Kuakini Medical Center

Abstract Cerebral venous congestion (CVC) has been identified as a hypothetic cause of cognitive impairment. Prior work has estimated that 15-30% of the population may have jugular venous narrowing, a potential cause of CVC, based on reviews of CT angiography (CTA) performed at a large academic medical center. However, few comprehensive studies exist. Therefore, for the current work, we reviewed fifty CTAs that were obtained for ischemic stroke triage and thrombectomy planning at a comprehensive stroke center in Hawaii (Queens Hospital, Honolulu HI). These brain CTAs were analyzed for arterial and venous variants and other abnormalities that might place the patient at increased risk for arterial injury and/or venous congestion, both of which may result in cognitive decline. The CTAs were analyzed retrospectively for every known level of venous and arterial stenosis, and CVC-associated pre-morbid symptoms were analyzed. Preliminary data support the hypothesis that venous anatomical anomalies may be a risk factor for cognitive impairment. CVC may be an under-diagnosed contributor to cognitive impairment, particularly in older patients.

Abstract The longevity-associated allele of FOXO3 is associated with a significant reduction in cardiovascular disease (CVD) risk in older adults. We hypothesized that dementia, which shares several risk factors with CVD, might also be related to FOXO3 genotype, particularly vascular dementia (VaD). Therefore, we utilized the Kuakini Honolulu Heart Program/Honolulu Asia Aging Study dataset to assess the relation of FOXO3 genotype to dementia risk. Preliminary analyses suggested that VaD had the strongest relation to FOXO3 genotype. Therefore, we performed larger, more detailed study of FOXO3 genotype and VaD risk in a 9-year nest case-control study. Chi-Square test was used to assess the association of dementia with FOXO3 genotype in a sample of 1504 Japanese-American male study participants, aged 71-93 years, at the baseline exam. General Linear Model was utilized to compare VaD risk factors between VaD cases and controls. Multivariate Logistic Regression was used to assess the association of VaD with FOXO3 genotype adjusting for birth year, education, APOE4 and other vascular risk factors. We found a significant protective association for carriers of the principal FOXO3 longevity-associated allele (SNP rs2802292 G allele-carriers) against VaD risk (OR = 0.66, 95% CI = 0.44-0.98, p = 0.0388). The protective association retained significance when controlling for common risk factors for VaD in a multivariate model. These data indicate a potential neuroprotective role for the FOXO3 longevity-associated genotype against vascular dementia. This finding merits validation studies in other cohort studies.

Abstract The longevity-associated FOXO3 G allele of SNP rs2802292 is associated with protection against mortality, however the impact of FOXO3 genotype on the association between hypertension and risk of intracerebral hemorrhage (ICH) has not been assessed. Therefore, we utilized the Kuakini Honolulu Heart Program (KHHP), a prospective population-based cohort of Japanese American men living in Hawaii that began in 1965 to study this relation. After excluding baseline prevalent stroke and those missing FOXO3 data, 6,469 men were included in the analysis. Age-adjusted prevalence of ICH by hypertension was assessed for the whole cohort after stratifying by FOXO3 genotype. Cox regression models, adjusted for age, cardiovascular risk factors, FOXO3 and APOE genotypes, were utilized to assess relative risk of hypertension on ICH. All models were created for the whole cohort and stratified by FOXO3 genotype, namely G allele carriers versus TT genotype. Overall, 183 subjects developed ICH over the 34-year follow-up period. Age-adjusted ICH prevalence was 0.90 versus 1.32 per 1,000 person-years follow-up in those without and with hypertension, respectively (p=0.002). After stratifying by FOXO3 genotype, this association was no longer significant in G allele carriers. In the whole cohort, hypertension was an independent predictor of ICH (RR=1.70, 95%CI 1.25, 2.32; p=0.0007). In stratified analyses, hypertension remained an independent predictor of ICH among the FOXO3 TT allele group (RR=2.02, 95% CI 1.33, 3.07; p=0.001), but not in FOXO3 G allele carriers (RR=1.39, 95% CI 0.88, 2.19; p=0.15). Thus, the longevity/resilience-associated FOXO3 G allele may mitigate the impact of hypertension on ICH risk in this population. Further study is needed in other populations.

Abstract BackgroundWhile studies have found that mid‐life hypertension increases risk of Alzheimer’s disease (AD), the association of late‐life hypertension with AD is still unclear, FOXO3 genotype influences mortality risk from cardio‐metabolic diseases (CHD, diabetes, and hypertension). We hypothesize that FOXO3 genotype affects the risk that late‐life hypertension poses to development of AD.MethodThe study involved 2,688 Japanese‐American men (mean age: 77.0 ± 4.1, range 71‐92) from the Kuakini Honolulu Heart Program with FOXO3 rs2802292 genotype, and information on incident AD from 1991 to 2012. Late‐life hypertension was defined as SBP/DBP ≥ 160/95 or taking anti‐hypertensive medication. Here, FOXO3 longevity haplotype (FOXO3‐LH) comprised minor allele frequencies of rs2802292 (G), rs2253310 (C), rs2802288 (A), rs2764264 (C), rs9398171 (C), rs12212067 (G), and rs3800230 (G). The association of FOXO3 genotype with late‐life hypertension and incident AD was assessed using a Cox proportional hazard model.ResultDuring 21 years of follow‐up, 513 people were diagnosed with incident AD. Age‐adjusted incidence rates of AD among late‐life hypertensive subjects showed that those with the rs2802292 longevity genotype TG/GG had a lower incidence than those with genotype TT (21.58 vs 24.49 per 1,000 person‐years; p = 0.038). A multivariable Cox model, adjusting for age, education, APOE‐ε4 and other CVD risk factors, showed late‐life hypertension protects men from AD only for those with a longevity genotype such as rs2802292 TG/GG (HR = 0.68, 95% CI 0.52–0.89; p = 0.0052), and with the FOXO3‐LH (HR = 0.59, 95% CI 0.39–0.91; p = 0.016), but this was not seen for the rs2802292 genotype TT (HR = 1.15, 95% CI 0.89–1.49; p = 0.28), nor in the absence of the FOXO3‐LH (HR = 1.14, 95% CI 0.88–1.49; p = 0.31).ConclusionThis study provides the first evidence that FOXO3 genotype influences the risk that late‐life hypertension has on developing Alzheimer’s disease. Only with the FOXO3 longevity genotype was there protection against a late‐life hypertension‐mediated increase in incident AD risk. The findings have implications for the effect of the FOXO3 longevity genotype on late‐life hypertension‐associated risk of AD. Without considering the effect of FOXO3 longevity genotype, one should be cautious about generalizations concerning the protective effect of late‐life hypertension on AD in the population.

[This corrects the article DOI: 10.1371/journal.pone.0231761.].

FOXO3 is a prominent longevity gene. To date, no-one has examined whether longevity-associated FOXO3 genetic variants protect against mortality in all individuals, or only in those with aging-related diseases. We therefore tested longevity-associated FOXO3 single nucleotide polymorphisms in a haplotype block for association with mortality in 3,584 elderly American men of Japanese ancestry, 2,512 with and 1,072 without a cardiometabolic disease (CMD). At baseline (1991–1993), 1,010 CMD subjects had diabetes, 1,919 had hypertension, and 738 had coronary heart disease (CHD). Follow-up until Dec 31, 2019 found that in CMD-affected individuals, longevity-associated alleles of FOXO3 were associated with significantly longer lifespan: haplotype hazard ratio 0.81 (95% CI 0.72-0.91; diabetes 0.77, hypertension 0.82, CHD 0.83). Overall, men with a CMD had higher mortality than men without a CMD (P=6x10-7). However, those men with a CMD who had the FOXO3 longevity genotype had similar survival as men without a CMD. In men without a CMD there was no association of longevity-associated alleles of FOXO3 with lifespan. Our study provides novel insights into the basis for the long-established role of FOXO3 as a longevity gene. We suggest that the FOXO3 longevity genotype increases lifespan only in at-risk individuals by protection against cardiometabolic stress.

The Cognitive Abilities Screening Instrument (CASI) is a screening test of global cognitive function used in research and clinical settings. However, the CASI was developed using face validity and has not been investigated via empirical tests such as factor analyses. Thus, we aimed to develop and test a parsimonious conceptualization of the CASI rooted in cognitive aging literature reflective of crystallized and fluid abilities. Secondary data analysis implementing confirmatory factor analyses where we tested the proposed two-factor solution, an alternate one-factor solution, and conducted a χ2 difference test to determine which model had a significantly better fit. N/A. Data came from 3,491 men from the Kuakini Honolulu-Asia Aging Study. The Cognitive Abilities Screening Instrument. Findings demonstrated that both models fit the data; however, the two-factor model had a significantly better fit than the one-factor model. Criterion validity tests indicated that participant age was negatively associated with both factors and that education was positively associated with both factors. Further tests demonstrated that fluid abilities were significantly and negatively associated with a later-life dementia diagnosis. We encourage investigators to use the two-factor model of the CASI as it could shed light on underlying cognitive processes, which may be more informative than using a global measure of cognition.

Background: The number of people with dementia is increasing in the world and it is of great public health concern. Previous observational studies, mainly from western countries, have reported that modifiable factors for development of dementia were cardiometabolic risk factors, related to genetically determined metabolic abilities and lifestyle. There are no studies comparing which modifiable factors relate to low cognitive scores among populations with the same genetic background but different lifestyle. Objective: The purpose of the present study is to describe factors related to low cognitive scores in Japanese men in two cohorts that are genetically similar but with different lifestyle exposures. Methods: Population-based cross-sectional data from the Kuakini Honolulu-Asia Aging Study (HAAS) in Hawaii and Shiga Epidemiological Study of Subclinical Atherosclerosis (SESSA) in Japan were analyzed. Participants were Japanese men aged 71-81 years (2,628 men in Hawaii and 349 men in Japan). Cognitive function was assessed using the Cognitive Abilities Screening Instrument (CASI), with low CASI score < 82. Related factors were obtained by questionnaire and measurements. Multivariable adjusted odds ratios of low CASI score by different factors among the two cohorts were calculated by logistic regression analysis. Results: Low CASI score was more common in elderly men in Hawaii compared to Japan (21.2% or 556/2,628 versus 12.3% or 43/349, p<0.001). After adjustment for age and educational attainment, these differences were no longer significant (Hawaii 20.3% versus Japan 17.9%, p=0.328). Odds ratios for low cognitive scores were 1.65 in Hawaii with history of stroke, and 1.93 in Japan with history of CHD. Higher odds of low cognitive score were seen with diabetes in Hawaii (OR=1.20), and with BMI≥25 in Japan (OR=1.88). Conclusion: We found different strengths of associations between cardiovascular diseases and cardiometabolic factors with low cognitive scores among genetically similar men in Hawaii and Japan with different lifestyles.