Ralph L. Sacco

Background: Carotid intima‐media thickness (IMT) is a measure of atherosclerosis and a predictor of vascular diseases. Traditional vascular risk factors and genetic variants do not completely explain the variation in carotid IMT. We sought to identify epigenetic factors that may contribute to the remaining carotid IMT variability. Methods and Results: An epigenome‐wide association study was performed in 61 Dominican families with 769 individuals. A cytosine nucleotide that precedes a guanine nucleotide methylation in blood‐derived DNA was measured using the Human MethylationEPIC BeadChip. Linear mixed model analyses were performed regressing bifurcation carotid IMT (bIMT) on beta values for cytosine nucleotide that precedes a guanine nucleotide sites, adjusting for covariates, followed by differentially methylated region (DMR) analysis. One‐sample Mendelian randomization analysis was conducted to investigate causal associations between DMRs and bIMT. Twenty‐five DMRs were associated with bIMT (Sidak P P =2.45×10 ⁻¹⁷ ) overlapping with the promoter of PM20D1 . All 11 cytosine nucleotides that precede a guanine nucleotide within the PM20D1 DMR were positively associated with bIMT ( P =0.0007–0.00006). Methylation of the PM20D1 DMR was associated with cis variants, including rs823154 (β=0.26; P =1.1×10 ⁻¹²¹ ). As reported in GTEx (Genotype‐Tissue Expression project), rs823154 is an expression quantitative trait locus for PM20D1 in multiple tissues, including the aorta ( P =2.3×10 ⁻⁶⁰ ) and blood ( P =4.0×10 ⁻⁷³ ), suggesting that hypermethylation of the PM20D1 DMR directs lower expression of the gene. Mendelian randomization analysis supported a causal role for PM20D1 DMR in bIMT ( P =0.049). Conclusions: Our study and previous expression quantitative trait locus studies provide converging evidence that reduced PM20D1 expression via hypermethylation of the promoter is associated with increased atherosclerosis.

The rapidly accelerating translation of biomedical advances is leading to revolutionary therapies that are often inaccessible to historically marginalized populations. We identified and synthesized recent guidelines and statements to propose 7 strategies to integrate equity within translational research in neurology: (1) learn history; (2) learn about upstream forces; (3) diversify and liberate; (4) change narratives and adopt best communication practices; (5) study social drivers of health and lived experiences; (6) leverage health technologies; and (7) build, sustain, and lead culturally humble teams. We propose that equity should be a major goal of translational research, equally important as safety and efficacy. ANN NEUROL 2024;95:432–441

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 P P <0.001). Conclusions: This large data set demonstrates consistently low rates of BP‐guideline adherence over 10 years. There is an opportunity for monitoring hypertensive management after stroke.

BACKGROUND: Short-term dual antiplatelet therapy (DAPT) reduces early stroke recurrence after mild noncardioembolic ischemic stroke (NCIS). We aim to evaluate temporal trends and determinants of DAPT prescription after mild NCIS in the Florida Stroke Registry, a statewide registry across Get With The Guidelines-Stroke participating hospitals. METHODS: In this cross-sectional analysis of a cohort study, we included patients with mild NCIS (National Institutes of Health Stroke Scale score ≤3) who were potentially eligible for DAPT across 168 Florida Stroke Registry participating hospitals between January 2010 and September 2022. Using antiplatelet prescription as the dependent variable (DAPT versus single antiplatelet therapy), we fit logistic regression models adjusted for patient-related factors, hospital-related factors, clinical presentation, vascular risk factors, and ischemic stroke subtype, to obtain adjusted odds ratios (aORs) with 95% CIs. RESULTS: From 283 264 Florida Stroke Registry ischemic stroke patients during the study period, 109 655 NCIS were considered eligible. Among these, 37 058 patients with National Institutes of Health Stroke Scale score >3 were excluded, resulting in a sample of 72 597 mild NCIS (mean age 68±14 years; female 47.3%). Overall, 24 693 (34.0%) patients with mild NCIS were discharged on DAPT and 47 904 (66.0%) on single antiplatelet therapy. DAPT prescription increased from 25.7% in 2010 to 52.8% in 2022 ( β /year 2.5% [95% CI, 1.5%–3.4%]). Factors associated with DAPT prescription were premorbid antiplatelet therapy (aOR, 4.66 [95% CI, 2.20–9.88]), large-artery atherosclerosis (aOR, 1.68 [95% CI, 1.43–1.97]), diabetes (aOR, 1.29 [95% CI, 1.13–1.47]), and hyperlipidemia (aOR, 1.24 [95% CI, 1.10–1.39]), whereas female sex (aOR, 0.83 [95% CI, 0.75–0.93]), being non-Hispanic Black patients (compared with non-Hispanic White patients; aOR, 0.78 [95% CI, 0.68–0.90]), admission to a Thrombectomy-capable Stroke Center (compared with Comprehensive Stroke Center; aOR, 0.78 [95% CI, 0.66–0.92]), time-to-presentation 1 to 7 days from last seen well (compared with <24 h; aOR, 0.86 [95% CI, 0.76–0.96]), and small-vessel disease stroke (aOR, 0.81 [95% CI, 0.72–0.94]) were associated with not receiving DAPT at discharge. CONCLUSIONS: Despite a temporal trend increase in DAPT prescription after mild NCIS, we found substantial underutilization of evidence-based DAPT associated with significant disparities in stroke care.

BACKGROUND: Sleep duration is associated with stroke risk and is 1 of 8 essential components of cardiovascular health according to the American Heart Association. As stroke disproportionately burdens Black and Hispanic populations in the United States, we hypothesized that long and short sleep duration would be associated with greater subclinical carotid atherosclerosis, a precursor of stroke, in the racially and ethnically diverse NOMAS (Northern Manhattan Study). METHODS: NOMAS is a study of community-dwelling adults. Self-reported nightly sleep duration and daytime sleepiness were collected between 2006 and 2011. Carotid plaque presence, total plaque area, and intima-media thickness were measured by ultrasound between 1999 and 2008. Linear and logistic regression models examined the cross-sectional associations of sleep duration groups (primary exposure) or daytime sleepiness (secondary exposure) with measures of carotid atherosclerosis. Models adjusted for age, time between ultrasound and sleep data collection, sex, race and ethnicity, education, health insurance, smoking, alcohol use, physical activity, body mass index, hypertension, diabetes, hypercholesterolemia, and cardiac disease. RESULTS: The sample (n=1553) had a mean age of 64.7±8.5 years and was 61.9% female, 64.8% Hispanic, and 18.2% non-Hispanic Black. Of the sample, 55.6% had carotid plaque, 22.3% reported nightly short sleep (<7 hours), 66.6% intermediate sleep (≥7 and <9 hours), and 11.1% had long sleep (≥9 hours). Compared with intermediate sleep, long sleep was associated with greater odds of carotid plaque presence relative to plaque absence (odds ratio, 1.6 [95% CI, 1.1–2.4]) and larger total plaque area (odds ratio, 1.4 [95% CI, 1.0–1.9]) after full covariate adjustment. Short sleep and daytime sleepiness were not significantly associated with any carotid measures. CONCLUSIONS: The association between long sleep and subclinical carotid atherosclerosis may explain prior associations between long sleep and stroke.

Objective: The purpose of this study is to assess the factors involved in considering neurology as a subspeciality, among medical students who identify as Black/African-American. Background: Currently, 2.8% of U.S. neurologists identify as Black/African-American. Previous studies have not fully explored factors associated with decisions among URiM students to pursue neurology as a specialty. Understanding these factors is critical as the field seeks to diversify. Design/Methods: A 27-question survey was created with the Qualtrics platform to assess beliefs about neurology and values that may guide choice in subspecialty decision making. The survey was sent nationally to various student groups, including the Student National Medical Association (SNMA), Students Interested in Neurology Groups (SIGN). Survey items were scores on a 1 to 5 Likert scale (1 = “strongly disagree”, 5 = “strongly agree”). An analysis of nonparametric variables (ie. Mann-Whitney U test) was conducted at a 95% confidence interval and descriptive statistics were used. Results: A subgroup of 76 Black/African-American medical students across all 4 years of medical school completed the survey; 97.4% were aged 18–34, 70.7% were female, 32.9% were first-generation, and 22.4% were interested in neurology. Of the overall complete responders (n=59), the most important values reported as agree/strongly when considering neurology as a subspeciality including opportunities to work with diverse patient populations (95%), community engagement/underrepresented communities (89.9%), length of neurology (83%), and level of interventions to address systemic bias and reduce health disparity (81.4%). Several differences were noted by choice in neurology: 1) perception of work/life balance and future family planning, 2) research opportunities, competitiveness, and length of training, 3) inclusivity and available interventions to address systemic bias. Conclusions: In our survey, several themes emerged between factors of Black/African-American medical students based on choice to pursue neurology. Understanding these factors may help in aligning values with efforts to increase diversity, inclusion, and equity. Disclosure: Ms. Maddy has nothing to disclose. Mr. Ezeh has nothing to disclose. Dr. Sacco has received personal compensation in the range of $100,000-$499,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Heart Association. The institution of Dr. Sacco has received research support from NIH, NINDS, NCATS, NIMHD. The institution of Dr. Sacco has received research support from FL Department of Health. Dr. Sacco has received research support from University of Washington, Seattle. Dr. Sacco has received publishing royalties from a publication relating to health care. Dr. Monteith has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lundbeck . Dr. Monteith has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Impel . Dr. Monteith has received personal compensation in the range of $0-$499 for serving as a Consultant for Abbvie. Dr. Monteith has received personal compensation in the range of $500-$4,999 for serving as a Consultant for LinPharma. Dr. Monteith has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Monteith has received personal compensation in the range of $500-$4,999 for serving as a Consultant for HMP Global . Dr. Monteith has received personal compensation in the range of $500-$4,999 for serving as a Consultant for American Headache Society . Dr. Monteith has received personal compensation in the range of $0-$499 for serving as a Consultant for American Academy of Neurology . Dr. Monteith has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lundbeck. Dr. Monteith has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alder. Dr. Monteith has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alder. Dr. Monteith has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva . Dr. Monteith has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for AAN . The institution of Dr. Monteith has received research support from AbbVie. The institution of Dr. Monteith has received research support from Amgen. The institution of Dr. Monteith has received research support from Teva. The institution of Dr. Monteith has received research support from Electrocore. The institution of Dr. Monteith has received research support from Novartis . The institution of Dr. Monteith has received research support from Amgen. The institution of Dr. Monteith has received research support from lilly. Dr. Monteith has received personal compensation in the range of $500-$4,999 for serving as a Education with Medscape. Dr. Monteith has received personal compensation in the range of $500-$4,999 for serving as a Education with Massachusetts Medical Society . Dr. Monteith has received personal compensation in the range of $500-$4,999 for serving as a Education with Academic CME. Dr. Monteith has received personal compensation in the range of $10,000-$49,999 for serving as a Education with Rockpointe. Dr. Monteith has received personal compensation in the range of $500-$4,999 for serving as a Speaker with Neuodiem. Dr. Monteith has a non-compensated relationship as a President Elect with Florida Society of Neurology that is relevant to AAN interests or activities. Dr. Monteith has a non-compensated relationship as a Editorial Board with...

Background: The impact of time to treatment on outcomes of endovascular thrombectomy (EVT) especially in patients presenting after 6 hours from symptom onset is not well characterized. We studied the differences in characteristics and treatment timelines of EVT-treated patients participating in the Florida Stroke Registry and aimed to characterize the extent to which time impacts EVT outcomes in the early and late time windows. Methods: Prospectively collected data from Get With the Guidelines–Stroke hospitals participating in the Florida Stroke Registry from January 2010 to April 2020 were reviewed. Participants were EVT patients with onset-to-puncture time (OTP) of ≤24 hours and categorized into early window treated (OTP ≤6 hours) and late window treated (OTP >6 and ≤24 hours). Association between OTP and favorable discharge outcomes (independent ambulation, discharge home and to acute rehabilitation facility) as well as symptomatic intracerebral hemorrhage and in-hospital mortality were examined using multilevel-multivariable analysis with generalized estimating equations. Results: Among 8002 EVT patients (50.9% women; median age [±SD], 71.5 [±14.5] years; 61.7% White, 17.5% Black, and 21% Hispanic), 34.2% were treated in the late time window. Among all EVT patients, 32.4% were discharged home, 23.5% to rehabilitation facility, 33.7% ambulated independently at discharge, 5.1% had symptomatic intracerebral hemorrhage, and 9.2% died. As compared with the early window, treatment in the late window was associated with lower odds of independent ambulation (odds ratio [OR], 0.78 [0.67–0.90]) and discharge home (OR, 0.71 [0.63–0.80]). For every 60-minute increase in OTP, the odds of independent ambulation reduced by 8% (OR, 0.92 [0.87–0.97]; P P =0.5) and the odds of discharged home reduced by 10% (OR, 0.90 [0.87–0.93]; P P =0.11) in the early and late windows, respectively. Conclusions: In routine practice, just over one-third of EVT-treated patients independently ambulate at discharge and only half are discharged to home/rehabilitation facility. Increased time from symptom onset to treatment is significantly associated with lower chance of independent ambulation and ability to be discharged home after EVT in the early time window.

Background: Brain arterial dilation and elongation characterize dolichoectasia, an arteriopathy associated with risk of stroke and death. We aim to determine whether brain arterial elongation increases the risk of stroke and death independent of brain arterial diameters. Methods: We analyzed 1210 stroke-free participants (mean age 71±9 years, 41% men, 65% Hispanic) with available time-of-flight magnetic resonance angiogram from the Northern Manhattan Study, a population-based cohort study across a multiethnic urban community. We obtained baseline middle cerebral artery M1-segment (MCA-M1) and basilar artery (BA) mean lengths and diameters using a semi-automated software. Cox proportional hazards models adjusted for brain arterial diameters and potential confounders yielded adjusted hazards ratios with 95% CIs for the primary outcomes of incident stroke and all-cause mortality, as well as secondary outcomes including noncardioembolic stroke, vascular death, and any vascular event. Results: Neither MCA-M1 nor BA lengths correlated with incident stroke or all-cause mortality. Both MCA-M1 and BA larger diameters correlated with all-cause mortality (MCA-M1 aHR, 1.52 [95% CI, 1.03–2.23], BA aHR, 1.28 [95% CI, 1.02–1.61]), as well as larger MCA-M1 diameters with vascular death (aHR, 1.84 [95% CI, 1.02–3.31]). Larger MCA-M1 and BA diameters did not correlate with incident stroke. However, larger BA diameters were associated with posterior circulation noncardioembolic stroke (aHR, 2.93 [95% CI, 1.07–8.04]). There were no statistical interactions between brain arterial lengths and diameters in relation to study outcomes. Conclusions: In a multiethnic cohort of stroke-free adults, brain arterial elongation did not correlate with risk of stroke or death, nor influenced the significant association between brain arterial dilation and vascular risk.

Background: The Florida Stroke Act, signed into law in 2004, set criteria for Comprehensive Stroke Centers (CSC). For a set time period, Florida hospitals were permitted to either receive national certification (NC) or could self-attest (SA) as fulfilling CSC criteria. The aim of this project was to evaluate the quality of ischemic stroke care in NC versus SA stroke centers in Florida, using well-known, guideline-driven ischemic stroke outcome metrics. Methods: A total of 37 CSCs (74% of Florida CSCs) in the Florida Stroke Registry from January 2013 through December 2018 were analyzed, including 19 SA CSCs and 18 NC (13 CSCs and 5 Thrombectomy-Capable Stroke Center). Hospital- and patient-level characteristics and stroke metrics were evaluated, adjusting for demographics, medical comorbidities, and stroke severity. Results: A total of 78 424 acute ischemic stroke cases, 36 089 from SA CSCs and 42 335 from NC CSC/Thrombectomy-Capable Stroke Centers were analyzed. NC centers had older patients (73 [61–83] versus 71 [60–81]; P P P P P P P P =0.001) and more likely to be treated with intravenous tissue-type plasminogen activator within 45 minutes (adjusted odds ratio, 1.61 [95% CI, 1.04–2.50]; P =0.04) compared with SA CSCs. Conclusions: Among Florida-Stroke Registry CSCs, acute ischemic stroke performance and treatment measures at NC centers are superior to SA CSCs. These findings have implications for stroke systems of care in Florida and support legislation updates requiring NC and removal of SA claims.

Background: Brain arterial diameters are novel imaging biomarkers of cerebrovascular disease, cognitive decline and dementia. Traditional vascular risk factors have been associated with brain arterial diameters but whether there may be genetic determinants of brain arterial diameters is unknown. Results: We studied 4150 participants from six geographically diverse population-based cohorts (40% European, 14% African, 22% Hispanic, 24% Asian ancestries). We measured brain arterial diameters for 13 segments and averaged them to obtain a global measure of brain arterial diameters as well as the posterior and anterior circulations. A genome-wide association study (GWAS) revealed 14 variants at one locus associated with global brain arterial diameter at genome-wide significance (P−8 ) (top SNP, rs7921574; β =0.06, P=1.54×10 ⁻⁸ ). This locus mapped to an intron of CNNM2 . A trans-ancestry GWAS meta-analysis identified two more loci at NT5C2 (rs10748839; P=2.54×10 ⁻⁸ ) and at AS3MT (rs10786721; P=4.97×10 ⁻⁸ ), associated with global brain arterial diameter. In addition, two SNPs co-localized with expression of CNNM2 (rs7897654, β=0.12, P=6.17×10 ⁻⁷ ) and AL356608 . 1 (rs10786719, β =-0.17, P=6.60×10 ⁻⁶ ) in brain tissue. For the posterior brain arterial diameter, two variants at one locus mapped to an intron of TCF25 were identified (top SNP, rs35994878; β =0.11, P=2.94×10 ⁻⁸ ). For the anterior brain arterial diameter, one locus at ADAP1 was identified in trans-ancestry genome-wide association analysis (rs34217249; P=3.11×10 ⁻⁸ ). Conclusion: Our study reveals three novel risk loci (CNNM2, NT5C2 and AS3MT) associated with brain arterial diameters. Our finding may elucidate the mechanisms by which brain arterial diameters influence the risk of stroke and dementia.