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Abstract Background Arterial stiffness is a degenerative modification in the arterial wall that significantly affects normal aging. Arterial hypertension is a major risk factor for cerebrovascular impairment. Pulse wave velocity (PWV) is an established gold standard for measuring arterial stiffness. Studies demonstrated that individuals with elevated blood pressure (BP) and PWV are more likely to experience worse cognitive decline compared to those with either condition alone. The aim of this review is to explore the clinical importance of arterial stiffness for cognitive function in older adults with hypertension. Methods The systematic review was reported following the PRISMA 2020 guidelines and Cochrane protocol and was registered in NIHR PROSPERO. PubMed, Embase, Web of Science, CINAHL, and Cochrane databases were searched for relevant publications up to December 2022. Articles were filtered by age and type of study and only those including a sample size of at least 500 individuals were selected. Screening of abstracts and full-text review of selected articles were carried out through Covidence. Results The full-text review included a total of 434 articles. Twenty-eight prospective studies have met the inclusion criteria. Selected studies used PWV as the main measurement of stiffness: 24 used carotid-femoral, 2 used brachial-ankle, 1 used aortic PWV, and 11 compared different measures. Studies demonstrated a strong association between increased BP and PWV with brain damage and cognitive deterioration among older adults. One study did not find an interaction with hypertension, while another study found that PWV but not BP was associated with cognitive decline. Few studies showed that the association between stiffness and cognitive outcomes was not significant after adjustment for BP. Several authors suggested that cognitive decline induced by stiff vasculature and hypertension benefited from antihypertensive therapy. Conclusion The results of this review demonstrated that arterial hypertension is an important factor linking arterial stiffness to cognitive health in older individuals. BP plays a crucial role in brain integrity, whereas PWV was shown to be a strong measure associated with cognitive decline. Together, they can lead to disabling cognitive outcomes. Early screening of stiffness, BP control, and compliance with treatment are essential for cerebrovascular disease prevention. Trial registration NIHR PROSPERO registry ID: CRD42022379887 .

IntroductionNeurobiological changes in the hippocampus are a common consequence of aging. However, there are differences in the rate of decline and overall volume loss in people with no cognitive impairment compared to those with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). This systematic literature review was conducted to determine the relationship between hippocampal atrophy and changes in hippocampal volume in the non-cognitively impaired brain and those with MCI or AD.MethodsThis systematic review was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. The PubMed database was searched up to September 15, 2022, for longitudinal magnetic resonance imaging studies reporting hippocampal atrophy or volume change in cognitively normal aging individuals and patients with MCI and/or AD. Study selection was divided into two steps: (1) identification and retrieval of relevant studies; (2) screening the studies by (a) title/abstract and (b) full text. Two teams, each consisting of two independent reviewers, determined whether the publications met the inclusion criteria for the systematic review. An evidence table was populated with data extracted from eligible publications and inclusion in the final systematic review was confirmed.ResultsThe systematic search identified 357 publications that were initially screened by title/abstract, of which, 115 publications were retrieved and reviewed by full text for eligibility. Seventeen publications met the eligibility criteria; however, during data extraction, two studies were determined to not meet the inclusion criteria and were excluded. The remaining 15 studies were included in the systematic review. Overall, the results of these studies demonstrated that the hippocampus and hippocampal subfields change over time, with both decreased hippocampal volume and increased rate of hippocampal atrophy observed. Hippocampal changes in AD were observed to be greater than hippocampal changes in MCI, and changes in MCI were observed to be greater than those in normal aging populations.ConclusionPublished literature suggests that the rate of hippocampal decline and extent of loss is on a continuum that begins in people without cognitive impairment and continues to MCI and AD, and that differences between no cognitive impairment, MCI, and AD are quantitative rather than qualitative.

Background Pulse‐wave velocity is a measure of arterial stiffness and a risk factor for cardiovascular disease. Recently, an estimated pulse‐wave velocity (ePWV) was introduced that was predictive of increased risk of cardiovascular disease. Our objective was to determine whether ePWV was associated with cerebral small‐vessel disease on magnetic resonance imaging. Methods and Results We included 1257 participants from the NOMAS (Northern Manhattan Study). The ePWV values were calculated using a nonlinear function of age and mean arterial blood pressure. The association between ePWV and white matter hyperintensity volume was assessed. Modification by race and ethnicity was evaluated. Associations between ePWV and other cerebral small‐vessel disease markers, covert brain infarcts, cerebral microbleeds, and enlarged perivascular spaces, were explored as secondary outcomes. Mean±SD age of the cohort was 64±8 years; 61% were women; 18% self‐identified as non‐Hispanic Black, 67% as Hispanic, and 15% as non‐Hispanic White individuals. Mean±SD ePWV was 11±2 m/s in the total NOMAS population and was similar across race and ethnic groups. The ePWV was significantly associated with white matter hyperintensity volume (β=0.23 [95% CI, 0.20–0.26]) after adjustment. Race and ethnicity modified the association between ePWV and white matter hyperintensity volume, with stronger associations in Hispanic and non‐Hispanic Black individuals. Significant associations were found between ePWV and covert brain infarcts, cerebral microbleeds, and perivascular spaces after adjustment. Conclusions The ePWV function may provide a vascular mechanism for deleterious cerebrovascular outcomes in individuals with cerebral small‐vessel disease and is particularly apparent in the racial and ethnic minorities represented in the NOMAS cohort.

Background and aims: The presence of aortic arch plaques (AAP) is significantly associated with increased cardiovascular morbidity and mortality. Few studies have examined the incidence of AAP progression and factors which may contribute to it using transthoracic echocardiography (TTE). The objective of this study was to utilize sequential imaging of the aortic arch using TTE to examine the rate of AAP progression and its risk factors in a cohort of older adults. Methods: Participants enrolled in both the Cardiovascular Abnormalities and Brain Lesion study (years 2005–2010) and the Subclinical Atrial Fibrillation and Risk of Ischemic Stroke study (2014–2019) who underwent TTE with assessment of aortic arch plaques at both time points represent the study cohort. Results: 300 participants were included in the study. Mean age was 67.8 ± 7.5 years at baseline, and 76.7 ± 6.8 years at follow-up; 197 (65.7%) were women. At baseline, 87 (29%) had no significant AAP, 182 (60.7%) had evidence of small AAP (2.0–3.9 mm) and 31 (10.3%) had evidence of large (≥4 mm) AAP. At the time of follow-up assessment, 157 (52.3%) of participants exhibited progression of AAP with 70 (23.3%) having mild progression and 87 (29%) having severe progression. There were no significant demographic or clinical predictors of AAP progression except baseline plaque thickness itself which was significantly lower in the group with AAP progression. Conclusions: Our study demonstrates a high prevalence of AAP on TTE exam in a population-based cohort of older adults with a high incidence of AAP progression. TTE is a useful test for baseline and follow up imaging of AAP, even in subjects with no or little AAP at baseline.

ObjectivesLimited research exists on COVID-19 associated brain fog, and on the long-term cognitive and psychiatric sequelae in racially and ethnically diverse patients. We characterize the neuropsychological sequelae of post-acute COVID-19 in a diverse cohort and investigate whether COVID-19 clinical severity remains associated with brain fog and cognitive deficits approximately 2 years post infection.MethodsA cross-sectional study of patients with a history of COVID-19 hospitalization (March-September 2020). COVID-19 clinical severity was indexed using the National Early Warning Score 2 and a comprehensive neuropsychological tele-battery was administered 2 years post discharge. Pearson's r correlations assessed association, while independent sample t-tests examined group differences. Significant outcomes were further analyzed using multiple regression and ANCOVAs, adjusting for key covariates.ResultsIn 41 adult patients (19 female, 30 Hispanic, 13 Black, mean age of 65 (SD = 15), COVID-19 level of severity was associated with greater number of endorsed brain fog symptoms (Pearson's r = .34, 95% CI [.04, .59]), worse overall cognitive functioning (global cognition: r = -.36, 95% CI [-.61, -.05]) and reduced performance on an attention and working memory task (digit span backwards: r = -.41, 95% CI [-.66, -.09]) at 2-year follow-up. Brain fog symptoms most associated with COVID-19 severity included difficulty focusing (r = .46, 95% CI [.18, .67]), detached (r = .41, 95% CI [.12, .64]) and feeling sleepy (r = .40, 95% CI [.11, .63]). Patients' cognitive performance was generally below average (global cognition z-score: M = -.96, SD = .66), with group differences based on sex and ethnicity evidenced on individual cognitive tests.DiscussionThis study emphasizes the importance of continued research on the long-term effects of COVID-19 infection on neuropsychological outcomes, particularly among underrepresented, health-disparate groups. Greater understanding of these associations could improve detection and treatment of those at increased risk of cognitive decline or impairment.

Abstract INTRODUCTION Neurogranin (Ng) is considered a biomarker for synaptic dysfunction in Alzheimer's disease (AD). In contrast, the inflammasome complex has been shown to exacerbate AD pathology. METHODS We investigated the protein expression, morphological differences of Ng, and correlated Ng to hyperphosphorylated tau in the post mortem brains of 17 AD cases and 17 age‐ and sex‐matched controls. In addition, we correlated the Ng expression with two different epitopes of apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC). RESULTS We show a reduction of Ng immunopositive neurons and morphological differences in AD compared to controls. Ng immunostaining was negatively correlated with neurofibrillary tangles, humanized anti‐ASC (IC100) positive neurons and anti‐ASC positive microglia, in AD. DISCUSSION The finding of a negative correlation between Ng and ASC speck protein expression in post mortem brains of AD suggests that the activation of inflammasome/ASC speck pathway may play an important role in synaptic degeneration in AD. Highlights We show the role that neurogranin plays on post‐synaptic signaling in specific hippocampal regions. We demonstrate that there could be clinical implications of using neurogranin as a biomarker for dementia. We describe the loss of plasticity and neuronal scaffolding proteins in the present of AD pathology. We show the response of neuroinflammation when tau proteins phosphorylate in hippocampal neurons. We show that there is a potential therapeutic target for the inflammasome, and future studies may show that IC100, a humanized monoclonal antibody directed against ASC, may slow the progression of neurodegeneration.

Background Life's Essential 8 (LE8) is a new metric to define cardiovascular health. We aimed to describe LE8 among Hispanics/Latinos and its association with incident hypertension. Methods and Results The HCHS/SOL (Hispanic Community Health Study/Study of Latinos) is a study of Hispanic/Latino adults aged 18 to 74 years from 4 US communities. At visit 1 (2008–2011), information on behavioral and clinical factors (diet, smoking status, physical activity, sleep duration, body mass index, blood pressure, cholesterol, fasting glucose, and medication use) were measured and used to estimate an LE8 score (range, 0–100) for 14 772 participants. Hypertension was defined as systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥80 mm Hg, or self‐reported use of antihypertensive medications. Among the 5667 participants free from hypertension at visit 1, we used Poisson regression models to determine the multivariable adjusted association between LE8 and incident hypertension in 2014 to 2017. All analyses accounted for the complex survey design of the study. Mean population age was 41 years, and 21.6% (SE, 0.7) had high cardiovascular health (LE8 ≥80). Mean LE8 score (68.2; SE, 0.3) varied by Hispanic/Latino background (P

Background Brain arterial diameters (BADs) are novel imaging biomarkers of cerebrovascular disease, cognitive decline, and dementia. Traditional vascular risk factors have been associated with BADs, but whether there may be genetic determinants of BADs is unknown. Methods and Results The authors studied 4150 participants from 6 geographically diverse population‐based cohorts (40% European, 14% African, 22% Hispanic, 24% Asian ancestries). Brain arterial diameters for 13 segments were measured and averaged to obtain a global measure of BADs as well as the posterior and anterior circulations. A genome‐wide association study revealed 14 variants at one locus associated with global BAD at genome‐wide significance (P

Background Guideline‐based hypertension management is integral to the prevention of stroke. We examine trends in antihypertensive medications prescribed after stroke and assess how well a prescriber's blood pressure (BP) medication choice adheres to clinical practice guidelines (BP‐guideline adherence). Methods and Results The FSR (Florida Stroke Registry) uses statewide data prospectively collected for all acute stroke admissions. Based on established guidelines, we defined optimal BP‐guideline adherence using the following hierarchy of rules: (1) use of an angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker as first‐line antihypertensive among diabetics; (2) use of thiazide‐type diuretics or calcium channel blockers among Black patients; (3) use of beta blockers among patients with compelling cardiac indication; (4) use of thiazide, angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker, or calcium channel blocker class as first line in all others; (5) beta blockers should be avoided as first line unless there is a compelling cardiac indication. A total of 372 254 cases from January 2010 to March 2020 are in the FSR with a diagnosis of acute ischemic stroke, hemorrhagic stroke, transient ischemic attack, or subarachnoid hemorrhage; 265 409 with complete data were included in the final analysis. Mean age was 70±14 years; 50% were women; and index stroke subtypes were 74% acute ischemic stroke, 11% intracerebral hemorrhage, 11% transient ischemic attack, and 4% subarachnoid hemorrhage. BP‐guideline adherence to each specific rule ranged from 48% to 74%, which is below quality standards of 80%, and was lower among Black patients (odds ratio, 0.7 [95% CI, 0.7–0.83]; P

Immunoglobulin A protects against infectious disease and contributes to autoimmune and inflammatory disorders. Here, the authors perform a genome-wide association study for serum IgA levels, identifying 20 genome-wide significant loci, providing new insights into the genetic regulation of IgA levels.

Background Premature ventricular contractions (PVCs) and nonsustained ventricular tachycardia (NSVT) are known to be associated with reduced left ventricular (LV) ejection fraction and adverse outcomes in patients with structural heart disease. The relationship between subclinical LV dysfunction and ventricular arrhythmias in the general population is not established. Methods and Results Participants in the SAFARIS (Subclinical Atrial Fibrillation and Risk of Ischemic Stroke) study with normal left ventricular ejection fraction (n=503; mean age 77 years, 63% women) underwent 14‐day electrocardiographic monitoring and 2‐dimensional echocardiography. Frequent PVCs were defined as PVCs >500 per 24 hours and NSVT as ≥4 consecutive ventricular ectopic beats. Reduced LV global longitudinal strain (GLS) was used as an indicator of subclinical LV dysfunction. Seventy‐six participants (15.1%) had PVCs >500/d, 117 (23.3%) had NSVT episodes. LV GLS was significantly reduced in both frequent PVCs and NSVT groups (P−15.8%) carried a 2‐fold increase in risk of ventricular arrhythmias (aOR, 2.18, P=0.029 for PVCs; aOR, 2.09, P=0.026 for NSVT). Conclusions PVCs and NSVT episodes were frequent in this community‐based elderly cohort with normal left ventricular ejection fraction and were independently associated with lower LV GLS. The association between LV dysfunction and ventricular arrhythmias is present at an early, subclinical stage, an observation that carries possible preventative implications.

OBJECTIVES:. Temporal trends and factors associated with the withdrawal of life-sustaining therapy (WLST) after acute stroke are not well determined. DESIGN:. Observational study (2008–2021). SETTING:. Florida Stroke Registry (152 hospitals). PATIENTS:. Acute ischemic stroke (AIS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH) patients. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Importance plots were performed to generate the most predictive factors of WLST. Area under the curve (AUC) for the receiver operating curve were generated for the performance of logistic regression (LR) and random forest (RF) models. Regression analysis was applied to evaluate temporal trends. Among 309,393 AIS patients, 47,485 ICH patients, and 16,694 SAH patients; 9%, 28%, and 19% subsequently had WLST. Patients who had WLST were older (77 vs 70 yr), more women (57% vs 49%), White (76% vs 67%), with greater stroke severity on the National Institutes of Health Stroke Scale greater than or equal to 5 (29% vs 19%), more likely hospitalized in comprehensive stroke centers (52% vs 44%), had Medicare insurance (53% vs 44%), and more likely to have impaired level of consciousness (38% vs 12%). Most predictors associated with the decision to WLST in AIS were age, stroke severity, region, insurance status, center type, race, and level of consciousness (RF AUC of 0.93 and LR AUC of 0.85). Predictors in ICH included age, impaired level of consciousness, region, race, insurance status, center type, and prestroke ambulation status (RF AUC of 0.76 and LR AUC of 0.71). Factors in SAH included age, impaired level of consciousness, region, insurance status, race, and stroke center type (RF AUC of 0.82 and LR AUC of 0.72). Despite a decrease in the rates of early WLST (< 2 d) and mortality, the overall rates of WLST remained stable. CONCLUSIONS:. In acute hospitalized stroke patients in Florida, factors other than brain injury alone contribute to the decision to WLST. Potential predictors not measured in this study include education, culture, faith and beliefs, and patient/family and physician preferences. The overall rates of WLST have not changed in the last 2 decades.

Background The association between common carotid artery intima‐media thickness (CCA‐IMT) and incident carotid plaque has not been characterized fully. We therefore aimed to precisely quantify the relationship between CCA‐IMT and carotid plaque development. Methods and Results We undertook an individual participant data meta‐analysis of 20 prospective studies from the Proof‐ATHERO (Prospective Studies of Atherosclerosis) consortium that recorded baseline CCA‐IMT and incident carotid plaque involving 21 494 individuals without a history of cardiovascular disease and without preexisting carotid plaque at baseline. Mean baseline age was 56 years (SD, 9 years), 55% were women, and mean baseline CCA‐IMT was 0.71 mm (SD, 0.17 mm). Over a median follow‐up of 5.9 years (5th–95th percentile, 1.9–19.0 years), 8278 individuals developed first‐ever carotid plaque. We combined study‐specific odds ratios (ORs) for incident carotid plaque using random‐effects meta‐analysis. Baseline CCA‐IMT was approximately log‐linearly associated with the odds of developing carotid plaque. The age‐, sex‐, and trial arm–adjusted OR for carotid plaque per SD higher baseline CCA‐IMT was 1.40 (95% CI, 1.31–1.50; I2=63.9%). The corresponding OR that was further adjusted for ethnicity, smoking, diabetes, body mass index, systolic blood pressure, low‐ and high‐density lipoprotein cholesterol, and lipid‐lowering and antihypertensive medication was 1.34 (95% CI, 1.24–1.45; I2=59.4%; 14 studies; 16 297 participants; 6381 incident plaques). We observed no significant effect modification across clinically relevant subgroups. Sensitivity analysis restricted to studies defining plaque as focal thickening yielded a comparable OR (1.38 [95% CI, 1.29–1.47]; I2=57.1%; 14 studies; 17 352 participants; 6991 incident plaques). Conclusions Our large‐scale individual participant data meta‐analysis demonstrated that CCA‐IMT is associated with the long‐term risk of developing first‐ever carotid plaque, independent of traditional cardiovascular risk factors.

Given the interdependence of multiple factors in age-related vestibular loss (e.g., balance, vision, cognition), it is important to examine the individual contributions of these factors with ARVL. While the relationship between the vestibular and visual systems has been well studied (Bronstein et al., 2015), little is known about the association of the peripheral vestibular system with neurodegenerative disorders (Cronin et al., 2017). Further, emerging research developments implicate the vestibular system as an opportunity for examining brain function beyond balance, and into other areas, such as cognition and psychological functioning. Additionally, the bidirectional impact of psychological functioning is understudied in ARVL. Recognition of ARVL as part of a multifaceted aging process will help guide the development of integrated interventions for patients who remain at risk for decline. In this review, we will discuss a wide variety of characteristics of the peripheral vestibular system and ARVL, how it relates to neurodegenerative diseases, and correlations between ARVL and balance, vision, cognitive, and psychological dysfunction. We also discuss clinical implications as well as future directions for research, with an emphasis on improving care for patients with ARVL.

Acute ischemic stroke impacts men and women differently. Here, the authors show how different lesion patterns in men and women are linked to the extent of stroke severity.

BackgroundWith our aging population, many individuals are at risk of developing age-related cognitive decline. Physical exercise has been demonstrated to enhance cognitive performance in aging adults. This study examined the effects of 8 weeks of aerobic exercise on cognitive performance and cardiorespiratory fitness in sedentary aging adults at risk for cognitive decline.MethodsFifty-two participants (age 62.9 ± 6.8, 76.9% female) engaged in eight weeks of moderate-to high-intensity exercise (19 in-person, 33 remotely). Global cognition was measured by the Repeatable Battery for the Assessment of Neuropsychological Status, the Delis-Kaplan Executive Function System, and the Digit Span subtest of the Wechsler Adult Intelligence Scale (WAIS) Fourth Edition. Cardiorespiratory fitness was measured via heart rate recovery at minute 1 (HRR1) and 2 (HRR2), and exercise engagement (defined as percent of total exercise time spent in the prescribed heart rate zone). We measured pre and post changes using paired t-tests and mixed effects models, and investigated the association between cardiorespiratory and cognitive performance using multiple regression models. Cohen's d were calculated to estimate effect sizes.ResultsOverall, 63.4 % of participants demonstrated high engagement (≥ 70% total exercise time spent in the prescribed heart rate zone). There were significant pre-post improvements in verbal fluency and verbal memory, and a significant decrement in working memory, but these were associated with small effect sizes (Cohen's d

Background The major risk factors for atherosclerotic cardiovascular disease differ by race or ethnicity but have largely been defined using populations of European ancestry. Despite the rising prevalence of cardiovascular disease in Africa there are few related data from African populations. Therefore, we compared the association of established cardiovascular risk factors with carotid‐intima media thickness (CIMT), a subclinical marker of atherosclerosis, between African, African American, Asian, European, and Hispanic populations. Methods and Results Cross‐sectional analyses of 34 025 men and women drawn from 15 cohorts in Africa, Asia, Europe, and North America were undertaken. Classical cardiovascular risk factors were assessed and CIMT measured using B‐mode ultrasound. Ethnic differences in the association of established cardiovascular risk factors with CIMT were determined using a 1‐stage individual participant data meta‐analysis with beta coefficients expressed as a percentage using the White population as the reference group. CIMT adjusted for risk factors was the greatest among African American populations followed by Asian, European, and Hispanic populations with African populations having the lowest mean CIMT. In all racial or ethnic groups, men had higher CIMT levels compared with women. Age, sex, body mass index, and systolic blood pressure had a significant positive association with CIMT in all races and ethnicities at varying magnitudes. When compared with European populations, the association of age, sex, and systolic blood pressure with CIMT was weaker in all races and ethnicities. Smoking (beta coefficient, 0.39; 95% CI, 0.09–0.70), body mass index (beta coefficient, 0.05; 95% CI, 0.01–0.08) and glucose (beta coefficient, 0.13; 95% CI, 0.06–0.19) had the strongest positive association with CIMT in the Asian population when compared with all other racial and ethnic groups. High‐density lipoprotein‐cholesterol had significant protective effects in African American (beta coefficient, −0.31; 95% CI, −0.42 to −0.21) and African (beta coefficient, −0.26; 95% CI, −0.31 to −0.19) populations only. Conclusions The strength of association between established cardiovascular risk factors and CIMT differed across the racial or ethnic groups and may be due to lifestyle risk factors and genetics. These differences have implications for race‐ ethnicity‐specific primary prevention strategies and also give insights into the differential contribution of risk factors to the pathogenesis of cardiovascular disease. The greatest burden of subclinical atherosclerosis in African American individuals warrants further investigations.

Background purposeA substantial number of patients with acute ischemic stroke (AIS) experience multiple acute lesions (MAL). We here aimed to scrutinize MAL in a large radiologically deep-phenotyped cohort.Materials and methodsAnalyses relied upon imaging and clinical data from the international MRI-GENIE study. Imaging data comprised both Fluid-attenuated inversion recovery (FLAIR) for white matter hyperintensity (WMH) burden estimation and diffusion-weighted imaging (DWI) sequences for the assessment of acute stroke lesions. The initial step featured the systematic evaluation of occurrences of MAL within one and several vascular supply territories. Associations between MAL and important imaging and clinical characteristics were subsequently determined. The interaction effect between single and multiple lesion status and lesion volume was estimated by means of Bayesian hierarchical regression modeling for both stroke severity and functional outcome.ResultsWe analyzed 2,466 patients (age = 63.4 ± 14.8, 39% women), 49.7% of which presented with a single lesion. Another 37.4% experienced MAL in a single vascular territory, while 12.9% featured lesions in multiple vascular territories. Within most territories, MAL occurred as frequently as single lesions (ratio ∼1:1). Only the brainstem region comprised fewer patients with MAL (ratio 1:4). Patients with MAL presented with a significantly higher lesion volume and acute NIHSS (7.7 vs. 1.7 ml and 4 vs. 3, pFDR < 0.001). In contrast, patients with a single lesion were characterized by a significantly higher WMH burden (6.1 vs. 5.3 ml, pFDR = 0.048). Functional outcome did not differ significantly between patients with single versus multiple lesions. Bayesian analyses suggested that the association between lesion volume and stroke severity between single and multiple lesions was the same in case of anterior circulation stroke. In case of posterior circulation stroke, lesion volume was linked to a higher NIHSS only among those with MAL.ConclusionMultiple lesions, especially those within one vascular territory, occurred more frequently than previously reported. Overall, multiple lesions were distinctly linked to a higher acute stroke severity, a higher total DWI lesion volume and a lower WMH lesion volume. In posterior circulation stroke, lesion volume was linked to a higher stroke severity in multiple lesions only.

The optimal management of patients with asymptomatic carotid stenosis (ACS) is the subject of extensive debate. According to the 2017 European Society for Vascular Surgery guidelines, carotid endarterectomy should (Class IIa; Level of Evidence: B) or carotid artery stenting may be considered (Class IIb; Level of Evidence: B) in the presence of one or more clinical/imaging characteristics that may be associated with an increased risk of late ipsilateral stroke (e.g., silent embolic infarcts on brain computed tomography/magnetic resonance imaging, progression in the severity of ACS, a history of contralateral transient ischemic attack/stroke, microemboli detection on transcranial Doppler, etc.), provided documented perioperative stroke/death rates are 5 years. Besides these clinical/imaging characteristics, there are additional individual, ethnic/racial or social factors that should probably be evaluated in the decision process regarding the optimal management of these patients, such as individual patient needs/patient choice, patient compliance with best medical treatment, patient sex, culture, race/ethnicity, age and comorbidities, as well as improvements in imaging/operative techniques/outcomes. The present multispecialty position paper will present the rationale why the management of patients with ACS may need to be individualized.

OBJECTIVES/GOALS: The goal of Miami CTSI’s Mentored Translational Research Scholars (KL2) Program is to identify outstanding early-stage investigators and prepare them to become the next generation of highly skilled independent researchers who translate fundamental knowledge and new technologies from the laboratory to the clinic and to the community. METHODS/STUDY POPULATION: Evaluation of the KL2 program focused on assessing progress in the following areas: 1) scholar productivity during and after graduating from the program; 2) continued engagement of KL2 program graduates in clinical and translational research; scholar productivity during and after graduating from the program; 3) outcomes such as establishing independent research careers, obtaining research funding, and establishing collaborations; and 4) research impact. We used a developmental evaluation approach and benefits-framework model to conduct program evaluation, incorporating both in a program-specific logic model. Bi-annual surveys were used to measure scholar feedback and progress, and utilization of CTSI services. RESULTS/ANTICIPATED RESULTS: Since 2013, the KL2 program has trained 21 scholars,17 of whom have completed training, and four are still in the program. Of the 21 scholars, 52% are female and 38% are underrepresented minorities (URM)–significantly higher than the 12% URM for overall CTSA KL2 scholars. Scholars have 176 total publications related to their KL2 projects and have received $52.4m in total research funding. In addition, 50% of the projects focused on health disparities. Overall, 48% of KL2 scholars have received large subsequent federal awards including three NIH K awards and six NIH R awards. Scholars actively utilized CTSI services during and after graduation. Programmatic enhancements such as adding institutional scholars and using scholar feedback to improve program resources were also implemented. DISCUSSION/SIGNIFICANCE: Miami CTSI’s KL2 program has demonstrated success in fulfilling its program goals. The process and outcome evaluation has provided a better understanding of program performance and progress and has demonstrated alignment with CTSI’s overall goals on addressing health disparities and its commitment to diversity and equity.

Abstract Background The goal was to characterize retinal vasculature by quantitative analysis of arteriole-to-venule (A/V) ratio and vessel density in fundus photos taken with the PanOptic iExaminer System. Methods The PanOptic ophthalmoscope equipped with a smartphone was used to acquire fundus photos centered on the optic nerve head. Two fundus photos of a total of 19 eyes from 10 subjects were imaged. Retinal vessels were analyzed to obtain the A/V ratio. In addition, the vessel tree was extracted using deep learning U-NET, and vessel density was processed by the percentage of pixels within vessels over the entire image. Results All images were successfully processed for the A/V ratio and vessel density. There was no significant difference of averaged A/V ratio between the first (0.77 ± 0.09) and second (0.77 ± 0.10) measurements (P = 0.53). There was no significant difference of averaged vessel density (%) between the first (6.11 ± 1.39) and second (6.12 ± 1.40) measurements (P = 0.85). Conclusions Quantitative analysis of the retinal vasculature was feasible in fundus photos taken using the PanOptic ophthalmoscope. The device appears to provide sufficient image quality for analyzing A/V ratio and vessel density with the benefit of portability, easy data transferring, and low cost of the device, which could be used for pre-clinical screening of systemic, cerebral and ocular diseases.

Carotid plaque is a subclinical measure of atherosclerosis. We have previously shown measures of carotid plaque to be heritable in a sample of 100 Dominican families and found evidence for linkage and association of common variants (CVs) on 7q36, 11p15, 14q32 and 15q23 with plaque presence. Our current study aimed to refine these regions further and identify rare variants (RVs) influencing plaque presence. Therefore, we performed targeted sequencing of the one LOD unit down region on 7q36, 11p15, 14q32 and 15q23 in 12 Dominican families with evidence for linkage to plaque presence. Gene-based RV analyses were performed using the Sequence Association Test for familial data (F-SKAT) under two filtering algorithms; 1. all exonic RVs and 2. non-synonymous RVs. Replication analyses were performed using a sample of 22 Dominican families and 556 unrelated Dominicans with Exome Array data. To identify additional non-synonymous RVs influencing plaque, we looked for co-segregation of RVs with plaque in each of the sequenced families. Our most strongly associated gene with evidence for replication was AMPD3 which showed suggestive association with plaque presence in the sequenced families (exonic RV p = 0.003, nonsynonymous RV p = 0.005) and replication families (exonic RV p = 0.04, nonsynonymous RV p = 0.02). Examination of the sequenced family pedigrees revealed two missense variants on chromosome 11 which co-segregated with plaque presence in one of our families; rs61751342 (located in DENND2B), and rs61760882 (located in RNF141). The rs61751342 missense variant is an eQTL for SCUBE2 in the atrial appendage. Notably, SCUBE2 encodes a protein which interacts with vascular endothelial growth factor (VEGF) receptor 2 to regulate VEGF-induced angiogenesis, thus providing biologic plausibility for this gene in atherosclerosis. In conclusion, using targeted sequencing of previously-identified linkage regions, we have identified suggestive evidence for the role of RVs in carotid plaque pathogenesis.

Low Gray-Scale Median (GSM) index is an ultrasonographic parameter of soft, lipid rich plaque morphology that has been associated with stroke and cardiovascular disease (CVD). We sought to explore the contribution of the modifiable and not-modifiable cardiovascular risk factors (RFs) to vulnerable plaque morphology measured by the low GSM index. A total of 1,030 stroke-free community dwelling individuals with carotid plaques present (mean age, 71.8 ± 9.1; 58% women; 56% Hispanic, 20% Non-Hispanic Black, 22% Non-Hispanic White) were assessed for minimum GSM (min GSM) using high-resolution B-mode carotid ultrasound. Multiple linear regression models were used to evaluate the association between RFs and minGSM after adjusting for sociodemographic characteristics. Within an individual, median plaque number was 2 (IQR: 1–3) and mean plaque number 2.3 (SD: 1.4). Mean minGSM was 78.4 ± 28.7 (IQR: 56–96), 76.3 ± 28.8 in men and 80 ± 28.5 in women; 78.7 ± 29.3 in Hispanics participants, 78.5 ± 27.2 in Non-Hispanic Black participants, and 78.2 ± 29 in Non-Hispanic white participants. In multivariable adjusted model, male sex (β = −5.78, p = 0.007), obesity BMI (β = −6.92, p = 0.01), and greater levels of fasting glucose (β = −8.02, p = 0.02) and LDL dyslipidemia (β = −6.64, p = 0.005) were positively associated with lower minGSM, while presence of glucose lowering medication resulted in a significant inverse association (β = 7.68, p = 0.04). Interaction (with p for interaction

Background and Objectives: Prediction of decline to dementia using objective biomarkers in high-risk patients with amnestic mild cognitive impairment (aMCI) has immense utility. Our objective was to use multimodal MRI to (1) determine whether accurate and precise prediction of dementia conversion could be achieved using baseline data alone, and (2) generate a map of the brain regions implicated in longitudinal decline to dementia.Methods: Participants meeting criteria for aMCI at baseline (N = 55) were classified at follow-up as remaining stable/improved in their diagnosis (N = 41) or declined to dementia (N = 14). Baseline T1 structural MRI and resting-state fMRI (rsfMRI) were combined and a semi-supervised support vector machine (SVM) which separated stable participants from those who decline at follow-up with maximal margin. Cross-validated model performance metrics and MRI feature weights were calculated to include the strength of each brain voxel in its ability to distinguish the two groups.Results: Total model accuracy for predicting diagnostic change at follow-up was 92.7% using baseline T1 imaging alone, 83.5% using rsfMRI alone, and 94.5% when combining T1 and rsfMRI modalities. Feature weights that survived the p < 0.01 threshold for separation of the two groups revealed the strongest margin in the combined structural and functional regions underlying the medial temporal lobes in the limbic system.Discussion: An MRI-driven SVM model demonstrates accurate and precise prediction of later dementia conversion in aMCI patients. The multi-modal regions driving this prediction were the strongest in the medial temporal regions of the limbic system, consistent with literature on the progression of Alzheimer’s disease.

BackgroundExtensive evidence supports a link between aerobic exercise and cognitive improvements in aging adults. A major limitation with existing research is the high variability in cognitive response to exercise. Our incomplete understanding of the mechanisms that influence this variability and the low adherence to exercise are critical knowledge gaps and major barriers for the systematic implementation of exercise for promoting cognitive health in aging. ObjectiveWe aimed to provide an in-person and remotely delivered intervention study protocol with the main goal of informing the knowledge gap on the mechanistic action of exercise on the brain by characterizing important mechanisms of neuroplasticity, cardiorespiratory fitness response, and genetics proposed to underlie cognitive response to exercise. MethodsThis is an open-label, 2-month, interventional study protocol in neurologically healthy sedentary adults. This study was delivered fully in-person and in remote options. Participants underwent a total of 30 sessions, including the screening session, 3 pretest (baseline) assessments, 24 moderate-to-vigorous aerobic exercise sessions, and 3 posttest assessments. We recruited participants aged 55 years and above, sedentary, and cognitively healthy. Primary outcomes were neuroplasticity, cognitive function, and cardiorespiratory fitness. Secondary outcomes included genetic factors, endothelium function, functional mobility and postural control, exercise questionnaires, depression, and sleep. We also explored study feasibility, exercise adherence, technology adaptability, and compliance of both in-person and remote protocols. ResultsThe recruitment phase and data collection of this study have concluded. Results are expected to be published by the end of 2021 or in early 2022. ConclusionsThe data generated in these studies will introduce tangible parameters to guide the development of personalized exercise prescription models for maximal cognitive benefit in aging adults. Successful completion of the specific aims will enable researchers to acquire the appropriate expertise to design and conduct studies by testing personalized exercise interventions in person and remotely delivered, likely to be more effective at promoting cognitive health in aging adults. Trial RegistrationClinicalTrials.gov NCT03804528; http://clinicaltrials.gov/ct2/show/NCT03804528 International Registered Report Identifier (IRRID)RR1-10.2196/33589

Objective: To personalize the prognostication of post-stroke outcome using MRI-detected cerebrovascular pathology, we sought to investigate the association between the excessive white matter hyperintensity (WMH) burden unaccounted for by the traditional stroke risk profile of individual patients and their long-term functional outcomes after a stroke.Methods: We included 890 patients who survived after an acute ischemic stroke from the MRI-Genetics Interface Exploration (MRI-GENIE) study, for whom data on vascular risk factors (VRFs), including age, sex, atrial fibrillation, diabetes mellitus, hypertension, coronary artery disease, smoking, prior stroke history, as well as acute stroke severity, 3- to−6-month modified Rankin Scale score (mRS), WMH, and brain volumes, were available. We defined the unaccounted WMH (uWMH) burden via modeling of expected WMH burden based on the VRF profile of each individual patient. The association of uWMH and mRS score was analyzed by linear regression analysis. The odds ratios of patients who achieved full functional independence (mRS < 2) in between trichotomized uWMH burden groups were calculated by pair-wise comparisons.Results: The expected WMH volume was estimated with respect to known VRFs. The uWMH burden was associated with a long-term functional outcome (β = 0.104, p < 0.01). Excessive uWMH burden significantly reduced the odds of achieving full functional independence after a stroke compared to the low and average uWMH burden [OR = 0.4, 95% CI: (0.25, 0.63), p < 0.01 and OR = 0.61, 95% CI: (0.42, 0.87), p < 0.01, respectively].Conclusion: The excessive amount of uWMH burden unaccounted for by the traditional VRF profile was associated with worse post-stroke functional outcomes. Further studies are needed to evaluate a lifetime brain injury reflected in WMH unrelated to the VRF profile of a patient as an important factor for stroke recovery and a plausible indicator of brain health.

ObjectiveNeuroimaging measurements of brain structural integrity are thought to be surrogates for brain health, but precise assessments require dedicated advanced image acquisitions. By means of quantitatively describing conventional images, radiomic analyses hold potential for evaluating brain health. We sought to: (1) evaluate radiomics to assess brain structural integrity by predicting white matter hyperintensities burdens (WMH) and (2) uncover associations between predictive radiomic features and clinical phenotypes.MethodsWe analyzed a multi-site cohort of 4,163 acute ischemic strokes (AIS) patients with T2-FLAIR MR images with total brain and WMH segmentations. Radiomic features were extracted from normal-appearing brain tissue (brain mask–WMH mask). Radiomics-based prediction of personalized WMH burden was done using ElasticNet linear regression. We built a radiomic signature of WMH with stable selected features predictive of WMH burden and then related this signature to clinical variables using canonical correlation analysis (CCA).ResultsRadiomic features were predictive of WMH burden (R2 = 0.855 ± 0.011). Seven pairs of canonical variates (CV) significantly correlated the radiomics signature of WMH and clinical traits with respective canonical correlations of 0.81, 0.65, 0.42, 0.24, 0.20, 0.15, and 0.15 (FDR-corrected p-valuesCV1–6 < 0.001, p-valueCV7 = 0.012). The clinical CV1 was mainly influenced by age, CV2 by sex, CV3 by history of smoking and diabetes, CV4 by hypertension, CV5 by atrial fibrillation (AF) and diabetes, CV6 by coronary artery disease (CAD), and CV7 by CAD and diabetes.ConclusionRadiomics extracted from T2-FLAIR images of AIS patients capture microstructural damage of the cerebral parenchyma and correlate with clinical phenotypes, suggesting different radiographical textural abnormalities per cardiovascular risk profile. Further research could evaluate radiomics to predict the progression of WMH and for the follow-up of stroke patients’ brain health.

Estimated glomerular filtration rate (eGFR) is a measure of kidney function used to define chronic kidney disease. Here, Morris et al. perform trans-ethnic genome-wide meta-analyses for eGFR in 312,468 individuals and identify novel loci and downstream putative causal genes.

Background Less than 40% of acute stroke patients have computed tomography (CT) imaging performed within 25 minutes of hospital arrival. We aimed to examine the race‐ethnic and sex differences in door‐to‐CT (DTCT) ≤25 minutes in the FSR (Florida Stroke Registry). Methods and Results Data were collected from 2010 to 2018 for 63 265 patients with acute ischemic stroke from the FSR and secondary analysis was performed on 15 877 patients with intravenous tissue plasminogen activator‐treated ischemic stroke. Generalized estimating equation models were used to determine predictors of DTCT ≤25. DTCT ≤25 was achieved in 56% of cases of suspected acute stroke, improving from 36% in 2010 to 72% in 2018. Women (odds ratio [OR], 0.90; 95% CI, 0.87–0.93) and Black (OR, 0.88; CI, 0.84–0.94) patients who had strokes were less likely, and Hispanic patients more likely (OR, 1.07; CI, 1.01–1.14), to achieve DTCT ≤25. In a secondary analysis among intravenous tissue plasminogen activator‐treated patients, 81% of patients achieved DTCT ≤25. In this subgroup, women were less likely to receive DTCT ≤25 (0.85, 0.77–0.94) whereas no significant differences were observed by race or ethnicity. Conclusions In the FSR, there was considerable improvement in acute stroke care metric DTCT ≤25 in 2018 in comparison to 2010. However, sex and race‐ethnic disparities persist and require further efforts to improve performance and reduce these disparities.

Background: Gut microbiota may impact cognitive function and decline, though data are limited. This pilot study examines the associations between gut dysbiosis products, plasma lipopolysaccharide (LPS) and soluble CD14 (sCD14), with cognitive decline and immune molecule activation among 40 participants in the longitudinal population-based Northern Manhattan Study. Methods: We selected stroke- and dementia-free participants at baseline with high activation levels of core components of the immune signaling pathways underlying microbiota metabolite-cognitive associations (IL-1, IL-17, TNF). Participants were followed with up to three complete neuropsychological assessments, at least 5 years apart. Results: Elevated sCD14 was associated with high levels of IL-1 pathway activation (p ​

OBJECTIVES/GOALS: The goal of this study is to highlight the unique characteristics of Miami CTSIs Master of Science in Clinical and Translational Investigation (MSCTI) as part of CTSIs overall translational workforce development program and to describe program outcomes. METHODS/STUDY POPULATION: The MSCTI at the University of Miami offers a structured, individualized, and mentored educational program that trains students in the principles and practice of translational science and clinical research. Based on student feedback and needs assessment, three courses were specifically created for the program to include additional scientific cognates and promote essential skills for the translational research workforce – team science and entrepreneurship, research ethics, and writing for clinical and translational science. A fourth course on applied statistics is currently under development that provides training in practical statistical knowledge required for clinician-researchers. Career trajectory of graduates and academic output were tracked through surveys and secondary data collection. RESULTS/ANTICIPATED RESULTS: The MSCTI Program has enrolled 76 students over its lifetime, including KL2 scholars, NIH K scholars and T32 trainees; with 25% of students holding foreign degrees. In addition to traditional outcomes such as funding and publications, qualitative case studies will highlight scientific impact and career progress of students. The program has performed exceptionally well in recruiting underrepresented persons in research, with 41% of the students identifying as Hispanic, and 52% of the students as female. Of the graduates, 84% have gone on to achieve leadership positions in NIH and pursue research careers in academic institutions, while 16% have moved to industry, government, or non-profit careers. Overall, 92% of graduates were engaged in research after two years of graduating from the program. DISCUSSION/SIGNIFICANCE: Miami CTSIs MSCTI Program has trained students with a wide range of incoming experience to establish successful careers in clinical and translational research and is a critical component of CTSIs translational workforce development program.

Background: Magnetic resonance imaging (MRI) serves as a cornerstone in defining stroke phenotype and etiological subtype through examination of ischemic stroke lesion appearance and is therefore an essential tool in linking genetic traits and stroke. Building on baseline MRI examinations from the centralized and structured radiological assessments of ischemic stroke patients in the Stroke Genetics Network, the results of the MRI-Genetics Interface Exploration (MRI-GENIE) study are described in this work.Methods: The MRI-GENIE study included patients with symptoms caused by ischemic stroke (N = 3,301) from 12 international centers. We established and used a structured reporting protocol for all assessments. Two neuroradiologists, using a blinded evaluation protocol, independently reviewed the baseline diffusion-weighted images (DWIs) and magnetic resonance angiography images to determine acute lesion and vascular occlusion characteristics.Results: In this systematic multicenter radiological analysis of clinical MRI from 3,301 acute ischemic stroke patients according to a structured prespecified protocol, we identified that anterior circulation infarcts were most prevalent (67.4%), that infarcts in the middle cerebral artery (MCA) territory were the most common, and that the majority of large artery occlusions 0 to 48 h from ictus were in the MCA territory. Multiple acute lesions in one or several vascular territories were common (11%). Of 2,238 patients with unilateral DWI lesions, 52.6% had left-sided infarct lateralization (P = 0.013 for χ2 test).Conclusions: This large-scale analysis of a multicenter MRI-based cohort of AIS patients presents a unique imaging framework facilitating the relationship between imaging and genetics for advancing the knowledge of genetic traits linked to ischemic stroke.

Background Among US Hispanics/Latinos, the largest ethnic minority population in the United States, hypertension incidence has not been thoroughly reported. The goal of this study was to describe the incidence of hypertension among US Hispanic/Latino men and women of diverse Hispanic/Latino background. Methods and Results We studied 6171 participants of the Hispanic Community Health Study/Study of Latinos, a diverse group of self‐identified Hispanics/Latinos from 4 US urban communities, aged 18 to 74 years, and free from hypertension in 2008 to 2011 and re‐examined in 2014 to 2017. Hypertension was defined as self‐reported use of anti‐hypertension medication, or measured systolic blood pressure ≥130 mm Hg, or diastolic blood pressure ≥80 mm Hg. Results were weighted given the complex survey design to reflect the target population. Among men, the 6‐year age‐adjusted probability of developing hypertension was 21.7% (95% CI, 19.5–24.1) and differed by Hispanic/Latino background. Specifically, the probability was significantly higher among men of Cuban (27.1%; 95% CI, 20.2–35.2) and Dominican (28.1%; 95% CI, 19.5–38.8) backgrounds compared with Mexican Americans (17.6%; 95% CI: 14.5–21.2). Among women, the 6‐year age‐adjusted probability of developing hypertension was 19.7% (95% CI, 18.1–21.5) and also differed by Hispanic/Latino background. Specifically, the probability was significantly higher among women of Cuban (22.6%; 95% CI, 18.3–27.5), Dominican (23.3%; 95% CI, 18.0–29.5), and Puerto Rican (28.2%; 95% CI, 22.7–34.4) backgrounds compared with Mexican Americans (16.0%; 95% CI, 13.9–18.4). Conclusions Hypertension incidence varies by Hispanic/Latino background, with highest incidence among those of Caribbean background.

Background Physical exercise and cognitive training have been recommended to improve cognitive outcomes poststroke, but a multifaceted strategy including aerobic, resistance, and cognitive training to facilitate poststroke recovery has not been investigated. We aimed to assess the feasibility, adherence, and safety of a combined aerobic, resistance, and cognitive training intervention (CARET+CTI) after stroke. Methods and Results We prospectively randomized patients presenting with recent stroke to a comparison of a supervised 12‐week CARET+CTI program and a control group receiving sham CARET+CTI. Participants were scheduled for 3 weekly CARET and CTI sessions. All participants underwent pre‐ and postintervention assessments of strength, endurance, and cognition. The primary outcomes were feasibility and adherence, defined as the ratio of scheduled and observed visits, and safety. We enrolled 131 participants, of whom 37 withdrew from the study. There were 17 (20%) withdrawals in the CARET+CTI and 20 (44%) in the control group. The observed‐over‐expected visit ratio was significantly higher in the intervention than in the control group (0.74±0.30 versus 0.54±0.38; P=0.003). A total of 99 adverse events were reported by 59 participants, none of which were serious and related to the intervention. Greater gains in physical, cognitive, and mood outcomes were found in the CARET+CTI group than in the control group, but were not statistically significant after adjustments. Conclusions A CARET+CTI intervention, after stroke, is safe, feasible, and has satisfactory participant adherence over 12 weeks. REGISTRATION URL: https://www.clini​caltr​ials.gov. Unique identifier: NCT02272426.

Abstract Background It remains unknow whether retinal tissue perfusion occurs in patients with Alzheimer’s disease. The goal was to determine retinal tissue perfusion in patients with clinical Alzheimer’s disease (CAD). Methods Twenty-four CAD patients and 19 cognitively normal (CN) age-matched controls were recruited. A retinal function imager (RFI, Optical Imaging Ltd., Rehovot, Israel) was used to measure the retinal blood flow supplying the macular area of a diameter of 2.5 mm centered on the fovea. Blood flow volumes of arterioles (entering the macular region) and venules (exiting the macular region) of the supplied area were calculated. Macular blood flow was calculated as the average of arteriolar and venular flow volumes. Custom ultra-high-resolution optical coherence tomography (UHR–OCT) was used to calculate macular tissue volume. Automated segmentation software (Orion, Voxeleron LLC, Pleasanton, CA) was used to segment six intra-retinal layers in the 2.5 mm (diameter) area centered on the fovea. The inner retina (containing vessel network), including retinal nerve fiber layer (RNFL), ganglion cell-inner plexiform layer (GCIPL), inner nuclear layer (INL) and outer plexiform layer (OPL), was segmented and tissue volume was calculated. Perfusion was calculated as the flow divided by the tissue volume. Results The tissue perfusion in CAD patients was 2.58 ± 0.79 nl/s/mm3 (mean ± standard deviation) and was significantly lower than in CN subjects (3.62 ± 0.44 nl/s/mm3, P

Increased left ventricular mass (LVM) is an intermediate phenotype for cardiovascular disease (CVD) and a predictor of stroke. Using families from the Dominican Republic, we have previously shown LVM to be heritable and found evidence for linkage to chromosome 12p11. Our current study aimed to further characterize the QTL by sequencing the 1 LOD unit down region in 10 families from the Dominican Republic with evidence for linkage to LVM. Within this region, we tested 5477 common variants [CVs; minor allele frequency (MAF) ≥5%] using the Quantitative Transmission-Disequilibrium Test (QTDT). Gene-based analyses were performed to test rare variants (RVs; MAF < 5%) in 181 genes using the family-based sequence kernel association test. A sample of 618 unrelated Dominicans from the Northern Manhattan Study (NOMAS) and 12 Dominican families with Exome Array data were used for replication analyses. The most strongly associated CV with evidence for replication was rs1046116 (Discovery families P = 9.0 × 10−4; NOMAS P = 0.03; replication families P = 0.46), a missense variant in PKP2. In nonsynonymous RV analyses, PKP2 was one of the most strongly associated genes (P = 0.05) with suggestive evidence for replication in NOMAS (P = 0.05). PKP2 encodes the plakophilin 2 protein and is a desmosomal gene implicated in arrythmogenic right ventricular cardiomyopathy and recently in arrhythmogenic left ventricular cardiomyopathy, which makes PKP2 an excellent candidate gene for LVM. In conclusion, sequencing of our previously reported QTL identified common and rare variants within PKP2 to be associated with LVM. Future studies are necessary to elucidate the role these variants play in influencing LVM.

The hippocampus in mammalian brain varies in size across individuals. Here, Hibar and colleagues perform a genome-wide association meta-analysis to find six genetic loci with significant association to hippocampus volume.

Stroke remains a leading cause of death and disability in the United States. No current treatments exist to promote cognitive recovery in survivors of stroke. A previous study from our laboratory determined that an acute bout of forced treadmill exercise was able to promote cognitive recovery in 3 month old male rats after middle cerebral artery occlusion (MCAo). In this study, we tested the hypothesis that 6 days of intense acute bout of forced treadmill exercise (physical exercise – PE) promotes cognitive recovery in 11–14 month old male rats. We determined that PE was able to ameliorate cognitive deficits as determined by contextual fear conditioning. Additionally, we also tested the hypothesis that PE promotes cognitive recovery in 11–13 month old reproductive senescent female rats. In contrast to males, the same intensity of exercise that decrease cognitive deficits in males was not able to promote cognitive recovery in female rats. Additionally, we determined that exercise did not lessen infarct volume in both male and female rats. There are many factors that contribute to higher stroke mortality and morbidities in women and thus, future studies will investigate the effects of PE in aged female rats to identify sex differences.

The current “one size fits all” approach to our cognitive aging population is not adequate to close the gap between cognitive health span and lifespan. In this review article, we present a novel model for understanding, preventing, and treating age-related cognitive impairment (ARCI) based on concepts borrowed from precision medicine. We will discuss how multiple risk factors can be classified into risk categories because of their interrelatedness in real life, the genetic variants that increase sensitivity to, or ameliorate, risk for ARCI, and the brain drivers or common mechanisms mediating brain aging. Rather than providing a definitive model of risk for ARCI and cognitive decline, the Precision Aging model is meant as a starting point to guide future research. To that end, after briefly discussing key risk categories, genetic risks, and brain drivers, we conclude with a discussion of steps that must be taken to move the field forward.

Background Nature exposures may be associated with reduced risk of heart disease. The present study examines the relationship between objective measures of neighborhood greenness (vegetative presence) and 4 heart disease diagnoses (acute myocardial infarction, ischemic heart disease, heart failure, and atrial fibrillation) in a population‐based sample of Medicare beneficiaries. Methods and Results The sample included 249 405 Medicare beneficiaries aged 65 years and older whose location (ZIP+4) in Miami‐Dade County, Florida, did not change from 2010 to 2011. Analyses examined relationships between greenness, measured by mean block‐level normalized difference vegetation index from satellite imagery, and 4 heart disease diagnoses. Hierarchical regression analyses, in a multilevel framework, assessed the relationship of greenness to each heart disease diagnosis, adjusting successively for individual sociodemographics, neighborhood income, and biological risk factors (diabetes mellitus, hypertension, and hyperlipidemia). Higher greenness was associated with reduced heart disease risk, adjusting for individual sociodemographics and neighborhood income. Compared with the lowest tertile of greenness, the highest tertile of greenness was associated with reduced odds of acute myocardial infarction by 25% (odds ratio, 0.75; 95% CI, 0.63–0.90), ischemic heart disease by 20% (odds ratio, 0.80; 95% CI, 0.77–0.83), heart failure by 16% (odds ratio, 0.84; 95% CI, 0.80–0.88), and atrial fibrillation by 6% (odds ratio, 0.94; 95% CI, 0.87–1.00). Associations were attenuated after adjusting for biological risk factors, suggesting that cardiometabolic risk factors may partly mediate the greenness to heart disease relationships. Conclusions Neighborhood greenness may be associated with reduced heart disease risk. Strategies to increase area greenness may be a future means of reducing heart disease at the population level.

ObjectiveHispanics/Latinos have some of the highest prevalence rates for cardiovascular disease risk factors, but stark differences exist by self-reported background. Cardiovascular disease risk factors negatively impact cognition in Hispanics/Latinos; less is known about these relationships by Hispanic/Latino backgrounds. We investigated cognitive associations with cardiovascular disease risk factor burden in a diverse cohort, the Hispanic Community Health Study/Study of Latinos.MethodsBaseline data from this observational study of cardiovascular disease and its antecedents was collected from 2008-2011. We included 7,121 participants 45-74 years old from Central American, Cuban, Dominican, Mexican, Puerto Rican, or South American backgrounds. Dichotomous indicators for hypertension, diabetes, hypercholesterolemia, obesity, and smoking were evaluated and totaled, with participants grouped by lowest (0-2), middle (3) or highest (4-5) burden. Cognitive testing included the Brief Spanish English Verbal Learning Test, letter fluency, and digit symbol substitution.ResultsIn separate fully-adjusted linear regression models, lower fluency and digit symbol substitution performance were restricted to the highest compared to the lowest burden group; whereas the middle burden group displayed impaired memory performance compared to the lowest burden group (p-values≤0.05). Background interacted with burden for learning and memory performance. That is, the association of burden level (i.e., lowest, middle, or highest) with cognitive performance was modified by background (e.g., Mexicans vs Cuban).ConclusionsHispanics/Latinos with higher levels of cardiovascular disease risk factor burden displayed lower levels of cognitive performance, with learning and memory performance modified by background.

White matter hyperintensity (WMH) burden is a critically important cerebrovascular phenotype linked to prediction of diagnosis and prognosis of diseases, such as acute ischemic stroke (AIS). However, current approaches to its quantification on clinical MRI often rely on time intensive manual delineation of the disease on T2 fluid attenuated inverse recovery (FLAIR), which hinders high-throughput analyses such as genetic discovery.In this work, we present a fully automated pipeline for quantification of WMH in clinical large-scale studies of AIS. The pipeline incorporates automated brain extraction, intensity normalization and WMH segmentation using spatial priors. We first propose a brain extraction algorithm based on a fully convolutional deep learning architecture, specifically designed for clinical FLAIR images. We demonstrate that our method for brain extraction outperforms two commonly used and publicly available methods on clinical quality images in a set of 144 subject scans across 12 acquisition centers, based on dice coefficient (median 0.95; inter-quartile range 0.94–0.95; p

Background Racial/ethnic disparities in acute stroke care may impact stroke outcomes. We compared outcomes by race/ethnicity among elderly Medicare beneficiaries in hospitals participating in the FL‐PR CReSD (Florida–Puerto Rico Collaboration to Reduce Stroke Disparities) registry with those in hospitals not participating in any quality improvement programs (non‐QI) in Florida and Puerto Rico (PR). Methods and Results The population included fee‐for‐service Medicare beneficiaries age 65+ in Florida and PR, discharged with primary diagnosis of ischemic stroke (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD‐9‐CM], codes 433, 434, 436) in 2010–2013. We used mixed logistic models to assess racial/ethnic differences in outcomes (in‐hospital, 30‐day, and 1‐year mortality, and 30‐day readmission) for CReSD and non‐QI hospitals, adjusted for demographic and clinical characteristics. The study included 62 CReSD hospitals (N=44 013, 84% white, 9% black, 4% Florida Hispanic, 1% PR Hispanic) and 113 non‐QI hospitals (N=14 422, 78% white, 7% black, 5% Florida Hispanic, 8% PR Hispanic). For patients treated at CReSD hospitals, there were no differences in risk‐adjusted in‐hospital mortality by race/ethnicity; blacks had lower 30‐day mortality versus whites (odds ratio, 0.86; 95% confidence interval, 0.77–0.97), but higher 30‐day readmission (hazard ratio, 1.09; 1.00–1.18) and 1‐year mortality (odds ratio, 1.13; 1.04–1.23); Florida Hispanics had lower 30‐day readmission (hazard ratio, 0.87; 0.78–0.98). PR Hispanic and black stroke patients treated at non‐QI hospitals had higher risk‐adjusted in‐hospital, 30‐day and 1‐year mortality, but similar 30‐day readmission versus whites treated in non‐QI hospitals. Conclusions Disparities in outcomes were less common in CReSD than non‐QI hospitals, suggesting the benefits of quality improvement programs, particularly those focusing on racial/ethnic disparities.

OBJECTIVES/GOALS: The goal of this project was to assess the scientific impact of Miami CTSI’s Mentored Career Development (KL2) Program using bibliometric tools and network visualization in addition to the traditional metrics used to provide a comprehensive evaluation. METHODS/STUDY POPULATION: Scholarly productivity of KL2 scholars were tracked using REDCap. For bibliometric data analysis and visualization, publications were queried using iCite (NIH Office of Portfolio Analysis) and Web of Science database. A total of 173 publications produced by eight KL2 scholars from 2013-2018 were analyzed and categorized into pre-award, during award, and post-award periods. iCite was used to assess scientific influence and translation. Scientific networks and collaboration were visualized using VOSviewer (Centre for Science and Technology Studies, Leiden University). CTSA Common Metrics were tracked using the Results Based Accountability framework. RESULTS/ANTICIPATED RESULTS: Albeit of modest size, the Miami CTSI’s KL2 Program had significant scientific productivity and impact in its first five years. Our KL2 scholars’ publications were cited twice as frequently as other papers in their fields. Further, 48% of publications post KL2 award were above the NIH 50th percentile and had higher citation impact compared to the average NIH-funded paper; 11% were in the top 10% NIH citation ranking. In contrast, only 20% of the publications pre-KL2 award were above the NIH 50th percentile. The program also promoted research collaboration; network visualizations indicate larger co-authorship and organization networks of KL2 scholars post-award. DISCUSSION/SIGNIFICANCE OF IMPACT: Bibliometric and data visualization approaches helped us better identify trends and gauge effectiveness of the KL2 program. These findings provided useful insight into the scientific influence and impact of our scholars’ work.

Background The American Heart Association Life's Simple 7 metric defines ideal cardiovascular health (CVH) on 7 factors: smoking, diet, physical activity, body mass index, blood sugar, blood pressure, and cholesterol. This metric has been used to define optimal brain health, but data relative to subclinical imaging biomarkers of brain aging are lacking. This study examines the association between Life's Simple 7 with white matter hyperintensity volume, silent brain infarcts, and cerebral volume. Methods and Results A subsample of stroke‐free participants from the population‐based Northern Manhattan Study underwent brain magnetic resonance imaging an average of 7 years after baseline. Linear and logistic regression models were constructed to estimate associations between the number of ideal CVH metrics achieved with imaging biomarkers of brain aging, adjusting for sociodemographics. Among 1031 participants (mean age at magnetic resonance imaging=72±8, 40% men, 19% black, 16% white, and 65% Hispanic), no one had ideal status in all 7 factors, 1% had ideal status in 6 factors, 18% in 4 to 5 factors, 30% in 3 factors, 33% in 2 factors, and 18% in 0 to 1 factors. The number of ideal CVH factors achieved was inversely associated with white matter hyperintensity volume (beta per factor=−0.047; P=0.04) and silent brain infarct (odds ratio per factor=0.84; 95% confidence interval=0.72–0.97) and positively associated with cerebral volume (beta per factor=0.300; P=0.002). Conclusions An increasing ideal CVH score was associated with less white matter hyperintensity volume and silent brain infarcts and greater cerebral volumes, supporting the Life's Simple 7 metric as a useful measure to quantify optimal brain health. Monitoring and promoting achievement of Life's Simple 7 ideal CVH factors may improve subclinical and clinical brain health outcomes.

Background and purposeCarotid plaque (CP), carotid intima media thickness (cIMT), and stiffness (STIFF) are pre-clinical markers of atherosclerosis and predictors of cerebrovascular disease (CVD). We sought to investigate whether STIFF is a significant determinant of cIMT and CP, which may provide an insight into the mechanism by which STIFF adds to the risk of CVD.MethodsWe analyzed 876 stroke-free subjects from the Northern Manhattan Study with available ultrasound measures. To obtain the associations with STIFF, we performed multivariable-adjusted regression, negative binomial regression (for CP number), and multinomial logistic regression (for plaque area).ResultsThe mean age was 64 ± 9 years; 63% women and 65% Caribbean Hispanics. The mean cIMT was 0.93 ± 0.9 mm, the mean diastolic diameter 6.24 ± 0.94 mm, and STIFF 8.6 ± 6.2 ln mmHg. Prevalence of CP was 57%, and the mean total plaque area was 22.6 ± 23.0 mm2. STIFF was positively associated with cIMT but not with CP. There was an association between diastolic diameter and thick plaque. For each millimeter increase in diastolic diameter, there was about a 20% increased risk of having thick plaque (vs. no plaque). In longitudinal analyses, each millimeter increase in diastolic diameter was associated with a 37% increased risk of incident plaque.ConclusionIncreased STIFF was associated with increased cIMT and carotid artery dilatation with greater plaque burden. Increased cIMT and plaque burden represent vascular remodeling likely resulting from the two different age-related mechanisms, one that includes diffuse wall thickening (cIMT) with STIFF and another that incorporates focal atherosclerosis (plaque) with luminal dilatation.