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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.

Background: Chronic hypoxia-ischemia is a putative mechanism underlying the development of white matter hyperintensities (WMH) and microstructural disruption in cerebral small vessel disease. WMH fall primarily within deep white matter (WM) watershed regions. We hypothesized that elevated oxygen extraction fraction (OEF), a signature of hypoxia-ischemia, would be detected in the watershed where WMH density is highest. We further hypothesized that OEF would be elevated in regions immediately surrounding WMH, at the leading edge of growth. Methods: In this cross-sectional study conducted from 2016 to 2019 at an academic medical center in St Louis, MO, participants (age >50) with a range of cerebrovascular risk factors underwent brain magnetic resonance imaging using pseudocontinuous arterial spin labeling, asymmetric spin echo, fluid-attenuated inversion recovery and diffusion tensor imaging to measure cerebral blood flow (CBF), OEF, WMH, and WM integrity, respectively. We defined the physiologic watershed as a region where CBF was below the 10th percentile of mean WM CBF in a young healthy cohort. We conducted linear regression to evaluate the relationship between CBF and OEF with structural and microstructural WM injury defined by fluid-attenuated inversion recovery WMH and diffusion tensor imaging, respectively. We conducted ANOVA to determine if OEF was increased in proximity to WMH lesions. Results: In a cohort of 42 participants (age 50–80), the physiologic watershed region spatially overlapped with regions of highest WMH lesion density. As CBF decreased and OEF increased, WMH density increased. Elevated watershed OEF was associated with greater WMH burden and microstructural disruption, after adjusting for vascular risk factors. In contrast, WM and watershed CBF were not associated with WMH burden or microstructural disruption. Moreover, OEF progressively increased while CBF decreased, in concentric contours approaching WMH lesions. Conclusions: Chronic hypoxia-ischemia in the watershed region may contribute to cerebral small vessel disease pathogenesis and development of WMH. Watershed OEF may hold promise as an imaging biomarker to identify individuals at risk for cerebral small vessel disease progression.

Background: The underlying mechanisms of incident lacunes regarding their spatial distribution remain largely unknown. We investigated the spatial distribution pattern and MRI predictors of incident lacunes in relation to white matter hyperintensity (WMH) over 14 years follow-up in sporadic small vessel disease. Methods: Five hundred three participants from the ongoing prospective single-center Radboud University Nijmegen Diffusion Tensor and Magnetic resonance Cohort (RUN DMC) were recruited with baseline assessment in 2006 and follow ups in 2011, 2015, and 2020. Three hundred eighty-two participants who underwent at least 2 available brain MRI scans were included. Incident lacunes were systematically identified, and the spatial relationship between incident lacunes located in subcortical white matter and WMH were determined using a visual rating scale. Adjusted multiple logistic regression and linear mixed-effect regression models were used to assess the association between baseline small vessel disease markers, WMH progression, and incident lacunes. Participants with atrial fibrillation were excluded in multivariable analysis. Results: Eighty incident lacunes were identified in 43 patients (mean age 66.5±8.2 years, 37.2% women) during a mean follow-up time of 11.2±3.3 years (incidence rate 10.0/1000 person-year). Sixty percent of incident lacunes were in the white matter, of which 48.9% showed no contact with preexisting WMH. Baseline WMH volume (odds ratio=2.5 [95% CI, 1.6–4.2]) predicted incident lacunes after adjustment for age, sex, and vascular risk factors. WMH progression was associated with incident lacunes independent of age, sex, baseline WMH volume, and vascular risk factors (odds ratio, 3.2 [95% CI, 1.5–6.9]). Baseline WMH volume and progression rate were higher in participants with incident lacunes in contact with preexisting WMH. No difference in vascular risk factors was observed regarding location or relation with preexisting WMH. Conclusions: The 2 different distribution patterns of lacunes regarding their relation to WMH may suggest distinct underlying mechanisms, one of which may be more closely linked to a similar pathophysiology as that of WMH. The longitudinal relation between WMH and lacunes further supports plausible shared mechanisms between the 2 key markers.

Background: Increased cerebral arterial pulsatility is associated with cerebral small vessel disease, recurrent stroke, and dementia despite the best medical treatment. However, no study has identified the rates and determinants of progression of arterial stiffness and pulsatility. Methods: In consecutive patients within 6 weeks of transient ischemic attack or nondisabling stroke (OXVASC [Oxford Vascular Study]), arterial stiffness (pulse wave velocity [PWV]) and aortic systolic, aortic diastolic, and aortic pulse pressures (aoPP) were measured by applanation tonometry (Sphygmocor), while middle cerebral artery (MCA) peak (MCA-PSV) and trough (MCA-EDV) flow velocity and Gosling pulsatility index (PI; MCA-PI) were measured by transcranial ultrasound (transcranial Doppler, DWL Doppler Box). Repeat assessments were performed at the 5-year follow-up visit after intensive medical treatment and agreement determined by intraclass correlation coefficients. Rates of progression and their determinants, stratified by age and sex, were determined by mixed-effects linear models, adjusted for age, sex, and cardiovascular risk factors. Results: In 188 surviving, eligible patients with repeat assessments after a median of 5.8 years. PWV, aoPP, and MCA-PI were highly reproducible (intraclass correlation coefficients, 0.71, 0.59, and 0.65, respectively), with progression of PWV (2.4%; P P P =0.22). However, PWV increased at a faster rate with increasing age (0.009 m/s per y/y; P P P =0.009). Higher aortic systolic blood pressure and diastolic blood pressure predicted a greater rate of progression of PWV and aoPP, but not MCA-PI, although current MCA-PI was particularly strongly associated with concurrent aoPP ( P Conclusions: Arterial pulsatility and aortic stiffness progressed significantly after 55 years of age despite the best medical treatment. Progression of stiffness and aoPP was determined by high blood pressure, but MCA-PI predominantly reflected current aoPP. Treatments targetting cerebral pulsatility may need to principally target aortic stiffness and pulse pressure to have the potential to prevent cerebral small vessel disease.

Supplemental Digital Content is available in the text., Background and Purpose— Breath holding (BH) and hyperventilation are used to assess abnormal cerebrovascular reactivity, often in relation to severity of small vessel disease and risk of stroke with carotid stenosis, but responses may be confounded by blood pressure (BP) changes. We compared effects of BP and end-tidal carbon dioxide (etCO2) on middle cerebral artery mean flow velocity (MFV) in consecutive transient ischemic attack and minor stroke patients. Methods— In the population-based, prospective OXVASC (Oxford Vascular Study) phenotyped cohort, change in MFV on transcranial Doppler ultrasound (ΔMFV, DWL-DopplerBox), beat-to-beat BP (Finometer), and etCO2 was measured during 30 seconds of BH or hyperventilation. Two blinded reviewers independently assessed recording quality. Dependence of ΔMFV on ΔBP and ΔetCO2 was determined by general linear models, stratified by quartiles. Results— Four hundred eighty-eight of 602 (81%) patients with adequate bone windows had high-quality recordings, more often in younger participants (64.6 versus 68.7 years; P

Background and Purpose— Bridging therapy with low-molecular-weight heparin reportedly leads to a worse outcome for acute cardioembolic stroke patients because of a higher incidence of intracerebral bleeding. However, this practice is common in clinical settings. This observational study aimed to compare (1) the clinical profiles of patients receiving and not receiving bridging therapy, (2) overall group outcomes, and (3) outcomes according to the type of anticoagulant prescribed. Methods— We analyzed data of patients from the prospective RAF and RAF-NOACs studies. The primary outcome was defined as the composite of ischemic stroke, transient ischemic attack, systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding observed at 90 days after the acute stroke. Results— Of 1810 patients who initiated oral anticoagulant therapy, 371 (20%) underwent bridging therapy with full-dose low-molecular-weight heparin. Older age and the presence of leukoaraiosis were inversely correlated with the use of bridging therapy. Forty-two bridged patients (11.3%) reached the combined outcome versus 72 (5.0%) of the nonbridged patients ( P =0.0001). At multivariable analysis, bridging therapy was associated with the composite end point (odds ratio, 2.3; 95% CI, 1.4–3.7; P P =0.005) and hemorrhagic (odds ratio, 2.4; 95% CI, 1.2–4.9; P =0.01) end points separately. Conclusions— Our findings suggest that patients receiving low-molecular-weight heparin have a higher risk of early ischemic recurrence and hemorrhagic transformation compared with nonbridged patients.

Introduction: Severity of leukoaraiosis detected on T2 MRI scans as white matter hyperintensities (WMH) is associated with infarct growth and poor poststroke outcomes in patients with acute ischemic stroke (AIS). Traditional vascular risk factors (VRF) such as age, hypertension (HTN), type 2 diabetes mellitus (T2D), and cigarette smoking are linked to WMH in large population-based studies, yet casual inferences for WMH in AIS patients are limited. We sought to examine the VRFs for evidence of causal relationships with WMH burden in AIS patients using mendelian randomization principles and polygenic risk score (PRS) methods. Method: We examined FLAIR MRIs obtained within 48 hours of AIS onset in 4,362 European Caucasian patients from the MRI-GENetics Interface Exploration (MRI-GENIE) study. WMH volume (WMHv) was measured using a fully automated deep-learning trained algorithm. We considered 13 VRFs: blood pressure (HTN, SBP, DBP, Pulse Pressure), lipid (total cholesterol, HDL, LDL, TG), BMI, T2D, atrial fibrillation, alcohol use and smoking. For each factor, we calculated a weighted PRS for each individual based on the most recent GWAS with various GWAS p-value cutoff. We then used linear regression to estimate associations between each PRS and log transformed WMHv, controlling for age, gender and principal components of genetic ancestries. Strata-specific estimates were combined using inverse-variance weighting based meta-analysis. Results: PRS of both SBP and DBP were positively and robustly associated with WMHv in the meta-analysis (p value of the association ranging from Conclusion: Using mendelian randomization, our results lend further evidence that high blood pressure is a causal risk factor for WMH in AIS patients. This result is consistent with previous epidemiological studies of leukoaraiosis in stroke-free populations, and it supports universal control of HTN as common contributor to WMH burden and the overall brain health.

Background and Purpose: We investigated white matter abnormalities in patients with spontaneous subarachnoid hemorrhage following aneurysmal rupture, by using tract-based spatial statistics. Methods: Sixteen patients with spontaneous subarachnoid hemorrhage due to aneurysmal rupture and 18 age- and sex-matched healthy control subjects were recruited. Voxel-wise statistical analysis of fractional anisotropy data was performed by using tract-based spatial statistics as implemented in the Functional Magnetic Resonance Imaging of the Brain Software Library. We calculated mean fractional anisotropy values across the tract skeleton and within 48 regions of interest based on the intersections between the fractional anisotropy skeleton and the probabilistic Johns Hopkins University white matter atlases. Results: Comparing the patient and control groups, the fractional anisotropy values of 44 regions of interest among the 48 regions of interest showed significant differences ( P P >0.05). Conclusions: By undertaking tract-based spatial statistics analysis, we detected wide-ranging white matter abnormalities in patients with spontaneous subarachnoid hemorrhage. Registration: URL: http://www.e-irb.com/index.jsp . Unique identifier: 2019-06-032.

Background and Purpose— Diffusion-weighted imaging (DWI) hyperintensities in intracerebral hemorrhage (ICH) are associated with increased risk of recurrent ICH, cognitive impairment, and death, but whether these lesions are specific to a subtype of ICH remains uncertain. We investigated the association between DWI lesions and ICH subtype and explored the risk factors for DWI lesions. Methods— In a systematic review of ICH studies, we identified those reporting prevalence of DWI lesions. Two reviewers independently assessed study eligibility and risk of bias and collected data. We determined the pooled prevalence of DWI lesions within 90 days after ICH onset for cerebral amyloid angiopathy- and hypertensive angiopathy-related ICH using random-effects meta-analysis. We calculated odds ratios to compare prevalence of DWI lesions by ICH subtype and to assess risk factors for DWI lesions. Results— Eleven studies (1910 patients) were included. The pooled prevalence of DWI lesions was 18.9% (95% CI, 11.1–26.7) in cerebral amyloid angiopathy- and 21.0% (95% CI, 15.3–26.6) in hypertensive angiopathy-related ICH. There was no difference in the prevalence of DWI lesions between cerebral amyloid angiopathy- (64/292 [21.9%]) and hypertensive angiopathy-related ICH (79/370 [21.4%]; odds ratio, 1.25; 95% CI, 0.73–2.15) in the 5 studies reporting data on both ICH pathogeneses. In all ICH, presence of DWI lesions was associated with neuroimaging features of microangiopathy (leukoaraiosis extension, previous ICH, and presence, and number of microbleeds) but not with vascular risk factors or the use of antithrombotic therapies. Conclusions— Prevalence of DWI lesions in acute ICH averages 20%, with no difference between cerebral amyloid angiopathy- and hypertensive angiopathy-related ICH. Detection of DWI lesions may add valuable information to assess the progression of the underlying microangiopathy.

Background: White matter hyperintensity (WMH), also known as leukoaraiosis, is commonly visualized as abnormal T2 signal in the deep and subcortical white matter on Magnetic Resonance Imaging (MRI). It is also commonly associated with aging, diabetes, hypertension and cerebrovascular disease. The Fazekas (F) scoring system is a subjective tool commonly used to assess WMH, but no volumetric analysis has been published showing how the scores correspond to true quantities of white matter disease. Methods: MRIs performed on inpatients and outpatients at our tertiary care institution between 2015 and 2017 were reviewed and their relative WMH was scored by one author trained in using the Fazekas scale. Using 3D Slicer 4.9, manual segmentations of WMH were completed and a 3D model was created to quantify the amount of WMH. Univariate analysis and ANOVA tests were run to determine the association of each Fazekas score with volume of WMH. Results: Among the 198 patients in our study (53% female), 163 had WMH (F1 n=66, F2 n=49, F3 n=48). Ranges of WMH in each group were 0.1-8.3 mL in Fazekas 1 (mean = 3.7, SD = 2.3), 6.0-17.7 mL in Fazekas 2 (mean = 10.8, SD = 3.1), and 14.2-77.2 mL in Fazekas 3 (mean = 35.2, SD = 17.9); if 11 outliers above 50 mL were excluded, the range for Fazekas 3 was 14.2-47.0 mL (mean = 27.1, SD = 8.9). When comparing data between groups, both the comparison between F1+2 (t-value = 14.1, p Conclusion: When accurately trained in assigning Fazekas scores to patient’s WMH, each of the scores appears to represent an approximate range of distinct volumes for WMH. Studies have shown that the presence and extent of WMH is a predictor for future development of stroke. These results should be validated in subsequent studies.

Background and Purpose: Leukoaraiosis is a poor prognostic marker for patients with acute ischemic stroke (AIS). This study sought to assess if severity of leukoaraiosis is associated with outcome in patients with AIS following endovascular thrombectomy, and to propose a leukoaraiosis-related modification to the ASPECTS score to improve its predictive value for good outcome. Methods: We analyzed consecutive patients with AIS that underwent mechanical thrombectomy for anterior circulation large vessel occlusion at our comprehensive stroke center. Leukoaraiosis burden was graded using the Fazekas scale (combined scores from two locations categorically divided into no leukoaraiosis (score = 0), mild (1-2), moderate (3-4) and severe (5-6)). The primary outcome measure was 90-day mRS. A proposed Leukoaraiosis-ASPECTS (“L-ASPECTS”) was calculated by subtracting values from the traditional ASPECT based on leukoaraiosis severity (1 point subtracted if mild, 2 if moderate, 3 if severe). Results: Of 174 included patients, 89 (51.2%) were female; average age was 68.0±9.1. 28 (16.1%) had no leukoaraiosis, 66 (37.9%) had mild, 62 (35.6%) had moderate, and 18 (10.3%) had severe. Leukoaraiosis severity was associated with worse 90-day mRS among all patients (p=0.0005) as well as those that were successfully revascularized (p=0.0002). A multivariate analysis confirmed that leukoaraiosis burden was associated with worse 90-day mRS among all patients (mild: p=0.006; moderate: p=0.002; severe: p=0.03), as well as those that underwent successful thrombectomies (p=0.005). Both L-ASPECTS and ASPECTS were associated with poor outcomes, but the association was stronger with L-ASPECTS (p Conclusion: Leukoaraiosis severity on pre-mechanical thrombectomy NCCT is associated with worse 90-day outcome in patients with AIS following endovascular recanalization, and is an independent risk factor for worse outcomes. A proposed L-ASPECTS score had stronger association with outcome than the traditional ASPECTS score.

Background: Women, compared with men, tend to have worse functional outcome after stroke. The gender effect is not fully explained by age, pre-stroke dependency, and stroke severity. We hypothesized that it might be due to different prognostic impacts of stroke-related brain lesions in women vs. men. Objective: To investigate if the effects of acute infarct volume and white matter hyperintensity (WMH) volume on initial stroke severity and 3-month functional outcome are modified by gender. Methods: This prospective study included 6748 patients with acute ischemic stroke ( Results: Women, compared with men, were older (mean 72 vs. 65, p2: adjusted OR [95%], 1.36 [1.09-1.69]). The association of WMH volume with 3-month mRS score was significantly modified by gender (p-for-interaction=0.049), with the WMH effect being greater in women (adjusted ORs of the highest vs. lowest quartile for the worse outcome: 2.47 in women vs. 1.51 in men). Conclusion: Women, compared with men, are probably more susceptible to the adverse effects of infarct volume and WMH volume on stroke severity and functional outcome.

Background and Purpose— Intracranial arterial dolichoectasia (IADE) is a poorly understood arteriopathy compared with intracranial atherosclerotic stenosis (ICAS). We aimed to investigate the risk factors of IADE and ICAS and their relationship with neuroimaging markers of cerebral small vessel disease in a population-based study. Methods— This study comprised 1237 participants (aged 57.2±9.4 years, 37.6% men) who underwent brain magnetic resonance imaging and magnetic resonance angiography. IADE was assessed based on basilar artery dolichoectasia (diameter, height of bifurcation, and laterality of basilar artery) and dilation of basilar artery and internal carotid artery (intracranial volume-adjusted diameter ≥2 SD). ICAS was defined as any degree of stenosis in at least 1 intracranial artery. The neuroimaging markers of cerebral small vessel disease, including lacunes, white matter hyperintensities, microbleeds, dilated perivascular spaces, and brain atrophy, were evaluated. Results— Basilar arterial dolichoectasia was observed in 3.6% (45/1237); intracranial arterial dilation in 5.9% (67/1142); and ICAS in 15.7% (194/1237). Older age, higher systolic blood pressure, diabetes mellitus, higher LDL-C (low-density lipoprotein cholesterol) and lower HDL-C (high-density lipoprotein cholesterol) were associated with the presence of ICAS (all P P P P P =0.01) and, to a lesser extent, associated with lacunes and microbleeds. Conclusions— IADE and ICAS had different risk factor profiles and associated with different imaging phenotypes of cerebral small vessel disease, suggesting different underlying mechanisms.

Background and Purpose— White matter lesions (WML) are associated with cognitive decline, increased stroke risk, and disability in old age. We hypothesized that superimposed acute cerebrovascular occlusion on chronic preexisting injury (leukoaraiosis) leads to worse outcome after minor cerebrovascular event, both using quantitative (volumetric) and qualitative (Fazekas scale) assessment, as well as relative total brain volume. Methods— WML volume assessment was performed in 425 patients with high-risk transient ischemic attack (TIA; motor/speech deficits >5 minutes) or minor strokes from the CATCH study (CT and MRI in the Triage of TIA and Minor Cerebrovascular Events to Identify High Risk Patients). Complete baseline characteristics and outcome assessment were available in 412 patients. Primary outcome was disability at 90 days, defined as modified Rankin Scale score of >1. Secondary outcomes were stroke progression, TIA recurrence, and stroke recurrence. Analysis was performed using descriptive statistics and regression models including interaction terms. Results— Median age was 69 years, 39.8% were female. Sixty-two patients (15%) had unfavorable outcome with disability at 90 days (modified Rankin Scale score >1). Higher Fazekas scores were strongly correlated with higher WML volume ( r =0.79). Both higher Fazekas score and higher WMH volume were associated with disability at 90 days in univariate regression (odds ratio 1.22; 95% confidence interval, 1.04–1.43 and odds ratio, 1.25 per milliliter increase; 95% confidence interval, 1.02–1.54, respectively) but not with stroke progression, TIA recurrence, or stroke recurrence. In multivariable-adjusted analyses, additive interaction terms were associated with unfavorable outcome (adjusted odds ratio 3.99, 95% confidence interval, 1.87–8.49). Conclusions— Our data suggest that quantitative and qualitative WML assessments are highly correlated and comparable in TIA/minor stroke patients. WML burden is associated with short-term outcome of patients with good prestroke function in the presence of intracranial stenosis/occlusion.

Background and Purpose— We aimed to determine the incidence of co-occurring cerebral ischemia, extent of cerebral small vessel disease, and vascular risk profile of patients with acute retinal ischemia. Methods— RETIS (Frequency of Acute Silent Brain Infarction and Systematic Evaluation of Stroke Risk in Retinal Ischemia) was a single-center, prospective, observational study comprising ophthalmologic examination, brain magnetic resonance imaging, and extensive diagnostic work-up of vascular risk factors and stroke cause. Silent brain infarctions were identified on diffusion-weighted imaging, leukoaraiosis was quantified on fluid-attenuated inversion recovery sequences, and carotid artery stenosis was assessed by carotid ultrasound. Results— Of 112 patients with retinal ischemia, 77 (68.8%) had retinal arterial occlusion, and 35 (31.3%) presented with amaurosis fugax. Silent brain infarctions were found in 17 (15.1%) patients. Internal carotid artery stenosis was present in 19 (17.0%) and severe leukoaraiosis in 29 (25.9%) patients. Atrial fibrillation was detected in 14 (12.5%) patients. Patients with silent brain infarctions had higher rates of internal carotid artery stenosis (35.3% versus 13.7%; P =0.029) than those without, whereas leukoaraiosis and vascular risk factors were comparable between groups. Internal carotid artery stenosis was the only significant predictor of silent brain infarctions in multivariate analysis (odds ratio, 4.27; 95% confidence interval, 1.06–17.23). Conclusions— Silent cerebral ischemia is present in about 1 in 7 patients with retinal ischemia. The high rate of symptomatic internal carotid artery stenosis suggests that large artery atherosclerosis plays a major role in the pathogenesis of acute retinal ischemia.

Background and Purpose— Acute minor neurological deficits are a common complaint in the emergency department and differentiation of transient ischemic attack/minor stroke from a stroke mimic is difficult. We sought to assess the ability of white matter hyperintensity (WMH) volume to aid the diagnosis in such patients. Methods— This is a post hoc analysis of the previously published SpecTRA study (Spectrometry in TIA Rapid Assessment) of adult patients that presented to the emergency department with acute minor neurological deficits between December 2013 and March 2017. WMH volumes were measured if fluid-attenuated inversion recovery imaging was available. Outcomes of interest were final diagnosis, symptoms at presentation, and 90-day stroke recurrence. Results— WMH volume was available for 1485 patients. Median age was 70 years (interquartile range, 59–80), and 46.7% were female. Mean WMH volume was higher in transient ischemic attack/minor strokes compared with stroke mimics (1.71 ln mL [95% CI, 1.63–1.79 ln mL] versus 1.15 ln mL [95% CI, 1.02–1.27 ln mL], P P =0.035). Conclusions— The combination of diffusion-weighted imaging positivity and high WMH volume was associated with lower odds of focal symptoms at presentation in patients seen with minor neurological deficits in the emergency department. This suggests that WMH volume might be an important consideration and the absence of focal symptoms at presentation should not discourage clinicians from further investigating patients with suspected cerebral ischemia.

Supplemental Digital Content is available in the text., Background and Purpose— Cerebral small vessel disease is characterized by a wide range of focal and global brain changes. We used a magnetic resonance imaging segmentation tool to quantify multiple types of small vessel disease–related brain changes and examined their individual and combined predictive value on cognitive and functional abilities. Methods— Magnetic resonance imaging scans of 560 older individuals from LADIS (Leukoaraiosis and Disability Study) were analyzed using automated atlas- and convolutional neural network–based segmentation methods yielding volumetric measures of white matter hyperintensities, lacunes, enlarged perivascular spaces, chronic cortical infarcts, and global and regional brain atrophy. The subjects were followed up with annual neuropsychological examinations for 3 years and evaluation of instrumental activities of daily living for 7 years. Results— The strongest predictors of cognitive performance and functional outcome over time were the total volumes of white matter hyperintensities, gray matter, and hippocampi (P

Background: White Matter Hyperintensities (WMH) are thought to represent end-stage white matter injury. Increasing WMH burden is associated with greater risk of stroke, infarct growth, and poor outcomes after stroke. Understanding the microstructural changes of normal appearing white matter (NAWM) that predate WMH development is therefore clinically relevant as it could identify targets for therapeutic intervention to reduce stroke risk and improve post-stroke outcomes. Diffusion tensor imaging-based axial (AD) and radial diffusivity (RD) can assess white matter axonal integrity and myelin status, respectively. In a cohort of patients with acute ischemic stroke (AIS), we measured NAWM and WMH AD and RD to elucidate the white matter microstructural changes associated with WMH burden. Methods: Brain MRI with diffusion tensor imaging sequences was acquired within 48 hours of admission on consecutive AIS patients. WMH volume (WMHv) was measured in a semi-automated manner. Median fractional anisotropy, mean diffusivity, RD, and AD values were calculated within NAWM and WMH in the hemisphere contralateral to the acute lesion. Linear regression analysis was performed to evaluate predictors of WMH. Level of significance was set at P < 0.05 for all analyses. Results: In 319 AIS patients, mean age was 67 +/- 15.9 years. Median WMHv was 6.19 cm3 (IQR 3.0-12.6 cm 3 ). Mean AD was significantly increased in WMH compared to NAWM (WMH: 1.29 vs. NAWM: 1.16 x 10 -3 , mm 2 /s; P < 0.0001). In multivariable linear regression, age (β = 0.18, P = 0.017) and NAWM AD (β = 42.3, P = 0.012) were independent predictors of WMHv. Diffusivity anisotropy metrics of WMH were not associated with WMHv. Conclusions: In patients with AIS, NAWM AD is an independent predictor of WMHv. Our findings suggest that loss of NAWM axonal integrity contributes to WMH development.

Introduction: The chance for a favorable outcome after mechanical thrombectomy (MT) for large vessel occlusion stroke decreases with the symptom onset-to-reperfusion time (OTR). Patients with severe leukoaraiosis are at increased risk for a poor outcome after MT. However, whether leukoaraiosis modulates to the association between OTR and 90-day functional outcome is uncertain. Methods: We retrospectively analyzed 144 consecutive patients with successful (TICI ≥2b/3) MT for anterior circulation LVO within 24 hours form OTR between January 2012 to November 2016. Leukoaraiosis was dichotomized to absent-to-mild (van Swieten scale score 0-2) versus moderate-to-severe (3-4) as assessed on admission head CT. Multiple linear, logistic, and ordinal regression analyses were used to determine the association between leukoaraiosis, OTR and 90-day modified Rankin Scale (mRS) score, after adjustment for pertinent covariates. Results: Leukoaraiosis was independently associated with OTR on multivariable linear regression ( p =0.003). The association between OTR and 90-day outcome depended on the degree of preexisting leukoaraiosis burden as shown by a significant leukoaraiosis-by-OTR interaction on multivariable logistic regression (OR 0.76, 95%-CI 0.58-0.98, p =0.037) and multivariable ordinal regression (OR 0.87, 95%-CI 0.78-0.97, p =0.011). Conclusions: The severity of pre-existing leukoaraiosis is associated with 90-day functional outcome and modulates the association between the OTR and 90-day mRS among patients undergoing MT within 24 hours from last known well. If confirmed, our results may have important implications for optimizing patient selection for acute stroke therapies.

Background: Prior studies have suggested that baseline leukoaraiosis before ICH may be associated with high mortality, initial large hematoma volume, and may be an independent risk factor for worse outcomes after ICH, yet leukoaraiosis is not included in prognostic criteria for ICH. We hypothesized that increased leukoaraiosis burden at baseline would be associated with worse outcomes in patients enrolled in the Safety of Pioglitazone for Hematoma Resolution in ICH (SHRINC) trial. Methods: Patients enrolled in SHRINC had a baseline brain MRI per protocol. We performed a retrospective analysis of leukoaraiosis measured on baseline MRI. Baseline leukoaraiosis scoring was measured using the Fazekas score (FS). Patients were stratified into two groups based on FS, none-mild (FS 0-1) and moderate-severe (FS 2-3). FS was evaluated as a treatment modifier for mRS, NIHSS and Barthel Index. Comparisons were performed by Chi-square, Fisher’s Exact or Wilcoxon rank sum, linear or logistic regression models were developed to test FS as a treatment effect modifier on outcomes. Results: A total of 78 subjects had baseline MRIs (37 PIO, 41 Placebo) suitable to determine FS. There was no difference in important prognostic variables between the two groups (Table). There was no significant interaction between FS and treatment group at 90 or 180 days regarding good outcome, NIHSS, Barthel index (p= 0.18, 0.31, 0.40, respectively). Conclusions: Our analysis revealed that the presence of baseline moderate to severe leukoaraiosis was not associated with baseline presentation nor treatment effect on outcomes. Our findings raise the question whether our traditional outcome measures are able to detect deficit due to leukoaraisosis and future studies should consider outcomes measures which can better quantify deficits attributable to leukoaraiosis.

Background and Purpose— There is increasing interest in defining stroke lesion volume thresholds to predict poststroke outcome. However, there is a paucity of data on factors that impact the association between critical infarct thresholds volume and outcome. We sought to determine whether lesion thresholds best predicting outcome depend on the degree of preexisting white matter hyperintensity (WMH) lesion burden. Methods— Magnetic resonance imaging infarct volumes were quantified in 414 consecutive patients with anterior circulation ischemic strokes evaluated between January 2014 and December 2014. The WMH lesion volume was graded according to the Fazekas scale and dichotomized to absent to mild versus moderate to severe. Receiver operator characteristics curves were calculated to determine the infarct volume threshold best predicting the 90-day outcome. Multivariable logistic regression was used to determine whether the critical lesion thresholds independently predicted a favorable 90-day outcome after adjusting for pertinent confounders. Results— The infarct volumes thresholds predicting the 90-day outcome for the entire cohort (standard thresholds) were ≤29.5 mL (modified Rankin scale [mRS] 0–1), ≤29.9 mL (mRS 0–2), and ≤34.1 mL (mRS 0–3). For patients with absent-to-mild WMH lesion burden, WMH-adjusted critical infarct thresholds were significantly greater than the standard infarct thresholds. In the fully adjusted multivariable regression models, the WMH-adjusted infarct thresholds correctly predicted the outcome to a similar degree as the standard thresholds. Conclusions— In this proof-of-concept study, the WMH lesion burden impacted the critical outcome-predicting infarct thresholds. If confirmed, using a WMH-adjusted infarct threshold could allow defining patients that have a favorable outcome despite having relatively large infarct volumes.

Background and Purpose— We performed a meta-analysis to assess whether leukoaraiosis on brain computed tomographic scans of acute ischemic stroke patients treated with intravenous thrombolysis is associated with an increased risk of symptomatic intracerebral hemorrhage (sICH) or poor functional outcome at 3 to 6 months after stroke, or both. Methods— We searched PubMed and pooled relevant data in meta-analyses using random effects models. Using odds ratios (OR), we quantified the strength of association between the presence and severity of leukoaraiosis and post-thrombolysis sICH or 3- to 6-month modified Rankin Score >2. Results— Eleven eligible studies (n=7194) were pooled in meta-analysis. The risk of sICH was higher in patients with leukoaraiosis (OR, 1.55; 95% confidence interval [CI], 1.17–2.06; P =0.002) and severe leukoaraiosis (OR, 2.53; 95% CI, 1.92–3.34; P P P I 2 , 75.7%; P =0.002). In adjusted analyses, leukoaraiosis was an independent predictor of poor outcome (n=3688; adjusted OR, 1.61; 95% CI, 1.44–1.79; P Conclusions— Leukoaraiosis might increase post-intravenous thrombolysis sICH risk and poor outcome poststroke. Despite increased sICH risk, intravenous tissue-type plasminogen activator treatment has net clinical benefit in patients with leukoaraiosis. Given the risk of bias/confounding, these results should be considered hypothesis-generating and do not justify withholding intravenous thrombolysis.

Background and Purpose— The genetic basis of white matter hyperintensities (WMH) is still unknown. This study examines the heritability of WMH in both sexes and in different brain regions, and the influence of age. Methods— Participants from the Older Australian Twins Study were recruited (n=320; 92 monozygotic and 68 dizygotic pairs) who volunteered for magnetic resonance imaging scans and medical assessments. Heritability, that is, the ratio of the additive genetic variance to the total phenotypic variance, was estimated using the twin design. Results— Heritability was high for total WMH volume (0.76), and for periventricular WMH (0.64) and deep WMH (0.77), and varied from 0.18 for the cerebellum to 0.76 for the occipital lobe. The genetic correlation between deep and periventricular WMH regions was 0.85, with one additive genetics factor accounting for most of the shared variance. Heritability was consistently higher in women in the cerebral regions. Heritability in deep but not periventricular WMH declined with age, in particular after the age of 75. Conclusions— WMH have a strong genetic influence but this is not uniform through the brain, being higher for deep than periventricular WMH and in the cerebral regions. The genetic influence is higher in women, and there is an age-related decline, most markedly for deep WMH. The data suggest some heterogeneity in the pathogenesis of WMH for different brain regions and for men and women.

Background and Purpose— Elevated fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis and is linked with mortality, cardiovascular events, and stroke. However, the role of FGF23 as a risk factor for subclinical cerebrovascular damage is unclear. Methods— We used multivariable linear and logistic regression to evaluate associations between FGF23, continuously and by quartiles, with white matter hyperintensity volume, expressed as percent intracranial volume (%ICV), and subclinical brain infarction (SBI) in a community-based stroke-free sample. Results— There were 1170 stroke-free Northern Manhattan Study (NOMAS) participants with FGF23 levels and quantitative magnetic resonance imaging data on white matter hyperintensity volume and SBI. Participants with FGF23 levels in the top quartile (range=85–1425 RU/mL) had greater white matter hyperintensity volume (β=0.19 %ICV; 95% CI, 0.04–0.33 %ICV; P =0.01) compared with those in the lowest quartile (range=15–49 RU/mL), adjusted for demographics, vascular risk factors, and estimated glomerular filtration rate. These findings remained significant in those without evidence of chronic kidney disease (estimated glomerular filtration rate 2 ). Elevated FGF23 was not associated with SBI overall after adjusting for demographic factors and estimated glomerular filtration rate, but sex modified the effect of FGF23 on odds of SBI ( P for interaction=0.03). FGF23 was associated with significantly greater odds of SBI only in men (odds ratio, 1.7; 95% CI, 1.1–2.7; P =0.03) after full adjustment. Conclusions— These cross-sectional community-based data from a diverse urban sample show an association between elevated FGF23 and small vessel disease and magnetic resonance imaging–defined brain infarction in men, independent of chronic kidney disease. Data on elevated FGF23 and subclinical cerebrovascular damage progression are needed.

Age-related cognitive impairment is arguably the greatest looming threat to aging populations in both the developed and developing world.1 Emerging evidence indicates that cerebral small vessel disease (SVD) is a major contributor to cognitive impairment,2 highlighting the importance of improved understanding of the molecular and physiological mechanisms leading to vascular brain injury. As a result, 2 of the 3 highest priority research areas for the next 5 to 10 years identified by National Institute of Neurological Disorders and Stroke’s (NINDS) Workgroup on Stroke Prevention Research in 2012 were focused on prevention of vascular cognitive impairment (VCI) and imaging biomarkers in stroke prevention.3 This important initiative of NINDS has further accelerated the neuroimaging research in VCI that was blossoming over the preceding 10 years. Novel magnetic resonance imaging (MRI) markers of ischemic and hemorrhagic tissue damage in the brain have been identified, and their associations with the underlying cerebrovascular pathologies and resulting cognitive changes are extensively studied.4 MRI-based studies yielded a large gamut of imaging markers that mediate vascular contributions to dementia. Silent infarcts, lacunes, white matter hyperintensities (WMH) on fluid-attenuated inversion recovery MRI, fractional anisotropy and mean diffusivity changes, and acute punctate infarcts on diffusion weighted MRI are examples of ischemic markers that have been increasingly studied during the past decade.5–7 Cerebral microbleeds (CMB) and cortical superficial siderosis are subtle hemorrhagic lesions visible on T2*-MRI, and they serve as key markers of the most common SVDs that contribute to VCI in elderly.5,8 Enlarged perivascular spaces (EPVS), identified on T1- and T2-weighted MRIs by radiologists for over 2 decades, are emerging as another VCI-related marker, especially because of their association with the type of SVD.5 Functional MRI provided measures of vascular dysfunction and resting-state functional connectivity, whereas diffusion tensor imaging …

Background and Purpose— The National Institutes of Health Stroke Scale (NIHSS) provides a reliable, quantitative measure of ischemic stroke severity and is predicted by the infarct size. We sought to determine whether leukoaraiosis severity affects the association between infarct size and NIHSS. Methods— NIHSS and diffusion-weighted imaging–defined infarct volumes from 312 prospectively enrolled patients with supratentorial, ischemic strokes were analyzed. Leukoaraiosis severity was graded according to the Fazekas scale and conceptually defined as absent (0; n=44), mild (1–2; n=106), moderate (3–4; n=105), and severe (5–6; n=57). ANCOVA was used to describe the effect of leukoaraiosis on the association between infarct volume and NIHSS. Multivariable linear regression models were constructed to assess whether the association of leukoaraiosis and infarct volume on NIHSS was independent of other clinically relevant covariates. Results— Overall, there was a significant correlation between the infarct volume and NIHSS ( r =0.591; P r =0.786 ( P r =0.498 ( P P P Conclusions— Leukoaraiosis significantly modulates the association between infarct volume and NIHSS. The clinical implications of these findings need further exploration in prospective studies but may be relevant to mitigate outcome differences in patients with stroke by aiding treatment decisions that rely on the NIHSS.

Supplemental Digital Content is available in the text., Background and Purpose— Epidemiological studies suggest that white matter hyperintensities (WMH) are extremely heritable, but the underlying genetic variants are largely unknown. Pathophysiological heterogeneity is known to reduce the power of genome-wide association studies (GWAS). Hypertensive and nonhypertensive individuals with WMH might have different underlying pathologies. We used GWAS data to calculate the variance in WMH volume (WMHV) explained by common single nucleotide polymorphisms (SNPs) as a measure of heritability (SNP heritability [HSNP]) and tested the hypothesis that WMH heritability differs between hypertensive and nonhypertensive individuals. Methods— WMHV was measured on MRI in the stroke-free cerebral hemisphere of 2336 ischemic stroke cases with GWAS data. After adjustment for age and intracranial volume, we determined which cardiovascular risk factors were independent predictors of WMHV. Using the genome-wide complex trait analysis tool to estimate HSNP for WMHV overall and within subgroups stratified by risk factors found to be significant in multivariate analyses. Results— A significant proportion of the variance of WMHV was attributable to common SNPs after adjustment for significant risk factors (HSNP=0.23; P=0.0026). HSNP estimates were higher among hypertensive individuals (HSNP=0.45; P=7.99×10−5); this increase was greater than expected by chance (P=0.012). In contrast, estimates were lower, and nonsignificant, in nonhypertensive individuals (HSNP=0.13; P=0.13). Conclusions— A quarter of variance is attributable to common SNPs, but this estimate was greater in hypertensive individuals. These findings suggest that the genetic architecture of WMH in ischemic stroke differs between hypertensives and nonhypertensives. Future WMHV GWAS studies may gain power by accounting for this interaction.

Background and Purpose— Abnormalities of the retinal circulation may be associated with cerebrovascular disease. We investigated associations between retinal microvascular abnormalities and (1) strokes and subclinical cerebral infarcts and (2) cerebral white matter lesions in a UK-based triethnic population-based cohort. Methods— A total of 1185 participants (age, 68.8±6.1 years; 77% men) underwent retinal imaging and cerebral magnetic resonance imaging. Cerebral infarcts and white matter hyperintensities were identified on magnetic resonance imaging, retinopathy was graded, and retinal vessels were measured. Results— Higher retinopathy grade (odds ratio [OR], 1.40 [95% confidence interval (95% CI), 1.16–1.70]), narrower arteriolar diameter (OR, 0.98 [95% CI, 0.97–0.99]), fewer symmetrical arteriolar bifurcations (OR, 0.84 [95% CI, 0.75–0.95]), higher arteriolar optimality deviation (OR, 1.16 [95% CI, 1.00–1.34]), and more tortuous venules (OR, 1.20 [95% CI, 1.09–1.32]) were associated with strokes/infarcts and white matter hyperintensities. Associations with quantitative retinal microvascular measures were independent of retinopathy. Conclusions— Abnormalities of the retinal microvasculature are independently associated with stroke, cerebral infarcts, and white matter lesions.

Objective: To investigate the relationship between leukoaraiosis (LA)and hemorrhagic transformation(HT)and neurological outcome at 3 months after recombinant tissue plasminogen activator(rt-PA) treatment in patients with acute ischemic stroke. Methods: Prospective clinical,1aboratory, and radiological data from patients with acute ischemic stroke who had received intravenous rt-PA therapy in our hospital were retrospectively reviewed. The severity ratings of LA were evaluated by Age-related white matter changes scale (ARWMC) scale. In order to detect hemorrhagic transformation, all the patients in thrombolysis group had the second head CT scan at 24 h after thrombolysis. sICH was assessed according to the European Collaborative Acute Stroke Study II (ECASS II) criteria. Hemorrhagic transformation after thrombolytic therapy and clinical neurological outcome based on modified Rankin scale(mRS)at 3 months were also analyzed. Favorable outcome as mRS 0-1 and unfavorable outcome as mRS 2-6 were defined. Results: 584 patients receiving intravenous rt-PA treatment in this study were finally enrolled. The mean age was (63.1 ± 9.7) years and 250 cases (42.9%) in women. Door to needle time was (170.4 ± 44.4) min, pretreatment National Institutes of Health Stroke Scale score was 13.76 ± 6.18. Hemorrhagic transformation was found in 83 cases (14.2%). Logistic regression analysis showed that the severity of LA was associated with hemorrhagic transformation, the odds ratios ranged from 2.017(95% CI 1.419 ~ 2.915) to 2.541 (95% CI 1.714 ~ 3.368). Dicho-Logistic regression analysis showed that WMHs Score was the independent risk factor of unfavorable neurological outcome ( OR = 1.735, 95% CI 1.236 ~ 2.442). Conclusion: The severity of LA is associated with an increased risk of sICH and poor functional outcome after IV or intra-arterial thrombolysis for acute ischemic stroke.

Background: Alterations to microstructural integrity in white matter hyperintensities (WMH) in patients with severe leukoaraiosis are poorly understood. Neurite density and orientation dispersion imaging (NODDI) produce better estimates of myelin density than diffusion tensor MRI (DTI) and therefore may provide additional in vivo insight into WMH pathophysiology. Methods: NODDI was acquired in a prospective study of acute ischemic stroke patients with advanced white matter disease (N=36). Neurite density (ND), and orientation dispersion (OD) were calculated along with model-free diffusion parameters: mean kurtosis (MK), axial kurtosis (AK), radial kurtosis (RK), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD) and fractional anisotropy (FA). Median values were measured in in the hemisphere contralateral to the incident stroke in regions of WMH and in normal appearing white matter (NAWM) and compared (paired Wilcoxon-exact test). Linear regression was performed to evaluate univariate predictors of log-transformed WMH volumes (log WMHv). Results: Patient characteristics were: mean±SD age 69±10 y, time-to-MRI 2.8±1.2 days, median [IQ] normalized WMHv 4.7 [2.3-9.3] and 61% men. MD, AD and RD were greater, while FA, MK, AK, RK, OD and ND were lower in WMH compared to NAWM (P Discussion: Diffusivity, kurtosis and ND and OD in acute stroke patients with moderate to severe leuokoaraiosis differed significantly between NAWM and WMH in the contralateral hemisphere. Reduced neurite density is suggestive of microstructural injury. Reduced OD is typically associated with greater organization, but might also reflect restricted extracellular space diffusivity. The association of MD, AD, AK and OD in NAWM with WMH burden suggests there is ongoing risk for developing future WMH.

Background and purpose: There are discrepancies between neurological severity and activities of daily life (ADL) after stroke. We investigated associations between neurological severity and ADL in patients with ischemic stroke at the convalescent rehabilitation stage. We particularly focused on the condition of leukoaraiosis on magnetic resonance imaging (MRI) and various clinical factors. Methods: The participants included 723 patients with ischemic stroke (484 men and 239 women; mean age, 73.2 ± 8.5 years; subtypes, lacunar infarction [n = 54], atherothrombosis [n = 305], artery-to-artery embolism [n = 105], cardiogenic embolism [n = 129], undetermined embolism [n = 93], and uncategorized ischemic stroke [n = 37]) which were transferred from acute care hospitals for inpatient convalescent rehabilitation. Leukoaraiosis was graded according to periventricular hyperintensity (PVH) and deep white matter hyperintensity on MRI. The National Institutes of Health Stroke Scale (NIHSS) was used to measure neurological severity and the Functional Independence Measure (FIM) was used to assess ADL at admission and discharge. Results: Multiple regression analysis revealed that total FIM scores were significantly associated with leukoaraiosis as estimated by PVH grade (P = 0.001) and NIHSS score (P < 0.001) both at admission and discharge for all patients, in addition to clinical factors, such as age, history of heart disease, and bilateral infarction lesions. In contrast, multiple regression analysis of NIHSS scores revealed no association with PVH. Conclusions: Our study revealed that ADL were associated with the degree of leukoaraiosis as indicated by PVH at the convalescent rehabilitation stage in patients with ischemic stroke. However, neurological severity was not associated with leukoaraiosis, likely because the progression patterns and anatomic backgrounds of PVH affect ADL and rehabilitation outcomes in post ischemic stroke.

Background and Purpose: Preclinical stroke scales may help identify patients likely to have large vessel occlusion (LVO) to facilitate rapid triage to thrombectomy-capable stroke centers. Scale misclassification may result in inaccurate decisions and possible harm. Pre-existing leukoaraiosis has been shown to attenuate the association between deficit type and stroke severity. We sought to determine whether leukoaraiosis affects the predictive ability of 5 commonly used LVO scales. Materials and Methods: We retrospectively analyzed 274 consecutive stroke patients with available brain MRI and vessel imaging. The following LVO scales were used: 3 Item Stroke Scale (3I/SS), Field Assessment Stroke Triage for Emergency Destination (FAST-ED), Rapid Arterial Occlusion Evaluation (RACE), Vision, Aphasia, Neglect (VAN) score, and Cincinnati Prehospital Stroke Severity Scale (CPSSS). For diagnostic scale accuracy, we assessed sensitivity, specificity, positive predictive value, negative predictive value, and kappa. Multivariable logistic regression was used to determine the scales’ predictive ability after adjustment for leukoaraiosis and potential confounders. Results: In unadjusted analyses, all scales predicted LVO (n=46; P Conclusion: The diagnostic accuracy of the tested LVO scales was attenuated by moderate-tosevere leukoaraiosis. If confirmed, this information may aid acute decision making and the design of studies that require LVO scale screening of patients likely to have concomitant leukoaraiosis.

Golsari et al1 evaluated the risk factors of silent brain infarctions and leukoaraiosis in 112 patients with acute retinal ischemia. A total of 77 (68.8%) had retinal arterial occlusion, and 17 (15.1%) had silent brain infarctions. By binary logistic regression analysis, internal carotid artery stenosis was significantly associated with silent brain infarctions with odds ratio (95% confidence interval) of 4.27 (1.06–17.23). I have some concerns about their study. First, the authors used 8 independent variables simultaneously for conducting logistic regression analysis. The number of events …

Background and Purpose— Women have worse poststroke outcomes than men. We evaluated sex-specific clinical and neuroimaging characteristics of white matter in association with functional recovery after acute ischemic stroke. Methods— We performed a retrospective analysis of acute ischemic stroke patients with admission brain MRI and 3- to 6-month modified Rankin Scale score. White matter hyperintensity and acute infarct volume were quantified on fluid-attenuated inversion recovery and diffusion tensor imaging MRI, respectively. Diffusivity anisotropy metrics were calculated in normal appearing white matter contralateral to the acute ischemia. Results— Among 319 patients with acute ischemic stroke, women were older (68.0 versus 62.7 years; P =0.004), had increased incidence of atrial fibrillation (21.4% versus 12.2%; P =0.04), and lower rate of tobacco use (21.1% versus 35.9%; P =0.03). There was no sex-specific difference in white matter hyperintensity volume, acute infarct volume, National Institutes of Health Stroke Scale, prestroke modified Rankin Scale score, or normal appearing white matter diffusivity anisotropy metrics. However, women were less likely to have an excellent outcome (modified Rankin Scale score P =0.005). In logistic regression analysis, female sex and the interaction of sex with fractional anisotropy, radial diffusivity, and axial diffusivity were independent predictors of functional outcome. Conclusions— Female sex is associated with decreased likelihood of excellent outcome after acute ischemic stroke. The correlation between markers of white matter integrity and functional outcomes in women, but not men, suggests a potential sex-specific mechanism.

We thank Dr Kawada for making important comments on our study. We fully agree with the notion that because of the small number of cases, the multivariate analysis has limitations. To date, there have been no larger prospective studies systematically investigating the occurrence of silent brain infarctions in patients with retinal ischemia in terms of pathogenesis and contributing factors. The results of our study thus have to be considered exploratory and await confirmation in future studies. However, the silent brain infarctions observed in our sample of patients with retinal ischemia were mostly small embolic cortical and subcortical lesions in the internal carotid artery (ICA) territory, and the association of silent brain infarctions with the presence of ipsilateral stenosis of the ICA was strong and is biologically plausible. This observation confirms …

Introduction: Severity of leukoaraiosis, or white matter hyperintensity (WMH) detected on T2 MRI, is associated with cognitive and functional decline and is a known risk factor for stroke and poor post-stroke outcomes. Fazekas score is a validated ordinal scale that accounts for WMH severity in the individual categories of periventricular (PVWM), deep WMH extent (DWMH) and deep WMH number of lesions (DWMNUM). Vascular risk factors (VRFs) are hypothesized to have differential effect on WMH lesion pathophysiology. We tested whether the Framingham Stroke Risk Score (FSRS), a collective score of several VRFs, is associated with WMH severity across individual Fazekas categories in a hospital-based cohort of patients with acute ischemic stroke (AIS). Methods: In 294 AIS patients, WMH was categorized into PVWM, DWMH, DWMNUM, and an average of all three categories per subject (“the condensed score”). Fazekas scores ranging 0-3 in each category were dichotomized (mild WMH≤1 vs. severe WMH ≥2). FSRS was calculated for each patient using a standardized formula awarding points for each FSRS variable (age, gender, systolic blood pressure, diabetes mellitus, cigarette smoking, coronary heart disease, left ventricular hypertrophy, atrial fibrillation) and added to obtain a total FSRS, which was then categorized into multiples of ten (FSRS ≥10, FSRS ≥20). Logistic regression models included binary FSRS category and Fazekas score for each WMH category using Stata 12. Results: As compared to AIS subjects with FSRS(Figure). Conclusions: In our cohort, FSRS predicts severity of leukoaraiosis across different Fazekas categories, suggesting compounded effect on WMH development from various VRFs comprising the FSRS. Future studies powered to discern the effect of individual elements of FSRS on WMH categories are warranted to further understand the pathophysiology of leukoaraiosis.

Introduction: Statin therapy might be associated with an increased risk of hemorrhagic stroke, which has been attributed to low LDL-cholesterol levels and antithrombotic effects. Hypothesis: Previous statin therapy is associated with surrogate markers of amyloid and hypertensive angiopathies in patients with cardioembolic stroke who need to start long-term oral anticoagulation (OA). Methods: A prospective multicenter study of patients included in the HERO study (Intracerebral Hemorrhage due to Oral Anticoagulants: Prediction of the Risk by Magnetic Resonance). Patients were naïve for OA and had an acute cardioembolic ischemic stroke (TIA or infarct). A MR examination was performed during admission to evaluate: 1) Microbleeds (-MB-, number, distribution, burden); 2) Leukoaraiosis (-LK- presence and degree); 3) Superficial siderosis (-SS-, presence). We collected data on the specific statin, the dose and the statin intensity (low, medium or high according to accepted classifications). We also recorded demographic data and traditional vascular risk factors. Results: We studied 470 patients (age 77.5±6.4 years, 43.7% were men). A total of 193 (41.1%) patients received prior treatment with any statin, of whom 43.5% received simvastatin and 41.3% atorvastatin. Statin intensity was low in 14.5%, medium in 61.1%, high in 16.5% and unknown in 10.8%. LK was detected in 82.5% and was severe in 19.8%. SS was detected in 20 (4.3%) patients. MBs were detected in 140 (29.8%) patients and the distribution was lobar in 55%, deep in 30% and both in 15%. Of the MB group 74 (53%) had 1 MB, 66 (47%) had >1 MB, and 11.4% had >5 MBs. The presence of MB, LK or SS was not related to the pre-treatment with statin. The statin intensity was not related to the presence of SS, the presence/degree of LK, and the presence/distribution/burden of MBs. MBs were detected with increased frequency in hypertensive patients (p=0.09). LK presence and degree were increased in patients with MB (p=0.012) and SS (p=0.041). Conclusion: In conclusion, prior treatment with statins is not associated with surrogate markers of bleeding-prone cerebral angiopathies in patients with cardioembolic stroke. Therefore previous statin treatment should not influence the decision to start long-term oral anticoagulation.

Introduction: There is limited data on the clinical significance of cerebral microbleeds (CMB) among patients with cerebral ischemia. The purpose of this study is to determine the prevalence of CMB in this population and assess the risk of in-hospital death. Methods: We analyzed consecutive stroke patients at two tertiary stroke centers in a two-year period. Patients without magnetic resonance imaging (MRI) or imaging confirmation of an ischemic stroke were excluded from this study. T2*-weighted MRIs were assessed for the number, location, and topography of CMBs as well as other acute and chronic cerebrovascular diseases. We compared the baseline characteristics and clinical information between patients with and without CMBs. Results: Out of 793 stroke patients evaluated in this study (mean age 62±14 years, 52% men, 60% African American, median admission NIHSS: 7), 127 patients (16%) had CMB on their brain imaging. Microbleeds were more prevalent among stroke patients with hypertension (OR: 2.3, 95% CI: 1.3-4.1), moderate-severe leukoaraiosis (OR 3.8, 95% CI: 1.6-6.2), and recurrent stroke (OR 1.7, 95% CI: 1.1-2.6). There was no significant difference between patients with and without CMBs in terms of sex, race, NIHSS, and discharge mRS. There was a trend toward higher risk of in-hospital mortality among patients with CMB and patients who had CMB in deep brain structures but neither reached a significant difference. However, the risk of in-hospital mortality was higher among patients with multiple (≥5) CMBs. After adjusting for potential confounders, the presence of ≥5 CMBs on T2*-MRI was independently (p Conclusion: Our results indicate that multiple CMBs are associated with higher mortality among stroke patients.

Introduction: Obstructive sleep apnea (OSA) is a biological plausible risk factor for leukoaraiosis (LA). We tested the hypothesis that polysomnographic (PSG) and sleep-related variables are associated to LA in OSA patients. Methods: Cross-sectional study in which PSG records, medical histories and brain 1.5T MRI were collected from all consecutive patients who had attended a Sleep Medicine Center between 2009-2014. LA was graded from 0 to 9 with the ’Atherosclerosis Risk In Communities’ study scale. OSA was defined by The International Classification of Sleep Disorders, 2014, and its severity categorizing according to apnea-hypopnea index (AHI, Results: From 82 OSA patients (77% male; mean age 58±9 years, range 19-91), 54 (66%) had LA. Mild-to-moderate LA was found in 13 patients (8 mild and 5 moderate LA) and non-to-minimal LA in 69 (41 minimal and 28 non LA). Spearman’s correlation coefficient between AHI and LA grade was 0.41 (p Conclusion: Patients with severe OSA had higher risk for mild to moderate LA when compared to patients with mild or moderate OSA.

Background and Purpose— Leukoaraiosis (LA) predominantly affects the subcortical white matter, but mounting evidence suggests an association with cortical microvascular dysfunction and potentially decreased cortical ischemic tolerance. Thus, we sought to assess whether preexisting LA is predictive of the cortical infarct volume after middle cerebral artery branch occlusion and whether it relates to a worse outcome. Methods— We analyzed data from 117 consecutive patients with middle cerebral artery branch occlusion as documented by admission computed tomography angiography. Baseline clinical, laboratory, and outcome data, as well as final cortical infarct volumes, were retrospectively analyzed from a prospectively collected database. LA severity was assessed on admission computed tomography using the van Swieten scale grading the supratentorial white matter hypoattenuation. Infarct volume predicting a favorable 90-day outcome (modified Rankin Scale score ≤2) was determined by receiver operating characteristic curves. Multivariable linear and logistic regression analyses were used to identify independent predictors of the final infarct volume and outcome. Results— Receiver operating characteristic curve analyses indicated that a final infarct volume of ≤27 mL best predicted a favorable 90-day outcome. Severe LA (odds ratio, 11.231; 95% confidence interval, 2.526–49.926; P =0.001) was independently associated with infarct volume >27 mL. Severe LA (odds ratio, 3.074; 95% confidence interval, 1.055–8.961; P =0.040) and infarct volume >27 mL (odds ratio, 9.156; 95% confidence interval, 3.191–26.270; P Conclusions— The presence of severe, subcortical LA contributes to larger cortical infarct volumes and worse functional outcomes adding to the notion that the brain is negatively affected beyond LA’s macroscopic boundaries.

Background and Purpose— The integrity of white matter tracts connecting different parts of the brain is important for rapid compensation for the lost function from ischemic stroke. Impaired white matter reserve capacity secondary to leukoaraiosis may facilitate detection of new symptomatic ischemic events that would otherwise remain inconspicuous after an initial ischemic stroke. We sought to identify whether the extent of leukoaraiosis was a predictor of risk of early stroke recurrence. Methods— We used Cox regression analysis in consecutive patients with ischemic stroke to determine the relationship between leukoaraiosis burden and symptomatic stroke recurrence within 90 days. We graded total leukoaraiosis, periventricular leukoaraiosis, and subcortical leukoaraiosis using the Fazekas scale as mild ( Results —There were 106 recurrent events in 2378 patients. The cumulative incidence of recurrence was 5.9% at 90 days. Kaplan–Meier estimate of recurrence-free survival rate was lower in patients with extensive leukoaraiosis ( P =0.04) and extensive periventricular leukoaraiosis ( P =0.02) but not in extensive subcortical leukoaraiosis ( P =0.09). Multivariable Cox regression analysis revealed a hazard ratio of 1.50 (95% confidence interval, 1.00–2.25) for extensive leukoaraiosis, 1.67 (95% confidence interval, 1.11–2.51) for extensive periventricular leukoaraiosis, and 1.42 (95% confidence interval, 0.94–2.12) for extensive subcortical leukoaraiosis. Conclusions— The extent of leukoaraiosis independently predicts 90-day recurrent stroke risk after ischemic stroke. This suggests that leukoaraiosis may be used for risk stratification in ischemic stroke.

Background and Purpose— Recently, a novel locus at 17q25 was associated with white matter hyperintensities (WMH) on MRI in stroke-free individuals. We aimed to replicate the association with WMH volume (WMHV) in patients with ischemic stroke. If the association acts by promoting a small vessel arteriopathy, it might be expected to also associate with lacunar stroke. Methods— We quantified WMH on MRI in the stroke-free hemisphere of 2588 ischemic stroke cases. Association between WMHV and 6 single-nucleotide polymorphisms at chromosome 17q25 was assessed by linear regression. These single-nucleotide polymorphisms were also investigated for association with lacunar stroke in 1854 cases and 51 939 stroke-free controls from METASTROKE. Meta-analyses with previous reports and a genetic risk score approach were applied to identify other novel WMHV risk variants and uncover shared genetic contributions to WMHV in community participants without stroke and ischemic stroke. Results— Single-nucleotide polymorphisms at 17q25 were associated with WMHV in ischemic stroke, the most significant being rs9894383 ( P =0.0006). In contrast, there was no association between any single-nucleotide polymorphism and lacunar stroke. A genetic risk score analysis revealed further genetic components to WMHV shared between community participants without stroke and ischemic stroke. Conclusions— This study provides support for an association between the 17q25 locus and WMH. In contrast, it is not associated with lacunar stroke, suggesting that the association does not act by promoting small-vessel arteriopathy or the same arteriopathy responsible for lacunar infarction.

Background and Purpose— Leukoaraiosis (LA) is associated with dementia, ischemic stroke, and intracerebral hemorrhage (ICH), but there are few data on how LA might impact outcomes after acute ICH. We tested the hypothesis that the severity of LA on magnetic resonance imaging is related to worse functional outcomes after spontaneous ICH. Methods— We prospectively identified patients with spontaneous acute ICH. LA was identified on magnetic resonance imaging and its severity was graded using the Fazekas method to include a score for the deep white matter and periventricular regions. Outcomes were obtained at 14 days, 28 days, and 3 months with the modified Rankin Scale (mRS; a validated scale from 0 [no symptoms] to 6 [dead]) and analyzed with multivariate logistic regression. Results— Higher Fazekas total (periventricular plus deep white matter) score correlated with higher mRS score at 14 days ( P =0.02) and 3 months ( P =0.02). This relationship was driven by the periventricular score, for which higher score (more severe disease) correlated with higher National Institute of Health Stroke Scale at 14 days ( P =0.03), and higher mRS score at 14 days ( P P =0.004), and 3 months ( P =0.005). A higher (more severe) Fazekas periventricular score was associated with dependence or death at 3 months (odds ratio, 1.8 per point; 95% confidence interval, 1.02–3.1; P =0.04) after correction for the ICH score. Conclusions— Increased LA is an independent predictor of worse functional outcomes in patients after spontaneous ICH. The pathophysiology associating LA with worse outcomes requires further study. These data may improve prognostication and selection for clinical trials.