD10 code G20 and categorized as White, Japanese, Filipino, Chinese, NHPI, or Other. Variables collected included: age, sex, residence (county), primary source of payment, discharge status, length of stay, in-hospital expiration, Charlson Comorbidity Index (CCI) and Deep Brain Stimulation (DBS) utilization. Bivariate analyses were performed: differences in age and CCI were further examined by multivariable linear regression and proportional odds models. RESULTS: Of 229,238 hospitalizations, 2428 had PD (Japanese: 31.3 %, White: 30.4 %, Filipino: 11.3 %, NHPI: 9.6 %, Chinese: 8.0 %). NHPI were younger compared to rest of the subgroups [estimate in years (95 % CI): Whites: 4.4 (3.0-5.8), Filipinos: 4.3 (2.7-5.9), Japanese: 7.7 (6.4-9.1), Chinese: 7.9 (6.1-9.7), p < 0.001)]. NHPI had a higher CCI compared to White, Japanese, and Chinese (p < 0.001). Among AA subgroups, Filipinos were younger and had a higher CCI compared to Japanese and Chinese (p < 0.001). There were no significant differences in DBS utilization among subgroups. CONCLUSIONS: NHPI and Filipinos with PD were hospitalized at a younger age and had a greater comorbidity burden compared to other AAs and Whites. Further research, ideally prospective studies, are needed to understand these racial disparities.

Solvent exposures and Parkinson disease risk in twins.

OBJECTIVE: Several case reports have linked solvent exposure to Parkinson disease (PD), but few studies have assessed associations with specific agents using an analytic epidemiologic design. We tested the hypothesis that exposure to specific solvents is associated with PD risk using a discordant twin pair design. METHODS: Ninety-nine twin pairs discordant for PD ascertained from the National Academy of Sciences/National Research Council World War II Veteran Twins Cohort were interviewed regarding lifetime occupations and hobbies using detailed job task-specific questionnaires. Exposures to 6 specific solvents selected a priori were estimated by expert raters unaware of case status. RESULTS: Ever exposure to trichloroethylene (TCE) was associated with significantly increased risk of PD (odds ratio [OR], 6.1; 95% confidence interval [CI] 1.2-33; p = 0.034), and exposure to perchloroethylene (PERC) and carbon tetrachloride (CCl(4) ) tended toward significance (respectively: OR, 10.5; 95% CI, 0.97-113; p = 0.053; OR, 2.3; 95% CI, 0.9-6.1; p = 0.088). Results were similar for estimates of exposure duration and cumulative lifetime exposure. INTERPRETATION: Exposure to specific solvents may increase risk of PD. TCE is the most common organic contaminant in groundwater, and PERC and CCl(4) are also ubiquitous in the environment. Our findings require replication in other populations with well-characterized exposures, but the potential public health implications are substantial.

Head injury, α-synuclein Rep1, and Parkinson's disease.

OBJECTIVE: To test the hypothesis that variability in SNCA Rep1, a polymorphic dinucleotide microsatellite in the promoter region of the gene encoding α-synuclein, modifies the association between head injury and Parkinson's disease (PD) risk. METHODS: Participants in the Farming and Movement Evaluation (FAME) and the Study of Environmental Association and Risk of Parkinsonism using Case-Control Historical Interviews (SEARCH), 2 independent case-control studies, were genotyped for Rep1 and interviewed regarding head injuries with loss of consciousness or concussion prior to Parkinson's disease (PD) diagnosis. Logistic regression modeling adjusted for potential confounding variables and tested interaction between Rep1 genotype and head injury. RESULTS: Consistent with prior reports, relative to medium-length Rep1, short Rep1 genotype was associated with reduced PD risk (pooled odds ratio [OR], 0.7; 95% confidence interval [CI], 0.5-0.9), and long Rep1 with increased risk (pooled OR, 1.4; 95% CI, 0.95-2.2). Overall, head injury was not significantly associated with PD (pooled OR, 1.3; 95% CI, 0.9-1.8). However, head injury was strongly associated with PD in those with long Rep1 (FAME OR, 5.4; 95% CI, 1.5-19; SEARCH OR, 2.3; 95% CI, 0.6-9.2; pooled OR, 3.5; 95% CI 1.4-9.2, p-interaction = 0.02). Individuals with both head injury and long Rep1 were diagnosed 4.9 years earlier than those with neither risk factor (p = 0.03). INTERPRETATION: While head injury alone was not associated with PD risk, our data suggest head injury may initiate and/or accelerate neurodegeneration when levels of synuclein are high, as in those with Rep1 expansion. Given the high population frequency of head injury, independent verification of these results is essential.

Incidence of Alzheimer's Disease in Men with Late-Life Hypertension Is Ameliorated by FOXO3 Longevity Genotype.

BACKGROUND: It is well established that mid-life hypertension increases risk of dementia, whereas the association of late-life hypertension with dementia is unclear. OBJECTIVE: To determine whether FOXO3 longevity-associated genotype influences the association between late-life hypertension and incident dementia. METHODS: Subjects were 2,688 American men of Japanese ancestry (baseline age: 77.0±4.1 years, range 71-93 years) from the Kuakini Honolulu Heart Program. Status was known for FOXO3 rs2802292 genotype, hypertension, and diagnosis of incident dementia to 2012. Association of FOXO3 genotype with late-life hypertension and incident dementia, vascular dementia (VaD) and Alzheimer's disease (AD) was assessed using Cox proportional hazards models. RESULTS: During 21 years of follow-up, 725 men were diagnosed with all-cause dementia, 513 with AD, and 104 with VaD. A multivariable Cox model, adjusting for age, education, APOEɛ4, and cardiovascular risk factors, showed late-life hypertension increased VaD risk only (HR = 1.71, 95% CI = 1.08-2.71, p = 0.022). We found no significant protective effect of FOXO3 longevity genotype on any type of dementia at the population level. However, in a full Cox model adjusting for age, education, APOEɛ4, and other cardiovascular risk factors, there was a significant interaction effect of late-life hypertension and FOXO3 longevity genotype on incident AD (ß= -0.52, p = 0.0061). In men with FOXO3 rs2802292 longevity genotype (TG/GG), late-life hypertension showed protection against AD (HR = 0.72; 95% CI = 0.55-0.95, p = 0.021). The non-longevity genotype (TT) (HR = 1.16; 95% CI = 0.90-1.51, p = 0.25) had no protective effect. CONCLUSION: This longitudinal study found late-life hypertension was associated with lower incident AD in subjects with FOXO3 genotype.

Externally validated deep learning model to identify prodromal Parkinson's disease from electrocardiogram.

Little is known about electrocardiogram (ECG) markers of Parkinson's disease (PD) during the prodromal stage. The aim of the study was to build a generalizable ECG-based fully automatic artificial intelligence (AI) model to predict PD risk during the prodromal stage, up to 5 years before disease diagnosis. This case-control study included samples from Loyola University Chicago (LUC) and University of Tennessee-Methodist Le Bonheur Healthcare (MLH). Cases and controls were matched according to specific characteristics (date, age, sex and race). Clinical data were available from May, 2014 onward at LUC and from January, 2015 onward at MLH, while the ECG data were available as early as 1990 in both institutes. PD was denoted by at least two primary diagnostic codes (ICD9 332.0; ICD10 G20) at least 30 days apart. PD incidence date was defined as the earliest of first PD diagnostic code or PD-related medication prescription. ECGs obtained at least 6 months before PD incidence date were modeled to predict a subsequent diagnosis of PD within three time windows: 6 months-1 year, 6 months-3 years, and 6 months-5 years. We applied a novel deep neural network using standard 10-s 12-lead ECGs to predict PD risk at the prodromal phase. This model was compared to multiple feature engineering-based models. Subgroup analyses for sex, race and age were also performed. Our primary prediction model was a one-dimensional convolutional neural network (1D-CNN) that was built using 131 cases and 1058 controls from MLH, and externally validated on 29 cases and 165 controls from LUC. The model was trained on 90% of the MLH data, internally validated on the remaining 10% and externally validated on LUC data. The best performing model resulted in an external validation AUC of 0.67 when predicting future PD at any time between 6 months and 5 years after the ECG. Accuracy increased when restricted to ECGs obtained within 6 months to 3 years before PD diagnosis (AUC 0.69) and was highest when predicting future PD within 6 months to 1 year (AUC 0.74). The 1D-CNN model based on raw ECG data outperformed multiple models built using more standard ECG feature engineering approaches. These results demonstrate that a predictive model developed in one cohort using only raw 10-s ECGs can effectively classify individuals with prodromal PD in an independent cohort, particularly closer to disease diagnosis. Standard ECGs may help identify individuals with prodromal PD for cost-effective population-level early detection and inclusion in disease-modifying therapeutic trials.

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. METHODS: The Honolulu Heart Program is a prospective population-based cohort study of 8006 Japanese-American men in Hawaii who were 45 to 68 years old at the baseline examination in 1965 to 1968. Dietary vitamin D intake was calculated using the Nutritionist IV Version 3 software from a 24-hour dietary recall. Subjects with prevalent stroke were excluded, leaving 7385 men followed through 1999 for incident stroke. Subjects were divided into quartiles of dietary vitamin D for analyses. RESULTS: 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 with the highest (all stroke: 6.38 versus 5.14 per 1000 person-years follow-up, P=0.030; thromboembolic stroke: 4.36 versus 3.30, P=0.033). Using Cox regression, adjusting for age, total kilocalories, body mass index, 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 hazard ratio, 1.22; 95% CI, 1.01-1.47; P=0.038; thromboembolic stroke hazard ratio, 1.27; 95% CI, 1.01-1.59; P=0.044) with the highest as the reference. We found no significant associations between dietary vitamin D and hemorrhagic stroke. CONCLUSIONS: 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.

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

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

Genetic modification of the association of paraquat and Parkinson's disease.

Paraquat is one of the most widely used herbicides worldwide. It produces a Parkinson's disease (PD) model in rodents through redox cycling and oxidative stress (OS) and is associated with PD risk in humans. Glutathione transferases provide cellular protection against OS and could potentially modulate paraquat toxicity. We investigated PD risk associated with paraquat use in individuals with homozygous deletions of the genes encoding glutathione S-transferase M1 (GSTM1) or T1 (GSTT1). Eighty-seven PD subjects and 343 matched controls were recruited from the Agricultural Health Study, a study of licensed pesticide applicators and spouses in Iowa and North Carolina. PD was confirmed by in-person examination. Paraquat use and covariates were determined by interview. We genotyped subjects for homozygous deletions of GSTM1 (GSTM1*0) and GSTT1 (GSTT1*0) and tested interaction between paraquat use and genotype using logistic regression. Two hundred and twenty-three (52%) subjects had GSTM1*0, 95 (22%) had GSTT1*0, and 73 (17%; all men) used paraquat. After adjustment for potential confounders, there was no interaction with GSTM1. In contrast, GSTT1 genotype significantly modified the association between paraquat and PD. In men with functional GSTT1, the odds ratio (OR) for association of PD with paraquat use was 1.5 (95% confidence interval [CI]: 0.6-3.6); in men with GSTT1*0, the OR was 11.1 (95% CI: 3.0-44.6; P interaction: 0.027). Although replication is needed, our results suggest that PD risk from paraquat exposure might be particularly high in individuals lacking GSTT1. GSTT1*0 is common and could potentially identify a large subpopulation at high risk of PD from oxidative stressors such as paraquat.