Treatment and Outcomes of Cervical Artery Dissection in Adults: A Scientific Statement From the American Heart Association.

Cervical artery dissection is an important cause of stroke, particularly in young adults. Data conflict on the diagnostic evaluation and treatment of patients with suspected cervical artery dissection, leading to variability in practice. We aim to provide an overview of cervical artery dissection in the setting of minor or no reported mechanical trigger with a focus on summarizing the available evidence and providing suggestions on the diagnostic evaluation, treatment approaches, and outcomes. Writing group members drafted their sections using a literature search focused on publications between January 1, 1990, and December 31, 2022, and included randomized controlled trials, prospective and retrospective observational studies, meta-analyses, opinion papers, case series, and case reports. The writing group chair and vice chair compiled the manuscript and obtained writing group members' approval. Cervical artery dissection occurs as a result of the interplay among risk factors, minor trauma, anatomic and congenital abnormalities, and genetic predisposition. The diagnosis can be challenging both clinically and radiologically. In patients with acute ischemic stroke attributable to cervical artery dissection, acute treatment strategies such as thrombolysis and mechanical thrombectomy are reasonable in otherwise eligible patients. We suggest that the antithrombotic therapy choice be individualized and continued for at least 3 to 6 months. The risk of recurrent dissection is low, and preventive measures may be considered early after the diagnosis and continued in high-risk patients. Ongoing longitudinal and population-based observational studies are needed to close the present gaps on preferred antithrombotic regimens considering clinical and radiographic prognosticators of cervical artery dissection.

Dietary oily fish intake is inversely associated with moderate-to-severe intracranial artery stenosis in older adults of indigenous Ecuadorian ancestry.

BACKGROUND AND AIMS: Information on the association between dietary oily fish intake and intracranial atherosclerosis is limited and contradictory. Inconsistencies might be in part related to heterogeneous designs and differences in race/ethnicity of study populations. We aim to assess whether oily fish intake is inversely associated with intracranial artery stenosis (ICAS) in frequent fish consumers of indigenous ancestry living in coastal Ecuador. METHODS: The study included 384 participants aged ≥60 years enrolled in the Atahualpa Project Cohort. Dietary oily fish intake was quantified systematically via validated surveys and all participants received a time-of-flight MRA of intracranial vessels. Poisson regression models, adjusted for demographics, level of education, traditional risk factors and severe tooth loss, were fitted to assess the association between amounts of oily fish intake and the number of intracranial arteries with moderate-to-severe (≥50 %) stenosis. RESULTS: Participants had a mean age of 67.7 ± 7 years, and 56 % were women. The mean oily fish intake was 8.9 ± 5.2 servings/week; 283 (74 %) participants consumed ≥5.2 servings/week (2nd to 4th quartiles of fish intake). Forty-three (11 %) participants had at least one major intracranial artery with moderate-to-severe stenosis. Both univariate and multivariate models showed a significant inverse association between consumption of oily fish in the 2nd to 4th quartiles and ≥50 % stenosis in at least one artery (ß: 0.46; 95 % C.I.: 0.27-077, and ß: 0.52; 95 % C.I.: 0.30-0.90, respectively). CONCLUSIONS: Consumption of more than five oily fish servings/week is associated with lower prevalence of moderate-to-severe ICAS in indigenous Ecuadorians.

Association of brain arterial diameters with demographic and anatomical factors in a multi-national pooled analysis of cohort studies.

BACKGROUND AND PURPOSE: Brain arterial diameters are markers of cerebrovascular disease. Demographic and anatomical factors may influence arterial diameters. We hypothesize that age, sex, height, total cranial volume (TCV), and persistent fetal posterior cerebral artery (fPCA) correlate with brain arterial diameters across populations. METHODS: Participants had a time-of-flight MRA from nine international cohorts. Arterial diameters of the cavernous internal carotid arteries (ICA), middle cerebral arteries (MCA), and basilar artery (BA) were measured using LAVA software. Regression models assessed the association between exposures and brain arterial diameters. RESULTS: We included 6,518 participants (mean age: 70 ± 9 years; 41% men). Unilateral fPCA was present in 13.2% and bilateral in 3.2%. Larger ICA, MCA, and BA diameters correlated with older age (Weighted average [WA] per 10 years: 0.18 mm, 0.11 mm, and 0.12 mm), male sex (WA: 0.24 mm, 0.13 mm, and 0.21 mm), and TCV (WA: for one TCV standard deviation: 0.24 mm, 0.29 mm, and 0.18 mm). Unilateral and bilateral fPCAs showed a positive correlation with ICA diameters (WA: 0.39 mm and 0.73 mm) and negative correlation with BA diameters (WA: -0.88 mm and -1.73 mm). Regression models including age, sex, TCV, and fPCA explained on average 15%, 13%, and 25% of the ICA, MCA, and BA diameter interindividual variation, respectively. Using height instead of TCV as a surrogate of head size decreased the R-squared by 3% on average. CONCLUSION: Brain arterial diameters correlated with age, sex, TCV, and fPCA. These factors should be considered when defining abnormal diameter cutoffs across populations.

Immune Markers Are Associated With Asymptomatic Intracranial Large Artery Stenosis and Future Vascular Events in NOMAS.

BACKGROUND: Inflammation contributes to atherosclerosis but is incompletely characterized in intracranial large artery stenosis (ICAS). We hypothesized that immune markers would be associated with ICAS and modify the risk ICAS confers on future vascular events. METHODS: This study included a subsample of stroke-free participants in the prospective NOMAS (Northern Manhattan Study), who had blood samples analyzed with a 60-plex immunoassay (collected from 1993 to 2001) and ICAS assessment with time-of-flight magnetic resonance angiography (obtained from 2003 to 2008). We dichotomized ICAS as either ≥50% stenosis or not (including no ICAS). We ascertained post-magnetic resonance imaging vascular events. We used least absolute shrinkage and selection operator procedures to select immune markers independently associated with ICAS. Then, we grouped selected immune markers into a derived composite Z score. Using proportional odds regression, we quantified the association of the composite immune marker Z score, ICAS, and risk of vascular events. RESULTS: Among 1211 participants (mean age, 71±9 years; 59% women; 65% Hispanic participants), 8% had ≥50% ICAS. Using least absolute shrinkage and selection operator regression, we identified CXCL9 (C-X-C motif chemokine ligand 9), HGF (hepatocyte growth factor), resistin, SCF (stem cell factor), and VEGF-A(vascular endothelial growth factor A) to have the strongest positive relationships with ≥50% ICAS in fully adjusted models. Selected markers were used to derive a composite immune marker Z score. Over an average follow-up of 12 years, we found that each unit increase in immune marker Z scores was associated with an 8% (95% CI, 1.05-1.11), 11% (95% CI, 1.06-1.16), and 5% (95% CI, 1.01-1.09) increased hazard of death, vascular death, and any vascular event, respectively, in adjusted models. We did not find a significant interaction between immune marker Z scores and ICAS in their relationship with any longitudinal outcome. CONCLUSIONS: Among a diverse stroke-free population, selected serum immune markers were associated with ICAS and future vascular events. Further study is needed to better understand their role in the pathogenesis of ICAS and as a potential therapeutic target in stroke prevention.

Determinants and Temporal Trends of Dual Antiplatelet Therapy After Mild Noncardioembolic 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 (ß/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.

Systemic immune-inflammation index and progression of white matter hyperintensities of presumed vascular origin. A longitudinal population study in community-dwelling older adults living in rural Ecuador.

BACKGROUND: Information on the association between the systemic immune-inflammation index (SII) and white matter hyperintensities (WMH) of presumed vascular origin is confined to cross-sectional studies. We sought to evaluate the impact of SII on WMH progression in community-dwelling older adults. METHODS: Following a longitudinal prospective study design, participants of a population-based cohort received baseline blood tests to calculate the SII (platelets x neutrophils / lymphocytes x 109 L) together with clinical interviews and brain MRIs. Participants with follow-up brain MRI were included in the analysis. Poisson regression models adjusted for demographics and cardiovascular risk factors were fitted to assess the incidence rate ratio of WMH progression by levels of the SII. RESULTS: Across 246 study participants (mean age: 65.5 ± 5.9 years; 55% women), the mean SII was 434.7 ± 193.8 × 109 L, and WMH progression was found in 101 (41%) individuals after a mean of 7.3 ± 1.5 years. A multivariate Poisson regression model showed increased WMH progression rate among individuals in the fourth quartile of the SII compared with those in the first quartile (IRR: 1.87; 95% C.I.: 1.02-3.41). CONCLUSIONS: Study results provided novel evidence of an independent association between the SII and WMH progression. The SII may be able to identify individuals at high risk of WMH progression.

Association of Brain Arterial Elongation With Risk of Stroke and Death in Stroke-Free Individuals: Results From NOMAS.

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.

Dietary oily fish intake and progression of diffuse subcortical damage of vascular origin: A longitudinal prospective study in community-dwelling older adults.

Introduction: Oily fish intake may reduce the progression of white matter hyperintensities (WMH) of presumed vascular origin due to their high content of omega-3 polyunsaturated fatty acids and other nutrients. However, information on this relationship is limited. We aimed to assess the association between oily fish intake and WMH progression in older adults living in rural coastal Ecuador. Methods: Participants of the Atahualpa Project Cohort received baseline clinical interviews and brain MRIs. Oily fish intake was calculated at every annual door-to-door survey from enrollment to the end of the study. Individuals who also received a follow-up brain MRI were included. Poisson regression models were fitted to assess the incidence rate ratio (IRR) of WMH progression according to the amount of oily fish intake, after adjusting for demographics, level of education and traditional vascular risk factors. Results: The study included 263 individuals of Amerindian ancestry aged ⩾60 years (mean age: 65.7 ± 6.2 years; 57% women). The mean oily fish intake was 8.3 ± 4 servings per week. Follow-up MRIs demonstrated WMH progression in 103 (39%) individuals after a median follow-up of 6.5 years. A multivariate Poisson regression model showed an inverse relationship between oily fish intake and WMH progression (IRR: 0.89; 95% CI: 0.84-0.95; p < 0.001). A similar model also revealed an inverse relationship between tertiles of oily fish intake and probabilities of WMH progression, which became significant when individuals allocated to the third tertile were compared to those in the first and second tertiles. Conclusion: Study results show an inverse relationship between the amount of oily fish intake and WMH progression in frequent fish consumers of Amerindian ancestry.

Patterns of progression of cerebral small vessel disease markers in older adults of Amerindian ancestry: a population-based, longitudinal prospective cohort study.

BACKGROUND: Progression of cerebral small vessel disease (cSVD) markers has been studied in different races/ethnic groups. However, information from individuals of Amerindian ancestry is lacking. We sought to evaluate progression patterns of cSVD markers in community-dwelling older adults of Amerindian ancestry. METHODS: Following a longitudinal prospective study design, participants of the Atahualpa Project Cohort aged ≥ 60 years received a baseline brain MRI and clinical interviews. Those who also received a brain MRI at the end of the study were included. Poisson regression models were fitted to assess cSVD markers progression according to their baseline load after a median follow-up of 6.5 ± 1.4 years. Logistic regression models were fitted to assess interrelations in the progression of the different cSVD markers at the end of the study. RESULTS: The study included 263 individuals (mean age: 65.7 ± 6.2 years). Progression of white matter hyperintensities (WMH) was noticed in 103 (39%) subjects, cerebral microbleeds in 25 (12%), lacunes in 12 (5%), and enlarged basal ganglia-perivascular spaces (BG-PVS) in 56 (21%). Bivariate Poisson regression models showed significant associations between WMH severity at baseline and progression of WMH and enlarged BG-PVS. These associations became non-significant in multivariate models adjusted for clinical covariates. Logistic regression models showed interrelated progressions of WMH, cerebral microbleeds and enlarged BG-PVS. The progression of lacunes was independent. CONCLUSIONS: Patterns of cSVD marker progression in this population of Amerindians are different than those reported in other races/ethnic groups. The independent progression of lacunes suggests different pathogenic mechanisms with other cSVD markers.

Associations Between Vascular Risk Factors and Perivascular Spaces in Adults with Intact Cognition, Mild Cognitive Impairment, and Dementia.

BACKGROUND: Perivascular spaces (PVS) are fluid-filled compartments surrounding small intracerebral vessels that transport fluid and clear waste. OBJECTIVE: We examined associations between PVS count, vascular and neurodegenerative risk factors, and cognitive status among the predominantly Hispanic participants of the FL-VIP Study of Alzheimer's Disease Risk. METHODS: Using brain MRI (n = 228), we counted PVS in single axial image through the basal ganglia (BG) and centrum semiovale (CSO). PVS per region were scored as 0 (none), 1 (<10), 2 (11-20), 3 (21-40), and 4 (>40). Generalized linear models examined PVS associations with vascular risk factors and a composite vascular comorbidity risk (VASCom) score. RESULTS: Our sample (mean age 72±8 years, 61% women, 60% Hispanic, mean education 15±4 years, 33% APOE4 carriers) was 59% hypertensive, 21% diabetic, 66% hypercholesteremic, and 30% obese. Mean VASCom score was 2.3±1.6. PVS scores ranged from 0-4 in the BG (mean 1.3±0.7) and CSO (mean 1.2±0.9), and 0-7 combined (mean 2.5±1.4). In multivariable regression models, BG PVS was associated with age (ß= 0.03/year, p < 0.0001), Hispanic ethnicity (ß= 0.29, p = 0.01), education (ß= 0.04/year, p = 0.04), and coronary bypass surgery (ß= 0.93, p = 0.02). CSO PVS only associated with age (ß= 0.03/year, p < 0.01). APOE4 and amyloid-ß were not associated with PVS. CONCLUSION: BG PVS may be a marker of subclinical cerebrovascular disease. Further research is needed to validate associations and identify mechanisms linking BG PVS and cerebrovascular disease markers. PVS may be a marker of neurodegeneration despite our negative preliminary findings and more research is warranted. The association between BG PVS and Hispanic ethnicity also requires further investigation.

Predictors of Recurrent Stroke After Embolic Stroke of Undetermined Source in the RE-SPECT ESUS Trial.

Background We sought to determine recurrent stroke predictors among patients with embolic strokes of undetermined source (ESUS). Methods and Results We applied Cox proportional hazards models to identify clinical features associated with recurrent stroke among participants enrolled in RE-SPECT ESUS (Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate Versus Acetylsalicylic Acid in Patients With Embolic Stroke of Undetermined Source) trial, an international clinical trial evaluating dabigatran versus aspirin for patients with ESUS. During a median follow-up of 19 months, 384 of 5390 participants had recurrent stroke (annual rate, 4.5%). Multivariable models revealed that stroke or transient ischemic attack before the index event (hazard ratio [HR], 2.27 [95% CI, 1.83-2.82]), creatinine clearance <50 mL/min (HR, 1.69 [95% CI, 1.23-2.32]), male sex (HR, 1.60 [95% CI, 1.27-2.02]), and CHA2DS2-VASc ≥4 (HR, 1.55 [95% CI, 1.15-2.08] and HR, 1.66 [95% CI, 1.21-2.26] for scores of 4 and ≥5, respectively) versus CHA2DS2-VASc of 2 to 3, were independent predictors for recurrent stroke. Conclusions In RE-SPECT ESUS trial, expected risk factors previously linked to other common stroke causes were associated with stroke recurrence. These data help define high-risk groups for subsequent stroke that may be useful for clinicians and for researchers designing trials among patients with ESUS. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02239120.

High Social Risk Influence Progression of White Matter Hyperintensities of Presumed Vascular Origin: A Prospective Study in Community-Dwelling Older Adults.

BACKGROUND: Information on cerebrovascular consequences of high social risk, as determined by the social determinants of health, is limited. We sought to evaluate the impact of high social risk on the progression of white matter hyperintensities (WMHs) of presumed vascular origin. METHODS: Following a longitudinal prospective study design, participants of the Atahualpa Project Cohort received baseline social risk determinations by means of social determinants of health components included in the Gijon's Social-Familial Evaluation Scale together with clinical interviews and brain magnetic resonance imagings. Those who also received follow-up brain magnetic resonance imaging at the end of the study were included. We used Poisson regression models adjusted for demographics, education levels and traditional cardiovascular risk factors to assess the incidence rate ratio of WMH progression according to the Gijon's Social-Familial Evaluation Scale score. RESULTS: The study included 263 individuals aged ≥60 years (mean age, 65.7±6.2 years; 57% women). The Gijon's Social-Familial Evaluation Scale mean score was 8.9±2.2 points. Follow-up magnetic resonance imagings revealed WMH progression in 103 (39%) individuals after a mean follow-up of 6.5 years (SD±1.4 years). Poisson regression models showed increased WMH progression rate among individuals in the third tertile of the Gijon's Social-Familial Evaluation Scale score compared with those in the first tertile (incidence rate ratio, 1.65 [95% CI, 1.05-2.61]; P=0.032). Separate Poisson regression models using individual social determinants of health components showed that poor social relationships (incidence rate ratio, 1.39 [95% CI, 1.10-1.77]; P=0.006) and deficient support networks (incidence rate ratio, 1.79 [95% CI, 1.19-2.69]; P=0.005) were independently associated with WMH progression, whereas family situation, economic status, and housing did not. CONCLUSIONS: Poor social relationships and deficient support networks were significantly associated with WMH progression in community-dwelling older adults living in a rural setting. Our findings may help planning cost-effective preventive policies to reduce progression of cerebral small vessel disease among vulnerable populations.

Internal Carotid Artery Angle Variations are Poorly Explained by Vascular Risk Factors: The Northern Manhattan Study.

OBJECTIVES: The internal carotid artery (ICA) angle of origin may contribute to atherogenesis by altered hemodynamics. We aim to determine the contribution of vascular risk factors and arterial wall changes to ICA angle variations. METHODS: We analyzed 1,065 stroke-free participants from the population-based Northern Manhattan Study who underwent B-mode ultrasound (mean age 68.7±8.9 years; 59% women). ICA angle was estimated at the intersection between the common carotid artery and the ICA center line projections. Narrower external angles translating into greater carotid bifurcation bending were considered unfavorable. Linear regression models were fitted to assess the relationship between ICA angle and demographics, vascular risk factors, and arterial wall changes including carotid intima-media thickness (cIMT) and plaque presence. RESULTS: ICA angles were narrower on the left compared to the right side (153±15.4 degrees versus 161.4±12.7 degrees, p<0.01). Mean cIMT was 0.9±0.1 mm and 54.3% had at least one plaque. ICA angle was not associated with cIMT or plaque presence. Unfavorable left and right ICA angles were associated with advanced age (per 10-year increase ß=-1.6; p=0.01, and -1.3; p=0.03, respectively) and being Black participant (ß=-4.6; p<0.01 and -2.9; p=0.04, respectively), while unfavorable left ICA angle was associated with being female (ß=-2.8; p=0.03) and increased diastolic blood pressure (per 10 mmHg increase ß=-2.1; p<0.01). Overall, studied factors explained less than 10% of the variance in ICA angle (left R2=0.07; right R2=0.05). CONCLUSION: Only a small portion of ICA angle variation were explained by demographics, vascular risk factors and arterial wall changes. Whether ICA angle is determined by other environmental or genetic factors, and is an independent risk factor for atherogenesis, requires further investigation.

Decreased Nighttime Heart Rate Variability and Progression of White Matter Hyperintensities of Presumed Vascular Origin. A Prospective Study in Community-Dwelling Older Adults.

OBJECTIVES: Evidence on the role of autonomic dysfunction on white matter hyperintensities (WMH) progression is limited. This study aims to assess the impact of a low nighttime heart rate variability (HRV) on WMH progression in community-dwelling older adults. MATERIALS AND METHODS: Following a prospective longitudinal study design, all individuals aged ≥60 years enrolled in the Atahualpa Project Cohort from 2012 to 2019 were invited to receive baseline HRV determinations through 24-h Holter monitoring, together with clinical interviews and brain MRIs. These individuals were periodically followed by means of annual door-to-door surveys, and those who also received brain MRIs at the end of the study (May 2021) were included in the analysis. Poisson regression models, adjusted for relevant confounders, were fitted to assess the incidence rate ratio (IRR) of WMH progression according to nighttime standard deviation of normal-to-normal R-R intervals (SDNN). RESULTS: This study included 254 individuals aged ≥60 years (mean age: 65.4 ± 5.9 years; 55% women). The mean nighttime SDNN was 116.8 ± 36.3 ms. Follow-up MRIs showed WMH progression in 103 (41%) individuals after a median follow-up of 6.5 years. In unadjusted analyses, nighttime SDNN was lower among participants who developed WMH progression than in those who did not (p < 0.001). A Poisson regression model, adjusted for relevant covariates, disclosed a significantly inverse association between nighttime SDNN and WMH progression (IRR: 0.99; 95% C.I.: 0.98-0.99; p = 0.014). CONCLUSIONS: Study results show an inverse association between nighttime SDNN and WMH progression, and provide support for the role of sympathetic overactivity in this relationship.

Cerebral Microbleeds, Cerebral Amyloid Angiopathy, and Their Relationships to Quantitative Markers of Neurodegeneration.

BACKGROUND AND OBJECTIVES: Age-related cognitive impairment is driven by the complex interplay of neurovascular and neurodegenerative disease. There is a strong relationship between cerebral microbleeds (CMBs), cerebral amyloid angiopathy (CAA), and the cognitive decline observed in conditions such as Alzheimer disease. However, in the early, preclinical phase of cognitive impairment, the extent to which CMBs and underlying CAA affect volumetric changes in the brain related to neurodegenerative disease remains unclear. METHODS: We performed cross-sectional analyses from 3 large cohorts: The Northern Manhattan Study (NOMAS), Alzheimer's Disease Neuroimaging Initiative (ADNI), and the Epidemiology of Dementia in Singapore study (EDIS). We conducted a confirmatory analysis of 82 autopsied cases from the Brain Arterial Remodeling Study (BARS). We implemented multivariate regression analyses to study the association between 2 related markers of cerebrovascular disease-MRI-based CMBs and autopsy-based CAA-as independent variables and volumetric markers of neurodegeneration as dependent variables. NOMAS included mostly dementia-free participants age 55 years or older from northern Manhattan. ADNI included participants living in the United States age 55-90 years with a range of cognitive status. EDIS included community-based participants living in Singapore age 60 years and older with a range of cognitive status. BARS included postmortem pathologic samples. RESULTS: We included 2,657 participants with available MRI data and 82 autopsy cases from BARS. In a meta-analysis of NOMAS, ADNI, and EDIS, superficial CMBs were associated with larger gray matter (ß = 4.49 ± 1.13, p = 0.04) and white matter (ß = 4.72 ± 2.1, p = 0.03) volumes. The association between superficial CMBs and larger white matter volume was more evident in participants with 1 CMB (ß = 5.17 ± 2.47, p = 0.04) than in those with ≥2 CMBs (ß = 1.97 ± 3.41, p = 0.56). In BARS, CAA was associated with increased cortical thickness (ß = 6.5 ± 2.3, p = 0.016) but not with increased brain weight (ß = 1.54 ± 1.29, p = 0.26). DISCUSSION: Superficial CMBs are associated with larger morphometric brain measures, specifically white matter volume. This association is strongest in brains with fewer CMBs, suggesting that the CMB/CAA contribution to neurodegeneration may not relate to tissue loss, at least in early stages of disease.

Risk for Subsequent SARS-CoV-2 Infection and Severe COVID-19 Among Community-Dwellers With Pre-Existing Cervicocephalic Atherosclerosis: A Population-Based Study.

BACKGROUND: COVID-19 patients may develop atherosclerosis-related complications. Whether a proportion of these patients already had asymptomatic cervicocephalic atherosclerosis before SARS-CoV-2 infection is not known. This study assessed whether pre-existing cervicocephalic atherosclerosis increased the susceptibility to SARS-CoV-2 infection or resulted in more severe or fatal COVID-19. METHODS: Individuals enrolled in the Atahualpa Project cohort who received head CT (for assessing carotid siphon calcifications) and B-mode ultrasounds (for measurement of the carotid intima-media thickness) prior to the pandemic were eligible for this study. Among this cohort, those who also received serological tests for detection of SARS-CoV-2 antibodies and clinical evaluations for assessment of COVID-19 severity were enrolled. Multivariate logistic regression and exposure-effect models were fitted to assess the association between pre-existing atherosclerosis biomarkers, and SARS-CoV-2 seropositivity and COVID-19 severity. RESULTS: Overall, 154 of 519 study participants (30%) had evidence of cervicocephalic atherosclerosis. A total of 325 (63%) individuals became SARS-CoV-2 positive, and 65 (23.5%) of seropositive individuals had severe or fatal COVID-19. The risk of SARS-CoV-2 seropositive status did not differ across individuals with and without atherosclerosis biomarkers (P = .360). Likewise, seropositive individuals with pre-existing atherosclerosis were not more prone to develop severe or fatal COVID-19 than those without evidence of atherosclerosis (P = .274). Average estimated exposure effects of pre-existing cervicocephalic atherosclerosis versus no atherosclerosis over SARS-CoV-2 seropositivity and COVID-19 severity were not significant. CONCLUSIONS: Pre-existing cervicocephalic atherosclerosis does not increase the risk of acquiring SARS-CoV-2 infection nor the severity of COVID-19 among seropositive individuals.

Risk Factors Control and Early Recurrent Cerebral Infarction in Patients with Symptomatic Intracranial Atherosclerotic Disease.

BACKGROUND: The risk of early recurrent cerebral infarction (RCI) is high in patients with symptomatic intracranial atherosclerotic disease (IAD). We sought to determine the relationship between risk factor control and early RCI risk among patients with symptomatic IAD. METHODS: We analyzed participants with symptomatic IAD in the multi-center prospective observational MYRIAD study. Risk factor control was assessed at 6-8-week follow-up. Optimal risk factor control was defined by target systolic blood pressure, being non-smoker, target physical activity, and antiplatelet and antilipidemic therapy compliance. Age-adjusted associations were calculated between risk factor control and RCI determined by MRI-evident new infarcts in the territory of the stenotic vessel at 6-8 weeks from the index event. RESULTS: Among 82 participants with clinical and brain MRI information available 6-8 weeks after the index event (mean age 63.5 ±12.5 years, 62.2% men), RCI occurred in 21 (25.6%) cases. At 6-8-week follow-up, 37.8% had target systolic blood pressure, 92.7% were non-smokers, 51.2% had target physical activity, and 98.8% and 86.6% were compliant with antiplatelet and antilipidemic therapy, respectively. Optimal risk factor control increased from 4.9% at baseline to 19.5% at 6-8-week follow-up (p=0.01). None of the participants with optimal risk factor control at follow-up had RCI (0% vs. 31.8%, p<0.01). CONCLUSIONS: Only one-fifth of MYRIAD participants had optimal risk factor control during early follow-up. Approximately half and two-thirds had physical inactivity and uncontrolled systolic blood pressure, respectively. These risk factors may represent important therapeutic targets to prevent early RCI in patients with symptomatic IAD.

Gut permeability and cognitive decline: A pilot investigation in the Northern Manhattan Study.

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 < 0.05), whereas in samples where only those molecules within the IL-17 and TNF pathways were increased, LPS and sCD14 levels were not elevated. LPS was associated with decline in global cognitive performance over 2-3 assessments (adjusted ß = -0.023 per SD per year, 95% CI:-0.036, -0.010). The association between sCD14 and cognitive decline was marginal (adjusted ß = -0.018 per SD per year, 95% CI:-0.040, 0.004). CONCLUSIONS: These preliminary data support the hypothesis that gut dysbiosis leads to systemic and neuro-inflammation, and subsequently cognitive decline. Further large targeted and untargeted gut microbiota-derived metabolomic studies are needed.

Intracranial dolichoectasia in patients with symptomatic intracranial atherosclerotic disease: Results from the MYRIAD study.

BACKGROUND AND PURPOSE: It is unknown whether intracranial atherosclerotic disease (ICAD), in addition to causing stenosis, also associates with abnormal arterial enlargement, a condition known as intracranial dolichoectasia (IDE). Across symptomatic ICAD patients, we aim to determine IDE prevalence and IDE impact on cerebral hemodynamics and recurrent cerebral ischemia. METHODS: We analyzed 98 participants (mean age 63.8 ± 11.9 years, 56.1% men) of the prospective observational study MYRIAD. Participants were enrolled within 21 days of an ischemic stroke or transient ischemic attack caused by moderate-to-severe ICAD. Semi-automatic vessel segmentation was used to determine diameters, length, and tortuosity-index of proximal intracranial arteries. Either ectasia (increased diameter) or dolichosis (increased length or TI) defined IDE. We assessed IDE association with new infarcts during 12-month follow-up, and IDE correlation with cerebral hemodynamics determined by quantitative MR-angiography (QMRA), MR-perfusion weighted-imaging, and transcranial Doppler breath-holding index. RESULTS: IDE was present in 35.7% of patients and 10.2% of symptomatic arteries. Basilar stenosis was associated with higher IDE prevalence (27.8% vs. 8.8%, p = 0.04), whereas other symptomatic arteries showed no association with IDE. Symptomatic arteries with IDE had lower hypoperfusion prevalence on MR-PWI (11.1% vs. 28.4%, p = 0.03). Increased diameter (r = 0.33, p<0.01) and tortuosity-index (r = 0.29, p = 0.01) showed positive correlation with QMRA flow rate. IDE was not associated with new infarcts during follow-up. CONCLUSIONS: IDE was common among symptomatic ICAD patients. IDE was not associated with stroke recurrence. Instead, increased diameter and tortuosity correlated with improved blood flow across the stenotic artery, suggesting that IDE may originate as an adaptive mechanism in ICAD.

Prevalence and Clinical Correlates of Intracranial Dolichoectasia in Individuals With Ischemic Stroke.

Background and Purpose: Acute ischemic stroke is a known complication of intracranial dolichoectasia (IDE). However, the frequency of IDE causing brain infarction is unknown. We aim to determine the prevalence and clinical correlates of IDE in acute ischemic stroke by employing an objective IDE definition for major intracranial arteries of the anterior and posterior circulation. Methods: Consecutive patients with acute ischemic stroke admitted to a tertiary-care hospital during a 4-month period were analyzed. Intracranial arterial diameter, length, and tortuosity were determined by semiautomatic vessel segmentation and considered abnormal if ≥2 SDs from the study population mean. Either ectasia (increased diameter) or dolichosis (increased length or tortuosity) of at least one proximal intracranial artery defined IDE. Symptomatic IDE was considered when the infarct was located in the territory supplied by an affected artery in the absence of any alternative pathogenic explanation. Multivariate models were fitted to determine IDE clinical correlates. Results: Among 211 cases screened, 200 patients (mean age 67±14 years, 47.5% men) with available intracranial vessel imaging were included. IDE was identified in 24% cases (5% with isolated ectasia, 9.5% with isolated dolichosis, and 9.5% with both ectasia and dolichosis). IDE was considered the most likely pathogenic mechanism in 12 cases (6% of the entire cohort), which represented 23.5% of strokes initially categorized as undetermined cause. In addition, 21% of small-artery occlusion strokes had the infarct territory supplied by a dolichoectatic vessel (3% of the entire cohort). IDE was independently associated with male sex (odds ratio, 4.2 [95% CI, 1.7­10.6]) and its component of ectasia was associated with advanced age (odds ratio, 3.5 [95% CI, 1.3­9.5]). Vascular risk profile was similar across patients with stroke with and without IDE. Conclusions: Our findings suggest that IDE is an arteriopathy frequently found in patients with acute ischemic stroke and is likely responsible for a sizable fraction of strokes initially categorized as of undetermined cause and perhaps also in those with small-artery occlusion.