National Estimates of Short- and Longer-Term Hospital Readmissions After Major Surgery Among Community-Living Older Adults.

Importance: Nationally representative estimates of hospital readmissions within 30 and 180 days after major surgery, including both fee-for-service and Medicare Advantage beneficiaries, are lacking. Objectives: To provide population-based estimates of hospital readmission within 30 and 180 days after major surgery in community-living older US residents and examine whether these estimates differ according to key demographic, surgical, and geriatric characteristics. Design, Setting, and Participants: A prospective longitudinal cohort study of National Health and Aging Trends Study data (calendar years 2011-2018), linked to records from the Centers for Medicare & Medicaid Services (CMS). Data analysis was conducted from April to August 2023. Participants included community-living US residents of the contiguous US aged 65 years or older who had at least 1 major surgery from 2011 to 2018. Data analysis was conducted from April 10 to August 28, 2023. Main Outcomes and Measures: Major operations and hospital readmissions within 30 and 180 days were identified through data linkages with CMS files that included both fee-for-service and Medicare Advantage beneficiaries. Data on frailty and dementia were obtained from the annual National Health and Aging Trends Study assessments. Results: A total of 1780 major operations (representing 9 556 171 survey-weighted operations nationally) were identified from 1477 community-living participants; mean (SD) age was 79.5 (7.0) years, with 56% being female. The weighted rates of hospital readmission were 11.6% (95% CI, 9.8%-13.6%) for 30 days and 27.6% (95% CI, 24.7%-30.7%) for 180 days. The highest readmission rates within 180 days were observed among participants aged 90 years or older (36.8%; 95% CI, 28.3%-46.3%), those undergoing vascular surgery (45.8%; 95% CI, 37.7%-54.1%), and persons with frailty (36.9%; 95% CI, 30.8%-43.5%) or probable dementia (39.0%; 95% CI, 30.7%-48.1%). In age- and sex-adjusted models with death as a competing risk, the hazard ratios for hospital readmission within 180 days were 2.29 (95% CI, 1.70-3.09) for frailty and 1.58 (95% CI, 1.15-2.18) for probable dementia. Conclusions and Relevance: In this nationally representative cohort study of community-living older US residents, the likelihood of hospital readmissions within 180 days after major surgery was increased among older persons who were frail or had probable dementia, highlighting the potential value of these geriatric conditions in identifying those at increased risk.

Adherence to key recommendations for design and analysis of stepped-wedge cluster randomized trials: A review of trials published 2016-2022.

BACKGROUND/AIMS: The stepped-wedge cluster randomized trial (SW-CRT), in which clusters are randomized to a time at which they will transition to the intervention condition - rather than a trial arm - is a relatively new design. SW-CRTs have additional design and analytical considerations compared to conventional parallel arm trials. To inform future methodological development, including guidance for trialists and the selection of parameters for statistical simulation studies, we conducted a review of recently published SW-CRTs. Specific objectives were to describe (1) the types of designs used in practice, (2) adherence to key requirements for statistical analysis, and (3) practices around covariate adjustment. We also examined changes in adherence over time and by journal impact factor. METHODS: We used electronic searches to identify primary reports of SW-CRTs published 2016-2022. Two reviewers extracted information from each trial report and its protocol, if available, and resolved disagreements through discussion. RESULTS: We identified 160 eligible trials, randomizing a median (Q1-Q3) of 11 (8-18) clusters to 5 (4-7) sequences. The majority (122, 76%) were cross-sectional (almost all with continuous recruitment), 23 (14%) were closed cohorts and 15 (9%) open cohorts. Many trials had complex design features such as multiple or multivariate primary outcomes (50, 31%) or time-dependent repeated measures (27, 22%). The most common type of primary outcome was binary (51%); continuous outcomes were less common (26%). The most frequently used method of analysis was a generalized linear mixed model (112, 70%); generalized estimating equations were used less frequently (12, 8%). Among 142 trials with fewer than 40 clusters, only 9 (6%) reported using methods appropriate for a small number of clusters. Statistical analyses clearly adjusted for time effects in 119 (74%), for within-cluster correlations in 132 (83%), and for distinct between-period correlations in 13 (8%). Covariates were included in the primary analysis of the primary outcome in 82 (51%) and were most often individual-level covariates; however, clear and complete pre-specification of covariates was uncommon. Adherence to some key methodological requirements (adjusting for time effects, accounting for within-period correlation) was higher among trials published in higher versus lower impact factor journals. Substantial improvements over time were not observed although a slight improvement was observed in the proportion accounting for a distinct between-period correlation. CONCLUSIONS: Future methods development should prioritize methods for SW-CRTs with binary or time-to-event outcomes, small numbers of clusters, continuous recruitment designs, multivariate outcomes, or time-dependent repeated measures. Trialists, journal editors, and peer reviewers should be aware that SW-CRTs have additional methodological requirements over parallel arm designs including the need to account for period effects as well as complex intracluster correlations.

Assessment of Regional Nursing Home Preparedness for and Regulatory Responsiveness to Wildfire Risk in the Western US.

Importance: It is uncertain whether emergency preparedness and regulatory oversight for US nursing homes are aligned with local wildfire risk. Objective: To evaluate the likelihood that nursing homes at elevated risk of wildfire exposure meet US Centers for Medicare & Medicaid Services (CMS) emergency preparedness standards and to compare the time to reinspection by exposure status. Design, Setting, and Participants: This cross-sectional study of nursing homes in the continental western US from January 1, 2017, through December 31, 2019, was conducted using cross-sectional and survival analyses. The prevalence of high-risk facilities within 5 km of areas at or exceeding the 85th percentile of nationalized wildfire risk across areas overseen by 4 CMS regional offices (New Mexico, Mountain West, Pacific/Southwest, and Pacific Northwest) was determined. Critical emergency preparedness deficiencies cited during CMS Life Safety Code Inspections were identified. Data analysis was performed from October 10 to December 12, 2022. Main Outcomes and Measures: The primary outcome classified whether facilities were cited for at least 1 critical emergency preparedness deficiency during the observation window. Regionally stratified generalized estimating equations were used to evaluate associations between risk status and the presence and number of deficiencies, adjusted for nursing home characteristics. For the subset of facilities with deficiencies, differences in restricted mean survival time to reinspection were evaluated. Results: Of the 2218 nursing homes in this study, 1219 (55.0%) were exposed to elevated wildfire risk. The Pacific/Southwest had the highest percentage of both exposed (680 of 870 [78.2%]) and unexposed (359 of 486 [73.9%]) facilities with 1 or more deficiencies. The Mountain West had the largest difference in the percentage of exposed (87 of 215 [40.5%]) vs unexposed (47 of 193 [24.4%]) facilities with 1 or more deficiencies. Exposed facilities in the Pacific Northwest had the greatest mean (SD) number of deficiencies (4.3 [5.4]). Exposure was associated with the presence of deficiencies in the Mountain West (odds ratio [OR], 2.12 [95% CI, 1.50-3.01]) and the presence (OR, 1.84 [95% CI, 1.55-2.18]) and number (rate ratio, 1.39 [95% CI, 1.06-1.83]) of deficiencies in the Pacific Northwest. Exposed Mountain West facilities with deficiencies were reinspected later, on average, than unexposed facilities (adjusted restricted mean survival time difference, 91.2 days [95% CI, 30.6-151.8 days]). Conclusions and Relevance: In this cross-sectional study, regional heterogeneity in nursing home emergency preparedness for and regulatory responsiveness to local wildfire risk was observed. These findings suggest that there may be opportunities to improve the responsiveness of nursing homes to and regulatory oversight of surrounding wildfire risk.

A scoping review described diversity in methods of randomization and reporting of baseline balance in stepped-wedge cluster randomized trials.

OBJECTIVES: In stepped-wedge cluster randomized trials (SW-CRTs), clusters are randomized not to treatment and control arms but to sequences dictating the times of crossing from control to intervention conditions. Randomization is an essential feature of this design but application of standard methods to promote and report on balance at baseline is not straightforward. We aimed to describe current methods of randomization and reporting of balance at baseline in SW-CRTs. STUDY DESIGN AND SETTING: We used electronic searches to identify primary reports of SW-CRTs published between 2016 and 2022. RESULTS: Across 160 identified trials, the median number of clusters randomized was 11 (Q1-Q3: 8-18). Sixty-three (39%) used restricted randomization-most often stratification based on a single cluster-level covariate; 12 (19%) of these adjusted for the covariate(s) in the primary analysis. Overall, 50 (31%) and 134 (84%) reported on balance at baseline on cluster- and individual-level characteristics, respectively. Balance on individual-level characteristics was most often reported by condition in cross-sectional designs and by sequence in cohort designs. Authors reported baseline imbalances in 72 (45%) trials. CONCLUSION: SW-CRTs often randomize a small number of clusters using unrestricted allocation. Investigators need guidance on appropriate methods of randomization and assessment and reporting of balance at baseline.

Sample size considerations for stepped wedge designs with subclusters.

The stepped wedge cluster randomized trial (SW-CRT) is an increasingly popular design for evaluating health service delivery or policy interventions. An essential consideration of this design is the need to account for both within-period and between-period correlations in sample size calculations. Especially when embedded in health care delivery systems, many SW-CRTs may have subclusters nested in clusters, within which outcomes are collected longitudinally. However, existing sample size methods that account for between-period correlations have not allowed for multiple levels of clustering. We present computationally efficient sample size procedures that properly differentiate within-period and between-period intracluster correlation coefficients in SW-CRTs in the presence of subclusters. We introduce an extended block exchangeable correlation matrix to characterize the complex dependencies of outcomes within clusters. For Gaussian outcomes, we derive a closed-form sample size expression that depends on the correlation structure only through two eigenvalues of the extended block exchangeable correlation structure. For non-Gaussian outcomes, we present a generic sample size algorithm based on linearization and elucidate simplifications under canonical link functions. For example, we show that the approximate sample size formula under a logistic linear mixed model depends on three eigenvalues of the extended block exchangeable correlation matrix. We provide an extension to accommodate unequal cluster sizes and validate the proposed methods via simulations. Finally, we illustrate our methods in two real SW-CRTs with subclusters.

Power analyses for stepped wedge designs with multivariate continuous outcomes.

Multivariate outcomes are common in pragmatic cluster randomized trials. While sample size calculation procedures for multivariate outcomes exist under parallel assignment, none have been developed for a stepped wedge design. In this article, we present computationally efficient power and sample size procedures for stepped wedge cluster randomized trials (SW-CRTs) with multivariate outcomes that differentiate the within-period and between-period intracluster correlation coefficients (ICCs). Under a multivariate linear mixed model, we derive the joint distribution of the intervention test statistics which can be used for determining power under different hypotheses and provide an example using the commonly utilized intersection-union test for co-primary outcomes. Simplifications under a common treatment effect and common ICCs across endpoints and an extension to closed-cohort designs are also provided. Finally, under the common ICC across endpoints assumption, we formally prove that the multivariate linear mixed model leads to a more efficient treatment effect estimator compared to the univariate linear mixed model, providing a rigorous justification on the use of the former with multivariate outcomes. We illustrate application of the proposed methods using data from an existing SW-CRT and present extensive simulations to validate the methods.

Joint Models for Estimating Determinants of Cognitive Decline in the Presence of Survival Bias.

BACKGROUND: Identifying determinants of cognitive decline is crucial for developing strategies to prevent Alzheimer's disease and related dementias. However, determinants of cognitive decline remain elusive, with inconsistent results across studies. One reason could be differential survival. Cognitive decline and many exposures of interest are associated with mortality making survival a collider. Not accounting for informative attrition can result in survival bias. Generalized estimating equations (GEE) and linear mixed-effects model (LME) are commonly used to estimate effects of exposures on cognitive decline, but both assume mortality is not informative. Joint models combine LME with Cox proportional hazards models to simultaneously estimate cognitive decline and the hazard of mortality. METHODS: Using simulations, we compared estimates of the effect of a binary exposure on rate of cognitive decline from GEE, weighted GEE using inverse-probability-of-attrition weights, and LME to joint models under several causal structures of survival bias. RESULTS: We found that joint models with correctly specified relationship between survival and cognition performed best, producing unbiased estimates and appropriate coverage. Even those with misspecified relationship between survival and cognition showed advantage under causal structures consistent with survival bias. We also compared these models in estimating the effect of education on cognitive decline after dementia diagnosis using Framingham Heart Study data. Estimates of the effect of education on cognitive decline from joint models were slightly attenuated with similar precision compared with LME. CONCLUSIONS: In our study, joint models were more robust than LME, GEE, and weighted GEE models when evaluating determinants of cognitive decline.

Non-Alcoholic Fatty Liver Disease, Liver Fibrosis, and Regional Amyloid-ß and Tau Pathology in Middle-Aged Adults: The Framingham Study.

BACKGROUND: Liver steatosis and fibrosis are emerging as risk factors for multiple extrahepatic health conditions; however, their relationship with Alzheimer's disease pathology is unclear. OBJECTIVE: To examine whether non-alcoholic fatty liver disease (NAFLD) and FIB-4, a non-invasive index of advanced fibrosis, are associated with brain amyloid-ß (Aß) and tau pathology. METHODS: The study sample included Framingham Study participants from the Offspring and Third generation cohorts who attended exams 9 (2011-2014) and 2 (2008-2011), respectively. Participants underwent 11C-Pittsburgh Compound-B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging and abdomen computed tomography, or had information on all components of the FIB-4 index. Linear regression models were used to assess the relationship of NAFLD and FIB-4 with regional tau and Aß, adjusting for potential confounders and multiple comparisons. RESULTS: Of the subsample with NAFLD information (N = 169; mean age 52±9 y; 57% males), 57 (34%) had NAFLD. Of the subsample with information on liver fibrosis (N = 177; mean age 50±10 y; 51% males), 34 (19%) had advanced fibrosis (FIB-4 > 1.3). Prevalent NAFLD was not associated with Aß or tau PET. However, FIB-4 index was significantly associated with increased rhinal tau (ß= 1.03±0.33, p = 0.002). Among individuals with prevalent NAFLD, FIB-4 was related to inferior temporal, parahippocampal gyrus, entorhinal and rhinal tau (ß= 2.01±0.47, p < 0.001; ß= 1.60±0.53, p = 0.007, and ß= 1.59±0.47, p = 0.003 and ß= 1.60±0.42, p = 0.001, respectively) and to Aß deposition overall and in the inferior temporal and parahippocampal regions (ß= 1.93±0.47, p < 0.001; ß= 1.59±0.38, p < 0.001, and ß= 1.52±0.54, p = 0.008, respectively). CONCLUSION: This study suggests a possible association between liver fibrosis and early Alzheimer's disease pathology, independently of cardio-metabolic risk factors.

Coronary Artery Calcium Assessed Years Before Was Positively Associated With Subtle White Matter Injury of the Brain in Asymptomatic Middle-Aged Men: The Framingham Heart Study.

BACKGROUND: Using magnetic resonance diffusion tensor imaging, we previously showed a cross-sectional association between carotid-femoral pulse wave velocity, a measure of aortic stiffness, and subtle white matter injury in clinically asymptomatic middle-age adults. While coronary artery calcium (CAC) is a robust measure of atherosclerosis, and a predictor of stroke and dementia, whether it predicts diffusion tensor imaging-based subtle white matter injury in the brain remains unknown. METHODS: In FHS (Framingham Heart Study), an observational study, third-generation participants were assessed for CAC (2002-2005) and brain magnetic resonance imaging (2009-2014). Outcomes were diffusion tensor imaging-based measures; free water, fractional anisotropy, and peak width of mean diffusivity. After excluding the participants with neurological conditions and missing covariates, we categorized participants into 3 groups according to CAC score (0, 0 < to 100, and >100) and calculated a linear trend across the CAC groups. In secondary analyses treating CAC score as continuous, we computed slope of the outcomes per 20 to 80th percentiles higher log-transformed CAC score using linear regression. RESULTS: In a total of 1052 individuals analyzed (mean age 45.4 years, 45.4% women), 71.6%, 22.4%, and 6.0% had CAC score of 0, 0 < to 100, and >100, respectively. We observed a significant linear trend of fractional anisotropy, but not other measures, across the CAC groups after multivariable adjustment. In the secondary analyses, CAC was associated with lower fractional anisotropy in men but not in women. CONCLUSIONS: CAC may be a promising tool to predict prevalent subtle white matter injury of the brain in asymptomatic middle-aged men.

Autonomic Imbalance and Risk of Dementia and Stroke: The Framingham Study.

Background and Purpose: The autonomic nervous system has been implicated in stroke and dementia pathophysiology. High resting heart rate and low heart rate variability indicate the effect of autonomic imbalance on the heart. We examined the associations of resting heart rate and heart rate variability with incident stroke and dementia in a community-based cohort of middle- and old-aged adults. Methods: The study sample included 1581 participants aged >60 years and 3271 participants aged >45 years evaluated for incident dementia and stroke, respectively, who participated in the Framingham Offspring cohort third (1983­1987) examination and had follow-up for neurology events after the seventh (1998­2001) examination. Heart rate variability was assessed through the standard deviation (SD) of normal-to-normal RR intervals and the root mean square of successive differences between normal heartbeats from 2-hour Holter monitor. Participants were followed-up for stroke and dementia incidence from exam 7 to a maximum of 10 years. Cox regression models were used to assess the link of resting heart rate and heart rate variability with stroke and dementia risk while adjusting for potential confounders, and interactions with age and sex were assessed. Results: Of the dementia (mean age, 55±6 years, 46% men) and stroke (mean age, 48±9 years, 46% men) samples, 133 and 127 developed dementia and stroke, respectively, during the follow-up. Overall, autonomic imbalance was not associated with dementia risk. However, age modified the associations such that SD of normal-to-normal intervals and root mean square of successive differences were associated with dementia risk in older people (hazard ratio [HR] [95% CI] per 1SD, 0.61 [0.38­0.99] and HR [95% CI] per 1SD, 0.34 [0.15­0.74], respectively). High resting heart rate was associated with increased stroke risk (HR [95% CI] per 10 bpm, 1.18 [1.01­1.39]), and high SD of normal-to-normal intervals was associated with lower stroke risk in men (HR [95% CI] per 1SD, 0.46 [0.26­0.79]) but not women (HR [95% CI] per 1SD, 1.25 [0.88­1.79]; P for interaction=0.003). Conclusions: Some measures of cardiac autonomic imbalance may precede dementia and stroke occurrence, particularly in older ages and men, respectively.

Pathways to housing stability and viral suppression for people living with HIV/AIDS: Findings from the Building a Medical Home for Multiply Diagnosed HIV-positive Homeless Populations initiative.

BACKGROUND: People with HIV with co-occurring substance use and mental health diagnoses who are unstably housed have poorer outcomes for retention in care and viral suppression. Navigation models are a potential strategy to help this vulnerable population obtain the necessary medical and non-medical services across multiple service systems. The Health Resources and Services Administration's Special Projects of National Significance: "Building a Medical Home for Multiply-Diagnosed HIV-positive Homeless Populations initiative 2012-2017 found that navigation models may be an effective intervention to support people with HIV with unstable housing improve HIV health outcomes. However, there is limited information about the mechanisms by which this intervention works. In this article, we explore the participant and program factors for achieving stable housing at 6 months and how these factors influence HIV health outcomes. METHODS AND FINDINGS: This was a prospective study of 471 unstably housed people with HIV enrolled in a navigation intervention across nine sites in the United Stated from 2013-2017. All sites provided HIV primary medical care. Eight sites were located in urban areas and one site served a predominantly rural population. Two sites were federally qualified health centers, three were city or county health departments, one site was a comprehensive HIV/AIDS service organization, and three sites were outpatient or mobile clinics affiliated with a university -based or hospital system. Data were collected via interview and medical chart review at baseline, post 6 and 12 months. Type and dose of navigation activities were collected via a standardized encounter form. We used a path analysis model with housing stability at 6 months as the mediator to examine the direct and indirect effects of participant's socio-demographics and risk factors and navigation on viral suppression and retention in care at 12 months. Housing stability at 6 months was associated with male gender, younger age, viral suppression at baseline, having a lower risk for opiate use, recent homelessness, lower risk of food insecurity, and a longer length of time living with HIV. Participants who increased self-efficacy with obtaining help by 6 months had significantly higher odds of achieving housing stability. Stable housing, fewer unmet needs, moderate to high risk for opiate use, and viral suppression at baseline had a direct effect on viral suppression at 12 months. The intensity of navigation contact had no direct effect on housing stability and a mixed direct effect on viral suppression. Recent diagnosis with HIV, women, greater social support, increased self-efficacy and higher intensity of navigation contact had a direct effect on improved retention in HIV primary care at 12 months. CONCLUSIONS: In this sample of people with HIV who are experiencing homelessness, housing stability had a significant direct path to viral suppression. Navigation activities did not have a direct effect on the path to housing stability but were directly related to retention in care. These results identify key populations and factors to target resources and policies for addressing the health and social unmet needs of people with HIV to achieve housing stability and HIV health outcomes.

Twenty-seven-year time trends in dementia incidence in Europe and the United States: The Alzheimer Cohorts Consortium.

OBJECTIVE: To determine changes in the incidence of dementia between 1988 and 2015. METHODS: This analysis was performed in aggregated data from individuals >65 years of age in 7 population-based cohort studies in the United States and Europe from the Alzheimer Cohort Consortium. First, we calculated age- and sex-specific incidence rates for all-cause dementia, and then defined nonoverlapping 5-year epochs within each study to determine trends in incidence. Estimates of change per 10-year interval were pooled and results are presented combined and stratified by sex. RESULTS: Of 49,202 individuals, 4,253 (8.6%) developed dementia. The incidence rate of dementia increased with age, similarly for women and men, ranging from about 4 per 1,000 person-years in individuals aged 65-69 years to 65 per 1,000 person-years for those aged 85-89 years. The incidence rate of dementia declined by 13% per calendar decade (95% confidence interval [CI], 7%-19%), consistently across studies, and somewhat more pronouncedly in men than in women (24% [95% CI 14%-32%] vs 8% [0%-15%]). CONCLUSION: The incidence rate of dementia in Europe and North America has declined by 13% per decade over the past 25 years, consistently across studies. Incidence is similar for men and women, although declines were somewhat more profound in men. These observations call for sustained efforts to finding the causes for this decline, as well as determining their validity in geographically and ethnically diverse populations.

Association of anthropometry and weight change with risk of dementia and its major subtypes: A meta-analysis consisting 2.8 million adults with 57 294 cases of dementia.

Uncertainty exists regarding the relation of body size and weight change with dementia risk. As populations continue to age and the global obesity epidemic shows no sign of waning, reliable quantification of such associations is important. We examined the relationship of body mass index, waist circumference, and annual percent weight change with risk of dementia and its subtypes by pooling data from 19 prospective cohort studies and four clinical trials using meta-analysis. Compared with body mass index-defined lower-normal weight (18.5-22.4 kg/m2 ), the risk of all-cause dementia was higher among underweight individuals but lower among those with upper-normal (22.5-24.9 kg/m2 ) levels. Obesity was associated with higher risk in vascular dementia. Similarly, relative to the lowest fifth of waist circumference, those in the highest fifth had nonsignificant higher vascular dementia risk. Weight loss was associated with higher all-cause dementia risk relative to weight maintenance. Weight gain was weakly associated with higher vascular dementia risk. The relationship between body size, weight change, and dementia is complex and exhibits non-linear associations depending on dementia subtype under scrutiny. Weight loss was associated with an elevated risk most likely due to reverse causality and/or pathophysiological changes in the brain, although the latter remains speculative.

Antihypertensive medications and risk for incident dementia and Alzheimer's disease: a meta-analysis of individual participant data from prospective cohort studies.

BACKGROUND: Dementia is a major health concern for which prevention and treatment strategies remain elusive. Lowering high blood pressure with specific antihypertensive medications (AHMs) could reduce the burden of disease. We investigated whether specific AHM classes reduced the risk for dementia. METHODS: We did a meta-analysis of individual participant data from eligible observational studies published between Jan 1, 1980, and Jan 1, 2019. Cohorts were eligible for inclusion if they prospectively recruited community-dwelling adults; included more than 2000 participants; collected data for dementia events over at least 5 years; had measured blood pressure and verified use of AHMs; included in-person exams, supplemented with additional data, to capture dementia events; and had followed up cases for mortality. We assessed the association of incident dementia and clinical Alzheimer's disease with use of five AHM classes, within strata of baseline high (systolic blood pressure [SBP] ≥140 mm Hg or diastolic blood pressure [DBP] ≥90 mm Hg) and normal (SBP <140 mm Hg and DBP <90 mm Hg) blood pressure. We used a propensity score to control for confounding factors related to the probability of receiving AHM. Study-specific effect estimates were pooled using random-effects meta-analyses. RESULTS: Six prospective community-based studies (n=31 090 well phenotyped dementia-free adults older than 55 years) with median follow-ups across cohorts of 7-22 years were eligible for analysis. There were 3728 incident cases of dementia and 1741 incident Alzheimer's disease diagnoses. In the high blood pressure stratum (n=15 537), those using any AHM had a reduced risk for developing dementia (hazard ratio [HR] 0·88, 95% CI 0·79-0·98; p=0·019) and Alzheimer's disease (HR 0·84, 0·73-0·97; p=0·021) compared with those not using AHM. We did not find any significant differences between one drug class versus all others on risk of dementia. In the normal blood pressure stratum (n=15 553), there was no association between AHM use and incident dementia or Alzheimer's disease. INTERPRETATION: Over a long period of observation, no evidence was found that a specific AHM drug class was more effective than others in lowering risk of dementia. Among people with hypertensive levels of blood pressure, use of any AHM with efficacy to lower blood pressure might reduce the risk for dementia. These findings suggest future clinical guidelines for hypertension management should also consider the beneficial effect of AHM on the risk for dementia. FUNDING: The Alzheimer's Drug Discovery Foundation and the National Institute on Aging Intramural Research Program.

Non-alcoholic fatty liver disease, liver fibrosis score and cognitive function in middle-aged adults: The Framingham Study.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is common and has been recently related to brain health. We aimed to assess the relationships of NAFLD and its severity, using the NAFLD fibrosis score (NFS), with cognitive performance. METHODS: Framingham study Offspring and 3rd generation participants were included if they attended exams 9 (2002-2008) and 2 (2008-2011), respectively, were free of dementia and stroke, and did not have excessive alcohol intake. Between 2008 and 2011, participants underwent Multi-detector computed tomography scans of the abdomen to determine NAFLD diagnosis and the NFS was used to categorize the severity of fibrosis. Cross-sectional relationships of NAFLD and the NFS with cognitive testing of memory, abstract reasoning, visual perception, attention and executive function were assessed, while adjusting for multiple cardiometabolic variables including visceral adipose tissue, diabetes and insulin resistance. RESULTS: Of the 1287 participants (mean age = 61±12 years, 48% men), 378 (29%) had NAFLD. The presence of NAFLD was not associated with cognitive function. However, among those with NAFLD (mean age = 61±12 years; 58% men), high compared to low risk of advanced fibrosis was associated with poorer performance on similarities (ß = -2.22 ± 0.83; P = 0.009) and trail-making B minus A (ß = -0.11 ± 0.05; P = 0.028), independently of potential confounders. CONCLUSIONS: Participants with high risk of advanced fibrosis may have poorer cognitive function compared to those with low risk, particularly in executive function and abstract reasoning. Future findings are necessary to evaluate the value of the NFS as a biomarker that predicts cognitive impairment and dementia and to explore the role of hepatic fibrosis in brain health.

Association of Accelerometer-Measured Light-Intensity Physical Activity With Brain Volume: The Framingham Heart Study.

Importance: Dementia risk may be attenuated by physical activity (PA); however, the specific activity levels optimal for dementia prevention are unclear. Moreover, most older adults are unable to meet the nationally recommended PA guidelines, set at 150 minutes of moderate to vigorous PA per week. Objective: To assess the association of total steps walked per day and total dose (intensity × duration) of PA with brain volumes on magnetic resonance imaging (MRI) among Framingham Heart Study participants. Design, Setting, and Participants: This cross-sectional, community-based cohort study of the association of accelerometry-determined PA with brain MRI measures in Framingham, Massachusetts, included the Framingham Heart Study third-generation (examination 2, 2008-2011) and offspring (examination 9, 2011-2014) cohorts. Of 4021 participants who agreed to wear an accelerometer and had valid data (≥10 hours/day for ≥3 days), 1667 participants who did not undergo brain MRI (n = 1604) or had prevalent dementia or stroke (n = 63) were excluded. Data analysis began in 2016 and was completed in February 2019. Exposures: Physical activity achieved using accelerometry-derived total activity (steps per day) and 2 intensity levels (light intensity and moderate to vigorous intensity). Main Outcomes and Measures: Differences in total brain volume and other MRI markers of brain aging. Results: The study sample of 2354 participants had a mean (SD) age of 53 (13) years, 1276 (54.2%) were women, and 1099 (46.7%) met the PA guidelines. Incremental light-intensity PA was associated with higher total brain volume; each additional hour of light-intensity PA was associated with approximately 1.1 years less brain aging (ß estimate, 0.22; SD, 0.07; P = .003). Among individuals not meeting the PA guidelines, each hour of light-intensity PA (ß estimate, 0.28; SD, 0.11; P = .01) and achieving 7500 steps or more per day (ß estimate, 0.44; SD, 0.18; P = .02) were associated with higher total brain volume, equivalent to approximately 1.4 to 2.2 years less brain aging. After adjusting for light-intensity PA, neither increasing moderate to vigorous PA levels nor meeting the threshold moderate to vigorous PA level recommended by the PA guidelines were significantly associated with total brain volume. Conclusions and Relevance: Every additional hour of light-intensity PA was associated with higher brain volumes, even among individuals not meeting current PA guidelines. These data are consistent with the notion that the potential benefits of PA on brain aging may accrue at a lower, more achievable level of intensity or duration.

Self-Reported Physical Activity and Relations to Growth and Neurotrophic Factors in Diabetes Mellitus: The Framingham Offspring Study.

AIMS: Circulating insulin-like growth factor- (IGF-) 1, vascular endothelial growth factor (VEGF), and brain-derived neurotrophic factor (BDNF) levels are often lower in individuals with diabetes mellitus (DM) and are important for repairing vascular and neuronal dysfunction. The purpose of this investigation was to determine the cross-sectional relations of physical activity to circulating concentrations of IGF-1, VEGF, and BDNF in individuals with and without DM. METHODS: In 1730 participants from the Framingham Offspring Study examination cycle 7, including those with DM (n = 179, mean age 64 years, 39% women) and without DM (n = 1551, mean age 60 years, 46% women), we related self-reported physical activity variables to circulating concentrations of IGF-1, VEGF, and BDNF using linear multivariable regression models. We also tested for interactions by age. Participants with prevalent cardiovascular disease, stroke, and dementia or taking hormone replacement therapy were excluded. RESULTS: In participants with DM, more ambulatory physical activity was associated with higher IGF-1 levels (ß ± standard error (SE) = 0.22 ± 0.08, p = 0.009), and more total physical activity was related to higher BDNF levels (ß ± SE = 0.18 ± 0.08, p = 0.035), but physical activity was not significantly related to circulating VEGF. In participants without DM, no associations were observed. Moreover, in the examination of interactions by age, the association of ambulatory physical activity with IGF-1 levels was only observed in older adults with DM (age ≥ 60 years, ß ± SE = 0.23 ± 0.11, p = 0.042) but not in middle-aged adults with DM (age < 60 years, ß ± SE = 0.06 ± 0.13, p = 0.645). CONCLUSION: Our results suggest that more physical activity is associated with higher circulating IGF-1 and BDNF in participants with DM. These results, dissecting interactions by both age and DM status, may also help to explain some of the inconsistent results in studies relating physical activity to growth and neurotrophic factors.

Association of metformin, sulfonylurea and insulin use with brain structure and function and risk of dementia and Alzheimer's disease: Pooled analysis from 5 cohorts.

OBJECTIVE: To determine whether classes of diabetes medications are associated with cognitive health and dementia risk, above and beyond their glycemic control properties. RESEARCH DESIGN AND METHODS: Findings were pooled from 5 population-based cohorts: the Framingham Heart Study, the Rotterdam Study, the Atherosclerosis Risk in Communities (ARIC) Study, the Aging Gene-Environment Susceptibility-Reykjavik Study (AGES) and the Sacramento Area Latino Study on Aging (SALSA). Differences between users and non-users of insulin, metformin and sulfonylurea were assessed in each cohort for cognitive and brain MRI measures using linear regression models, and cognitive decline and dementia/AD risk using mixed effect models and Cox regression analyses, respectively. Findings were then pooled using meta-analytic techniques, including 3,590 individuals with diabetes for the prospective analysis. RESULTS: After adjusting for potential confounders including indices of glycemic control, insulin use was associated with increased risk of new-onset dementia (pooled HR (95% CI) = 1.58 (1.18, 2.12);p = 0.002) and with a greater decline in global cognitive function (ß = -0.014±0.007;p = 0.045). The associations with incident dementia remained similar after further adjustment for renal function and excluding persons with diabetes whose treatment was life-style change only. Insulin use was not related to cognitive function nor to brain MRI measures. No significant associations were found between metformin or sulfonylurea use and outcomes of brain function and structure. There was no evidence of significant between-study heterogeneity. CONCLUSIONS: Despite its advantages in controlling glycemic dysregulation and preventing complications, insulin treatment may be associated with increased adverse cognitive outcomes possibly due to a greater risk of hypoglycemia.