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Background: The association between heart rate (HR) and pulmonary embolism (PE) outcomes has not been well studied. Furthermore, optimal cutoffs to identify low-risk and intermediate- to high-risk patients are not well known. Research Question: Does an association exist between baseline HR and PE outcome across the continuum of HR values? Study Design and Methods: The current study included 44,331 consecutive nonhypotensive patients with symptomatic PE from the Registro Informatizado de la Enfermedad TromboEmbólica registry between 2001 and 2021. Outcomes included 30-day all-cause and PE-specific mortality. We used hierarchical logistic regression to assess the association between admission HR and outcomes. Results: A positive relationship was found between admission HR and 30-day all-cause and PE-related mortality. Considering an HR of 80 to 99 beats/min as a reference, patients in the higher HR strata showed higher rates of all-cause death (adjusted OR, 1.5 for HR of 100-109 beats/min; adjusted OR, 1.7 for HR of 110-119 beats/min; adjusted OR, 1.9 for HR of 120-139 beats/min; and adjusted OR, 2.4 for HR of ≥ 140 beats/min). Patients in the lower strata of HR showed significantly lower rates of 30-day all-cause mortality compared with the same reference group (adjusted OR, 0.6 for HR of 60-79 beats/min; and adjusted OR, 0.5 for HR of < 60 beats/min). The findings for 30-day PE-related mortality were similar. For identification of low-risk patients, a cutoff value of 80 beats/min (vs 110 beats/min) increased the sensitivity of the simplified Pulmonary Embolism Severity Index (sPESI) from 93.4% to 98.8%. For identification of intermediate- to high-risk patients, a cutoff value of 140 beats/min (vs 110 beats/min) increased the specificity of the Bova score from 93.2% to 98.0%. Interpretation: In nonhypotensive patients with acute symptomatic PE, a high HR portends an increased risk of all-cause and PE-related mortality. Modifying the HR cutoff in the sPESI and the Bova score improves prognostication of patients with PE.

Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of stroke worldwide and confers a high risk of stroke recurrence, despite aggressive management of risk factors.This study identified the role of risk factors and risk of vascular events in subjects with asymptomatic ICAS for improved risk stratification.Stroke-free participants in the NOMAS (Northern Manhattan Study) trial, prospectively followed since 1993, underwent a brain magnetic resonance angiogram from 2003 to 2008. The study rated stenosis in 11 brain arteries as: 0: no stenosis; 1: 50% or luminal irregularities; 2: 50%-69%; and 3: ≥70% stenosis or flow gap. The study ascertained vascular events during the post-magnetic resonance imaging (MRI) period. Proportional odds regression quantified the association of pre-MRI exposures, and proportional hazard adjusted models were built to identify the risk of events in the post-MRI period.The included sample included 1,211 participants from NOMAS (mean age: 71 ± 9 years; 59% women; 65% Hispanic; 45% had any stenosis). Older age (OR: 1.02 per year; 95% CI: 1.01 to 1.04), hypertension duration (OR: 1.01 per year; 95% CI: 1.00 to 1.02), higher number of glucose-lowering drugs (OR: 1.64 per each medication; 95% CI: 1.24 to 2.15), and high-density lipoprotein (OR: 0.96 per mg/dL; 95% CI: 0.92 to 0.99) were associated with ICAS. The highest event risk was noted among participants with ICAS ≥70% (5.5% annual risk of vascular events; HR: 2.1; 95% CI:1.4 to 3.2; compared with those with no ICAS).ICAS is an imaging marker of established atherosclerotic disease in stroke-free subjects, and incidental diagnosis of ICAS should trigger a thorough assessment of vascular health.

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, 1.7–10.6]) and its component of ectasia was associated with advanced age (odds ratio, 3.5 [95% CI, 1.3–9.5]). 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.

The association between cervical internal carotid artery (cICA) tortuosity and atherosclerosis is a matter of debate. Additionally, some genetic syndromes characterized by connective tissue remodeling are associated with arterial tortuosity, raising the possibility that cICA tortuosity may not only be atherosclerotic. In this study, we hypothesized that cICA tortuosity is not associated with imaging biomarkers of atherosclerosis.The Northern Manhattan Study (NOMAS) was a prospective, multiethnic cohort of stroke-free individuals who underwent brain MRA, carotid ultrasound and transthoracic echocardiogram from 2003-2008. The cICA tortuosity was scored in each carotid as 0 = no tortuosity, 1 = tortuosity90°, 2 = tortuosity ≥90°. A summary cICA tortuosity score (possible range 0-4) was created by adding up the tortuosity score from each carotid. Participants were assessed for atherosclerotic markers by using B‑mode carotid sonography and transthoracic echocardiography.Of 558 participants 178 (31.9%) had any cervical ICA tortuosity (tortuosity score0). The cICA tortuosity score was higher in women and was associated with diastolic and systolic blood pressures and height (all P 0.05). In models adjusted for demographics and risk factors, only the association with diastolic blood pressure remained significant (β = 0.002, P = 0.02). Similarly, cICA tortuosity was associated with larger aortic root diameter (B = 1.03 ± 0.36, P = 0.004) but not with other markers of carotid or aortic atherosclerosis.Cervical ICA tortuosity is associated with a higher diastolic blood pressure and larger aortic root diameter but not with other measures of atherosclerosis. Determining the risks of vascular events associated with this non-atherosclerotic phenotype may help for a better risk stratification for individuals with cICA tortuosity.

Cervical carotid artery (cCA) dolichoectasia (DE) is characterized by elongation, tortuosity, and/or dilatation. The prevalence of cCA DE has been reported 13-31% in population-based and 14-58% in hospital-based studies. The exact mechanisms of this aberrant arterial remodeling are unknown. Although atherosclerosis has often been implicated, the evidence has conflicting results that would support atherosclerosis as the underlying pathology. Actually, other nonatherosclerotic mechanisms related to connective tissue remodeling may play a role. Such mechanism is supported by epidemiological evidence that cCA DE is associated with carotid dissections. Similarly, cCA DE has been associated with vascular risk factors, but inconsistently. Fewer studies have evaluated the risk of vascular events in people with cCA DE. Cross-sectionally, cCA DE is associated with cerebrovascular disease, including white matter hyperintensities, lacunar stroke, and stroke overall. The often-conflicting results may in part be due to the heterogeneity of the population studies and variable definitions used. Preferential use of objective measure of cCA DE, such as carotid length, is advisable, and may help comparing result among different studies. Prospectively, people with cCA DE have a higher risk of vascular events, although it is uncertain if the risk of stroke is also higher in this population. In the absence of alternative stroke etiologies, stroke patients with cCA DE should be considered to have had a cryptogenic stroke and treated with daily antiplatelet therapy. Further population-based studies are needed to clarify whether specific therapies may be implement to reduce the risk of events among people with cCA DE.

Left-sided staphylococcal, streptococcal, and enterococcal infective endocarditis (IE) is associated with poor clinical outcomes. Our primary aim is to compare clinical outcomes of staphylococcal, streptococcal, and enterococcal IE patients who undergo valve replacement surgery and outcomes of patients who are treated solely with antibiotics.All patients were treated medically or surgically for left-sided staphylococcal, streptococcal, or enterococcal IE at our institution from 1998 to 2014 and were retrospectively studied. The primary outcome of interest was 30-day and 1-year mortality, and secondary outcomes included posttreatment septic shock, embolic events, stroke, and end-stage renal disease at 30 days. Inverse probability treatment weights, derived from propensity scores, were used to balance the medical and surgical cohorts across clinical risk factors, The Society of Thoracic Surgeon scores, and pathogens. Outcomes were compared comprehensively and in a staphylococcal-only subanalysis.Study population consisted of 245 surgical patients and 164 medical patients. Mortality at 30 days was higher in the medical cohort, both in aggregate and for staphylococcal only (all, 7% vs 16%, P.001; staphylococcal only, 7% vs 22%, P.001). Surgical patients had a higher incidence of septic shock and renal dysfunction; however, stroke and embolic events at 30 days were not different between cohorts. Cox survival analysis demonstrated that surgical treatment provided a 1-year survival benefit, with a hazard ratio of 0.48 (95% confidence interval, 0.36 to 0.64) that was robust regardless of pathogen.Compared with medical management, valve replacement surgery in patients with left-sided staphylococcal, streptococcal, or enterococcal IE appears to confer a survival advantage at 30 days and 1 year.

Background and Purpose— To test the hypothesis that covert brain infarcts (CBIs) are more likely to be located in noneloquent brain areas compared with clinical strokes and that CBI etiological subtypes carry a differential risk of vascular events compared with people without CBI. Methods— We used brain magnetic resonance imaging from 1290 stroke-free participants in the NOMAS (Northern Manhattan Study) to evaluate for CBI. We classified CBI as cardioembolic (ie, known atrial fibrillation), large artery atherosclerosis (extracranial and intracranial), penetrating artery disease, and cryptogenic (no apparent cause). CBI localized in the nonmotor areas of the right hemisphere were considered noneloquent. We then evaluated risk of events by CBI subtype with adjusted Cox proportional models. Results— At the time of magnetic resonance imaging, 236 participants (18%) had CBI (144 [61%] distal cryptogenic, 29 [12%] distal cardioembolic, 26 [11%] large artery atherosclerosis, and 37 [16%] penetrating artery disease). Smaller (per mm, odds ratio, 0.8 [0.8–0.9]) and nonbrain stem infarcts (odds ratio, 0.2 [0.1–0.6]) were more likely to be covert. During the follow-up period (10.4±3.1 years), 398 (31%) died (162 [13%] of vascular death) and 117 (9%) had a stroke (99 [85%]) were ischemic. Risks of events varied by CBI subtype, with the highest risk of stroke (hazard ratio, 2.2 [1.3–3.7]) and vascular death (hazard ratio, 2.24 [1.29–3.88]) noted in participants with intracranial large artery atherosclerosis-related CBI. Conclusions— CBI can be classified into subtypes that have differential outcomes. Certain CBI subtypes such as those related to intracranial large artery atherosclerosis have a high risk of adverse vascular outcomes and could warrant consideration of treatment trials.

Purposeto describe the clinical characteristics of patients with confirmed SARS-CoV-2 infection in primary care and to analyze the predictive role of different risk factors on prognosis, especially living conditions.MethodsRetrospective longitudinal observational retrospective study by reviewing medical records from a primary care center since March 1 to April 30, 2020. Case definition of confirmed SARS-CoV-2 infection, sociodemographic data, clinical characteristics, comorbidity and living conditions were collected. The statistical analysis consisted in description of the sample, comparison of prognosis groups and analysis of prognostic factors.ResultsA sample of 70 patients with confirmed SARS-CoV-2 infection was obtained, with comorbidity mainly related to arterial hypertension, overweight/obesity, hypercholesterolemia, diabetes and chronic pulmonary pathology. Pneumonia was present in 66%. Exitus occurred in 14% of the sample. Factors associated with mortality were advanced age (84 vs 55; pConclusionsThe study reflects the clinical practice of a primary care center. This kind of studies are essential to strengthen and reorganize the Health System and to try to anticipate the medium- to long-term consequences of COVID-19 on global health.

Introduction Genetic and imaging studies demonstrate a link between vascular morphology and migraine with aura (MA). We examined the relationship between basilar artery (BA) curvature and MA in a population-based cohort of stroke-free participants. Methods This cross-sectional study included participants from the MRI substudy of the Northern Manhattan Study. Participants had structured migraine assessments at enrollment and underwent brain MR angiography. BA curvature was defined as the sum of the total BA horizontal deviation from midline at the distal tip, mid-pons, and vertebrobasilar junction, and was the primary independent variable in logistic regression analyses. BA measurements were obtained blinded to migraine status. We compared groups of all migraine vs no migraine, migraine without aura (MwoA) vs no migraine, and MA vs no migraine. Results Of 880 participants, 146 had MwoA and 32 had MA. Average BA curvatures were 15.2 ± 8.9 mm in non-migraineurs, 15.8 ± 9.3 mm in MwoA, and 18.5 ± 11.4 mm in MA. In an adjusted model, greater BA curvature was associated with MA (OR 1.042 per mm, 95% CI 1.006–1.080) but not with MwoA (OR 1.014 per mm, 95% CI 0.993–1.035), when compared to non-migraineurs. Conclusions Greater BA curvature was associated with MA. Given aura typically originates from the occipital cortex, understanding the physiopathology of this association may provide clues to migraine's underlying mechanisms and relationship with stroke.

Background Several comorbidities have been associated with an increased risk of severity and mortality in coronavirus disease 2019 (COVID-19), including hypertension, diabetes, cerebrovascular disease, chronic kidney disease, and chronic obstructive pulmonary disease. Purpose In this systematic review and meta-analysis, we attempted to investigate the association between heart failure (HF) and poor outcome in patients with COVID-19. Methods We performed a systematic literature search from PubMed, EuropePMC, SCOPUS, Cochrane Central Database, and medRxiv with the search terms, “Heart failure” and “COVID-19”. The outcome of interest was mortality and poor prognosis (defined by incidence of severe COVID-19 infection, admission to ICU, and use of ventilator) in patients with preexisting heart failure with coronavirus disease. Results We identified 204 potential articles from our search, and 22 duplicates were removed. After screening of the titles and abstracts of the remaining 182 articles we identified 92 potentially relevant articles. We excluded 74 studies due to the following reasons: four studies were systematic reviews, two studies were meta-analyses, three articles were literature reviews, and 65 articles did not report on the outcome of interest. Finally, we included the remaining 18 studies in our qualitative synthesis and meta-analysis. There were 21,640 patients from 18 studies. HF was associated with hospitalization in COVID19 HR was 2.37 [1.48, 3.79; p, Highlights • Individuals with preexisting cardiovascular diseases have been shown to have poor outcomes with COVID 19 • Patients with preexisting Heart failure suffer from decreased circulatory and physiological reserves, which renders them to a more severe course of disease • Patients with Heart Failure are at increased risk for poor outcomes such as hospitalization, and death from COVID-19. • Significant difference in mortality between patients with and without HF was observed, those with Heart failure showing higher mortality rates.

As the life expectancy of people living with HIV (PLWH) on combination antiretroviral therapy (cART) increases, so does morbidity from cerebrovascular disease and neurocognitive disorders. Brain arterial remodeling stands out as a novel investigational target to understand the role of HIV in cerebrovascular and neurocognitive outcomes. We therefore conducted a review of publications in PubMed, EMBASE, Web of Science and Wiley Online Library, from inception to April 2021. We included search terms such as HIV, cART, brain, neuroimmunity, arterial remodeling, cerebrovascular disease, and neurocognitive disorders. The literature shows that, in the post-cART era, PLWH continue to experience an increased risk of stroke and neurocognitive disorders (albeit milder forms) compared to uninfected populations. PLWH who are immunosuppressed have a higher proportion of hemorrhagic strokes and strokes caused by opportunistic infection and HIV vasculopathy, while PLWH on long-term cART have higher rates of ischemic strokes, compared to HIV-seronegative controls. Brain large artery atherosclerosis in PLWH is associated with lower CD4 nadir and higher CD4 count during the stroke event. HIV vasculopathy, a form of non-atherosclerotic outward remodeling, on the other hand, is associated with protracted immunosuppression. HIV vasculopathy was also linked to a thinner media layer and increased adventitial macrophages, suggestive of non-atherosclerotic degeneration of the brain arterial wall in the setting of chronic central nervous system inflammation. Cerebrovascular architecture seems to be differentially affected by HIV infection in successfully treated versus immunosuppressed PLWH. Brain large artery atherosclerosis is prevalent even with long-term immune reconstitution post-cART. HIV-associated changes in brain arterial walls may also relate to higher rates of HIV-associated neurocognitive disorders, although milder forms are more prevalent in the post-cART era. The underlying mechanisms of HIV-associated pathological arterial remodeling remain poorly understood, but a role has been proposed for chronic HIV-associated inflammation with increased burden on the vasculature. Neuroimaging may come to play a role in assessing brain arterial remodeling and stratifying cerebrovascular risk, but the data remains inconclusive. An improved understanding of the different phenotypes of brain arterial remodeling associated with HIV may reveal opportunities to reduce rates of cerebrovascular disease in the aging population of PLWH on cART.

BACKGROUND: In clinical practice, calcifications seen on CT studies within the large brain arteries are often referred as a surrogate marker for cholesterol-mediated atherosclerosis. However, limited data exists to support the association between calcification and atherosclerosis. In this study, we examined if intracranial arterial calcifications were associated with cholesterol-mediated intracranial large artery atherosclerosis (ILAA) within the arteries of the Circle of Willis in an autopsy based sample. METHODS: We carried out a cross-sectional analysis of histopathological characteristics of brain large arteries obtained from autopsy cases. Brain large arteries were examined for evidences of calcifications, which were rated as macroscopic (coalescent) and microscopic (scattered). In addition to calcification, we also obtained measurement of the arterial wall and the presence of ILAA and non-atherosclerotic arterial fibrosis. We built hierarchical models adjusted for demographic and vascular risk factors to assess the relationship between calcification and ILAA. RESULTS: In univariate analysis, the presence of any arterial calcifications was associated with cerebral infarcts (29% v. 14%, p

Background and Purpose: Mycotic aneurysms (MA) are rare neurovascular complications of infective endocarditis (IE). The natural history and outcomes of MA under contemporary medical therapy have not been well characterized. The purpose of this study is to describe treatments and outcomes of patients with ruptured and unruptured MA in IE, specifically in relation to medical versus surgical/endovascular treatment. Methods: Retrospective chart review was performed at 3 US academic medical centers of adult patients with IE and MA. Information was collected regarding risk factors, imaging, treatments, and outcomes, including ischemic stroke, intracerebral hemorrhage, MA size changes, and inhospital mortality. Results: Thirty-five patients with IE had 63 MA. Nineteen patients had at least one ruptured MA; 13 patients underwent invasive treatment and 6 received antibiotics alone. Of 19 patients on antibiotics alone (6 with at least one ruptured MA and 13 with unruptured MA), 14 underwent repeat imaging and 5 had enlarging MA. Of 16 patients treated invasively, 2 had unruptured MA initially treated with antibiotics but ultimately underwent intervention. No MA ruptured after aneurysm discovery. Fifteen patients underwent cardiothoracic surgery (CTS), of which 11 had unsecured MA and 4 had secured MA. No patients suffered perioperiative neurological events attributable to their MA. Three patients treated with antibiotics alone and 3 patients treated invasively died from causes unrelated to their MAs. Conclusions: For patients with unruptured MA, treatment with antibiotics alone may have similar outcomes to invasive treatment. Further investigation is warranted to determine the risk of undergoing CTS with unsecured MA.

Introduction: Intracranial artery calcification (IAC) is a common radiological finding on Computed Tomography (CT) scan. Although IAC occurs with aging, it is uncertain whether IAC varies by stroke subtypes. Method: We included patients admitted to our hospital with acute stroke. We quantified calcification volume of both clinoid and siphon carotid arteries, vertebral arteries at the V4 segment, and the basilar artery using an in-house quantification tool for non-contrast brain CT. Stroke etiological subtypes were determined according to the Trial of Organon in Acute Stroke Trial (TOAST) classification system independent of the calcification quantification. Demographic and clinical information was extracted from the medical records. We determined the prevalence of IAC in 51% of patients. (31% anterior, 7% posterior, and 14 % in both circulations) Result: We included 694 patients with stroke history (mean age 68 ± 16, range 21-101, 55% women, 71% nonwhite or mixed). IAC was associated with male sex (OR 1.47 [95%-CI 1.41-2.08), older age (OR 1.05 [95%-CI, 1.04-1.06]), hypertension (OR 1.55 [95%-CI, 1.01-2.36], dyslipidemia (OR 1.54 [95%-CI, 1.06-2.25]), and smoking (OR 1.79 [95%-CI, 1.18-2.71]). Anterior IAC was associated with dyslipidemia (OR 1.57 [95%-CI, 1.08-2.28], smoking (1.9 [95%-CI, 1.25-2.88]), and older age (OR 1.05 [95%-CI, 1.36-1.66). Posterior IAC was associated with myocardial infarction (OR 1.58 [95%-CI, 1.01-2.47] and older age (OR 1.02 [95%-CI, 1.01-1.03]. In multivariate analyses, any IAC was associated with small artery disease stroke (OR 1.01[95%-CI, 1.41-3.98]). Stratifying by circulations, however, demonstrated that the association was only with posterior (OR 1.22[95%-CI, 1.02-2.28]) and not anterior IAC (OR 1.20[95%-CI, 0.86-1.1.69]). There was no association between IAC and intracranial large artery stenoses OR (1.22[95%-CI, 0.78-1.1.92]). Conclusion: IAC is a marker of arterial disease, and its prevalence relates to vascular risk factors and small artery disease strokes. Understanding the mechanism by which IAC may relate to small artery disease may help us understand small artery stroke physiopathology and discover novel therapies for its treatment.

A family history of Alzheimer’s disease (AD) increases risk for AD in an individual by 1.5-to 3-fold. Heritability of AD risk may be due in part to the aggregation of neurodegeneration and cerebrovascular changes with cognitive endophenotypes within families. The purpose of this study was to determine the extent to which cognitive functioning in middle-aged adults is associated with objectively-measured neurodegenerative and cerebrovascular neuroimaging markers linked to risk for clinical AD in their parents, and the extent to which these associations differ by race/ethnicity and language, as proxy variables for social advantage. Middle-aged children enrolled in the Offspring study (n=356; 53.1±10.1 years old; 13% Non-Hispanic White, 27% Non-Hispanic Black, 26% Latinx tested in English, 34% Latinx tested in Spanish; 65% women; 13.5±3.4 years education) were administered the NIH Toolbox, a computerized neuropsychological battery, in their preferred language. Older adults were a subset of the Washington-Heights Inwood Columbia Aging Project (77.3±6.6 years old; 75% women; 10.0±4.6 years education) who underwent T1w- and T2w-MRI and who had a child enrolled in the Offspring study. We tested the associations of parental MRI measures reflecting neurodegeneration (hippocampal volume, cortical thickness) and cerebrovascular disease (white matter hyperintensity (WMH) volume, presence of infarct) with cognitive tests scores in Offspring participants. We further stratified the models by race/ethnicity. Better offspring cognitive scores aggregated lower parental neurodegeneration and cerebrovascular disease among Non-Hispanic White and Latinx participants, and with lower parental cerebrovascular disease alone among Non-Hispanic Black participants. Associations were generally strongest in Non-Hispanic White participants compared to the other groups. These results suggest a more consistent link between offspring cognitive endophenotype and parental brain health in intergenerational AD transmission among Non-Hispanic White participants compared to racial/ethnic and minority groups in which other social factors may be adding variance.

BACKGROUND To investigate a comprehensive array of magnetic resonance imaging (MRI)-based biomarkers of cerebrovascular disease (CVD) in a cohort of people living with HIV (PLWH) and relate these imaging biomarkers to cognition. SETTINGS Cross-sectional, community-based study. METHODS Participants were PLWH in New York City, aged 50 years or older. They underwent a brain magnetic resonance angiography or MRI to ascertain 7 MRI markers of CVD: silent brain infarcts, dilated perivascular spaces, microhemorrhages, white matter hyperintensity volume, white matter fractional anisotropy and mean diffusivity (measures of white matter integrity), and intracranial large artery stenosis. Participants underwent a battery of neurocognitive tests to obtain individual and global cognitive scores representative of various aspects of cognition. RESULTS We included 85 participants (mean age 60 ± 6 years, 48% men, 78% non-Hispanic Black), most of them with well-controlled HIV (75% with CD4 cell count > 200 cells/mm3 and viral load < 400 copies/mL at or near the time of the MRI scan). Silent brain infarcts, intracranial large artery stenosis, and poor white matter integrity were associated with poorer performance in at least one cognitive domain, but the sum of these 3 MRI markers of CVD was associated with lower working memory (B = -0.213, P = 0.028), list learning (B = -0.275, P = 0.019), and global cognition (B = -0.129, P = 0.007). CONCLUSIONS We identified silent brain infarcts, intracranial large artery stenosis, and poor white matter integrity as exposures that may be modifiable and may, therefore, influence cognitive decline. In addition, these MRI markers of CVD may help in identifying PLWH at higher risk of cognitive decline, which may be more amenable to targeted therapies.

Background and Aims Fabry disease may be treated by enzyme replacement therapy (ERT), but the impact of chronic kidney disease (CKD) on the response to therapy remains unclear. The aim of the present study was to analyse the incidence and predictors of clinical events in Fabry disease patients on ERT. Method Multicentre retrospective observational analysis of patients diagnosed and treated with ERT for Fabry disease. The primary outcome was the first renal, neurological or cardiological events or death during a follow-up of 60 months (24-120). Results In 69 patients (42 males, 27 females, mean age 44.6 ±13.7 years), at the end of follow-up, eGFR and the left ventricular septum thickness remained stable and the urinary albumin: creatinine ratio tended to decrease, but this decrease only approached significance in patients on agalsidase-beta (242 to 128 mg/g (p = 0.05). At the end of follow-up, 21 (30%) patients had suffered an incident clinical event: 6 renal, 2 neurological and 13 cardiological (including 3 deaths). Events were more frequent in patients with baseline eGFR ≤60 ml/min/1.73 m2 (log Rank 12.423, p=0.001), and this remained significant even after excluding incident renal events (log Rank 4.086, p=0.043), being these differences more relevant in females (log Rank 18.514, p Conclusion GFR at the initiation of ERT is the main predictor of clinical events, both in males and in females, suggesting that start of ERT prior to the development of CKD is associated with better outcomes. For the first time, we show that initiation of ERT in women before renal function deteriorates has a similar or even larger impact as in Fabry males to prevent clinical events.

OBJECTIVE Adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology by their 5th decade. Compared with the general population, traditional vascular risks in adults with DS are rare, allowing examination of cerebrovascular disease in this population and insight into its role in AD without the confound of vascular risk factors. We examined in vivo magnetic resonance imaging (MRI)-based biomarkers of cerebrovascular pathology in adults with DS, and determined their cross-sectional relationship with age, beta-amyloid pathology, and mild cognitive impairment or clinical AD diagnostic status. METHODS Participants from the Biomarkers of Alzheimer's Disease in Down Syndrome study (n = 138, 50 ± 7 years, 39% women) with MRI data and a subset (n = 90) with amyloid positron emission tomography (PET) were included. We derived MRI-based biomarkers of cerebrovascular pathology, including white matter hyperintensities (WMH), infarcts, cerebral microbleeds, and enlarged perivascular spaces (PVS), as well as PET-based biomarkers of amyloid burden. Participants were characterized as cognitively stable (CS), mild cognitive impairment-DS (MCI-DS), possible AD dementia, or definite AD dementia based on in-depth assessments of cognition, function, and health status. RESULTS There were detectable WMH, enlarged PVS, infarcts, and microbleeds as early as the 5th decade of life. There was a monotonic increase in WMH volume, enlarged PVS, and presence of infarcts across diagnostic groups (CS < MCI-DS < possible AD dementia < definite AD dementia). Higher amyloid burden was associated with a higher likelihood of an infarct. INTERPRETATION The findings highlight the prevalence of cerebrovascular disease in adults with DS and add to a growing body of evidence that implicates cerebrovascular disease as a core feature of AD and not simply a comorbidity. ANN NEUROL 2020;88:1165-1177.

PURPOSE OF REVIEW: Intracranial atherosclerosis (ICAS) is the most common cause of stroke throughout the world. It also increases the risk of recurrent stroke and dementia. As a complex and multifactorial disease, ICAS is influenced by multiple genetic, biological, and environmental factors. This review summarizes the candidate gene and genome-wide studies aimed at discovering genetic risk factors of ICAS. RECENT FINDINGS: Numerous studies have focused on the association between single nucleotide polymorphisms (SNPs) of atherosclerosis-related genes and the risk of ICAS. Variants in adiponectin Q (ADIPOQ), ring finger protein 213 (RNF213), apolipoprotein E (APOE), phosphodiesterase 4D (PDE4D), methylenetetrahydrofolate reductase (MTHFR), lipoprotein lipase (LPL), α-adducin (ADD1) genes, angiotensin-converting enzyme (ACE), as well as other genes related to renin-angiotensin-aldosterone system have been associated with ICAS. SUMMARY: We review the available evidences on the candidate genes and SNPs associated with genetic susceptibility to ICAS, and point out future developments of this field. Genetic discoveries could have clinical implications for intracranial atherosclerotic disease.

Registro Informatizado de Enfermedad Tromboembólica Investigators., [Objective] Overlap exists between the risk factors for coronary artery disease and venous thromboembolism (VTE). However, a paucity of data is available on the incidence of major acute cardiovascular events (MACE) and major adverse limb events (MALE) among patients presenting with VTE. Moreover, it is unknown whether the rate of cardiovascular outcomes differs among patients with unprovoked vs provoked VTE., [Methods] We analyzed the data from 2009 to 2017 in the Registro Informatizado de Enfermedad Tromboembólica registry, an ongoing, multicenter, international registry of consecutive patients with a diagnosis of objectively confirmed VTE. The query was restricted it to patients with data entry for the arterial outcomes. The baseline prevalence of coronary artery disease risk factors was compared between patients with provoked (ie, immobility, cancer, surgery, travel >6 hours, hormonal causes) and unprovoked VTE. After the initial VTE event, we followed up patients for the composite primary outcome of incident MACE (ie, stroke, myocardial infarction, unstable angina) and/or MALE (ie, major limb events). We used the χ2 test for baseline associations and a Cox proportional hazard for multivariate analysis. We used IBM SPSS, version 24 (IBM Corp, Armonk, NY) for statistical analysis. A P value of, [Results] We analyzed the data from 41,259 patients with VTE, of whom 22,633 (55.6%) had experienced a provoked VTE. During follow-up, the patients with provoked VTE were more likely to develop MACE or MALE than were patients with unprovoked VTE (hazard ratio [HR], 1.3; 95% confidence interval [CI], 1.1-1.5). The association of arterial events with recent immobility (HR, 1.4; 95% CI, 1.5-12.1) and cancer (HR, 1.7; 95% CI, 1.4-1.9) was strong. After adjusting for multiple conventional cardiovascular risk factors, provoked VTE, compared with unprovoked VTE, was significantly associated with an increased hazard for MACE (HR, 1.4; 95% CI, 1.1-1.7). Cancer remained a significant adjusted predictor for both MACE (HR, 1.7; 95% CI, 1.4-2.1) and MALE (HR, 2.1; 95% CI 1.01-4.6) in those with provoked VTE., [Conclusions] Among patients with VTE, provoked cases, specifically those with cancer-associated VTE, have an increased risk of major arterial events.

Background and Purpose- To test the hypothesis that covert brain infarcts (CBIs) are more likely to be located in noneloquent brain areas compared with clinical strokes and that CBI etiological subtypes carry a differential risk of vascular events compared with people without CBI. Methods- We used brain magnetic resonance imaging from 1290 stroke-free participants in the NOMAS (Northern Manhattan Study) to evaluate for CBI. We classified CBI as cardioembolic (ie, known atrial fibrillation), large artery atherosclerosis (extracranial and intracranial), penetrating artery disease, and cryptogenic (no apparent cause). CBI localized in the nonmotor areas of the right hemisphere were considered noneloquent. We then evaluated risk of events by CBI subtype with adjusted Cox proportional models. Results- At the time of magnetic resonance imaging, 236 participants (18%) had CBI (144 [61%] distal cryptogenic, 29 [12%] distal cardioembolic, 26 [11%] large artery atherosclerosis, and 37 [16%] penetrating artery disease). Smaller (per mm, odds ratio, 0.8 [0.8-0.9]) and nonbrain stem infarcts (odds ratio, 0.2 [0.1-0.6]) were more likely to be covert. During the follow-up period (10.4±3.1 years), 398 (31%) died (162 [13%] of vascular death) and 117 (9%) had a stroke (99 [85%]) were ischemic. Risks of events varied by CBI subtype, with the highest risk of stroke (hazard ratio, 2.2 [1.3-3.7]) and vascular death (hazard ratio, 2.24 [1.29-3.88]) noted in participants with intracranial large artery atherosclerosis-related CBI. Conclusions- CBI can be classified into subtypes that have differential outcomes. Certain CBI subtypes such as those related to intracranial large artery atherosclerosis have a high risk of adverse vascular outcomes and could warrant consideration of treatment trials.

Coronavirus Disease 2019 (COVID‐19) has infected more than 3.0 million people worldwide and killed more than 200,000 as of April 27, 2020. In this White Paper, we address the cardiovascular co‐morbidities of COVID‐19 infection; the diagnosis and treatment of standard cardiovascular conditions during the pandemic; and the diagnosis and treatment of the cardiovascular consequences of COVID‐19 infection. In addition, we will also address various issues related to the safety of healthcare workers and the ethical issues related to patient care in this pandemic.

Background: Cervical internal carotid artery (ICA) tortuosity has been associated with vascular risk and stroke as well as genetic disorders related to abnormal extracellular matrix remodeling. It is plausible that dystrophic or aberrant arterial remodeling may therefore relate to cervical ICA tortuosity. We hypothesized that cervical ICA tortuosity relates to carotid dilatation, but not to traditional ultrasound (US) markers of atherosclerosis. Methods: Subjects of the NOMAS with available time-of-flight MRA were included in our study. Cervical ICA tortuosity was defined as a bend in the distal cervical ICA of > 90° as seen on MRA. We excluded subjects with < 5 cm of the cervical ICA visualized. Distensibility was calculated as the percentage excursion of the right CCA diastolic diameter during systole, which was assessed by high-resolution B-mode US of the right common carotid artery (CCA). We used multivariable logistic regression analyses to estimate odds ratios for the association of cervical ICA tortuosity and Doppler measures of carotid wall aging. Results: We visualized cervical ICA tortuosity in 468 NOMAS participants (mean age 64±8 years, 70% women, 70% Hispanic). It was present in 23% of subjects. In unadjusted models, cervical ICA tortuosity was more common in women (OR 2.34, 95% CI 1.34-4.11), Hispanics (OR 1.85, 95%CI 1.06-3.25) and those with higher diastolic blood pressures (OR per mm Hg 1.04, 95%CI 1.01-1.06), and less common among smokers (OR 0.23, 95%CI 0.07-0.78). In models adjusted for demographic and vascular risks, right CCA tortuosity was associated with ipsilateral larger CCA DD (OR 1.42, 95%CI 1.02-1.96) and borderline associated with lower distensibility (OR 0.94, 95%CI 0.87-1.01, P=0.06) but not with ipsilateral ICA IMT (OR 0.26, 95%CI 0.14-4.77), number of plaques (OR 1.08, 95%CI 0.76-1.53), maximum plaque thickness (OR 0.96, 95%CI 0.73-1.27), or plaque area (1.00, 95%CI 0.97-1.05). Conclusions: Cervical ICA tortuosity associates with ipsilateral cervical ICA dilatation and lower distensibility, but not with traditional US markers of atherosclerosis. The association with diastolic blood pressure suggests a role of steady, rather than pulsatile, hemodynamics in aberrant cervical ICA remodeling.

Introduction: Penetrating arteries supplying the basal ganglia and the brain stem are often affected by chronic hypertension whereas distal branching arteries supplying the brain convexity and corona radiata may be injured by hypoperfusion. We hypothesized that under equal systemic flow dynamics, distal branching brain arteries will have a lower pressure peak than penetrating arteries. Methods: We used an Anatomically Detailed Arterial Network (ADAN) model to predict pressure waveforms for brain and systemic arteries. The anatomical details were obtained from published literature and match for an average man, height of 170 cms and body surface area of 1.65 m2. Arterial length and radius were obtained from published literature for each organ. Standard governing equations for the flow of an incompressible fluid in compliant pipes are considered in each arterial segment. Proper coupling conditions at junctions are also postulated, as well as terminal Windkessel models. Results: Compared to systemic arteries, brain arteries have an early peak in flow and pressure, followed by a gradual decline in flow and pressure over time (figure 1). The posterior parietal artery has the lowest MAP and pulse pressure of the four brain arteries tested, even if the pulsatility and resistance indices remained relatively the same. Consequently, the pressure pulse peak for the posterior parietal artery hovers around 80 mmhg compared with approximately 110 mmHg for the lenticulostriate arteries and the middle cerebral and basilar arteries. Lenticulostriate arteries had similar hemodynamic profiles to the large artery branches of the circle of Willis. Conclusion: Penetrating brain arteries are susceptible to high pressure remodeling because of their immediate branching from a large artery, while distal cortical arteries are more susceptible to hypoperfusion. These regional susceptibilities to systemic hemodynamic may influence brain health and contribute to neurodegeneration.

Background: Cerebral hemodynamic dysfunction is associated with brain small artery disease and poorer cognition. With aging, systemic arteries stiffen, magnifying the spread of pulsatility to distal organs. The brain is especially susceptible to pulsatility due to low impedance to flow. Increased pulsatility causes abnormal brain arteriolar remodeling in animal models. Therefore, we hypothesize that measures of aortic stiffness relate to poorer cerebral autoregulation, an in-vivo measure of arteriolar function. Methods: We recruited participants in the Washington Heights-Inwood Community Aging Project for this study. For autoregulation, both middle cerebral arteries were insonated at a depth of 50-58 mm. End-tidal CO2 (EtCO2) was measured continuously with a facemask. After ten minutes of baseline recording, a mixture of air enriched with 5% CO2 was administered through the facemask for 2 minutes. Cerebrovascular reactivity was calculated as % change in mean CBFV (mCBFV) per 1 mm increase in mean EtCO2 during CO2 inhalation. We averaged the right and left CO2 reactivity percentage. For aortic stiffness, we acquired carotid-femoral pulse wave velocity (cfPWV) with non-invasive oscillometry using the Vicorder system (Skidmore Medical Limited, Bristol, UK). We used generalized linear model to obtain beta estimates of the association between CO2 reactivity and cfPWV. Results: We included 158 participants (mean age 77±6.4 years, 67% women, 40% non-Hispanic black, 38% non-Hispanic white, and 20% Hispanic). Hypertension was present in 54% of the participants. cfPWV was associated with poorer CO2 reactivity (B=-0.038, P=0.047), independent of age, sex, ethnicity, and hypertension. Brachial pulse pressure (B=0.007, P=0.38) and mean arterial pressure (B=-0.017, P=0.21) were not associated with CO2 reactivity, and adding brachial pulse pressure and mean arterial pressure to the adjusted model did not change the association between cfPWV and poorer CO2 reactivity. Conclusions: Aortic stiffness is associated with poorer CO2 reactivity independent of traditional measures of hypertension, a marker of cerebral autoregulation and arteriolar health. Poorer CO2 reactivity may mediate the reported effects of aortic stiffness on brain outcomes.

Objectives To test associations between subclinical brain infarcts (SBIs) and functional decline independently of intervening clinical vascular events and other vascular risk factors. Design Longitudinal follow‐up for a mean 7.3 years. Generalized estimating equation models were used to test associations between SBIs, number of perivascular spaces (PVSs), baseline Barthel Index (BI), and change in BI, adjusting for sociodemographic, vascular, and cognitive risk factors and for stroke and myocardial infarction occurring during follow‐up. Setting Population‐based prospective cohort study. Participants Stroke‐free individuals from the racially and ethnically diverse Northern Manhattan Study (N=1,290). Measurements Annual functional assessments using the BI (range 0–100). Results Mean age was 70.6 ± 9.0, 40% of participants were male, 66% were Hispanic, 193 (16%) had SBIs, and 508 (42%) had large PVSs. SBIs were not associated with baseline BI. In a fully adjusted model, there was a change in BI of –0.85 points per year (95% confidence interval (CI)=–1.01 to –0.69); those with SBI had an additional change in BI 0f –0.88 points (95% CI=–1.43 to –0.32). There were no associations between PVS and baseline BI or change in BI. Conclusion In a large population‐based study, we found a strong and independent association between “subclinical” markers of cerebrovascular injury and important clinical, person‐centered functional trajectories. Future research could clarify the evolution of such subclinical markers over time and test strategies to prevent their progression and minimize related disability. J Am Geriatr Soc 66:2144–2150, 2018.

Objective To test whether HIV is associated with brain large artery vulnerable intima. Design Cross-sectional study of autopsied HIV-positive (HIV+) cases sex and age-matched to HIV-negative (HIV-) controls. Methods Brain large arteries from 302 autopsied cases (50% HIV+) were evaluated morphometrically for the presence of atherosclerosis, size of necrotic core, and fibrous cap thickness. Intima vulnerability was measured as intima elastolytic score [0-5, based on intimal metalloproteinases (MMP)-2, MMP-3, and MMP-9, and tissue inhibitor for MMP-1 and MMP-2 staining], intima inflammatory score (0-3, based on intimal presence of CD3 and CD68 cells and TNF-α staining), neoangiogenesis (factor VIII staining), and apoptosis (caspase 3 staining). Hierarchical generalized linear models were used to obtain the beta estimates and their 95% confidence intervals, adjusting for demographics and vascular risk factors. Results The prevalence of atherosclerosis did not differ by HIV status. Necrotic cores filled larger proportions of the intima in HIV+ individuals with CD4 cell count above 200 cells/μl at death compared to HIV- controls (adjusted B = 11.6%, P = 0.04). HIV+ individuals had greater elastolytic scores (adjusted B = 0.34, P = 0.02), especially those with less than 200 CD4 cells/μl at death (adjusted B = 0.41, P = 0.01). Intima inflammation, neoangiogenesis, and apoptosis were not different among HIV+ cases versus HIV- controls. Conclusion Individuals with HIV and CD4 cell count at least 200 cells/μl at death had relatively larger necrotic cores, whereas those with HIV and CD4 cell count below 200 cells/μl at death had evidence of increased connective tissue remodeling in the intima. These findings suggest an increased potential for endothelial erosion, thrombosis, and plaque rupture that may relate to higher risk for vascular events.

Background Stroke as a complication of infective endocarditis portends a poor prognosis, yet risk factors for stroke subtypes have not been well defined. Aim To identify risk factors associated with ischaemic and haemorrhagic strokes. Methods A retrospective patient chart review was performed at a single US academic centre to identify risk factors and imaging for patients who were 18 years or older with infectious endocarditis (IE) and stroke diagnoses. Differences in patient characteristics by stroke status were assessed using univariate analysis, χ2 or student's t-test as well as logistic regression models for multivariable analyses and correlation matrices to identify possible collinearity between variables and to obtain odds ratios (OR) and their 95% confidence intervals. Results A final sample of 1157 participants was used for this analysis. The total number of non-surgical strokes was 178, with a prevalence of 15.4% (78% ischaemic, 10% parenchymal haemorrhages, 8% subarachnoid haemorrhages and 4% mixed ischaemic/haemorrhagic). Multivariate risk factors for ischaemic stroke included prior stroke (OR 2.0, 1.3-3.1), Staphylococcus infection (OR 2.0, 1.3-3.0), mitral vegetations (OR 2.2, 1.4-3.3) and valvular abscess (OR 2.7, 1.7-4.3). Risk factors for haemorrhagic stroke included fungal infection (OR 6.4, 1.2-34.0), male gender (OR 3.5, 1.4-8.3) and rheumatic heart disease (OR 3.3, 1.1-10.4). Conclusion Among patients with IE, there exist characteristics that relate differentially to ischaemic and haemorrhagic stroke risk.

Background and Purpose— Cognition and education influence functional trajectories, but whether associations differ with subclinical brain infarcts (SBI) or white matter hyperintensity volume (WMHV) is unknown. We hypothesized that SBI and WMHV moderated relationships between cognitive performance and education and functional trajectories. Methods— A total of 1290 stroke-free individuals underwent brain magnetic resonance imaging and were followed for 7.3 years (mean) with annual functional assessments with the Barthel index (range, 0–100). Magnetic resonance imaging measurements included pathology-informed SBI (PI-SBI) and WMHV (% total cranial volume). Generalized estimating equation models tested associations between magnetic resonance imaging variables and baseline Barthel index and change in Barthel index, adjusting for demographic, vascular, cognitive, and social risk factors, and stroke and myocardial infarction during follow-up. We tested interactions among education level, baseline cognitive performance (Mini-Mental State score), and functional trajectories and ran models stratified by levels of magnetic resonance imaging variables. Results— Mean age was 70.6 (SD, 9.0) years; 19% had PI-SBI, and mean WMHV was 0.68%. Education did not modify associations between cognition and functional trajectories. PI-SBI modified associations between cognition and functional trajectories ( P =0.04) with a significant protective effect of better cognition on functional decline seen only in those without PI-SBI. There was no significant interaction for WMHV ( P =0.8). PI-SBI, and greater WMHV, were associated with 2- to 3-fold steeper functional decline, holding cognition constant. Conclusions— PI-SBI moderated the association between cognition and functional trajectories, with 3-fold greater decline among those with PI-SBI (compared with no PI-SBI) and normal baseline cognition. This highlights the strong and independent association between subclinical markers and patient-centered trajectories over time.

Background and Purpose— Human immunodeficiency virus (HIV) infection has been shown to increase both ischemic and hemorrhagic stroke risks, but there are limited data on the safety and outcomes of intravenous thrombolysis with tPA (tissue-type plasminogen activator) for acute ischemic stroke in HIV-infected patients. Methods— A retrospective chart review of intravenous tPA-treated HIV patients who presented with acute stroke symptoms was performed in 7 large inner-city US academic centers (various search years between 2000 and 2017). We collected data on HIV, National Institutes of Health Stroke Scale score, ischemic stroke risk factors, opportunistic infections, intravenous drug abuse, neuroimaging findings, and modified Rankin Scale score at last follow-up. Results— We identified 33 HIV-infected patients treated with intravenous tPA (mean age, 51 years; 24 men), 10 of whom were stroke mimics. Sixteen of 33 (48%) patients had an HIV viral load less than the limit of detection while 10 of 33 (30%) had a CD4 count 3 . The median National Institutes of Health Stroke Scale score at presentation was 9, and mean time from symptom onset to tPA was 144 minutes (median, 159). The median modified Rankin Scale score for the 33-patient cohort was 1 and for the 23-patient actual stroke cohort was 2, measured at a median of 90 days poststroke symptom onset. Two patients had nonfatal hemorrhagic transformation (6%; 95% confidence interval, 1%–20%), both in the actual stroke group. Two patients had varicella zoster virus vasculitis of the central nervous system, 1 had meningovascular syphilis, and 7 other patients were actively using intravenous drugs (3 cocaine, 1 heroin, and 3 unspecified), none of whom had hemorrhagic transformation. Conclusions— Most HIV-infected patients treated with intravenous tPA for presumed and actual acute ischemic stroke had no complications, and we observed no fatalities. Stroke mimics were common, and thrombolysis seems safe in this group. We found no data to suggest an increased risk of intravenous tPA-related complications because of concomitant opportunistic infections or intravenous drug abuse.

Key Points Question What is the association of small vessel cerebrovascular disease, operationalized as white matter hyperintensities (WMH), with cortical thinning in a racially and ethnically diverse population of older adults? Findings In this cohort study of 303 older adults, increased parietal WMH volume was associated with left entorhinal cortex thinning over 4 years, while both total and parietal WMH were associated with frontal and parietal cortical thinning; cortical thinning, in turn, was associated with worse memory. The association between WMH and cortical thinning was strongest among Black participants. Meaning In this study, WMH were associated with cortical thinning in older adults, particularly non-Hispanic Black participants, in a pattern similar to the neurodegeneration in early stages of Alzheimer disease., This cohort study examines whether white matter hyperintensity volume is associated with cortical thinning and subsequent memory functioning and whether the association between white matter hyperintensity volume and cortical thinning differs among racial and ethnic groups., Importance Small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMH), is associated with cognitive decline and risk of clinical Alzheimer disease (AD). One way in which small vessel cerebrovascular disease could contribute to AD is through the promotion of neurodegeneration; the effect of small vessel cerebrovascular disease on neurodegeneration may differ across racial and ethnic groups. Objective To examine whether WMH volume is associated with cortical thinning over time and subsequent memory functioning and whether the association between WMH volume and cortical thinning differs among racial and ethnic groups. Design, Setting, and Participants This longitudinal community-based cohort study included older adults from northern Manhattan who were participants in the Washington Heights–Inwood Columbia Aging Project. Participants underwent two 3T magnetic resonance imaging (MRI) scans a mean of 4 years apart. Data were collected from March 2011 to January 2020. Exposures Total and regional WMH volumes. Main Outcomes and Measures The association of total and regional WMH volumes with cortical thinning over time was tested using general linear models in a vertexwise analysis. Cortical thinning was measured vertexwise by symmetrized percent change between 2 time points. The association of changes in cortical thickness with memory and whether this association differed by race and ethnicity was also analyzed. Delayed memory was a secondary outcome. Results In 303 participants (mean [SD] age, 73.16 [5.19] years, 181 [60%] women, 96 [32%] non-Hispanic White, 113 [37%] Non-Hispanic Black, 94 [31%] Hispanic), baseline WMH volumes were associated with cortical thinning in medial temporal and frontal/parietal regions. Specifically, total WMH volume was associated with cortical thinning in the right caudal middle frontal cortex (P = .001) and paracentral cortex (P = .04), whereas parietal WMH volume was associated with atrophy in the left entorhinal cortex (P = .03) and right rostral middle frontal (P

Objectives Embolic stroke is a frequent complication of infective endocarditis yet lacks acute treatment as intravenous thrombolysis should be avoided due to high risk of intracerebral hemorrhage. Mechanical thrombectomy for large vessel occlusion may be a promising treatment but there is limited data on safety outcomes in infective endocarditis. Materials and methods In this multi-center retrospective case series, we reviewed data from patients with infective endocarditis-related large vessel occlusion who underwent mechanical thrombectomy in 9 US hospitals. Results We identified 15 patients at 9 hospitals. A minority presented with signs suggesting infection (2 patients (14%) had fever, 7 (47%) were tachycardic, 2 (13%) were hypotensive, and 8 (53%) had leukocytosis). The median National Institute of Health Stroke Score decreased from 19 (range 9-25) at presentation to 7 post-thrombectomy (range 0-22, median best score post-thrombectomy), and the median modified Rankin Scale on or after discharge for survivors was 3 (range 0-6). Approximately 57% of patients had a modified Rankin Scale between 0 and 3 on or after discharge. Hemorrhagic transformation was observed in 7/15 (47%). The mechanical thrombectomy group had 2/9 petechial hemorrhagic transformation (22%), compared to 4/6 parenchymal hematomas (67%) in the tissue plasminogen activator + mechanical thrombectomy group. Conclusions Our findings suggest that patients with large vessel occlusion due to infective endocarditis may not present with overt signs of infection. Mechanical thrombectomy may be an effective treatment in this patient population for whom intravenous thrombolysis should be avoided.

Objectives: To test the hypothesis that brain arterial diameters are associated with cognitive performance, particularly in arteries supplying domain-specific territories. Methods: Stroke-free participants in the Northern Manhattan Study were invited to have a brain MRI from 2003–2008. The luminal diameters of 13 intracranial arterial segments were obtained using time-of-flight magnetic resonance angiogram (MRA), and then averaged and normalized into a global score and region-specific arterial diameters. Z-Scores for executive function, semantic memory, episodic memory and processing speed were obtained at MRI and during follow-up. Adjusted generalized additive models were used to assess for associations. Results: Among the 1034 participants with neurocognitive testing and brain MRI, there were non-linear relationships between left anterior (ACA) and middle cerebral artery (MCA) diameter and semantic memory Z-scores (χ2=10.00; DF=3; p=.019), and left posterior cerebral artery (PCA) and posterior communicating artery (Pcomm) mean diameter and episodic memory Z-scores (χ2=9.88; DF=3; p=.020). Among the 745 participants who returned for 2nd neuropsychological testing, on average 5.0±0.4 years after their MRI, semantic memory change was associated non-linearly with the left PCA/Pcomm mean diameter (χ2=13.09; DF=3; p=.004) and with the right MCA/ACA mean diameter (χ2=8.43; DF=3; p=.03). In both cross-sectional and longitudinal analyses, participants with the larger brain arterial diameters had more consistently lower Z-scores and greater decline than the rest of the participants. Conclusions: Brain arterial diameters may have downstream effects in brain function presenting as poorer cognition. Identifying the mechanisms and the directionality of such interactions may increase the understanding of the vascular contribution to cognitive impairment and dementia. (JINS, 2018, 24, 335–346)

Objective— In people without previous stroke, covert findings on serial magnetic resonance imaging (MRI) of incident brain infarcts and worsening leukoaraiosis are associated with increased risk for ischemic stroke and dementia. We evaluated whether various measures of blood pressure (BP) and heart rate are associated with these MRI findings. Approach and Results— In the CHS (Cardiovascular Health Study), a longitudinal cohort study of older adults, we used relative risk regression to assess the associations of mean, variability, and trend in systolic BP, diastolic BP, and heart rate measured at 4 annual clinic visits between 2 brain MRIs with incident covert brain infarction and worsening white matter grade (using a 10-point scale to characterize leukoaraiosis). We included participants who had both brain MRIs, no stroke before the follow-up MRI, and no change in antihypertensive medication status during follow-up. Among 878 eligible participants, incident covert brain infarction occurred in 15% and worsening white matter grade in 27%. Mean systolic BP was associated with increased risk for incident covert brain infarction (relative risk per 10 mm Hg, 1.28; 95% confidence interval, 1.12–1.47), and mean diastolic BP was associated with increased risk for worsening white matter grade (relative risk per 10 mm Hg, 1.45; 95% confidence interval, 1.24–1.69). These findings persisted in secondary and sensitivity analyses. Conclusions— Elevated mean systolic BP is associated with increased risk for covert brain infarction, and elevated mean diastolic BP is associated with increased risk for worsening leukoaraiosis. These findings reinforce the importance of hypertension in the development of silent cerebrovascular diseases, but the pathophysiologic relationships to BP for each may differ.

Background We hypothesized that the clinical course of venous thromboembolism in patients with active cancer may differ according to the specificities of primary tumor site. Aim and Methods We used data from RIETE (international registry of patients with venous thromboembolism) to compare the clinical venous thromboembolism-related outcomes during the course of anticoagulation in patients with one of the 4 more frequent cancers (breast, prostate, colorectal, or lung cancer). Results As of September 2014, 3947 cancer patients were recruited, of whom 938 had breast, 629 prostate, 1189 colorectal, and 1191 lung cancer. Overall, 55% had metastatic disease (42%, 36%, 53%, and 72%, respectively). During the course of anticoagulant therapy (mean duration, 139 days), the rate of thromboembolic recurrences was similar to the rate of major bleeding in patients with breast (5.6 [95% confidence interval (CI), 3.8-8.1] vs 4.1 [95% CI, 2.7-5.9] events per 100 patient-years) or colorectal cancer (10 [95% CI, 7.6-13] vs 12 [95% CI, 9.4-15] per 100 patient-years). In contrast, in patients with prostate cancer, the rate of venous thromboembolic recurrences was half the rate of major bleeding (6.9 [95% CI, 4.4-10] vs 13 [95% CI, 9.2-17] events per 100 patient-years), whereas in those with lung cancer, the rate of thromboembolic recurrences was twofold higher than the rate of major bleeding (27 [95% CI, 22-23] vs 11 [95% CI, 8.6-15] per 100 patient-years). Conclusions Significant differences in the clinical profile of venous thromboembolic-related outcomes were observed according to the site of cancer. These findings suggest the development of cancer-specific anticoagulant strategies as an area for further research.

Background and Purpose— We tested the hypothesis that posterior brain arteries differ pathologically from anterior brain arteries and that this difference varies with age. Methods— Brain large arteries from 194 autopsied individuals (mean age 56±17 years, 63% men, 25% nonwhite, 17% with brain infarcts) were analyzed to obtain the areas of arterial layers and lumen as well as the relative content of elastin, collagen, and amyloid. Visual rating was used to determine the prevalence of atheroma, calcification, vasa vasorum , pattern of intima thickening, and internal elastic lamina gaps. We used multilevel models adjusting for age, sex, ethnicity, vascular risk factors, artery type and location, and multiple comparisons. Results— Of 1362 large artery segments, 5% had vasa vasorum, 5% had calcifications, 15% had concentric intimal thickening, and 11% had atheromas. Posterior brain arteries had thinner walls, less elastin, and more concentric intima thickening than anterior brain arteries. Compared to anterior brain arteries, the basilar artery had higher arterial area encircled by the internal elastic lamina, whereas the vertebral arteries had higher prevalence of elastin loss, concentric intima thickening, and nonatherosclerotic stenosis. In younger individuals, vertebral artery calcifications were more likely than calcification in anterior brain arteries, but this difference attenuated with age. Conclusions— Posterior brain arteries differ pathologically from anterior brain arteries in the degree of wall thickening, elastin loss, and concentric intimal thickening.

Background and Purpose— Chronic infections and cardiac dysfunction are risk factors for stroke. We hypothesized that blood biomarkers of infection (procalcitonin) and cardiac dysfunction (midregional proatrial natriuretic peptide [MR-proANP]), previously associated with small vessel stroke and cardioembolic stroke are also associated with subclinical cerebrovascular damage, including silent brain infarcts and white matter hyperintensity volume. Methods— The NOMAS (Northern Manhattan Study) was designed to assess risk factors for incident vascular disease in a multiethnic cohort. A subsample underwent brain magnetic resonance imaging and had blood samples available for biomarker measurement (n=1178). We used logistic regression models to estimate the odds ratios and 95% confidence intervals (95% CIs) for the association of these biomarkers with silent brain infarcts after adjusting for demographic, behavioral, and medical risk factors. We used linear regression to assess associations with log-white matter hyperintensity volume. Results— Mean age was 70±9 years; 60% were women, 66% Hispanic, 17% black, and 15% were white. After adjusting for risk factors, subjects with procalcitonin or MR-proANP in the top quartile, compared with the lowest quartile were more likely to have silent brain infarcts (adjusted odds ratio for procalcitonin, 2.2; 95% CI, 1.3–3.7 and for MR-proANP, 3.3; 95% CI, 1.7–6.3) and increased white matter hyperintensity volume (adjusted mean change in log-white matter hyperintensity volume for procalcitonin, 0.29; 95% CI, 0.13–0.44 and for MR-proANP, 0.18; 95% CI, 0.004–0.36). Conclusions— Higher concentrations of procalcitonin, a marker of infection, and MR-proANP, a marker of cardiac dysfunction, are independently associated with subclinical cerebrovascular damage. If further studies demonstrate an incremental value for risk stratification, biomarker-guided primary prevention studies may lead to new approaches to prevent cerebrovascular disease.

There is an increasing appreciation of the cardiovascular implications of nonalcoholic fatty liver disease with advanced fibrosis (NAFLD-fibrosis). However, data regarding stroke risk are limited. We sought to investigate whether NAFLD-fibrosis is associated with stroke in addition to heart disease.We performed a cross-sectional study using data from the United States National Health and Nutrition Examination Survey (2005-2014). After excluding participants with competing causes of liver disease, the Fibrosis-4 score (FIB-4) and NAFLD Fibrosis Score (NFS) were calculated. First, we used a composite measure to classify participants: NAFLD-fibrosis was defined as having at least one score above its validated cut-off. Second, we also used the FIB-4 and NFS scores individually. The key outcome was prevalent stroke, and we also evaluated heart disease; both were self-reported. Multivariable logistic regression assessed the association between NAFLD-fibrosis and these outcomes while adjusting for demographic variables and cardiovascular risk factors.We identified 1653 participants with NAFLD-fibrosis from a sample of 27,040 participants. In total, 753 had prior stroke. An association between NAFLD-fibrosis and stroke was seen when using the FIB-4 score (OR 1.87, 95% CI 1.00-3.50) but not the NFS (OR 1.31, 95% CI 0.92-1.87). NAFLD-fibrosis was associated with heart disease (OR 1.46, 95% CI 1.06-2.01) using the composite measure and both scores individually.NAFLD-fibrosis may be associated with stroke in addition to heart disease, with differences depending on the measure used to define NAFLD-fibrosis.

ObjectiveTo test the hypothesis that patients with deep intracerebral hemorrhage (ICH) would encounter hematoma expansion (HE) more frequently compared to patients with lobar ICH.MethodsPatients with ICH with neuroimaging to calculate HE were analyzed from the multicenter Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) cohort. Patients with laboratory coagulopathy or preceding anticoagulant use were excluded to assess relationships of ICH location alone (deep vs lobar) with HE, defined as >33% relative growth. Odds ratios (ORs) and 95% confidence intervals (CIs) for these relationships were estimated with logistic regression. Sensitivity and specificity determined HE thresholds best associated with poor 3-month outcomes (modified Rankin score 4-6) stratified by location.ResultsThere were 1,049 patients with deep and 408 patients with lobar ICH analyzed. Deep ICH locations were more likely to have HE (adjusted OR 1.57, 95% CI 1.08–2.29) after adjustment for age, sex, race, baseline hematoma size, and intraventricular hemorrhage. However, this difference was nonsignificant (adjusted OR 1.35, 95% CI 0.81–2.24) after controlling for time from symptom onset to admission CT in a subgroup analysis of 729 patients with these data. Yet, the threshold of HE best associated with poor outcomes was smaller in deep (30%) compared to lobar (50%) ICH.ConclusionsWhile HE was more frequent in deep than lobar ICH, this could be due to differences in symptom onset to admission CT times in our cohort. However, patients with deep ICH appear particularly vulnerable to the deleterious effects of small volumes of HE. Further studies should clarify whether ICH location needs to be considered in HE treatment paradigms.

Introduction Cardiac magnetic resonance imaging (CMR) is the gold standard for the assessment of left ventricular (LV) function. However, traditional sequences are time-consuming and require breath-holding. Our aim was to evaluate the image quality of LV functional assessment with a novel, accelerated, free-breathing cine sequence and to compare LV functional parameters between it and a traditional sequence. Methods This was a prospective cohort study of 31 patients with cardiomyopathy. All studies were performed on a 1.5 Tesla scanner. LV function was first determined using contiguous short axis slices covering the left ventricle from the base to the apex acquired with the standard cine sequence. Next, the accelerated sequence was acquired for each patient. The Wilcoxon Matched-Pair Sign Rank Test was used to compare image quality between the accelerated and traditional cine imaging sequences. Standard and accelerated left ventricular volumes and ejection fraction were compared using linear regression. Bland-Altman plots were then constructed to evaluate agreement, interobserver and intraobserver variability for left ventricular volumes and ejection fraction. Results Mean acquisition time was 29 s for the accelerated sequence vs. 410 s for the traditional sequence. Qualitative assessment of image quality was similar for both sequences (p = 0.23). There were no significant differences in terms of LVEDV, LVESV, LVSV, LV mass and LVEF when calculated from either sequence with very good agreement between the standard and accelerated sequences. The mean differences with 95% limits of agreement were as follows: LV mass (−0.6, −22.9 g, 21.6 g), LVEDV (5.1 mL, −18.4 mL, 28.9 mL), LVEF (−0.3, −5.4, 4.7), LVESV (4.0 mL, −12.0 mL, 20.0 mL), LVSV (1.1 mL, −13.3 mL, 15.5 mL). Interobserver variability ranged from 0.1 to 6.3% while intraobserver variability ranged from 0.1 to 1.8%. Conclusions The accelerated free-breathing cine sequence performed similarly to standard of care multi breath-hold cine imaging and was acquired in a fraction of the time without the need for breath-holding. If applied to clinical practice, this sequence can significantly reduce scanning time and facilitate CMR scanning in those patients who are unable to breath-hold.

Introduction: Adiponutrin, encoded by the patatin-like phospholipase domain-containing 3 gene ( PNPLA3 ), is involved in lipid metabolism. The PNPLA3 gene rs738409 C>G single nucleotide polymorphism (SNP), particularly when homozygous, is strongly associated with non-alcoholic fatty liver disease, which has been associated with vascular disease. We hypothesized that this PNPLA3 SNP is associated with covert brain infarction (CBI). Methods: We performed a cross-sectional analysis of individuals with rs738409 genotype data in the Northern Manhattan Study MRI sub-study. The exposure was rs738409 allele frequency; noncarriers (CC genotype) served as the reference. The primary outcome was the presence of any CBI. Secondary outcomes were independently adjudicated CBI mechanism categories based on available baseline and follow-up history and imaging data: large artery atherosclerosis, cardioembolism, small vessel disease, and embolism of unknown source (EUS). Multivariable logistic regression was used to assess the relationship between SNP frequency and CBI. Principle component analysis was used to account for population-specific variations in SNP distributions. Models were adjusted for principal components, demographics, vascular risk factors, and alcohol, statin, and antiplatelet use. Results: The sample included 1,063 Northern Manhattan Study participants (mean age 70 ± 9 years, 61% women). The G allele frequency was 24%, with 381 GC heterozygotes and 67 GG homozygotes. The prevalence of CBI was 18% (N=185): 10% (N=19) large artery atherosclerosis, 12% (N=22) cardioembolism, 16% (N=30) small vessel disease, and 62% (N=114) EUS. Individuals heterozygous for the G allele were not at greater odds of any CBI (OR 0.8; 95% CI 0.6-1.2) or any individual type of CBI, compared to CC homozygotes. The odds of any CBI were also not increased among GG homozygotes (OR 1.6; 95% CI 0.8-3.2). However, GG homozygotes were at higher odds of EUS (OR 2.3; 95% CI 1.1-4.8), but not CBI due to other mechanisms. Conclusion: Homozygosity for the PNPLA3 rs738409[G] SNP was associated with greater odds of EUS and may account for some unexplained strokes. Further study is warranted to understand the contribution of PNPLA3 variants to cerebrovascular disease.

Introduction: Genetic and imaging studies demonstrate a link between vascular morphology and migraine with aura (MA). As aura typically originates from the occipital cortex, the vertebrobasilar system that supplies this area is of particular interest. We examined the relationship between basilar artery (BA) curvature and MA in a large, population-based cohort of stroke-free participants. Methods: We analyzed Northern Manhattan Study participants who had undergone time of flight MRA at 1.5 Tesla. Migraine, with or without aura, was ascertained through structured interviews. BA curvature was defined as the sum of the total horizontal deviation of the BA at the distal tip, mid-pons, and vertebrobasilar junction, and was used as the primary independent variable in unadjusted and adjusted logistic regression analyses. BA measurements were obtained blinded to migraine status. Results: Of 805 participants (mean age 70±9.3 years, 55% women, 66% Hispanic), migraine without aura was present in 13% (N=105) and MA in 3% (N=24). MA was more common among women (P=0.03) and Hispanics (P=0.001). Mean BA curvature was 16 ± 10 mm. In unadjusted analysis, BA curvature was greater in participants with MA than those without MA (19 vs 15 mm, P=0.02). In a model adjusted for demographics, vascular risk factors, head size and height, greater BA curvature was associated with MA (OR 1.06 per mm, 95% CI 1.01-1.11) compared to participants with no migraine. The association between BA curvature and migraine without aura did not reach significance (OR 1.01, 95% CI 0.99-1.04). Conclusions: Greater BA curvature was associated with migraine with aura but not migraine without aura. Understanding the physiopathology of this association may provide clues to the underlying mechanisms of migraine and the relationship between migraine and stroke.

Background: Individuals with stroke due to high-degree intracranial stenosis (i.e. > 70% by WASID criteria have a high 1-year risk of stroke recurrence. Whether high-degree intracranial stenosis in stroke-free individuals increases the risk of vascular events is less certain. We hypothesized that high-degree intracranial stenosis in stroke-free individuals is associated with risk of death and vascular events. Methods: Participants in the population-based Northern Manhattan Study (NOMAS) with available time-of-flight MRA were included in this study. We rated intracranial stenosis using WASID criteria and defined high-degree intracranial stenosis if the lumen was reduced by > 70% in the anterior, middle, or posterior cerebral arteries or in the basilar, vertebral or intracranial carotid arteries. Death and vascular events were prospectively ascertained, blinded to stenosis status. Stroke outcomes were subtypes according to the Trial of Organon in Acute Stroke Trial (TOAST) criteria. Results: We included 1,206 NOMAS participants (mean age 70.6±9 years, 60.5% women, 65.7% Hispanic). The participants were followed for an average of 10.4 years (IQR 9.5-12.6). The prevalence of high-degree intracranial stenosis was 3.5% (74% isolated anterior circulation, 21% isolated posterior circulation, and 5% anterior and posterior circulation). In univariate analysis, high-degree intracranial stenosis was associated with older age (P=0.003), hypertension (P=0.02) and diabetes (0.02). The risk of vascular death and stroke was higher among stroke-free individuals with high-degree intracranial stenosis (table), and in particular with strokes due to large artery atherosclerosis. Conclusions: Evidence of high-degree intracranial stenosis among stroke-free individuals identifies those at risk of vascular events and may be used to select individuals for testing aggressive measures to reduce vascular risks.

To test the hypothesis that brain arterial aging is associated with the pathologic diagnosis of Alzheimer disease (AD).Brain large arteries were assessed for diameter, gaps in the internal elastic lamina (IEL), luminal stenosis, atherosclerosis, and lumen-to-wall ratio. Elastin, collagen, and amyloid were assessed with Van Gieson, trichrome, and Congo red staining intensities, and quantified automatically. Brain infarcts and AD (defined pathologically) were assessed at autopsy. We created a brain arterial aging (BAA) score with arterial characteristics associated with aging after adjusting for demographic and clinical variables using cross-sectional generalized linear models.We studied 194 autopsied brains, 25 (13%) of which had autopsy evidence of AD. Brain arterial aging consisted of higher interadventitial and lumen diameters, thickening of the wall, increased prevalence of IEL gaps, concentric intima thickening, elastin loss, increased amyloid deposition, and a higher IEL proportion without changes in lumen-to-wall ratio. In multivariable analysis, a high IEL proportion (B = 1.96, p = 0.030), thick media (B = 3.50, p = 0.001), elastin loss (B = 6.16, p0.001), IEL gaps (B = 3.14, p = 0.023), and concentric intima thickening (B = 7.19, p0.001) were used to create the BAA score. Adjusting for demographics, vascular risk factors, atherosclerosis, and brain infarcts, the BAA score was associated with AD (B = 0.022, p = 0.002).Aging of brain large arteries is characterized by arterial dilation with a commensurate wall thickening, elastin loss, and IEL gaps. Greater intensity of arterial aging was associated with AD independently of atherosclerosis and brain infarcts. Understanding the drivers of arterial aging may advance the knowledge of the pathophysiology of AD.

Purpose Disability is a potential risk for stroke survivors. This study aims to identify disability risk factors associated with stroke and their relative importance and relationships from a national behavioral risk factor dataset. Methods Data of post-stroke individuals in the U.S (n=19,603) including 397 variables were extracted from a publically available national dataset and analyzed. Data mining algorithms including C4.5 and linear regression with M5s methods were applied to build association models for post-stroke disability using Weka software. The relative importance and relationship of 70 variables associated with disability were presented in infographics for clinicians to understand easily. Results Fifty-five percent of post-stroke patients experience disability. Exercise, employment and satisfaction of life were relatively important factors associated with disability among stroke patients. Modifiable behavior factors strongly associated with disability include exercise (OR: 0.46, P

Introduction Nonalcoholic fatty liver disease (NAFLD) has been associated with greater cerebral white matter hyperintensity (WMH) volume and microbleeds. The adiponutrin (PNPLA3) rs738409 G variant, a robust NAFLD susceptibility variant, has been variably associated with carotid atherosclerosis. We hypothesized that this variant is associated with WMH volume, microbleeds, covert brain infarction (CBI), and small perivascular spaces. Methods We performed a cross-sectional analysis of the Northern Manhattan Study-MRI Substudy. The associations between the rs738409 G variant allele and outcomes were assessed using linear regression for WMH volume, logistic regression for microbleeds and CBI, and Poisson regression for small perivascular spaces. Models were adjusted for age, sex, principal components, diabetes, and body mass index. Results We included 1063 Northern Manhattan Study participants who had brain MRI and genotype data available (mean age 70 ± 9 years, 61% women). The G allele frequency was 24%. The prevalence of any microbleeds and CBI were 8% and 18%, respectively. The median WMH volume and small perivascular space count score were 7.7 mL and 6, respectively. GG homozygosity, but not heterozygosity, was associated with WMH volume (β = 0.27; 95% CI, 0.03, 0.51) compared to non-carriers. Having at least one G allele was associated with the presence of microbleeds (Odds ratio, 1.78; 95% CI, 1.02, 3.12); the association was attenuated in other models. No associations were observed for CBI and small perivascular spaces. Conclusion The PNPLA3 rs738409 G allele was associated with greater WMH volume, and inconsistent associations with microbleeds were seen.