Will T. Longstreth

BACKGROUND: Ischemic stroke preventive therapies have been slow to emerge due to a limited understanding of the underlying molecular mechanisms. We aimed to discover new protein risk factors that are potential etiologic factors and may be candidates for therapeutic intervention. METHODS: We included ARIC study (Atherosclerosis Risk in Communities) and CHS (Cardiovascular Health Study) participants without prevalent stroke at the time of proteomic profiling (1990–1992 in ARIC and 1992–1993 in CHS). Relative concentrations of proteins in blood were assessed with aptamers (n=4954). Ischemic stroke events were adjudicated through 2019 in ARIC and 2015 in CHS. Study-specific Cox regression adjusting for ischemic stroke risk factors was used to estimate associations between proteins and incident ischemic stroke. Study-specific estimates were combined using fixed-effects meta-analysis. Replication was conducted in 2 independent cohorts (AGES-Reykjavik, UK Biobank). Proteins with a false discovery rate q value P −5 ), of which 26 are novel. In 2 independent cohorts, 37 (84%) associations were directionally concordant, and 26 (59%) met criteria for replication. Mendelian randomization analyses suggested MMP12 (matrix metallopeptidase-12) and CNTN1 (contactin-1) may be causally related to ischemic stroke risk. In multivariable Mendelian randomization analyses, higher MMP12 levels had a direct protective effect on ischemic stroke risk, while CNTN1 had a direct harmful effect. CONCLUSIONS: This proteomic and genomic investigation of ischemic stroke identified novel risk biomarkers and 2 potential etiologic CNTN1 factors that are regulated in response to atherosclerosis and obesity. If future studies confirm our findings, these results may have implications for the development of new preventive therapies.

Left ventricular injury (LVI) can be detected by cardiac magnetic resonance (CMR) imaging with high sensitivity; however, the implication of these findings on brain health longitudinally is uncertain. We aimed to evaluate the association between LVI biomarkers detected by CMR and the risk of developing ischemic stroke and dementia. We analyzed the prospective, observational cohort of participants in the Multi-Ethnic Study of Atherosclerosis (MESA) study (median follow-up of 8.7 years). MESA is a population-based cohort recruited from 6 communities. The complete case analysis (CCA) sample included stroke-free participants who underwent CMR at Exam 5 (2010-2012). The multiple imputation (MI) sample consisted of stroke-free participants at Exam 5, irrespective of CMR collection. Missing CMR variables were imputed because of the nonrandom missingness of CMR data. The primary exposure was LVI defined by LV ejection fraction < 50% or circumferential strain ≥ -10 in any LV apical wall. Secondary exposures were left ventricular ejection fraction (LVEF) and strain as continuous measures. Primary outcomes were (1) incident ischemic stroke and (2) newly diagnosed all-cause dementia. Cox proportional hazard models were adjusted for demographic and clinical covariates. There were 2,584 (11.7% with LVI [mean age 71, 65% male], 88.3% without LVI [mean age 69, 44% male]) and 4,594 participants in the CCA and MI cohorts, respectively. Incident ischemic stroke occurred in 18 (6%) participants with and 65 (3%) without LVI in the CCA sample (302 or 12% with and 18 or 6% without LVI in the MI sample). Both groups had similar rates of cardiovascular disease (6% vs 4%, p = 0.143). LVI was significantly associated with incident ischemic stroke in the MI cohort (adjusted hazard ratio [HR] 1.82, 95% CI 1.08-3.09), but not in the CCA cohort. LV apical peak strain was significantly associated with newly diagnosed dementia only in the MI cohort (adjusted HR 1.06, 95% CI 1.01-1.12). LVEF per 10% was significantly associated with newly diagnosed dementia in both cohorts (adjusted HR in MI cohort 0.73, 95% 0.59-0.90). CMR-detected LVI is associated with incident ischemic stroke and newly diagnosed dementia. Further studies are needed to validate CMR biomarkers of brain injury risk.

Cardiac dysfunction and heart failure are linked to cognitive impairment, but the underlying brain pathology remains undetermined. We investigated associations between cardiac function (measured by echocardiography or cardiac MRI), clinical heart failure, and structural markers on brain MRI, including volumes of gray and white matter (WM), the hippocampus, and white matter hyperintensities (WMHs). We leverage data from 7 prospective, community-based cohorts across Europe and the United States, all part of the Cross-Cohort Collaboration. The included cohorts were the Age, Gene/Environment Susceptibility-Reykjavik Study, Atherosclerosis Risk in Communities study, Austrian Stroke Prevention Study, Cardiovascular Health Study, Framingham Heart Study, Rotterdam Study, and Study of Health in Pomerania (SHIP-START and SHIP-TREND). Each cohort performed cross-sectional multivariable linear regression analyses, after which estimates were pooled through random-effects meta-analysis. Heterogeneity was assessed by the I² index (%). Among 10,889 participants (mean age: 66.8 years, range 52.0–76.0; 56.7% women), markers of systolic dysfunction were consistently associated with smaller total brain volume (TBV) (e.g., adjusted standardized mean difference for moderate to severe dysfunction −0.19, 95% CI −0.31 to −0.07, I² = 20%). Impaired relaxation and restrictive diastolic dysfunction were also associated with smaller TBV (e.g., for impaired relaxation −0.08, 95% CI −0.15 to −0.01, I² = 32%) and hippocampal volume (−0.18, 95% CI −0.33 to −0.03, I² = 0%), with similar results for the E/A-ratio. Systolic and diastolic dysfunction was not consistently associated with volume of WMHs. Among 5 cohorts with available data, 302 (3.4%) participants had clinical heart failure, which was associated with smaller brain volumes, particularly in the hippocampus (−0.13, 95% CI −0.23 to −0.02, I² = 1%). In this large study among community-dwelling adults, subclinical cardiac dysfunction was associated with brain imaging markers of neurodegeneration. These findings encourage longitudinal investigations on the effect of maintaining cardiac function on brain health.

The objective of this study was to estimate the incidence, timing, and type of new cancer diagnosis among patients with cryptogenic stroke. We used data from the ARCADIA trial, which enrolled patients with cryptogenic stroke and atrial cardiopathy. Participants were prospectively followed, and serious adverse events were assessed every 3 months or sooner if investigators were alerted between visits to an event. Kaplan-Meier statistics were used to estimate the cumulative incidence of a cancer diagnosis within the first year after randomization. Among 878 participants without baseline history of cancer, 13 (1.5%) were diagnosed with incident cancer in the year after randomization, comprising 12 solid cancers (3 prostate, 2 breast, 2 gastrointestinal, and 5 other primary sites) and 1 hematologic cancer (non-Hodgkin lymphoma). The cumulative incidences of a cancer diagnosis were 0% at 3 months, 0.6% (95% CI 0.2%-1.5%) at 6 months, and 2.0% (95 CI 1.1%-3.4%) at 1 year. The median time from index stroke to cancer diagnosis was 261 days (interquartile range 183-358). In a multicenter cryptogenic stroke cohort with prospective follow-up, the 1-year cumulative incidence of a cancer diagnosis was 2%. This rate may be an underestimation because of the clinical trial population and exclusion of cancers diagnosed immediately after stroke. ClinicalTrials.gov Identifier: NCT03192215. Registered June 20, 2017. First patient enrolled February 1, 2018.

The term "embolic stroke of undetermined source" (ESUS) encompasses a substantial but heterogeneous population of patients with ischemic stroke, underscoring the importance of identifying personalized treatment strategies. In subgroups of patients randomized in ESUS trials, we evaluated the effectiveness of anticoagulation compared with antiplatelet therapy in secondary ischemic stroke prevention. A study-level meta-analysis was conducted on randomized controlled trials of patients with ESUS, comparing anticoagulation with antiplatelet therapy. The primary efficacy outcome was recurrent ischemic stroke, and safety outcomes were major bleeding and death. Subgroups assessed were age, sex, presence of patent foramen ovale (PFO), left atrial enlargement (LAE), and atrial cardiopathy. Pooled risk ratios (RRs) were meta-analyzed. Cochrane Risk of Bias Tool 2.0 was used for risk-of-bias assessment. A total of 7 randomized controlled trials involving 14,804 patients were analyzed, with 7,406 patients treated with anticoagulation and 7,398 treated with antiplatelet therapy. Compared with antiplatelet therapy, anticoagulation was associated with a similar rate of recurrent ischemic stroke (RR 0.91, 95% CI 0.80-1.05; I² = 0%). In ESUS with PFO, anticoagulation was associated with significantly lower risk of ischemic stroke (RR 0.59, 95% CI 0.35-0.98; I² = 0%). Heterogeneity was present in those with LAE: antiplatelet therapy was superior in trials allowing cardiac monitoring after randomization (RR 6.65, 95% CI 1.26-35.08; I² = 0%), but anticoagulation was superior in trials prohibiting cardiac monitoring after randomization (RR 0.25 95% CI 0.07-0.89). Subgroups based on age, sex, or presence of atrial cardiopathy did not benefit from anticoagulation over antiplatelet therapy. In this meta-analysis, an empiric anticoagulation approach is not beneficial for patients with ESUS. This finding highlights the importance of an individualized treatment strategy. Such a strategy should include prolonged cardiac monitoring for atrial fibrillation, particularly in patients with moderate-to-severe LAE. Anticoagulation treatment showed promise in patients with medically treated PFO. Other subgroups did not benefit from anticoagulation therapy. Large prospective studies within ESUS subgroups are needed to validate our findings.

Cardiovascular disease contributes significantly to disease burden among many Indigenous populations. However, data on stroke incidence in Indigenous populations are sparse. We aimed to investigate what is known of stroke incidence in Indigenous populations of countries with a very high Human Development Index (HDI), locating the research in the broader context of Indigenous health. We identified population-based stroke incidence studies published between 1990 and 2022 among Indigenous adult populations of developed countries using PubMed, Embase, and Global Health databases, without language restriction. We excluded non-peer-reviewed sources, studies with fewer than 10 Indigenous people, or not covering a 35- to 64-year minimum age range. Two reviewers independently screened titles, abstracts, and full-text articles and extracted data. We assessed quality using "gold standard" criteria for population-based stroke incidence studies, the Newcastle-Ottawa Scale for risk of bias, and CONSIDER criteria for reporting of Indigenous health research. An Indigenous Advisory Board provided oversight for the study. From 13,041 publications screened, 24 studies (19 full-text articles, 5 abstracts) from 7 countries met the inclusion criteria. Age-standardized stroke incidence rate ratios were greater in Aboriginal and Torres Strait Islander Australians (1.7-3.2), American Indians (1.2), Sámi of Sweden/Norway (1.08-2.14), and Singaporean Malay (1.7-1.9), compared with respective non-Indigenous populations. Studies had substantial heterogeneity in design and risk of bias. Attack rates, male-female rate ratios, and time trends are reported where available. Few investigators reported Indigenous stakeholder involvement, with few studies meeting any of the CONSIDER criteria for research among Indigenous populations. In countries with a very high HDI, there are notable, albeit varying, disparities in stroke incidence between Indigenous and non-Indigenous populations, although there are gaps in data availability and quality. A greater understanding of stroke incidence is imperative for informing effective societal responses to socioeconomic and health disparities in these populations. Future studies into stroke incidence in Indigenous populations should be designed and conducted with Indigenous oversight and governance to facilitate improved outcomes and capacity building. PROSPERO registration: CRD42021242367.

Higher YKL-40 levels in the CSF are a known biomarker of brain inflammation. We explored the utility of plasma YKL-40 as a biomarker for accelerated brain aging and dementia risk. We performed cross-sectional and prospective analyses of 4 community-based cohorts in the United States or Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, Atherosclerosis Risk in the Communities study, Coronary Artery Risk Development in Young Adults study, and Framingham Heart Study (FHS). YKL-40 was measured from stored plasma by a single laboratory using Mesoscale Discovery with levels log transformed and standardized within each cohort. Outcomes included MRI total brain volume, hippocampal volume, and white matter hyperintensity volume (WMHV) as a percentage of intracranial volume, a general cognitive composite derived from neuropsychological testing (SD units [SDU]), and the risk of incident dementia. We sought to replicate associations with dementia in the clinic-based ACE csf cohort, which also had YKL-40 measured from the CSF. Meta-analyses of MRI outcomes included 6,558 dementia-free participants, and for analysis of cognition, 6,670. The blood draw preceded MRI/cognitive assessment by up to 10.6 years across cohorts. The mean ages ranged from 50 to 76 years, with 39%-48% male individuals. In random-effects meta-analysis of study estimates, each SDU increase in log-transformed YKL-40 levels was associated with smaller total brain volume (β = -0.33; 95% CI -0.45 to -0.22; p < 0.0001) and poorer cognition (β = -0.04; 95% CI -0.07 to -0.02; p < 0.01), following adjustments for demographic variables. YKL-40 levels did not associate with hippocampal volume or WMHV. In the FHS, each SDU increase in log YKL-40 levels was associated with a 64% increase in incident dementia risk over a median of 5.8 years of follow-up, following adjustments for demographic variables (hazard ratio 1.64; 95% CI 1.25-2.16; p < 0.001). In the ACE csf cohort, plasma and CSF YKL-40 were correlated (r = 0.31), and both were associated with conversion from mild cognitive impairment to dementia, independent of amyloid, tau, and neurodegeneration status. Higher plasma YKL-40 levels were associated with lower brain volume, poorer cognition, and incident dementia. Plasma YKL-40 may be useful for studying the association of inflammation and its treatment on dementia risk.