Search

The paper aimed to compare how factors previously identified as predictive factors for cognitive decline and dementia related to cognitive performance on the one hand and brain health on the other. To that aim, multiple linear regression was applied to the AGES-Reykjavik study epidemiological data. Additionally, a regression analysis was performed for change in cognition over 5 years, using the same exposure factors. The study ran from 2002 to 2011, and the sample analyzed included 1707 participants between the ages of 66 and 90. The data contains MR imaging, cognitive testing, background data, and physiological measurements. Overall, we conclude that risk factors linked to dementia relate differently to cognition and brain health. Mobility, physical strength, alcohol consumption, coronary artery disease, and hypertension were associated with cognition and brain volume. Smoking, depression, diabetes, and body fat percentage were only associated with brain volume, not cognitive performance. Modifiable factors previously linked to cognitive reserve, such as educational attainment, participation in leisure activities, multilingualism and good self-reported health, were associated with cognitive function but did not relate to brain volume. These findings show that, within the same participant pool, cognitive reserve proxy variables have a relationship with cognitive performance but have no association with relative brain volume measured simultaneously. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-022-00642-z.

This study aimed to investigate the longitudinal associations between social network (SN) and the risk of lower cognitive function, mild cognitive impairment (MCI), and dementia among cognitively normal individuals 65 years and older.Data from the Age, Gene/Environment Susceptibility (AGES) Reykjavik Study on 2816 participants (aged 65 to 96 years) were used to examine the associations using multiple logistic and linear regression models. SN included questions on frequency of contact with family and friends as well as information on marital status, resulting in a score ranging from 0 (poor social network) to 3 (good social network). Cognitive function outcomes included the speed of processing (SP), executive function (EF) and memory function (MF). MCI and dementia were diagnosed using a detailed assessment according to international guidelines.At baseline 0.5, 7.0, 41.7 and 50.8% reported a score of 0, 1, 2 and 3, respectively. During a mean follow-up time of 5.2 years, 7.1% (n = 188) of cognitively intact participants developed MCI and 3.0% (n = 79) developed dementia. Longitudinal analyses demonstrated that participants who had low SN were significantly more likely to have declines in MF (β = - 0.533, P = 0.014) compared to high SN. Social networks were not independently associated with the decline of SP and EF during follow-up. According to fully adjusted models using logistic regression, SN was significantly associated with incidence risk of MCI (OR = 2.030, P = 0.014 and OR = 1.847 P = 0.001). These associations were largely independent of other lifestyle factors, depression and genetic disposition.Community-dwelling older adults who have poor social networks have a higher risk of declining memory function as well as a higher risk of mild cognitive impairment than older adults who have a higher social network. This study included numbers of relevant covariates in the study analysis, thereby significantly contributing to the literature on cognitive aging.

Background: The gut microbiota may play a role in cognitive function and decline. Animal models support mechanisms involving short-chain fatty acid production, amino acid metabolism, and purine metabolism. There is need to replicate these findings in population-based human studies. Methods: Data were from 570 participants who attended the Yr. 30 follow-up exam (2015-16, ages 48-60 y, 45%:55% Black:White race, 45%:55% M:F sex), provided a fecal sample, and completed a cognitive battery of 6 assessments: Montreal Cognitive Assessment (MoCA), Digit Symbol Substitution Test (DSST), Rey-Auditory Verbal Learning Test (RAVLT), Stroop, and Letter and Category Fluency. A global cognition score was derived from the 6 assessments using principal components analysis. Species and metabolic pathways were assigned to whole-metagenomics sequence data using standard reference databases. Multivariable-adjusted linear regression was used to test associations between distinct microbial features and measures of cognition, controlling for false discovery rate (FDR). Results: Sequence data mapped to 106 species and 312 metabolic pathways. In multivariable-adjusted regression analysis, adjusted for socio-demographics, health behaviors, and BMI, 5 species and 5 metabolic pathways were significantly associated with measures of cognitive function, FDR < 0.20 (Figure) . These species/pathways are involved in purine and pyrimidine metabolism and short-chain fatty acid production. Conclusion: Identified pathways play a role in neurodevelopment and in the gut-brain axis of physiologic communications. Our findings suggest long-term relationships between gut microbiota composition and cognitive function.

BackgroundNeurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro-axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels and its genetic correlation with neurological traits could therefore provide new insights into shared molecular mechanisms underlying neurodegenerative disorders.MethodsTo identify the genetic variations underlying blood NfL levels, we conducted an ancestry-specific meta-analyses of genome-wide association studies (GWAS) based on 18,532 participants from 11 cohorts of European and 1142 participants (3 cohorts) of African-American ancestry. In the post-GWAS analyses, we performed expression quantitative trait loci (eQTL) analysis, LD-regression, and genetic risk score (GRS) association analysis with neurological traits.ResultsIn the European ancestry GWAS meta-analysis, we identified two genome-wide significant (P< 5x10−8) loci at 16p12 (UMOD), and 17q24 (SLC39A11). In the African-American ancestry GWAS meta-analysis, we identified three novel loci at 1q43 (FMN2), 12q14, and 12q21. Genetic correlation based on the European ancestry meta-analysis with neurological traits showed a strong genetic correlation of NfL with Alzheimer’s disease(AD) (rg= 0.32,P= 1.74x10−6), total-tau (rg= 2.01,P= 1.03x10−6), amyloid-beta (Aβ)-40 (rg= 0.80,P= 6.92x10−6), and Aβ-42 (rg= 1.03,P= 4.39x10−5). A higher genetic risk score based on NfL-associated genetic variants was also related to increased plasma levels of total-tau (P= 1.97x10−4), Aβ-40 (P= 2.24x10−5), Aβ-42 (P= 2.92x10−4) in the Rotterdam Study.ConclusionThis large-scale GWAS meta-analysis revealed multiple novel genetic loci of NFL levels in blood in participants from European and African-American ancestry. Significant genetic correlation of genes underlying NfL with AD, Aβ-42, and total-tau may indicate a common underlying pathway of neurodegeneration.

Background Hypertension is a well-established risk factor for cognitive impairment, brain atrophy, and dementia. However, the relationship of other types of hypertensions, such as isolated hypertension on brain health and its comparison to systolic-diastolic hypertension (where systolic and diastolic measures are high), is still relatively unknown. Due to its increased prevalence, it is important to investigate the impact of isolated hypertension to help understand its potential impact on cognitive decline and future dementia risk. In this study, we compared a variety of global brain measures between participants with isolated hypertension to those with normal blood pressure (BP) or systolic-diastolic hypertension using the largest cohort of healthy individuals. Methods Using the UK Biobank cohort, we carried out a cross-sectional study using 29,775 participants (mean age 63 years, 53% female) with BP measurements and brain magnetic resonance imaging (MRI) data. We used linear regression models adjusted for multiple confounders to compare a variety of global, subcortical, and white matter brain measures. We compared participants with either isolated systolic or diastolic hypertension with normotensives and then with participants with systolic-diastolic hypertension. Results The results showed that participants with isolated systolic or diastolic hypertension taking BP medications had smaller gray matter but larger white matter microstructures and macrostructures compared to normotensives. Isolated systolic hypertensives had larger total gray matter and smaller white matter traits when comparing these regions with participants with systolic-diastolic hypertension. Conclusions These results provide support to investigate possible preventative strategies that target isolated hypertension as well as systolic-diastolic hypertension to maintain brain health and/or reduce dementia risk earlier in life particularly in white matter regions.

ImportanceCerebral small vessel disease (SVD) causes a quarter of strokes and is the most common pathology underlying vascular cognitive impairment and dementia. An important step to developing new treatments is better trial methodology. Disease mechanisms in SVD differ from other stroke etiologies; therefore, treatments need to be evaluated in cohorts in which SVD has been well characterized. Furthermore, SVD itself can be caused by a number of different pathologies, the most common of which are arteriosclerosis and cerebral amyloid angiopathy. To date, there have been few sufficiently powered high-quality randomized clinical trials in SVD, and inconsistent trial methodology has made interpretation of some findings difficult.ObservationsTo address these issues and develop guidelines for optimizing design of clinical trials in SVD, the Framework for Clinical Trials in Cerebral Small Vessel Disease (FINESSE) was created under the auspices of the International Society of Vascular Behavioral and Cognitive Disorders. Experts in relevant aspects of SVD trial methodology were convened, and a structured Delphi consensus process was used to develop recommendations. Areas in which recommendations were developed included optimal choice of study populations, choice of clinical end points, use of brain imaging as a surrogate outcome measure, use of circulating biomarkers for participant selection and as surrogate markers, novel trial designs, and prioritization of therapeutic agents using genetic data via Mendelian randomization.Conclusions and RelevanceThe FINESSE provides recommendations for trial design in SVD for which there are currently few effective treatments. However, new insights into understanding disease pathogenesis, particularly from recent genetic studies, provide novel pathways that could be therapeutically targeted. In addition, whether other currently available cardiovascular interventions are specifically effective in SVD, as opposed to other subtypes of stroke, remains uncertain. FINESSE provides a framework for design of trials examining such therapeutic approaches.

The apolipoprotein E allele 4 (APOE-ε4) is established as a major genetic risk factor for cognitive decline and late-onset Alzheimer's disease. Accumulating evidence has linked ε4 carriership to abnormal structural brain changes across the adult lifespan. To better understand the underlying causal mechanisms, we investigated the extent to which the effect of the ε4 allele on cognition is mediated by structural brain imaging markers in the population-based Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik). This study included 4527 participants (aged 76.3 ± 5.4 at baseline) who underwent the brain magnetic resonance imaging assessment (of brain tissue volumes, white matter lesion volume, subcortical and cortical infarcts, and cerebral microbleeds) and a battery of neuropsychological tests at baseline. Causal mediation analysis was used to quantify the mediation of the ε4 effect on cognition by these MRI markers, both individually and jointly. We observed that about 9% of the total effect of ε4 carriership on cognition was mediated by white matter lesion volume. This proportion increased to 25% when total brain tissue volume was jointly considered with white matter lesion volume. In analyses separating ε4 homozygotes from ε4 heterozygotes, the effect on global cognition of specifically ε4 homozygosity appeared to be partially mediated by cerebral microbleeds, particularly lobar microbleeds. There was no evidence of mediation of the ε4 effect by cortical or subcortical infarcts. This study shows that the ε4 effect on cognition is partly mediated by white matter lesion volume and total brain tissue volume. These findings suggest the joint role of cerebral small vessel disease and neurodegeneration in the ε4-cognition relationship.

Normal and pathologic neurobiological processes influence brain morphology in coordinated ways that give rise to structural covariance patterns across brain regions and individuals. We present a mega-analysis of structural covariance with magnetic resonance imaging of 50,699 healthy and diseased individuals (12 studies, 130 sites, and 12 countries) over their lifespan (ages 5 through 97). Patterns of structural covariance (PSC) were highly heritable (0.05< h2 -log10[p-value] > 8.8): 1245 previously unreported, and 69% of them independently replicated (-log10[p-value] = 4.5). Associations revealed an imaging phenotypic landscape between 2003 PSCs and 49 clinical and cognitive traits at multiple scales. We constructed machine learning-derived individualized imaging signatures for various disease diagnoses using PSC features at multiple scales, suggesting that disease effects on the brain were better manifested in a multi-scale continuum than on any single scale. Experimental results were integrated into the Multi-scale Structural Imaging Covariance (MuSIC) atlas and made publicly accessible through the BRIDGEPORT web portal (https://www.cbica.upenn.edu/bridgeport/). Our results reveal strong associations between brain structural covariance, genetics, and clinical phenotypes, supporting that PSCs can serve as an endophenotypic anatomic dictionary in future research.

Racial residential segregation is associated with multiple adverse health outcomes in Black individuals. Yet, the influence of structural racism and racial residential segregation on brain aging is less understood. In this study, we investigated the association between cumulative exposure to racial residential segregation over 25 years (1985–2010) in young adulthood, as measured by the Getis-Ord Gi* statistic, and year 25 measures of brain volume (cerebral, gray matter, white matter, and hippocampal volumes) in midlife. We studied 290 Black participants with available brain imaging data who were enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a prospective cohort study. CARDIA investigators originally recruited 2,637 Black participants aged 18–30 years from 4 field centers across the United States. We conducted analyses using marginal structural models, incorporating inverse probability of treatment weighting and inverse probability of censoring weighting. We found that compared with low/medium segregation, greater cumulative exposure to a high level of racial residential segregation throughout young adulthood was associated with smaller brain volumes in general (e.g., for cerebral volume, β = –0.08, 95% confidence interval: −0.15, −0.02) and with a more pronounced reduction in hippocampal volume, though results were not statistically significant. Our findings suggest that exposure to segregated neighborhoods may be associated with worse brain aging.

The proportion of aging populations affected by dementia is increasing. There is an urgent need to identify biological aging markers in mid-life before symptoms of age-related dementia present for early intervention to delay the cognitive decline and the onset of dementia. In this cohort study involving 1,676 healthy participants (mean age 40) with up to 15 years of follow up, we evaluated the associations between cognitive function and two classes of novel biological aging markers: blood-based epigenetic aging and neuroimaging-based brain aging. Both accelerated epigenetic aging and brain aging were prospectively associated with worse cognitive outcomes. Specifically, every year faster epigenetic or brain aging was on average associated with 0.19-0.28 higher (worse) Stroop score, 0.04-0.05 lower (worse) RAVLT score, and 0.23-0.45 lower (worse) DSST (all false-discovery-rate-adjusted p

Introduction Much debate exists about the role of light to moderate alcohol intake and subsequent cognitive function. The apolipoprotein E genotype may modify the relationship. Methods Using data from the Honolulu-Asia Aging Study, a longitudinal population-based cohort (n = 2,416), Cox proportional hazards regression analyses were performed to measure midlife alcohol intake (average age = 52 years) and later life cognitive function (average age = 87 years) and to explore the role of apolipoprotein E genotype. Results No protective effect of light drinking (>1 drink/month– 1 drink/day) or moderate drinking (>1–2 drinks/day) was observed in the cohort in adjusted models (HR = 1.013, CI:0.88–1.16; HR = 1.104, CI:0.91–1.34, respectively). Heavy drinking (>2–4 drinks/day) and very heavy drinking (>4 drinks/day) increased the risk for incident moderate cognitive impairment (HR = 1.355, CI:1.09–1.68; HR = 1.462, CI:1.04–2.05, respectively). When examining the relationship by apolipoprotein E ε4 carrier status, a similar dose-response pattern was observed in both groups with higher hazard ratios for those carrying at least one copy of the apolipoprotein E ℇ4 allele. As alcohol level increased, the age at incident moderate cognitive impairment decreased, especially among those with at least one apolipoprotein E ℇ4 allele. Discussion We did not observe a significant protective effect for light to moderate drinking in midlife and subsequent cognitive impairment in this cohort. Heavy drinking increased the risk for moderate cognitive impairment and decreased the age at incidence, as did carrying at least one allele of the apolipoprotein E ℇ4 gene.

RATIONALE AND OBJECTIVE: The safety of intensive blood pressure (BP) targets is controversial for persons with chronic kidney disease (CKD). We studied the effects of hypertension treatment on cerebral perfusion and structure in those with and without CKD. STUDY DESIGN: Neuroimaging substudy of a randomized trial. SETTING & PARTICIPANTS: A subset of participants in the Systolic Blood Pressure Intervention Trial who underwent brain MRI studies. Presence of baseline CKD was assessed by estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR). INTERVENTION: Participants were randomly assigned to intensive (systolic BP 30 mg/g (N=151), the effects of intensive versus standard BP treatment on change in global cerebral blood flow, WMLs and total brain volume were 1.91 ml/100g/min (95% CI −3.01, 6.82), 0.003 cm(3) (asinh transformed, 95% CI −0.13, 0.13), and −7.0 cm(3) (95% CI −13.3, −0.3), respectively. The overall treatment effects on cerebral blood flow and total brain volume were not modified by baseline eGFR or UACR; however the effect on WMLs was attenuated in participants with albuminuria (interaction p-value 0.04). LIMITATIONS: Measurement variability due to multi-site design. CONCLUSIONS: Among hypertensive adults with primarily early kidney disease, intensive versus standard blood pressure treatment did not appear to have a detrimental effect on brain perfusion or structure. The findings support the safety of intensive blood pressure treatment targets on brain health in persons with early kidney disease. FUNDING: The Systolic Blood Pressure Intervention Trial was funded by the National Institutes of Health (including the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke), and this substudy was funded by the National Institutes of Diabetes and Digestive and Kidney Diseases. TRIAL REGISTRATION: SPRINT was registered at ClinicalTrials.gov with the study number NCT01206062.

Meta-analyses incorporating the Systolic Blood Pressure Intervention Trial (SPRINT) have shown a reduced incidence of dementia with blood pressure lowering. However, mechanistic explanations for this effect are lacking, apart from slowed progression of cerebral white matter lesions (WML). Here we examine possible biomarkers of angiogenesis related to small vessel brain disease including bFGF, FLT1, PLGF, TIE-2, VEGF, VEGF-C, and VEGF-D. The biomarkers were assayed in plasma at baseline and during follow-up (median follow-up = 3.8 years) in a subgroup of participants 60 to 89 years old from SPRINT (N=517). We modeled changes in each biomarker using robust linear mixed models accounting for treatment group, time since randomization, and kidney function. Participants were 69.8 ± 7.1 (standard deviation) years of age, 42.1% female, with a mean systolic blood pressure (SBP) of 138.2 ± 17.0 mm Hg. At baseline, none of the biomarkers were associated with WML lesion volume or total brain volumes adjusting for age (all p>0.05), while FLT1, PLGF, and TIE-2 were negatively associated with frontal gray matter cerebral blood flow (partial correlations of -0.11, -0.10, and -0.12 respectively, all p

Background: Multivariable prognostic models in the general population predict individual risk of developing Alzheimer’s disease (AD) or all-cause dementia, which can aid selection of high-risk individuals for clinical trials and prevention. While development of new models flourished across the past decades, external validation for the majority of models is lacking. We aimed to evaluate the external performance of prediction models for all-cause dementia or AD in the general population. Methods: We identified 17 published prognostic models for external validation in the AGES-Reykjavik Study, a prospective population-based cohort study (n=5343 without dementia at baseline; 76.6±5.7 years, 58% woman). Predictive performance was assessed with c statistics (discrimination) and calibration plots, using the models’ prediction horizon (5-10 years), outcome (AD or all-cause dementia), and modelling technique (logistic, Cox, or competing risk regression). Findings: During 45,021 person-years of follow-up 1099 participants developed dementia, and during 40,917 person-years of follow-up 492 participants developed AD. The mean observed risk of dementia was 10.1% [95% CI: 9.2-11.0] for six years and 22.8% [21.5-24.1] for ten years; the risk for AD was 5.6% [4.9-6.3] and 12.1% [11.0-13.2], respectively. Models ranged from 2-11 predictors; notably, all five models with a c statistic >.75 (.76-.81) contained cognitive testing as a predictor, while all models with lower c statistics (.67-.75) did not. Calibration ranged from good to poor, including systematic risk overestimation or overestimation for particularly the highest risk group. Interpretation: The majority of models demonstrated acceptable, but not strong, discrimination and only few calibrated well. Models that overestimate predicted risks may be acceptable for exclusion purposes, but lack the ability to accurately identify individuals at higher risk for clinical trials and prevention. Both updating existing models or developing new models aimed at identifying high-risk individuals, as well as more external validation studies of dementia prediction models are warranted. Funding: National Institute on Aging; National Eye Institute; National Institute on Deafness and Other Communication Disorders; National Heart, Lung and Blood Institute; National Institute on Aging Intramural Research Program; Hjartavernd (the Icelandic Heart Association); the Althingi (Icelandic Parliament); Alzheimer Nederland; the Dutch Research Council (NWO)/ZonMw Declaration of Interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. Ethics Approval Statement: AGES-RS was approved by the Icelandic National Bioethics Committee (VSN: 00-063), the Icelandic Data Protection Authority (Iceland), and by the Institutional Review Board for the National Institute on Aging, National Institutes of Health (USA). Written informed consent was obtained from all participants.

ALDH2*2 is a loss of function mutation common in East Asian populations associated with facial flushing on exposure to alcohol and increased risk of certain cancers. Conversely, absence of the ALDH2*2 mutation is associated with increased risk of hypertension and cerebral microbleeds, and two recent studies report a higher frequency of ALDH2*2 alleles in nonagenarians compared to population control samples. We used survival analysis to investigate the association between ALDH2*2 and risk of cognitive impairment and death after controlling for midlife alcohol consumption and other covariates. Participants are 621 Japanese-American men (72 to 92) enrolled in the Honolulu Asia Aging Study (HAAS) and assessed for cognitive impairment for up to 20 years. Impairment was defined as crossing below a threshold score of 74 on the Cognitive Assessment Screening Instrument (CASI). Age at death was determined by Hawaii state death certificate. Ounces of ethyl alcohol consumed per month was assessed by structured interview (number, frequency, and type of beverage) conducted 25 years prior to baseline cognitive assessment. Persons heterozygous for the ALDH2*2 variant have reduced risk of cognitive impairment and reduced risk of death, compared to homozygote non-carriers. Covarying by alcohol exposure had no effect on observed associations. This study replicates previous findings associating ALDH2*2 with longevity, and provides evidence the protective effect extends to cognition. This poster details the statistical analysis carried out to obtain these results.

Introduction: We aim to investigate the longitudinal associations between social participation and the risk of developing mild cognitive impairment (MCI|) and dementia over 5 years of follow-up among cognitively normal older adults. Methods: A total of 2802 participants had complete follow-up data from Age-Gene/Environment-Susceptibility-Reykjavik-Study. Social participation was assessed by a questionnaire asking the frequency of contact with children, relatives, friends and neighbors. MCI and dementia were diagnosed according to international guidelines and by a team composed of a geriatrician, neurologist, neuropsychologist, and neuroradiologist. Logistic regression analysis was used to assess the associations. Results: At baseline 8% (n=225) reported no social participation. Among cognitively normal participants at baseline, 5.6% (n=243) developed mild cognitive impairment and 2.4% (n= 103) developed dementia during a mean follow-up time of 5.2 years. After full adjustment with covariates including age, gender, education, marital status, vitamin D levels, depression and APOE ε4, those with no social participation at baseline were significantly more likely to develop MCI at follow-up (OR=1.953, P=0.001). However, social participation at baseline was not associated with higher dementia diagnosis at follow-up (OR= 1.490, P=0.194). Conclusions: Community-dwelling old adults who are socially inactive are more likely to develop MCI than those who are socially active. Social participation might independently indicate impending changes in cognitive function among older adults.

Introduction: Whether multiple unique trajectories in fasting glucose (FG) and insulin resistance (HOMA-IR) are present during young adulthood and if such trajectories are associated with cognitive function in middle adulthood is unclear. Hypothesis: We hypothesized that a high-increasing trajectory of FG and HOMA-IR in the absence of diabetes during young adulthood would be associated with lower level of cognitive function in midlife compared to a low trajectory. Methods: We studied 2,650 CARDIA participants, age 18 to 30 years (1985-1986) to determine FG and HOMA-IR at baseline and 7, 10, 15, and 20 year follow-up exams (≥ 8 hours fasting and not pregnant). Using latent class analysis (SAS Proc Traj), we determined trajectory groups for FG and HOMA-IR through year 20. Cognitive function was assessed at year 25 (2010-2011) with three cognitive tests including the Digit Symbol Substitution Test (DSST; a test of sustained attention, psychomotor speed, working memory, and executive function), Rey-Auditory Verbal Learning Test (RAVLT; verbal memory), and Stroop Test (executive function). We used multivariable linear regression to estimate adjusted means for each cognitive test according to trajectory group for both FG and HOMA-IR for individuals free from diabetes during follow-up, after adjustment for potential confounding factors. Results: We identified three trajectory groups for FG and HOMA-IR for individuals free from diabetes in middle adulthood, qualitatively low-stable to increasing, moderate-increasing, and high-increasing. Compared to the low FG trajectory group, the high FG trajectory group had significantly lower mean score for the RAVLT, shown in the Table . Otherwise, cognitive test scores generally did not differ according to FG or HOMA-IR trajectory group. Conclusion: In this community-based sample of individuals free from diabetes, a high-increasing FG trajectory through young adulthood was associated with worse memory in midlife.

Background: The parenchyma of the pineal gland, an endocrine gland in the brain, produces the circadian hormone melatonin. Previously, we found low levels of melatonin were associated with an increased risk for advanced prostate cancer. This study used data from men in the Age, Gene/Environment Susceptibility-Reykjavik (AGES-Reykjavik) Study to evaluate the relationship between pineal volume, melatonin levels, and prostate cancer risk. Methods: Participants were enrolled in the AGES-Reykjavik Study from 2002 to 2006 and underwent detailed clinical assessments at baseline that included biospecimen collection, MRI of the brain, medical history, and health questionnaires on dietary and lifestyle factors. We included 802 men who had information on pineal size, where parenchyma, calcification, and cyst volume were estimated individually and manually from the MRIs. Cox proportional hazards regression was used to calculate hazard ratios and 95% confidence intervals for risk of prostate cancer during follow-up through 2014, comparing parenchyma volume tertiles. Results: There was a positive association between pineal parenchyma volume and urinary levels of melatonin. During follow-up, 135 men were diagnosed with prostate cancer, 30 of which were advanced prostate cancer. Men with volumes in the upper tertile had no statistically significant increased risk of prostate cancer compared to men with volumes in the lowest tertile (HR: 1.0, 95% CI: 0.7, 1.5), and men with volumes in the middle tertile had only a borderline statistically significant decreased risk of prostate cancer compared to men with volumes in the lowest tertile (HR: 0.7, 95% CI: 0.4, 1.0). Compared to men without pineal cysts, there was a borderline statistically significant association between men with pineal cysts and decreased risk of prostate cancer (HR: 0.7, 95% CI: 0.5, 1.0). Compared to men without pineal calcifications, there was no statistically significant association between men with pineal calcifications and increased risk of prostate cancer (HR: 1.1, 95% CI: 0.7, 1.6). Conclusions: Pineal parenchyma volume was associated with melatonin levels, but there was no statistically significant association between parenchyma volume alone and prostate cancer risk. Further studies are needed to investigate the relationship between pineal parenchyma volume, presence of calcifications and cysts, melatonin, and prostate cancer. Citation Format: Latifa A. Bazzi, Lara Sigurdardottir, Sigurdur Sigurdsson, Unnur Valdimarsdottir, Johanna Torfadottir, Thor Aspelund, Lenore Launer, Tamara Harris, Vilmundur Gudnason, Lorelei Mucci, Sarah Markt. Pineal gland volume and risk of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5045.

Introduction: In addition to average blood pressure (BP) values, BP variability has been suggested to be associated with lower cognitive function. It is unclear how long-term BP variability throughout young adulthood is associated with cerebrovascular structure (e.g., hippocampus) and function in midlife. Methods: Using data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, which recruited healthy young adults ages 18 to 30 years (mean age 25 years) in 1985-1986, we assessed average BP over visits and visit-to visit BP variability (average real variability [ARV], defined as the absolute differences of BP between successive BP measurements) during 25-year follow-up (8 visits). Normal brain volume, abnormal brain volume, brain integrity assessed by fractional anisotropy, and cerebral blood flow were calculated by 3-Tesla MRI at the Year 25 follow-up (n=557, 52.2 % women, and 34.5 % African Americans). Results: For the 557 participants, mean ARV of SBP was 7.8±3.1 mm Hg. Higher ARV of SBP was associated with lower normal total brain volume, gray matter, and hippocampus after adjustment for covariates including intracranial volume and average BP during follow-up (Table). Higher average SBP during follow-up was associated with higher abnormal brain volume and lower integrity in the whole brain and the white matter, and lower blood flow in the hippocampus. Conclusions: Long-term visit-to-visit BP variability for 25 years beginning in young adulthood was associated with midlife cerebrovascular structural and functional alterations, independent of average BP during follow-up. Focusing not only on BP values alone but also on visit-to-visit BPV may be important to identify younger adults who may be at risk for developing lower cognitive function later.

Background: Subclinical liver disease may be a risk factor for cognitive impairment. Obesity is related to metabolic processes that affect brain structures underlying cognitive decline. Nonalcoholic fatty liver disease (NAFLD) is an obesity-related condition with high cardiovascular disease (CVD) morbidity. In a population-based cross-sectional sample of black and white adults free from prevalent liver or cerebrovascular disease, we tested the hypothesis that NAFLD is associated with early measures of brain health independent of BMI or visceral adipose tissue (VAT). Methods: Participants from the Coronary Artery Risk Development in Young Adults study (Y25 exam; age 43-55 years) with concurrent CT quantification of liver fat and brain magnetic resonance (MR) images were included. NAFLD was defined after exclusion of other causes of liver fat. 3T brain MR images provided estimates of normal tissue volume (NTV) and total (CBF-tot) and gray matter (CBF-GM) cerebral blood flow. NTV was adjusted for intracranial volume (ICV, brain plus cerebral spinal fluid). CBF was adjusted for total tissue volume (TTV, total brain tissue perfused). Linear regression models tested associations. Results: Mean liver attenuation (LA) was 56.9 HU (range 16.6-81.3). NAFLD prevalence was 11%. Lower LA (higher liver fat) was associated with reduced NTV, CBF-tot and CBF-GM after adjusting for ICV, demographics, and health behaviors (p Conclusion: Increased liver fat and CT-defined NAFLD are negatively associated with early brain health, reflected in MR measures of structure and perfusion. BMI and VAT attenuate the relationship providing insight into the potential role of obesity in brain health and disease.

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.

To study white matter lesions (WMLs) and 5-year cognitive decline in elderly Japanese-American men.Longitudinal cohort study.Population-based study in Honolulu, Hawaii.Japanese-American men aged 74 to 95 from the Honolulu-Asia Aging Study (HAAS) who were free of prevalent dementia, underwent a protocol brain MRI scan at the fifth HAAS examination (1994-1996), and returned for cognitive testing 5 years later (N=267).WMLs were dichotomized as present (grade 3-9, 38.2%) or absent (grade 1-2, 61.8%). Cognitive function was measured using the Cognitive Abilities Screening Instrument (CASI), and 5-year cognitive decline was defined as a drop in CASI score of 12 points or more (1 standard deviation).Men with WMLs on MRI at baseline were significantly more likely to experience cognitive decline at 5 years than those without (22.4% vs 34.4%, P=.03). Using multiple logistic regression, adjusting for age, education, apolipoprotein (Apo)E4 allele, large or small infarcts on MRI, baseline CASI score, and hypertension, those with WMLs were significantly more likely to develop 5-year cognitive decline (odds ratio=2.00, 95% confidence interval=1.10-3.65, P=.02). This association was stronger in men who were cognitively intact and free of the ApoE4 genotype and clinical stroke at baseline.Presence of WMLs on MRI was significantly associated with higher odds of 5-year cognitive decline in older Japanese-American men. Presence of WMLs may help identify people at risk for developing dementia, who may benefit from early intervention.

Objective To estimate whether migraine in mid-life is associated with mortality from cardiovascular disease, other causes, and all causes. Design Population based cohort study. Setting Reykjavik, Iceland. Participants 18 725 men and women, born 1907-35 and living in Reykjavik and adjacent communities. Main outcome measures Mortality from cardiovascular disease, non-cardiovascular disease, and all causes. Questionnaires and clinical measures were obtained in mid-life (mean age 53, range 33-81) in the Reykjavik Study (1967-91). Headache was classified as migraine without aura, migraine with aura, or non-migraine headache. Median follow-up was 25.9 years (0.1-40.2 years), with 470 990 person years and 10 358 deaths: 4323 from cardiovascular disease and 6035 from other causes. We used Cox regression to estimate risk of death in those with migraine compared with others, after adjusting for baseline risk factors. Results People with migraine with aura were at increased risk of all cause mortality (adjusted (for sex and multivariables) hazard ratio 1.21, 95% confidence interval 1.12 to 1.30) and mortality from cardiovascular disease (1.27, 1.13 to 1.43) compared with people with no headache, while those with migraine without aura and non-migraine headache were not. Further examination of mortality from cardiovascular disease shows that people with migraine with aura were at increased risk of mortality from coronary heart disease (1.28, 1.11 to 1.49) and stroke (1.40, 1.10 to 1.78). Women with migraine with aura were also at increased risk of mortality from non-cardiovascular disease (1.19, 1.06 to 1.35). Conclusions Migraine with aura is an independent risk factor for cardiovascular and all cause mortality in men and women. The risk of mortality from coronary heart disease and stroke mortality is modestly increased in people with migraine, particularly those with aura.

The objective of this study is to investigate the relationship between lowlevels of human serum albumin (HSA) and the incidence of coronary heart disease (CHD) in a cohort of elderly Japanese-American men. Using data from the Honolulu Heart Program's fourth examination (1991-1993), HSA levels of 998 Japanese American men aged 71-93 years was compared with plasma levels of fibrinogen, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, diastolic BP, BMI, and fasting blood glucose. HSA was significantly negatively associated with age and fibrinogen, and significantly positively associated with total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, diastolic BP, BMI and fasting blood glucose. After adjusting for age, tertiles of HSA were significantly positively associated with total cholesterol, HDL cholesterol and triglycerides, and significantly negatively associated with fibrinogen. Using multivariate stepwise regression, significant correlations were seen between HSA and fibrinogen, cholesterol, age, HDL cholesterol and triglycerides, and a borderline correlation was seen with systolic blood pressure. However, the model R-square for all variables was only 0.10. In conclusion, HSA levels are significantly associated with several traditional cardiovascular risk factors, particularly serum lipid levels.

A full list of authors and affiliations appears on page 5 of this article., The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10-14), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10-11; ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10-11). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population., peer-reviewed

To evaluate the association between insulin resistance (IR) and executive dysfunction in a large, population-based study of older persons without diabetes mellitus (DM) or dementia.Cross-sectional study.Outpatient clinic in Greve in Chianti and Bagno a Ripoli, Italy.A total of 597 subjects aged 65 to 93 without DM or dementia.Anthropometric measurements; plasma fasting levels of glucose, insulin, cholesterol (total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol), and insulin-like growth factor-1 (IGF-1); homeostasis model assessment (HOMA) to estimate degree of IR; Trail Making Test (TMT) A; TMT-B; TMT-B minus TMT-A (DIFF B-A); and Mini-Mental State Examination (MMSE).IR (HOMA) was associated with longer TMT-B (correlation coefficient (r)=0.11; P=.006) and DIFF B-A times (r=0.10; P=.022). Subjects in the upper tertile of IR were older and had longer TMT-B and DIFF B-A than participants in the lowest tertile. After adjusting for age, sex, and years of formal education, IR was significantly correlated with TMT-A, TMT-B, and DIFF B-A. After adjusting for age, sex, education, body mass index, waist:hip girth ratio, HDL-C, triglycerides, IGF-1, hypertension, drug intake, and physical activity, the results did not significantly change. After introducing MMSE score into the model, IR continued to be an independent determinant of TMT-A (beta=11.005; P=.021), TMT-B (beta=28.379; P.001), and DIFF B-A (beta=17.374; P=.011).IR is independently associated with frontal cortex function evidenced by poor TMT times in older persons without DM or dementia.

To investigate whether total and/or regional adiposity measured by anthropometry and radiographic studies influences cognitive decline in older adults and whether this association is explained by hormones and inflammatory factors known to be secreted by adipose tissue.Prospective cohort study.Two clinical centers.Three thousand fifty-four elderly individuals enrolled in the Health ABC Study. Adiposity measures included body mass index, waist circumference, sagittal diameter, total fat mass by dual-energy x-ray absorptiometry, and subcutaneous and visceral fat by abdominal computed tomography. We examined the association between baseline body fat measures and change in Modified Mini-Mental State Examination (3MS) score, sequentially adjusting for confounding and mediating variables, including comorbid diseases, adipocytokines, and sex hormones. Main Outcome Measure Scores from the 3MS, administered at the first, third, fifth, and eighth annual clinical examinations.All baseline adiposity measures varied significantly by sex. In mixed-effects models, the association between total and regional adiposity and change in 3MS score varied significantly by sex, with the highest adiposity tertile being associated with greater cognitive declines in men (for each adiposity measure, P.05) but not in women (for interaction, P.05). Total fat mass was significantly associated with greater change in 3MS scores among men (lowest tertile, -1.6; middle tertile, -2.2; highest tertile, -2.7; P = .006), even after adjusting for mediators.Higher levels of all adiposity measures were associated with worsening cognitive function in men after controlling for metabolic disorders, adipocytokines, and sex hormone levels. Conversely, there was no association between adiposity and cognitive change in women.