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BACKGROUNDAlthough convalescent plasma has been widely used to treat severe coronavirus disease 2019 (COVID-19), data from randomized controlled trials that support its efficacy are limited.METHODSWe conducted a randomized, double-blind, controlled trial among adults hospitalized with severe and critical COVID-19 at 5 sites in New York City (USA) and Rio de Janeiro (Brazil). Patients were randomized 2:1 to receive a single transfusion of either convalescent plasma or normal control plasma. The primary outcome was clinical status at 28 days following randomization, measured using an ordinal scale and analyzed using a proportional odds model in the intention-to-treat population.RESULTSOf 223 participants enrolled, 150 were randomized to receive convalescent plasma and 73 to receive normal control plasma. At 28 days, no significant improvement in the clinical scale was observed in participants randomized to convalescent plasma (OR 1.50, 95% confidence interval [CI] 0.83-2.68, P = 0.180). However, 28-day mortality was significantly lower in participants randomized to convalescent plasma versus control plasma (19/150 [12.6%] versus 18/73 [24.6%], OR 0.44, 95% CI 0.22-0.91, P = 0.034). The median titer of anti-SARS-CoV-2 neutralizing antibody in infused convalescent plasma units was 1:160 (IQR 1:80-1:320). In a subset of nasopharyngeal swab samples from Brazil that underwent genomic sequencing, no evidence of neutralization-escape mutants was detected.CONCLUSIONIn adults hospitalized with severe COVID-19, use of convalescent plasma was not associated with significant improvement in day 28 clinical status. However, convalescent plasma was associated with significantly improved survival. A possible explanation is that survivors remained hospitalized at their baseline clinical status.TRIAL REGISTRATIONClinicalTrials.gov, NCT04359810.FUNDINGAmazon Foundation, Skoll Foundation.

Background: Variability in dementia rates across racial and ethnic groups has been estimated at 60%. Studies suggest disparities in Caribbean Hispanic and Black populations, but community-based data are limited., Objective: Estimate the prevalence of mild cognitive impairment (MCI) and dementia in the racially and ethnically diverse community-based Northern Manhattan Study cohort and examine sociodemographic, vascular risk factor, and brain imaging correlates., Methods: Cases of MCI and dementia were adjudicated by a team of neuropsychologists and neurologists and prevalence was estimated across race/ethnic groups. Ordinal proportional odds models were used to estimate race/ethnic differences in the prevalence of MCI or dementia adjusting for sociodemographic variables (model 1), model 1 plus potentially modifiable vascular risk factors (model 2), and model 1 plus structural imaging markers of brain integrity (model 3)., Results: There were 989 participants with cognitive outcome determinations (mean age 69±9 years; 68% Hispanic, 16% Black, 14% White; 62% women; mean (±SD) follow-up five (±0.6) years). Hispanic and Black participants had greater likelihood of MCI (20%) and dementia (5%) than White participants accounting for age and education differences. Hispanic participants had greater odds of MCI or dementia than both White and Black participants adjusting for sociodemographic variables, vascular risk factors, and brain imaging factors. White matter hyperintensity burden was significantly associated with greater odds of MCI or dementia (OR = 1.3, 1.1 to 1.6), but there was no significant interaction by race/ethnicity., Conclusion: In this diverse community-based cohort, cross-sectional data revealed significant race/ethnic disparities in the prevalence of MCI and dementia. Longer follow-up and incidence data are needed to further clarify these relationships.

Background: How cerebrovascular disease and neurodegeneration affect each other to impact cognition is not yet known. We aimed to test whether Alzheimer's disease-signature (AD) cortical thickness mediates the association between cholinergic white matter lesion load and change in domain-specific cognition., Methods: Clinically stroke-free participants from the Northern Manhattan Study with both regional white matter hyperintensity volume (WMHV) and gray matter measurements were included (N = 894). Tract-specific WMHVs were quantified through FSL using the Johns Hopkins University white matter tract atlas. We used Freesurfer 5.1 to estimate regional cortical thickness. We fit structural equation models, including multiple indicator latent change score models, to examine associations between white matter hyperintensity volume (WMHV) in cholinergic tracts, AD-signature region cortical thickness (CT), and domain-specific cognition., Results: Our sample (N = 894) had a mean (SD) age = 70 (9) years, years of education = 10 (5), 63% women, and 67% Hispanics/Latinos. Greater cholinergic WMHV was significantly related to worse processing speed at baseline (standardized β = -0.17, SE = 0.05, p = .001) and over time (standardized β = -0.28, SE = 0.09, p = .003), with a significant indirect effect of AD-signature region CT (baseline: standardized β = -0.02, SE = 0.01, p = .023; change: standardized β = -0.03, SE = 0.02, p = .040)., Conclusions: Cholinergic tract WMHV is associated with worse processing speed, both directly and indirectly through its effect on AD-signature region CT., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Purpose- An excess incidence of strokes among blacks versus whites has been shown, but data on disparities related to Hispanic ethnicity remain limited. This study examines race/ethnic differences in stroke incidence in the multiethnic, largely Caribbean Hispanic, NOMAS (Northern Manhattan Study), and whether disparities vary by age. Methods- The study population included participants in the prospective population-based NOMAS, followed for a mean of 14±7 years. Multivariable-adjusted Cox proportional hazards models were constructed to estimate the association between race/ethnicity and incident stroke of any subtype and ischemic stroke, stratified by age. Results- Among 3298 participants (mean baseline age 69±10 years, 37% men, 24% black, 21% white, 52% Hispanic), 460 incident strokes accrued (400 ischemic, 43 intracerebral hemorrhage, 9 subarachnoid hemorrhage). The most common ischemic subtype was cardioembolic, followed by lacunar infarcts, then cryptogenic. The greatest incidence rate was observed in blacks (13/1000 person-years), followed by Hispanics (10/1000 person-years), and lowest in whites (9/1000 person-years), and this order was observed for crude incidence rates until age 75. By age 85, the greatest incidence rate was in Hispanics. Blacks had an increased risk of stroke versus whites overall in multivariable models that included sociodemographics (hazard ratio, 1.51 [95% CI, 1.13-2.02]), and stratified analyses showed that this disparity was driven by women of age ≥70. The increased rate of stroke among Hispanics (age/sex-adjusted hazard ratio, 1.48 [95% CI, 1.13-1.93]) was largely explained by education and insurance status (a proxy for socieoeconomic status; hazard ratio after further adjusting for these variables, 1.17 [95% CI, 0.85-1.62]) but remained significant for women age ≥70. Conclusions- This study provides novel data regarding the increased stroke risk among Caribbean Hispanics in this elderly population. Results highlight the need to create culturally tailored campaigns to reach black and Hispanic populations to reduce race/ethnic stroke disparities and support the important role of low socioeconomic status in driving an elevated risk among Caribbean Hispanics.

Background/objectives: Inflammatory biomarkers have been associated with stroke and mortality, but inflammation may also have detrimental effects beyond acute events. We hypothesized that serum concentrations of interleukin-6 (IL6) and lipoprotein-associated phospholipase A2 (LpPLA2) were inversely associated with long-term functional decline independently of vascular risk factors, stroke and myocardial infarction (MI) occurring during follow-up., Design: Prospective population based cohort study., Setting: The Northern Manhattan Study., Participants (including the Sample Size): Race/ethnically diverse stroke-free individuals in northern Manhattan aged ≥40 years (n = 3298)., Intervention: None., Measurements: Annual functional assessments with the Barthel index (BI), for a median of 13 years. BI was analyzed as a continuous variable (range 0-100). Baseline demographics, risk factors, and laboratory studies were collected, including IL6 (n = 1679), LpPLA2 mass (n = 1912) and activity (n = 1937). Separate mixed models estimated standardized associations between each biomarker and baseline functional status and change over time, adjusting for demographics, vascular risk factors, social variables, cognition, and depression measured at baseline, and stroke and MI occurring during follow-up., Results: Mean age was 69 (SD 10) years, 35% were male, 53% Hispanic, 74% hypertensive, and 16-24% diabetic. LogIL6 was associated with decline in BI over time (-0.13 points per year, 95% CI -0.24, -0.02) and marginally with baseline BI (-0.20, 95% CI -0.40, 0.01). LpPLA2 activity levels were associated with baseline BI (-0.36, 95% CI -0.68, -0.04) but not change over time, and LpPLA2 mass levels were not associated with either., Conclusion: In this large population-based study, higher serum inflammatory biomarker levels were associated with disability, even when adjusting for baseline covariates and stroke and MI occurring during follow-up., Competing Interests: Dr. Sacco receives grant support from the NIH, AHA, and Boehringer Ingelheim. Dr. Elkind receives compensation for providing consultative services for Biotelemetry/Cardionet, BMSPfizer Partnership, Boehringer-Ingelheim, and Sanofi-Regeneron; serves as an expert witness for Merck/Organon (Nuvaring and stroke), BMS-Sanofi Partnership (Plavix and stroke), and Hi-Tech (DMAA and stroke); serves on the National, Founders Affiliate, and New York City chapter boards of the American Heart Association/American Stroke Association; and receives royalties from UpToDate for chapters related to cryptogenic stroke. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: We examined whether greater depressive symptoms were associated with domain-specific cognitive performance, change in cognition, and MRI markers of brain atrophy and subclinical cerebrovascular disease in a diverse sample of older adults from the Northern Manhattan Study., Methods: Data were analyzed from the Northern Manhattan Study, a prospective cohort study of mostly Caribbean Hispanic, stroke-free, older adults. A total of 1,111 participants had baseline measures of depressive symptoms, measured as the Center of Epidemiological Studies-Depression Scale, MRI markers, and cognitive function. A Center of Epidemiological Studies-Depression score ≥16 was considered indicative of greater depressive symptoms. Multivariable linear and logistic regression models were used to examine the associations of interest., Results: At baseline, 22% of participants had greater depressive symptoms. Greater depressive symptoms were significantly associated with worse baseline episodic memory in models adjusted for sociodemographic, vascular risk factor, behavioral, and antidepressive medication variables (β [95% confidence interval] = -0.21 [-0.33 to -0.10], p = 0.0003). Greater depressive symptoms were also associated with smaller cerebral parenchymal fraction (β [95% confidence interval] = -0.56 [-1.05 to -0.07], p = 0.02) and increased odds of subclinical brain infarcts (odds ratio [95% confidence interval] = 1.55 [1.00-2.42], p = 0.05), after adjustment for sociodemographic, behavioral, and vascular risk factor variables. Greater depressive symptoms were not significantly associated with white matter hyperintensity volume, hippocampal volume, or change in cognition over an average of 5 years. Results were unchanged when stabilized inverse probability weights were applied to address selective attrition during the study period., Conclusions: In this sample of mostly Caribbean Hispanic, stroke-free, older adults, greater depressive symptoms were associated with worse episodic memory, smaller cerebral volume, and silent infarcts., (© 2018 American Academy of Neurology.)

Background: Cerebral microbleeds (CMBs) represent intracerebral hemorrhages due to amyloid angiopathy or exposure to modifiable risk factors. Few community-based stroke-free studies including blacks and Hispanics have been done., Methods and Results: The Northern Manhattan Study (NOMAS) is a stroke-free, racially and ethnically diverse cohort study. Brain MRI was performed in 1290 participants, 925 of whom had available T2* gradient-recall echo data. We used multivariable logistic regression to examine the association of sociodemographics, vascular risk factors, apolipoprotein E (APOE) genotype, and brain MRI markers with CMB presence and location. The prevalence of CMBs in our cohort was 5%. Of the 46 participants with CMBs, 37% had only deep CMBs, 48% had only lobar CMBs, and 15% had CMBs in both locations. The difference in CMB distribution was not statistically significant across race/ethnic group or APOE genotype. In multivariable analyses, age (OR [95% CI]: 1.09 [1.04, 1.15]) and SBIs (2.58 [1.01, 6.59]) were positively associated with CMB presence, and diabetes medication use was negatively associated (0.25 [0.07, 0.86])., Conclusions: CMBs may represent the severity of vascular disease in this racially and ethnically diverse cohort. Larger studies are needed to elucidate the association between diabetes medication use and CMB presence., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Objective: We investigated white matter lesion load and global and regional brain volumes in relation to domain-specific cognitive performance in the stroke-free Northern Manhattan Study (NOMAS) population., Methods: We quantified white matter hyperintensity volume (WMHV), total cerebral volume (TCV), and total lateral ventricular (TLV) volume, as well as hippocampal and cortical gray matter (GM) lobar volumes in a subgroup. We used general linear models to examine MRI markers in relation to domain-specific cognitive performance, adjusting for key covariates., Results: MRI and cognitive data were available for 1,163 participants (mean age 70 ± 9 years; 60% women; 66% Hispanic, 17% black, 15% white). Across the entire sample, those with greater WMHV had worse processing speed. Those with larger TLV volume did worse on episodic memory, processing speed, and semantic memory tasks, and TCV did not explain domain-specific variability in cognitive performance independent of other measures. Age was an effect modifier, and stratified analysis showed that TCV and WMHV explained variability in some domains above age 70. Smaller hippocampal volume was associated with worse performance across domains, even after adjusting for APOE ε4 and vascular risk factors, whereas smaller frontal lobe volumes were only associated with worse executive function., Conclusions: In this racially/ethnically diverse, community-based sample, white matter lesion load was inversely associated with cognitive performance, independent of brain atrophy. Lateral ventricular, hippocampal, and lobar GM volumes explained domain-specific variability in cognitive performance., (© 2015 American Academy of Neurology.)

Background: To test the hypothesis that leisure time physical activity (PA) is associated with cognitive status., Methods: We assessed cognition using the Mini-Mental Status Examination (MMSE) at enrollment and using the modified Telephone Interview for Cognitive Status (TICS-m) administered annually since 2001 in the Northern Manhattan Study. Baseline measures of leisure time PA were collected via in-person questionnaires. Total PA was categorized into 3 groups based on the metabolic equivalent (MET) score, a composite of total reported intensity and time. We used linear regression models to examine the association of PA with MMSE, and generalized estimating equations for change in TICS-m over time., Results: There were 3,298 stroke-free participants with MMSE data (mean MMSE 26.0 ± 3.8) and 2,279 with TICS-m scores available. Compared to no PA, those with the upper quartile of MET scores had greater baseline MMSE scores (adjusted β = 0.4, p = 0.01) but no association with change in TICS-m over time. There were interactions (p < 0.05) between PA and both insurance and education; compared to no PA, those in the upper quartile of MET scores had a greater MMSE score only among those with Medicaid/no insurance (adjusted β = 0.83, p = 0.0005) and those who did not complete high school (adjusted β = 0.68, p = 0.001)., Conclusions: Increased levels of PA were associated with better baseline MMSE, particularly among those with socioeconomic disadvantages, but not with cognitive decline., (© 2013 S. Karger AG, Basel.)