Evaluating Cognitive Impairment in a Large Health Care System: The Cognition in Primary Care Program.

Background: The prevalence of Alzheimer's disease and related disorders (ADRD) is rising. Primary care providers (PCPs) will increasingly be required to play a role in its detection but lack the training to do so. Objective: To develop a model for cognitive evaluation which is feasible in primary care and evaluate its implementation in a large health system. Methods: The Cognition in Primary Care Program consists of web-based training together with integrated tools built into the electronic record. We implemented the program among PCPs at 14 clinics in a large health system. We (1) surveyed PCPs to assess the impact of training on their confidence to evaluate cognition, (2) measured the number of cognitive assessments they performed, and (3) tracked the number of patients diagnosed with mild cognitive impairment (MCI). Results: Thirty-nine PCPs completed the training which covered how to evaluate cognition. Survey response rate from those PCPs was 74%. Six months after the end of the training, they reported confidence in assessing cognition (mean 4.6 on 5-point scale). Cognitive assessments documented in the health record increased from 0.8 per month before the training to 2.5 in the six months after the training. Patients who were newly diagnosed with MCI increased from 4.2 per month before the training to 6.0 per month in the six months after the training. Conclusions: This model for cognitive evaluation in a large health system was shown to increase cognitive testing and increase diagnoses of MCI. Such improvements are essential for the timely detection of ADRD.

Validation of the shortened version of the Canine Behavioral Assessment and Research Questionnaire (C-BARQ) using participants from the Dog Aging Project.

The Canine Behavioral Assessment and Research Questionnaire (C-BARQ) is a 100-item owner-completed survey instrument used for assessing behavior and temperament of companion dogs. The shortened version of the C-BARQ (C-BARQ(S)) consists of 42 items of the long C-BARQ. We aimed to validate the shortened C-BARQ(S) by comparing it with the long questionnaire in the same human-dog pair. We examined data from a nationwide cohort of companion dogs enrolled in the large-scale longitudinal Dog Aging Project (DAP) study. Among 435 participating owners who completed both the long and shortened versions of the C-BARQ within 60 days of each other, agreement between individual questions of the long and shortened C-BARQ using an unweighted kappa statistic and percent agreement was examined. Associations between the two questionnaires for mean behavior and temperament domain scores and mean miscellaneous category scores were assessed using Pearson correlation coefficients. Of 435 dogs in the study, the mean (SD) age was 7.3 (4.3) years and 216 (50%) were female. Kappa values between the long and shortened C-BARQ for individual questions within the 14 behavior and temperament domains and a miscellaneous category ranged from fair to moderate (0.23 to 0.40 for 21 items and 0.41 to 0.58 for 26 items, respectively). Pearson correlation coefficients above 0.60 between both questionnaires for 12 of the 14 mean behavior and temperament domain scores and a category of miscellaneous items were observed. Kappa values for individual questions between the long and shortened C-BARQ ranged from fair to moderate and correlations between mean domain scores ranged from moderate to strong.

Subclinical vascular composites predict clinical cardiovascular disease, stroke, and dementia: The Multi-Ethnic Study of Atherosclerosis (MESA).

BACKGROUND AND AIMS: Subclinical cardiovascular disease (CVD) measures may reflect biological pathways that contribute to increased risk for coronary heart disease (CHD) events, stroke, and dementia beyond conventional risk scores. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) followed 6814 participants (45-84 years of age) from baseline in 2000-2002 to 2018 over 6 clinical examinations and annual follow-up interviews. MESA baseline subclinical CVD procedures included: seated and supineblood pressure, coronary calcium scan, radial artery tonometry, and carotid ultrasound. Baseline subclinical CVD measures were transformed into z-scores before factor analysis to derive composite factor scores. Time to clinical event for all-cause CVD, CHD, stroke and ICD code-based dementia events were modeled using Cox proportional hazards models reported as area under the curve (AUC) with 95% Confidence Intervals (95%CI) at 10 and 15 years of follow-up. All models included all factor scores together, and adjustment for conventional risk scores for global CVD, stroke, and dementia. RESULTS: After factor selection, 24 subclinical measures aggregated into four distinct factors representing: blood pressure, atherosclerosis, arteriosclerosis, and cardiac factors. Each factor significantly predicted time to CVD events and dementia at 10 and 15 years independent of each other and conventional risk scores. Subclinical vascular composites of atherosclerosis and arteriosclerosis best predicted time to clinical events of CVD, CHD, stroke, and dementia. These results were consistent across sex and racial and ethnic groups. CONCLUSIONS: Subclinical vascular composites of atherosclerosis and arteriosclerosis may be useful biomarkers to inform the vascular pathways contributing to events of CVD, CHD, stroke, and dementia.

Estimates of Incidence and Predictors of Fatiguing Illness after SARS-CoV-2 Infection.

This study aimed to estimate the incidence rates of post-COVID-19 fatigue and chronic fatigue and to quantify the additional incident fatigue caused by COVID-19. We analyzed electronic health records data of 4,589 patients with confirmed COVID-19 during February 2020-February 2021 who were followed for a median of 11.4 (interquartile range 7.8-15.5) months and compared them to data from 9,022 propensity score-matched non-COVID-19 controls. Among COVID-19 patients (15% hospitalized for acute COVID-19), the incidence rate of fatigue was 10.2/100 person-years and the rate of chronic fatigue was 1.8/100 person-years. Compared with non-COVID-19 controls, the hazard ratios were 1.68 (95% CI 1.48-1.92) for fatigue and 4.32 (95% CI 2.90-6.43) for chronic fatigue. The observed association between COVID-19 and the significant increase in the incidence of fatigue and chronic fatigue reinforces the need for public health actions to prevent SARS-CoV-2 infections.

The impact of falls on activities of daily living in older adults: A retrospective cohort analysis.

BACKGROUND: Falls contribute to impairments in activities of daily living (ADLs), resulting in significant declines in the quality of life, safety, and functioning of older adults. Understanding the magnitude and duration of the effect of falls on ADLs, as well as identifying the characteristics of older adults more likely to have post-fall ADL impairment is critical to inform fall prevention and post-fall intervention. The purpose of this study is to 1) Quantify the association between falls and post-fall ADL impairment and 2) Model trajectories of ADL impairment pre- and post-fall to estimate the long-term impact of falls and identify characteristics of older adults most likely to have impairment. METHOD: Study participants were from the Ginkgo Evaluation of Memory Study, a randomized controlled trial in older adults (age 75+) in the United States. Self-reported incident falls and ADL scores were ascertained every 6 months over a 7-year study period. We used Cox proportional hazards analyses (n = 2091) to quantify the association between falls and ADL impairment and latent class trajectory modeling (n = 748) to visualize trajectories of ADL impairment pre-and post-fall. RESULTS: Falls reported in the previous 6 months were associated with impairment in ADLs (HR: 1.42; 95% CI 1.32, 1.52) in fully adjusted models. Based on trajectory modeling (n = 748), 19% (n = 139) of participants had increased, persistent ADL impairment after falling. Participants who were female, lived in a neighborhood with higher deprivation, or experienced polypharmacy were more likely to have ADL impairment post-fall. CONCLUSIONS: Falls are associated with increased ADL impairment, and this impairment can persist over time. It is crucial that all older adults, and particularly those at higher risk of post-fall ADL impairment have access to comprehensive fall risk assessment and evidence-based fall prevention interventions, to help mitigate the negative impacts on ADL function.

Association analysis of mitochondrial DNA heteroplasmic variants: methods and application.

We rigorously assessed a comprehensive association testing framework for heteroplasmy, employing both simulated and real-world data. This framework employed a variant allele fraction (VAF) threshold and harnessed multiple gene-based tests for robust identification and association testing of heteroplasmy. Our simulation studies demonstrated that gene-based tests maintained an appropriate type I error rate at α=0.001. Notably, when 5% or more heteroplasmic variants within a target region were linked to an outcome, burden-extension tests (including the adaptive burden test, variable threshold burden test, and z-score weighting burden test) outperformed the sequence kernel association test (SKAT) and the original burden test. Applying this framework, we conducted association analyses on whole-blood derived heteroplasmy in 17,507 individuals of African and European ancestries (31% of African Ancestry, mean age of 62, with 58% women) with whole genome sequencing data. We performed both cohort- and ancestry-specific association analyses, followed by meta-analysis on both pooled samples and within each ancestry group. Our results suggest that mtDNA-encoded genes/regions are likely to exhibit varying rates in somatic aging, with the notably strong associations observed between heteroplasmy in the RNR1 and RNR2 genes (p<0.001) and advance aging by the Original Burden test. In contrast, SKAT identified significant associations (p<0.001) between diabetes and the aggregated effects of heteroplasmy in several protein-coding genes. Further research is warranted to validate these findings. In summary, our proposed statistical framework represents a valuable tool for facilitating association testing of heteroplasmy with disease traits in large human populations.

Association of fractal dimension and other retinal vascular network parameters with cognitive performance and neuroimaging biomarkers: The Multi-Ethnic Study of Atherosclerosis (MESA).

INTRODUCTION: Retinal vascular network changes may reflect the integrity of the cerebral microcirculation, and may be associated with cognitive impairment. METHODS: Associations of retinal vascular measures with cognitive function and MRI biomarkers were examined amongst Multi-Ethnic Study of Atherosclerosis (MESA) participants in North Carolina who had gradable retinal photographs at Exams 2 (2002 to 2004, n = 313) and 5 (2010 to 2012, n = 306), and detailed cognitive testing and MRI at Exam 6 (2016 to 2018). RESULTS: After adjustment for covariates and multiple comparisons, greater arteriolar fractal dimension (FD) at Exam 2 was associated with less isotropic free water of gray matter regions (ß = -0.0005, SE = 0.0024, p = 0.01) at Exam 6, while greater arteriolar FD at Exam 5 was associated with greater gray matter cortical volume (in mm3 , ß = 5458, SE = 20.17, p = 0.04) at Exam 6. CONCLUSION: Greater arteriolar FD, reflecting greater complexity of the branching pattern of the retinal arteries, is associated with MRI biomarkers indicative of less neuroinflammation and neurodegeneration.

Evaluating the Sick Quitting Hypothesis for Frailty Status and Reducing Alcohol Use Among People With HIV in a Longitudinal Clinical Cohort Study.

ABSTRACT: "Sick quitting," a phenomenon describing reductions in alcohol consumption following poor health, may explain observations that alcohol appears protective for frailty risk. We examined associations between frailty and reductions in drinking frequency among people with HIV (PWH). At six Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) sites between January 2012 and August 2021, we assessed whether frailty, measured through validated modified frailty phenotype, precedes reductions in drinking frequency. We associated time-updated frailty with quitting and reducing frequency of any drinking and heavy episodic drinking (HED), adjusted for demographic and clinical characteristics in Cox models. Among 5,654 PWH reporting drinking, 60% reported >monthly drinking and 18% reported ≥monthly HED. Over an average of 5.4 years, frail PWH had greater probabilities of quitting (HR: 1.56, 95% confidence interval [95% CI] [1.13-2.15]) and reducing (HR: 1.35, 95% CI [1.13-1.62]) drinking frequency, as well as reducing HED frequency (HR: 1.58, 95% CI [1.20-2.09]) versus robust PWH. Sick quitting likely confounds the association between alcohol use and frailty risk, requiring investigation for control.

Identifying patterns of reported findings on long-term cardiac complications of COVID-19: a systematic review and meta-analysis.

INTRODUCTION: Prior reviews synthesized findings of studies on long-term cardiac complications of COVID-19. However, the reporting and methodological quality of these studies has not been systematically evaluated. Here, we conducted a systematic review and meta-analysis on long-term cardiac complications of COVID-19 and examined patterns of reported findings by study quality and characteristics. METHODS: We searched for studies examining long-term cardiac complications of COVID-19 that persisted for 4 weeks and over. A customized Newcastle-Ottawa scale (NOS) was used to evaluate the quality of included studies. Meta-analysis was performed to generate prevalence estimates of long-term cardiac complications across studies. Stratified analyses were further conducted to examine the prevalence of each complication by study quality and characteristics. The GRADE approach was used to determine the level of evidence for complications included in the meta-analysis. RESULTS: A total number of 150 studies describing 57 long-term cardiac complications were included in this review, and 137 studies reporting 17 complications were included in the meta-analysis. Only 25.3% (n = 38) of studies were of high quality based on the NOS quality assessment. Chest pain and arrhythmia were the most widely examined long-term complications. When disregarding study quality and characteristics, summary prevalence estimates for chest and arrhythmia were 9.79% (95% CI 7.24-13.11) and 8.22% (95% CI 6.46-10.40), respectively. However, stratified analyses showed that studies with low-quality scores, small sample sizes, unsystematic sampling methods, and cross-sectional design were more likely to report a higher prevalence of complications. For example, the prevalence of chest pain was 22.17% (95% CI 14.40-32.55), 11.08% (95% CI 8.65-14.09), and 3.89% (95% CI 2.49-6.03) in studies of low, medium, and high quality, respectively. Similar patterns were observed for arrhythmia and other less examined long-term cardiac complications. CONCLUSION: There is a wide spectrum of long-term cardiac complications of COVID-19. Reported findings from previous studies are strongly related to study quality, sample sizes, sampling methods, and designs, underscoring the need for high-quality epidemiologic studies to characterize these complications and understand their etiology.

Identification of circulating proteins associated with general cognitive function among middle-aged and older adults.

Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p < 4.9E-5, n up to 7289). Of these, 45 were replicated using SomaScan data, and three were replicated using Olink data at Bonferroni-corrected significance. Enrichment analysis linked the proteins associated with general cognitive function to cell signaling pathways and synapse architecture. Mendelian randomization analysis implicated higher levels of NECTIN2, a protein mediating viral entry into neuronal cells, with higher Alzheimer's disease (AD) risk (p = 2.5E-26). Levels of 14 other protein measures were implicated as consequences of AD susceptibility (p < 2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets.

Association Between Whole Blood-Derived Mitochondrial DNA Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk.

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). P<0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1-SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04-1.12; P<0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (ß=0.091; P=0.11) or in the reverse direction (ß=-0.012; P=0.076). Additional bidirectional Mendelian randomization analyses revealed that low-density lipoprotein cholesterol had a causal effect on mtDNA CN (ß=-0.084; P<0.001), but the reverse direction was not significant (P=0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low-density lipoprotein cholesterol level (P=0.52), whereas there was a strong direct causal effect of higher low-density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (ß=-0.092; P<0.001). Conclusions Our findings indicate that high low-density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.

Developing a cognitive assessment toolkit for primary care: qualitative assessment of providers' needs and perceptions of usability in clinical practice.

BACKGROUND: Burden of dementia is expected to substantially increase. Early dementia is underdiagnosed in primary care. Given the benefits of active management of dementia, earlier detection in primary care is imperative. The aim of this study was to understand primary care provider (PCP) perceptions of implementing a cognitive assessment toolkit in primary care. METHODS: PCPs in a large health system in the US were recruited to a qualitative study utilizing semi-structured interviews. Interviews captured provider perceptions of options for implementing a cognitive assessment toolkit derived from the Gerontological Society of America (GSA) KAER (Kickstart, Assess, Evaluate, Refer) toolkit, including a workflow and adapted clinical tools. A content analysis approach distinguished themes and exemplary quotes. RESULTS: Ten PCPs were interviewed. They found the toolkit useful, felt the term Kickstart was not specific to dementia care, and stressed that addressing cognitive evaluation would need to be easy to implement in a clinical workflow. Finally, providers knew many resources for referral but were unsure how to help patients navigate options. CONCLUSIONS: Providers stressed simplicity, ease, and efficiency for implementation of a cognitive assessment toolkit. Incorporating these findings into the development of clinical tools and workflows may increase cognitive evaluations conducted by PCPs.

Global implementation research capacity building to address cardiovascular disease: An assessment of efforts in eight countries.

Cardiovascular diseases are the leading causes of morbidity and mortality worldwide, but implementation of evidence-based interventions for risk factors such as hypertension is lacking, particularly in low and middle income countries (LMICs). Building implementation research capacity in LMICs is required to overcome this gap. Members of the Global Research on Implementation and Translation Science (GRIT) Consortium have been collaborating in recent years to establish a research and training infrastructure in dissemination and implementation to improve hypertension care. GRIT includes projects in Ghana, Guatemala, India, Kenya, Malawi, Nepal, Rwanda, and Vietnam. We collected data from each site on capacity building activities using the Potter and Brough (2004) model, mapping formal and informal activities to develop (a) structures, systems and roles, (b) staff and infrastructure, (c) skills, and (d) tools. We captured information about sites' needs assessments and metrics plus program adaptations due to the COVID-19 pandemic. All sites reported capacity building activities in each layer of the Capacity Pyramid, with the largest number of activities in the Skills and Tools categories, the more technical and easier to implement categories. All sites included formal and informal training to build Skills. All sites included a baseline needs assessment to guide capacity building activities or assess context and inform intervention design. Sites implementing evidence-based hypertension interventions used common implementation science frameworks to evaluate implementation outcomes. Although the COVID-19 pandemic affected timelines and in-person events, all projects were able to pivot and carry out planned activities. Although variability in the activities and methods used existed, GRIT programs used needs assessments to guide locally appropriate design and implementation of capacity building activities. COVID-19 related changes were necessary, but strong collaborations and relationships with health ministries were maintained. The GRIT Consortium is a model for planning capacity building in LMICs.

A review of frailty instruments in human medicine and proposal of a frailty instrument for dogs.

Over the last few decades, frailty has become a pillar of research and clinical assessment in human gerontology. This complex syndrome, characterized by loss of physiologic reserves leading to decreased resilience to stressors, is of critical importance because it predicts higher risks of poor health outcomes, including mortality. Thus, identifying frailty among the elderly human population has become a key focus of gerontology. This narrative review presents current scientific literature on frailty in both humans and animals. The authors discuss the need for an accessible frailty instrument for companion dogs suitable for general use in veterinary medicine and the advances that would be facilitated by this instrument. A phenotypic frailty instrument for companion dogs, utilizing components that are easily collected by owners, or in the general practice setting, is proposed. The authors elaborate on the domains (physical condition, physical activity, mobility, strength, cognitive task performance, and social behavior), factors that will be included, and the data from the Dog Aging Project that inform each domain.

An Examination of the Joint Effect of the Social Environment and Air Pollution on Dementia Among US Older Adults.

Evidence suggests exposure to air pollution increases the risk of dementia. Cognitively stimulating activities and social interactions, made available through the social environment, may slow cognitive decline. We examined whether the social environment buffers the adverse effect of air pollution on dementia in a cohort of older adults. Methods: This study draws from the Ginkgo Evaluation of Memory Study. Participants aged 75 years and older were enrolled between 2000 and 2002 and evaluated for dementia semi-annually through 2008. Long-term exposure to particulate matter and nitrogen dioxide was assigned from spatial and spatiotemporal models. Census tract-level measures of the social environment and individual measures of social activity were used as measures of the social environment. We generated Cox proportional hazard models with census tract as a random effect and adjusted for demographic and study visit characteristics. Relative excess risk due to interaction was estimated as a qualitative measure of additive interaction. Results: This study included 2,564 individuals. We observed associations between increased risk of dementia and fine particulate matter (µg/m3), coarse particulate matter (µg/m3), and nitrogen dioxide (ppb); HRs per 5 unit increase were 1.55 (1.01, 2.18), 1.31 (1.07, 1.60), and 1.18 (1.02, 1.37), respectively. We found no evidence of additive interaction between air pollution and the neighborhood social environment. Conclusions: We found no consistent evidence to suggest a synergistic effect between exposure to air pollution and measures of the social environment. Given the many qualities of the social environment that may reduce dementia pathology, further examination is encouraged.

Tobacco Smoking and Pack-Years Are Associated With Frailty Among People With HIV.

BACKGROUND: Tobacco smoking increases frailty risk among the general population and is common among people with HIV (PWH) who experience higher rates of frailty at younger ages than the general population. METHODS: We identified 8608 PWH across 6 Centers for AIDS Research Network of Integrated Clinical Systems sites who completed ≥2 patient-reported outcome assessments, including a frailty phenotype measuring unintentional weight loss, poor mobility, fatigue, and inactivity, and scored 0-4. Smoking was measured as baseline pack-years and time-updated never, former, or current use with cigarettes/day. We used Cox models to associate smoking with risk of incident frailty (score ≥3) and deterioration (frailty score increase by ≥2 points), adjusted for demographics, antiretroviral medication, and time-updated CD4 count. RESULTS: The mean follow-up of PWH was 5.3 years (median: 5.0), the mean age at baseline was 45 years, 15% were female, and 52% were non-White. At baseline, 60% reported current or former smoking. Current (HR: 1.79; 95% confidence interval: 1.54 to 2.08) and former (HR: 1.31; 95% confidence interval: 1.12 to 1.53) smoking were associated with higher incident frailty risk, as were higher pack-years. Current smoking (among younger PWH) and pack-years, but not former smoking, were associated with higher risk of deterioration. CONCLUSIONS: Among PWH, smoking status and duration are associated with incident and worsening frailty.

Change in gait speed and fall risk among community-dwelling older adults with and without mild cognitive impairment: a retrospective cohort analysis.

BACKGROUND: Although slow gait speed is an established risk factor for falls, few studies have evaluated change in gait speed as a predictor of falls or considered variability in effects by cognitive status. Change in gait speed may be a more useful metric because of its potential to identify decline in function. In addition, older adults with mild cognitive impairment are at an elevated risk of falls. The purpose of this research was to quantify the association between 12-month change in gait speed and falls in the subsequent 6 months among older adults with and without mild cognitive impairment. METHODS: Falls were self-reported every six months, and gait speed was ascertained annually among 2,776 participants in the Ginkgo Evaluation of Memory Study (2000-2008). Adjusted Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for fall risk relative to a 12-month change in gait speed. RESULTS: Slowing gait speed over 12 months was associated with increased risk of one or more falls (HR:1.13; 95% CI: 1.02 to 1.25) and multiple falls (HR:1.44; 95% CI: 1.18 to 1.75). Quickening gait speed was not associated with risk of one or more falls (HR 0.97; 95% CI: 0.87 to 1.08) or multiple falls (HR 1.04; 95% CI: 0.84 to 1.28), relative to those with a less than 0.10 m/s change in gait speed. Associations did not vary by cognitive status (pinteraction = 0.95 all falls, 0.25 multiple falls). CONCLUSIONS: Decline in gait speed over 12 months is associated with an increased likelihood of falls among community-dwelling older adults, regardless of cognitive status. Routine checks of gait speed at outpatient visits may be warranted as a means to focus fall risk reduction efforts.

Subclinical Vascular Composites Predict Clinical Cardiovascular Disease, Stroke, and Dementia: The Multi-Ethnic Study of Atherosclerosis (MESA).

Background: Subclinical cardiovascular disease (CVD) measures may reflect biological pathways that contribute to increased risk for coronary heart disease (CHD) events, stroke, and dementia beyond conventional risk scores. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) followed 6,814 participants (45-84 years of age) from baseline in 2000-2002 to 2018 over 6 clinical examinations and annual follow-up interviews. MESA baseline subclinical CVD procedures included: seated and supine blood pressure, coronary calcium scan, radial artery tonometry, and carotid ultrasound. Baseline subclinical CVD measures were transformed into z-scores before factor analysis to derive composite factor scores. Time to clinical event for all CVD, CHD, stroke and ICD code-based dementia events were modeled using Cox proportional hazards models reported as area under the curve (AUC) with 95% Confidence Intervals (95%CI) at 10 and 15 years of follow-up. All models included all factor scores together and adjustment for conventional risk scores for global CVD, stroke, and dementia. Results: After factor selection, 24 subclinical measures aggregated into four distinct factors representing: blood pressure, arteriosclerosis, atherosclerosis, and cardiac factors. Each factor significantly predicted time to CVD events and dementia at 10 and 15 years independent of each other and conventional risk scores. Subclinical vascular composites of arteriosclerosis and atherosclerosis best predicted time to clinical events of CVD, CHD, stroke, and dementia. These results were consistent across sex and racial and ethnic groups. Conclusions: Subclinical vascular composites of arteriosclerosis and atherosclerosis may be useful biomarkers to inform the vascular pathways contributing to events of CVD, CHD, stroke, and dementia.

Association of Mitochondrial DNA Copy Number With Brain MRI Markers and Cognitive Function: A Meta-analysis of Community-Based Cohorts.

BACKGROUND AND OBJECTIVES: Previous studies suggest that lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer disease (AD) and AD-related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults. METHODS: We included dementia-free participants from 9 diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5-20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs ≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed mendelian randomization (MR) analyses to assess causality. RESULTS: We included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (ß = 0.04; 95% CI 0.02-0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition. DISCUSSION: Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the United States. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community.

Air pollution and plasma amyloid beta in a cohort of older adults: Evidence from the Ginkgo Evaluation of Memory study.

Air pollution has been linked to Alzheimer's disease and related dementias (ADRD), but the mechanisms connecting air pollution to ADRD have not been firmly established. Air pollution may cause oxidative stress and neuroinflammation and contribute to the deposition of amyloid beta (Aß) in the brain. We examined the association between fine particulate matter<2.5 µm in diameter (PM2.5), particulate matter<10 µm in diameter (PM10), nitrogen dioxide (NO2), and plasma based measures of Aß1-40, Aß1-42 and Aß1-42/Aß1-40 using data from 3044 dementia-free participants of the Ginkgo Evaluation of Memory Study (GEMS). Air pollution exposures were estimated at residential addresses that incorporated address histories dating back to 1980, resulting in one-, five-, 10- and 20- year exposure averages. Aß was measured at baseline (2000-2002) and then again at the end of the study (2007-2008) allowing for linear regression models to assess cross-sectional associations and linear random effects models to evaluate repeated measures. After adjustment for socio-demographic and behavioral covariates, we found small positive associations between each air pollutant and Aß1-40 but no association with Aß1-42 or the ratio measures in cross sectional analysis. In repeat measures analysis, we found larger positive associations between each air pollutant and all three outcomes. We observed a 4.43% (95% CI 3.26%, 5.60%) higher Aß1-40 level, 9.73% (6.20%, 13.38%) higher Aß1-42 and 1.57% (95% CI: 0.94%, 2.20%) higher Aß1-42/Aß1-40 ratio associated with a 2 µg/m3 higher 20-year average PM2.5. Associations with other air pollutants were similar. Our study contributes to the broader evidence base on air pollution and ADRD biomarkers by evaluating longer air pollution exposure averaging periods to better mimic disease progression and provides a modifiable target for ADRD prevention.