Family history aggregation unit-based tests to detect rare genetic variant associations with application to the Framingham Heart Study.

A challenge in standard genetic studies is maintaining good power to detect associations, especially for low prevalent diseases and rare variants. The traditional methods are most powerful when evaluating the association between variants in balanced study designs. Without accounting for family correlation and unbalanced case-control ratio, these analyses could result in inflated type I error. One cost-effective solution to increase statistical power is exploitation of available family history (FH) that contains valuable information about disease heritability. Here, we develop methods to address the aforementioned type I error issues while providing optimal power to analyze aggregates of rare variants by incorporating additional information from FH. With enhanced power in these methods exploiting FH and accounting for relatedness and unbalanced designs, we successfully detect genes with suggestive associations with Alzheimer disease, dementia, and type 2 diabetes by using the exome chip data from the Framingham Heart Study.

Association of Incident Stroke Risk With an IL-18-Centered Inflammatory Network Biomarker Composite.

BACKGROUND: A coordinated network of circulating inflammatory molecules centered on the pleotropic pro-atherogenic cytokine interleukin-18 (IL-18) is linked to cerebral small vessel disease. We sought to validate the association of this inflammatory biomarker network with incident stroke risk, cognitive impairment, and imaging metrics in a sample of the Framingham Offspring Cohort. METHODS: Using available baseline measurements of serum levels of IL-18, GDF (growth and differentiation factor)-15, soluble form of receptor for advanced glycation end products, myeloperoxidase, and MCP-1 (monocyte chemoattractant protein-1) from Exam 7 of the Framingham Offspring Cohort (1998-2001), we constructed a population-normalized, equally weighted log-transformed mean Z-score value representing the average level of each serum analyte to create an inflammatory composite score (ICS5). Multivariable regression models were used to determine the association of ICS5 with incident stroke, brain magnetic resonance imaging features, and cognitive testing performance. RESULTS: We found a significant association between ICS5 score and increased risk for incident all-cause stroke (hazard ratio, 1.48 [95% CI, 1.05-2.08]; P=0.024) and ischemic stroke (hazard ratio, 1.51 [95% CI, 1.03-2.21]; P=0.033) in the Exam 7 cohort of 2201 subjects (mean age 62±9 years; 54% female) aged 45+ years with an all-cause incident stroke rate of 6.1% (135/2201) and ischemic stroke rate of 4.9% (108/2201). ICS5 and its component serum markers are all associated with the Framingham Stroke Risk Profile score (ß±SE, 0.19±0.02; P<0.0001). In addition, we found a significant inverse association of ICS5 with a global cognitive score, derived from a principal components analysis of the neuropsychological battery used in the Framingham cohort (-0.08±0.03; P=0.019). No association of ICS5 with magnetic resonance imaging metrics of cerebral small vessel disease was observed. CONCLUSIONS: Circulating serum levels of inflammatory biomarkers centered on IL-18 are associated with an increased risk of stroke and cognitive impairment in the Framingham Offspring Cohort. Linking specific inflammatory pathways to cerebral small vessel disease may enhance individualized quantitative risk assessment for future stroke and vascular cognitive impairment.

Impaired kidney function, cerebral small vessel disease and cognitive disorders: the Framingham Heart Study.

BACKGROUND AND HYPOTHESIS: It remains unclear whether the relation of chronic kidney disease (CKD) with cognitive dysfunction is independent of blood pressure (BP). We evaluated kidney function in relation to premorbid BP measurements, cerebral small vessel disease (CSVD), and incident mild cognitive impairment (MCI) and dementia in Framingham Offspring Cohort participants. METHODS: We included Framingham Offspring participants free of dementia, attending an examination during midlife (exam cycle 6, baseline) for ascertainment of kidney function status, with brain magnetic resonance imaging late in life (exam cycles 7-9), cognitive outcome data, and available interim hypertension and BP assessments. We related CKD (estimated glomerular filtration rate <60 ml/min/1.73 m2) and albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g) to CSVD markers and cognitive outcomes using multivariable regression analyses. RESULTS: Among 2604 participants (mean age 67.4 ± 9.2, 64% women, 7% had CKD, and 9% albuminuria), albuminuria was independently associated with covert infarcts [adjusted OR, 1.55 (1.00-2.38); P = 0.049] and incident MCI and dementia [adjusted hazard ratio (HR), 1.68 (1.18-2.41); P = 0.005 and 1.71, (1.11-2.64); P = 0.015, respectively]. CKD was not associated with CSVD markers but was associated with a higher risk of incident dementia [HR, 1.53 (1.02-2.29); P = 0.041]. While albuminuria was predictive of the Alzheimer's disease subtype [adjusted HR = 1.68, (1.03-2.74); P = 0.04), CKD was predictive of vascular dementia [adjusted HR, 2.78 (1.16-6.68); P = 0.023]. CONCLUSIONS: Kidney disease was associated with CSVD and cognitive disorders in asymptomatic community dwelling participants. The relation was independent of premorbid BP, suggesting that the link between kidney and brain disease may involve additional mechanisms beyond BP-related injury.

Nonalcoholic fatty liver disease, liver fibrosis, and structural brain imaging: The Cross-Cohort Collaboration.

BACKGROUND AND PURPOSE: Prior studies reported conflicting findings regarding the association of nonalcoholic fatty liver disease (NAFLD) and liver fibrosis with measures of brain health. We examined whether NAFLD and liver fibrosis are associated with structural brain imaging measures in middle- and old-age adults. METHODS: In this cross-sectional study among dementia- and stroke-free individuals, data were pooled from the Offspring and Third Generation cohorts of the Framingham Heart Study (FHS), the Rotterdam Study (RS), and the Study of Health in Pomerania. NAFLD was assessed through abdominal imaging. Transient hepatic elastography (FibroScan) was used to assess liver fibrosis in FHS and RS. Linear regression models were used to explore the relation of NAFLD and liver fibrosis with brain volumes, including total brain, gray matter, hippocampus, and white matter hyperintensities, adjusting for potential confounders. Results were combined using fixed effects meta-analysis. RESULTS: In total, 5660 and 3022 individuals were included for NAFLD and liver fibrosis analyses, respectively. NAFLD was associated with smaller volumes of total brain (ß = -3.5, 95% confidence interval [CI] = -5.4 to -1.7), total gray matter (ß = -1.9, 95% CI = -3.4 to -0.3), and total cortical gray matter (ß = -1.9, 95% CI = -3.7 to -0.01). In addition, liver fibrosis (defined as liver stiffness measure ≥8.2 kPa) was related to smaller total brain volumes (ß = -7.3, 95% CI = -11.1 to -3.5). Heterogeneity between studies was low. CONCLUSIONS: NAFLD and liver fibrosis may be directly related to brain aging. Larger and prospective studies are warranted to validate these findings and identify liver-related preventive strategies for neurodegeneration.

A novel neuroimaging signature for ADRD risk stratification in the community.

INTRODUCTION: Early risk stratification for clinical dementia could lead to preventive therapies. We identified and validated a magnetic resonance imaging (MRI) signature for Alzheimer's disease (AD) and related dementias (ARDR). METHODS: An MRI ADRD signature was derived from cortical thickness maps in Framingham Heart Study (FHS) participants with AD dementia and matched controls. The signature was related to the risk of ADRD and cognitive function in FHS. Results were replicated in the University of California Davis Alzheimer's Disease Research Center (UCD-ADRC) cohort. RESULTS: Participants in the bottom quartile of the signature had more than three times increased risk for ADRD compared to those in the upper three quartiles (P < 0.001). Greater thickness in the signature was related to better general cognition (P < 0.01) and episodic memory (P = 0.01). Results replicated in UCD-ADRC. DISCUSSION: We identified a robust neuroimaging biomarker for persons at increased risk of ADRD. Other cohorts will further test the validity of this biomarker.

Associations of cerebral amyloid beta and tau with cognition from midlife.

INTRODUCTION: Understanding early neuropathological changes and their associations with cognition may aid dementia prevention. This study investigated associations of cerebral amyloid and tau positron emission tomography (PET) retention with cognition in a predominately middle-aged community-based cohort and examined factors that may modify these relationships. METHODS: 11C-Pittsburgh compound B amyloid and 18F-flortaucipir tau PET imaging were performed. Associations of amyloid and tau PET with cognition were evaluated using linear regression. Interactions with age, apolipoprotein E (APOE) ε4 status, and education were examined. RESULTS: Amyloid and tau PET were not associated with cognition in the overall sample (N = 423; mean: 57 ± 10 years; 50% female). However, younger age (< 55 years) and APOE ε4 were significant effect modifiers, worsening cognition in the presence of higher amyloid and tau. DISCUSSION: Higher levels of Aß and tau may have a pernicious effect on cognition among APOE ε4 carriers and younger adults, suggesting a potential role for targeted early interventions. HIGHLIGHTS: Risk and resilience factors influenced cognitive vulnerability due to Aß and tau. Higher fusiform tau associated with poorer visuospatial skills in younger adults. APOE ε4 interacted with Aß and tau to worsen cognition across multiple domains.

Leptin bioavailability and markers of brain atrophy and vascular injury in the middle age.

INTRODUCTION: We investigated the associations of leptin markers with cognitive function and magnetic resonance imaging (MRI) measures of brain atrophy and vascular injury in healthy middle-aged adults. METHODS: We included 2262 cognitively healthy participants from the Framingham Heart Study with neuropsychological evaluation; of these, 2028 also had available brain MRI. Concentrations of leptin, soluble leptin receptor (sOB-R), and their ratio (free leptin index [FLI]), indicating leptin bioavailability, were measured using enzyme-linked immunosorbent assays. Cognitive and MRI measures were derived using standardized protocols. RESULTS: Higher sOB-R was associated with lower fractional anisotropy (FA, ß = -0.114 ± 0.02, p < 0.001), and higher free water (FW, ß = 0.091 ± 0.022, p < 0.001) and peak-width skeletonized mean diffusivity (PSMD, ß = 0.078 ± 0.021, p < 0.001). Correspondingly, higher FLI was associated with higher FA (ß = 0.115 ± 0.027, p < 0.001) and lower FW (ß = -0.096 ± 0.029, p = 0.001) and PSMD (ß = -0.085 ± 0.028, p = 0.002). DISCUSSION: Higher leptin bioavailability was associated with better white matter (WM) integrity in healthy middle-aged adults, supporting the putative neuroprotective role of leptin in late-life dementia risk. HIGHLIGHTS: Higher leptin bioavailability was related to better preservation of white matter microstructure. Higher leptin bioavailability during midlife might confer protection against dementia. Potential benefits might be even stronger for individuals with visceral obesity. DTI measures might be sensitive surrogate markers of subclinical neuropathology.

Age differences in the change in cognition after stroke.

OBJECTIVE: To compare changes in cognitive trajectories after stroke between younger (18-64) and older (65+) adults, accounting for pre-stroke cognitive trajectories. MATERIALS AND METHODS: Pooled cohort study using individual participant data from 3 US cohorts (1971-2019), the Atherosclerosis Risk In Communities Study (ARIC), Framingham Offspring Study (FOS), and REasons for Geographic And Racial Differences in Stroke Study (REGARDS). Linear mixed effect models evaluated the association between age and the initial change (intercept) and rate of change (slope) in cognition after compared to before stroke. Outcomes were global cognition (primary), memory and executive function. RESULTS: We included 1,292 participants with stroke; 197 younger (47.2 % female, 32.5 % Black race) and 1,095 older (50.2 % female, 46.4 % Black race). Median (IQR) age at stroke was 59.7 (56.6-61.7) (younger group) and 75.2 (70.5-80.2) years (older group). Compared to the young, older participants had greater declines in global cognition (-1.69 point [95 % CI, -2.82 to -0.55] greater), memory (-1.05 point [95 % CI, -1.92 to -0.17] greater), and executive function (-3.72 point [95 % CI, -5.23 to -2.21] greater) initially after stroke. Older age was associated with faster declines in global cognition (-0.18 points per year [95 % CI, -0.36 to -0.01] faster) and executive function (-0.16 [95 % CI, -0.26 to -0.06] points per year for every 10 years of higher age), but not memory (-0.006 [95 % CI, -0.15 to 0.14]), after compared to before stroke. CONCLUSION: Older age was associated with greater post-stroke cognitive declines, accounting for differences in pre-stroke cognitive trajectories between the old and the young.

Temporal Trends in the Remaining Lifetime Risk of Cardiovascular Disease Among Middle-Aged Adults Across 6 Decades: The Framingham Study.

BACKGROUND: The remaining lifetime risk (RLR) is the probability of developing an outcome over the remainder of one's lifespan at any given age. The RLR for atherosclerotic cardiovascular disease (ASCVD) in three 20-year periods were assessed using data from a single community-based cohort study of predominantly White participants. METHODS: Longitudinal data from the Framingham study in 3 epochs (epoch 1, 1960-1979; epoch 2, 1980-1999; epoch 3, 2000-2018) were evaluated. The RLR of a first ASCVD event (myocardial infarction, coronary heart disease death, or stroke) from 45 years of age (adjusting for competing risk of death) in the 3 epochs were compared overall, and according to the following strata: sex, body mass index, blood pressure and cholesterol categories, diabetes, smoking, and Framingham risk score groups. RESULTS: There were 317 849 person-years of observations during the 3 epochs (56% women; 94% White) and 4855 deaths occurred. Life expectancy rose by 10.1 years (men) to 11.9 years (women) across the 3 epochs. There were 1085 ASCVD events over the course of 91 330 person-years in epoch 1, 1330 ASCVD events over the course of 107 450 person-years in epoch 2, and 775 ASCVD events over the course of 119 069 person-years in epoch 3. The mean age at onset of first ASCVD event was greater in the third epoch by 8.1 years (men) to 10.3 years (women) compared with the first epoch. The RLR of ASCVD from 45 years of age declined from 43.7% in epoch 1 to 28.1% in epoch 3 (P<0.0001), a finding that was consistent in both sexes (RLR [epoch 1 versus epoch 3], 36.3% versus 26.5% [women]; 52.5% versus 30.1% [men]; P<0.001 for both). The lower RLR of ASCVD in the last 2 epochs was observed consistently across body mass index, blood pressure, cholesterol, diabetes, smoking, and Framingham risk score strata (P<0.001 for all). The RLR of coronary heart disease events and stroke declined in both sexes (P<0.001). CONCLUSIONS: Over the past 6 decades, mean life expectancy increased and the RLR of ASCVD decreased in the community-based, predominantly White Framingham study. The residual burden of ASCVD underscores the importance of continued and effective primary prevention efforts with better screening for risk factors and their effective treatment.

Gene-mapping study of extremes of cerebral small vessel disease reveals TRIM47 as a strong candidate.

Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5' UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer's disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work.

Obesity impacts the expression of Alzheimer's disease-related genes: The Framingham Heart Study.

INTRODUCTION: We investigated associations of obesity with the expression of Alzheimer's disease (AD)-related genes in a large community-based cohort. METHODS: The sample consisted of 5619 participants from the Framingham Heart Study. Obesity metrics included body mass index (BMI) and waist-to-hip ratio (WHR). Gene expression was measured for a set of 74 AD-related genes, derived by integrating genome-wide association study results with functional genomics data. RESULTS: Obesity metrics were associated with the expression of 21 AD-related genes. The strongest associations were observed with CLU, CD2AP, KLC3, and FCER1G. Unique associations were noted with TSPAN14, SLC24A4 for BMI, and ZSCAN21, BCKDK for WHR. After adjustment for cardiovascular risk factors, 13 associations remained significant for BMI and 8 for WHR. Dichotomous obesity metrics exhibited unique associations with EPHX2 for BMI, and with TSPAN14 for WHR. DISCUSSION: Obesity was associated with AD-related gene expression; these findings shed light on the molecular pathways linking obesity to AD.

Higher Dietary Inflammatory Index scores are associated with brain MRI markers of brain aging: Results from the Framingham Heart Study Offspring cohort.

INTRODUCTION: We investigated cross-sectional associations between the Dietary Inflammatory Index (DII) and measures of brain volume and cerebral small vessel disease among participants of the Framingham Heart Study Offspring cohort. METHODS: A total of 1897 participants (mean ± standard deviation, age 62±9) completed Food Frequency Questionnaires and brain magnetic resonance imaging (MRI). RESULTS: Higher (pro-inflammatory) DII scores, averaged across a maximum of three time points, were associated with smaller total brain volume (beta ± standard error: -0.16 ± 0.03; P < .0001) after adjustment for demographic, clinical, and lifestyle covariates. In addition, higher DII scores were associated with smaller total gray matter volume (-0.08 ± 0.03; P = .003) and larger lateral ventricular volume (0.04 ± 0.02; P = .03). No associations were observed with other brain MRI measures. DISCUSSION: Our findings showed associations between higher DII scores and global brain MRI measures. As we are one of the first groups to report on the associations between higher DII scores and brain volume, replication is needed to confirm our findings.

Vascular risk factors as predictors of epilepsy in older age: The Framingham Heart Study.

OBJECTIVE: Stroke is the most common cause of epilepsy in older age. Subclinical cerebrovascular disease is believed to underlie some of the 30%-50% of late-onset epilepsy without a known cause (Li et al. Epilepsia. 1997;38:1216; Cleary et al. Lancet. 2004;363:1184). We studied the role of modifiable vascular risk factors in predicting subsequent epilepsy among participants ages 45 or older in the Framingham Heart Study (FHS), a longitudinal, community-based study. METHODS: Participants of the Offspring Cohort who attended FHS exam 5 (1991-1995) were included who were at least 45-years-old at that time, had available vascular risk factor data, and epilepsy follow-up (n = 2986, mean age 58, 48% male). Adjudication of epilepsy cases included review of medical charts to exclude seizure mimics and acute symptomatic seizures. The vascular risk factors studied included hypertension, diabetes mellitus, smoking, and hyperlipidemia. The role of the Framingham Stroke Risk Profile score was also investigated. Cox proportional hazards regression models were used for the analyses. RESULTS: Fifty-five incident epilepsy cases were identified during a mean of 19 years of follow-up. Hypertension was associated with a near 2-fold risk (hazard ratio [HR]: 1.93, 95% confidence interval [CI]: 1.10-3.37, p = .022) of developing epilepsy, even after adjustment for prevalent and interim stroke. In secondary analysis, excluding patients with normal blood pressure who were receiving anti-HTN (anti-hypertensive) treatment (n = 2613, 50 incident epilepsy cases) the association was (HR: 2.44, 95% CI: 1.36-4.35, p = .003). SIGNIFICANCE: Our results offer further evidence that hypertension, a potentially modifiable and highly prevalent vascular risk factor in the general population, increases 2- to 2.5-fold the risk of developing late-onset epilepsy.

Insomnia symptom severity and cognitive performance: Moderating role of APOE genotype.

INTRODUCTION: We evaluated whether insomnia symptom severity was associated with cognitive function, and whether this relationship was modified by biomarkers associated with Alzheimer's disease risk. METHODS: We examined insomnia symptoms and neuropsychological performance 3.4 years later in 511 dementia-free Framingham Heart Study participants (62.65 ± 8.7 years, 50.9% male). Additionally, we explored insomnia symptoms combined with self-reported short habitual sleep duration and effect modification by apolipoprotein E (APOE) ε4 allele status. RESULTS: More severe insomnia symptoms were associated with lower performance on global cognition, and immediate and delayed Logical Memory recall, especially when insomnia symptoms were combined with short sleep duration. The association between insomnia symptoms and poorer memory recall was more pronounced in APOE ε4 allele carriers. DISCUSSION: Insomnia symptom severity was associated with worse subsequent global cognitive and memory performance, which was especially apparent in APOE ε4 allele carriers, suggesting that poor sleep might be particularly detrimental when the brain is already vulnerable to neurodegeneration.

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.

Digital Peripheral Arterial Tonometry and Cardiovascular Disease Events: The Framingham Heart Study.

Background and Purpose: Novel noninvasive measures of vascular function are emerging as subclinical markers for cardiovascular disease (CVD) and may be useful to predict CVD events. The purpose of our prospective study was to assess associations between digital peripheral arterial tonometry (PAT) measures and first-onset major CVD events in a sample of FHS (Framingham Heart Study) participants. Methods: Using a fingertip PAT device, we assessed pulse amplitude in Framingham Offspring and Third Generation participants (n=3865; mean age, 55±14 years; 52% women) at baseline and in 30-second intervals for 4 minutes during reactive hyperemia. The PAT ratio (relative hyperemia index) was calculated as the post-to-pre occlusion pulse signal ratio in the occluded arm, relative to the same ratio in the control (nonoccluded) arm, and corrected for baseline vascular tone. Baseline pulse amplitude and PAT ratio during hyperemia are measures of pressure pulsatility and microvascular function in the finger, respectively. We used Cox proportional hazards regression to relate PAT measures in the fingertip to incident CVD events. Results: During follow-up (median, 9.2 years; range, 0.04­10.0 years), 270 participants (7%) experienced new-onset CVD events (n=270). In multivariable models adjusted for cardiovascular risk factors, baseline pulse amplitude (hazard ratio [HR] per 1 SD, 1.04 [95% CI, 0.90­1.21]; P=0.57) and PAT ratio (HR, 0.95 [95% CI, 0.84­1.08]; P=0.43) were not significantly related to incident composite CVD events, including myocardial infarction or heart failure. However, higher PAT ratio (HR, 0.76 [95% CI, 0.61­0.94]; P=0.013), but not baseline pulse amplitude (HR, 1.15 [95% CI, 0.89­1.49]; P=0.29), was related to lower risk for incident stroke. In a sensitivity analysis by stroke subtype, higher PAT ratio was related to lower risk of incident ischemic stroke events (HR, 0.68 [95% CI, 0.53­0.86]; P=0.001). Conclusions: Novel digital PAT measures may represent a marker of stroke risk in the community.

Circulating Monocyte Chemoattractant Protein-1 and Risk of Stroke: Meta-Analysis of Population-Based Studies Involving 17 180 Individuals.

Rationale: Proinflammatory cytokines have been identified as potential targets for lowering vascular risk. Experimental evidence and Mendelian randomization suggest a role of MCP-1 (monocyte chemoattractant protein-1) in atherosclerosis and stroke. However, data from large-scale observational studies are lacking. Objective: To determine whether circulating levels of MCP-1 are associated with risk of incident stroke in the general population. Methods and Results: We used previously unpublished data on 17 180 stroke-free individuals (mean age, 56.7±8.1 years; 48.8% men) from 6 population-based prospective cohort studies and explored associations between baseline circulating MCP-1 levels and risk of any stroke, ischemic stroke, and hemorrhagic stroke during a mean follow-up interval of 16.3 years (280 522 person-years at risk; 1435 incident stroke events). We applied Cox proportional-hazards models and pooled hazard ratios (HRs) using random-effects meta-analyses. After adjustments for age, sex, race, and vascular risk factors, higher MCP-1 levels were associated with increased risk of any stroke (HR per 1-SD increment in ln-transformed MCP-1, 1.07; 95% CI, 1.01-1.14). Focusing on stroke subtypes, we found a significant association between baseline MCP-1 levels and higher risk of ischemic stroke (HR, 1.11 [1.02-1.21]) but not hemorrhagic stroke (HR, 1.02 [0.82-1.29]). The results followed a dose-response pattern with a higher risk of ischemic stroke among individuals in the upper quartiles of MCP-1 levels as compared with the first quartile (HRs, second quartile: 1.19 [1.00-1.42]; third quartile: 1.35 [1.14-1.59]; fourth quartile: 1.38 [1.07-1.77]). There was no indication for heterogeneity across studies, and in a subsample of 4 studies (12 516 individuals), the risk estimates were stable after additional adjustments for circulating levels of IL (interleukin)-6 and high-sensitivity CRP (C-reactive protein). Conclusions: Higher circulating levels of MCP-1 are associated with increased long-term risk of stroke. Our findings along with genetic and experimental evidence suggest that MCP-1 signaling might represent a therapeutic target to lower stroke risk.Visual Overview: An online visual overview is available for this article.

Associations of the Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay diet with cardiac remodelling in the community: the Framingham Heart Study.

Normal cardiac function is directly associated with the maintenance of cerebrovascular health. Whether the Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) diet, designed for the maintenance of neurocognitive health, is associated with cardiac remodelling is unknown. We evaluated 2512 Framingham Offspring Cohort participants who attended the eighth examination cycle and had available dietary and echocardiographic data (mean age 66 years; 55 % women). Using multivariable regression, we related the cumulative MIND diet score (independent variable) to left ventricular (LV) ejection fraction, left atrial emptying fraction, LV mass (LVM), E/e' ratio (dependent variables; primary), global longitudinal strain, global circumferential strain (GCS), mitral annular plane systolic excursion, longitudinal segmental synchrony, LV hypertrophy and aortic root diameter (secondary). Adjusting for age, sex and energy intake, higher cumulative MIND diet scores were associated with lower values of indices of LV diastolic (E/e' ratio: logß = -0·03) and systolic function (GCS: ß = -0·04) and with higher values of LVM (logß = 0·02), all P ≤ 0·01. We observed effect modification by age in the association between the cumulative MIND diet score and GCS. When we further adjusted for clinical risk factors, the associations of the cumulative MIND diet score with GCS in participants ≥66 years (ß = -0·06, P = 0·005) and LVM remained significant. In our community-based sample, relations between the cumulative MIND diet score and cardiac remodelling differ among indices of LV structure and function. Our results suggest that favourable associations between a higher cumulative MIND diet score and indices of LV function may be influenced by cardiometabolic and lifestyle risk factors.

Bone Mineral Density Measurements and Association With Brain Structure and Cognitive Function: The Framingham Offspring Cohort.

BACKGROUND: Bone mineral density (BMD) is a potential surrogate marker of lifetime estrogen exposure previously linked to increased risk of Alzheimer dementia among elderly women. We examine the association between BMD in the "young old" with imaging biomarkers of brain aging and cognitive performance. METHODS: Offspring participants (N=1905, mean age 66) of a population-based cohort who had BMD, brain imaging and detailed cognitive assessment were included in the study. Sex-stratified, linear, and logistic regression models were used for analysis. RESULTS: Higher femoral neck BMD was associated with lower white matter hyperintensity burden and better performance on Trails B-A in both sexes, even after adjustment for cerebrovascular risk factors. Among women, the positive association with Trails B-A performance was seen only in APOE4 allele carriers. Higher BMD measurements were linked to better visual reproductions test performance in men. Finally, among women, higher femoral trochanter BMD was associated with better logical memory and Hooper visual organization test performance. CONCLUSION: Among the "young old," higher BMD is associated with less white matter hyperintensity burden and better, domain-specific, cognitive performance. This suggests that lifetime estrogen exposure may modulate the degree of cumulative vascular brain injury independent of cerebrovascular risk factors.

Incidence of Transient Ischemic Attack and Association With Long-term Risk of Stroke.

Importance: Accurate estimation of the association between transient ischemic attack (TIA) and risk of subsequent stroke can help to improve preventive efforts and limit the burden of stroke in the population. Objective: To determine population-based incidence of TIA and the timing and long-term trends of stroke risk after TIA. Design, Setting, and Participants: Retrospective cohort study (Framingham Heart Study) of prospectively collected data of 14 059 participants with no history of TIA or stroke at baseline, followed up from 1948-December 31, 2017. A sample of TIA-free participants was matched to participants with first incident TIA on age and sex (ratio, 5:1). Exposures: Calendar time (TIA incidence calculation, time-trends analyses), TIA (matched longitudinal cohort). Main Outcomes and Measures: The main outcomes were TIA incidence rates; proportion of stroke occurring after TIA in the short term (7, 30, and 90 days) vs the long term (>1-10 years); stroke after TIA vs stroke among matched control participants without TIA; and time trends of stroke risk at 90 days after TIA assessed in 3 epochs: 1954-1985, 1986-1999, and 2000-2017. Results: Among 14 059 participants during 66 years of follow-up (366 209 person-years), 435 experienced TIA (229 women; mean age, 73.47 [SD, 11.48] years and 206 men; mean age, 70.10 [SD, 10.64] years) and were matched to 2175 control participants without TIA. The estimated incidence rate of TIA was 1.19/1000 person-years. Over a median of 8.86 years of follow-up after TIA, 130 participants (29.5%) had a stroke; 28 strokes (21.5%) occurred within 7 days, 40 (30.8%) occurred within 30 days, 51 (39.2%) occurred within 90 days, and 63 (48.5%) occurred more than 1 year after the index TIA; median time to stroke was 1.64 (interquartile range, 0.07-6.6) years. The age- and sex-adjusted cumulative 10-year hazard of incident stroke for patients with TIA (130 strokes among 435 cases) was 0.46 (95% CI, 0.39-0.55) and for matched control participants without TIA (165 strokes among 2175) was 0.09 (95% CI, 0.08-0.11); fully adjusted hazard ratio [HR], 4.37 (95% CI, 3.30-5.71; P < .001). Compared with the 90-day stroke risk after TIA in 1948-1985 (16.7%; 26 strokes among 155 patients with TIA), the risk between 1986-1999 was 11.1% (18 strokes among 162 patients) and between 2000-2017 was 5.9% (7 strokes among 118 patients). Compared with the first epoch, the HR for 90-day risk of stroke in the second epoch was 0.60 (95% CI, 0.33-1.12) and in the third epoch was 0.32 (95% CI, 0.14-0.75) (P = .005 for trend). Conclusions and Relevance: In this population-based cohort study from 1948-2017, the estimated crude TIA incidence was 1.19/1000 person-years, the risk of stroke was significantly greater after TIA compared with matched control participants who did not have TIA, and the risk of stroke after TIA was significantly lower in the most recent epoch from 2000-2017 compared with an earlier period from 1948-1985.