Does Thrombosis Play a Causal Role in Lacunar Stroke and Cerebral Small Vessel Disease?

BACKGROUND: The importance of thromboembolism in the pathogenesis of lacunar stroke (LS), resulting from cerebral small vessel disease (cSVD), is debated, and although antiplatelets are widely used in secondary prevention after LS, there is limited trial evidence from well-subtyped patients to support this approach. We sought to evaluate whether altered anticoagulation plays a causal role in LS and cSVD using 2-sample Mendelian randomization. METHODS: From a recent genome-wide association study (n=81 190), we used 119 genetic variants associated with venous thrombosis at genome-wide significance (P<5*10-8) and with a linkage disequilibrium r2<0.001 as instrumental variables. We also used genetic associations with stroke from the GIGASTROKE consortium (62 100 ischemic stroke cases: 10 804 cardioembolic stroke, 6399 large-artery stroke, and 6811 LS). In view of the lower specificity for LS with the CT-based phenotyping mainly used in GIGASTROKE, we also used data from patients with magnetic resonance imaging-confirmed LS (n=3199). We also investigated associations with more chronic magnetic resonance imaging features of cSVD, namely, white matter hyperintensities (n=37 355) and diffusion tensor imaging metrics (n=36 533). RESULTS: Mendelian randomization analyses showed that genetic predisposition to venous thrombosis was associated with an increased odds of any ischemic stroke (odds ratio [OR], 1.19 [95% CI, 1.13-1.26]), cardioembolic stroke (OR, 1.32 [95% CI, 1.21-1.45]), and large-artery stroke (OR, 1.41 [95% CI, 1.26-1.57]) but not with LS (OR, 1.07 [95% CI, 0.99-1.17]) in GIGASTROKE. Similar results were found for magnetic resonance imaging-confirmed LS (OR, 0.94 [95% CI, 0.81-1.09]). Genetically predicted risk of venous thrombosis was not associated with imaging markers of cSVD. CONCLUSIONS: These findings suggest that altered thrombosis plays a role in the risk of cardioembolic and large-artery stroke but is not a causal risk factor for LS or imaging markers of cSVD. This raises the possibility that antithrombotic medication may be less effective in cSVD and underscores the necessity for further trials in well-subtyped cohorts with LS to evaluate the efficacy of different antithrombotic regimens in LS.

Improved Dementia Prediction in Cerebral Small Vessel Disease Using Deep Learning-Derived Diffusion Scalar Maps From T1.

BACKGROUND: Cerebral small vessel disease is the most common pathology underlying vascular dementia. In small vessel disease, diffusion tensor imaging is more sensitive to white matter damage and better predicts dementia risk than conventional magnetic resonance imaging sequences, such as T1 and fluid attenuation inversion recovery, but diffusion tensor imaging takes longer to acquire and is not routinely available in clinical practice. As diffusion tensor imaging-derived scalar maps-fractional anisotropy (FA) and mean diffusivity (MD)-are frequently used in clinical settings, one solution is to synthesize FA/MD from T1 images. METHODS: We developed a deep learning model to synthesize FA/MD from T1. The training data set consisted of 4998 participants with the highest white matter hyperintensity volumes in the UK Biobank. Four external validations data sets with small vessel disease were included: SCANS (St George's Cognition and Neuroimaging in Stroke; n=120), RUN DMC (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort; n=502), PRESERVE (Blood Pressure in Established Cerebral Small Vessel Disease; n=105), and NETWORKS (n=26), along with 1000 normal controls from the UK Biobank. RESULTS: The synthetic maps resembled ground-truth maps (structural similarity index >0.89 for MD maps and >0.80 for FA maps across all external validation data sets except for SCANS). The prediction accuracy of dementia using whole-brain median MD from the synthetic maps is comparable to the ground truth (SCANS ground-truth c-index, 0.822 and synthetic, 0.821; RUN DMC ground truth, 0.816 and synthetic, 0.812) and better than white matter hyperintensity volume (SCANS, 0.534; RUN DMC, 0.710). CONCLUSIONS: We have developed a fast and generalizable method to synthesize FA/MD maps from T1 to improve the prediction accuracy of dementia in small vessel disease when diffusion tensor imaging data have not been acquired.

Association of Plasma Neurofilament Light With Small Vessel Disease Burden in Nondemented Elderly: A Longitudinal Study.

BACKGROUND AND PURPOSE: Neurofilament light chain (NfL) is a promising predictive biomarker of active axonal injury and neuronal degeneration diseases. We aimed to evaluate if an increase in plasma NfL levels could play a monitoring role in the progression of cerebral small vessel disease (CSVD) among the nondemented elders, which are highly prevalent in elderly individuals and associated with an increased risk of stroke and dementia. METHODS: The study included 496 nondemented participants from the Alzheimer disease neuroimaging initiative database. All participants underwent plasma NfL measurements and 3.0-Tesla magnetic resonance imaging of the brain; 387 (78.0%) underwent longitudinal measurements. The number of cerebral microbleeds, lacunar infarcts, and volumetric white matter hyperintensities, as well as Fazekas scores, were measured. Cross-sectional and longitudinal associations between CSVD burden and NfL levels were evaluated using multivariable-adjusted models. RESULTS: Plasma NfL was higher in the moderate-severe CSVD burden group (45.2±16.0 pg/mL) than in the nonburden group (34.3±15.1 pg/mL; odds ratio [OR]=1.71 [95% CI, 1.24-2.35]) at baseline. NfL was positively associated with the presence of cerebral microbleeds (OR=1.29 [95% CI, 1.01-1.64]), lacunar infarcts (OR=1.43 [95% CI, 1.06-1.93]), and moderate-severe white matter hyperintensities (OR=1.67 [95% CI, 1.24-2.25]). Longitudinally, a higher change rate of NfL could predict more progression of CSVD burden (OR=1.38 [95% CI, 1.08-1.76]), white matter hyperintensities (OR=1.41 [95% CI, 1.10-1.79]), and lacunar infarcts (OR=1.99 [95% CI, 1.42-2.77]). CONCLUSIONS: Plasma NfL level is a valuable noninvasive biomarker that supplements magnetic resonance imaging scans and possibly reflects the severity of CSVD burden. Furthermore, high plasma NfL levels tend to represent an increased CSVD risk, and dynamic increases in NfL levels might predict a greater progression of CSVD.

Cilostazol for Secondary Prevention of Stroke and Cognitive Decline: Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Cilostazol, a phosphodiesterase 3' inhibitor, is used in Asia-Pacific countries for stroke prevention, but rarely used elsewhere. In addition to weak antiplatelet effects, it stabilizes endothelium, aids myelin repair and astrocyte-neuron energy transfer in laboratory models, effects that may be beneficial in preventing small vessel disease progression. METHODS: A systematic review and meta-analysis of unconfounded randomized controlled trials of cilostazol to prevent stroke, cognitive decline, or radiological small vessel disease lesion progression. Two reviewers searched for papers (January 1, 2019 to July 16, 2019) and extracted data. We calculated Peto odds ratios (ORs) and 95% CIs for recurrent ischemic, hemorrhagic stroke, death, adverse symptoms, with sensitivity analyses. The review is registered (CRD42018084742). RESULTS: We included 20 randomized controlled trials (n=10 505), 18 in ischemic stroke (total n=10 449) and 2 in cognitive impairment (n=56); most were performed in Asia-Pacific countries. Cilostazol decreased recurrent ischemic stroke (17 trials, n=10 225, OR=0.68 [95% CI, 0.57-0.81]; P<0.0001), hemorrhagic stroke (16 trials, n=9736, OR=0.43 [95% CI, 0.29-0.64]; P=0.0001), deaths (OR=0.64 [95% CI, 0.49-0.83], P<0.0009), systemic bleeding (n=8387, OR=0.73 [95% CI, 0.54-0.99]; P=0.04), but increased headache and palpitations, compared with placebo, aspirin, or clopidogrel. Cilostazol reduced recurrent ischemic stroke more when given long (>6 months) versus short term without increasing hemorrhage, and in trials with larger proportions (>40%) of lacunar stroke. Data were insufficient to assess effects on cognition, imaging, functional outcomes, or tolerance. CONCLUSIONS: Cilostazol appears effective for long-term secondary stroke prevention without increasing hemorrhage risk. However, most trials related to Asia-Pacific patients and more trials in Western countries should assess its effects on cognitive decline, functional outcome, and tolerance, particularly in lacunar stroke and other presentations of small vessel disease.

Higher Pulsatility in Cerebral Perforating Arteries in Patients With Small Vessel Disease Related Stroke, a 7T MRI Study.

Background and Purpose- Cerebral small vessel disease (SVD) is a major cause of stroke and dementia, but underlying disease mechanisms are still largely unknown, partly because of the difficulty in assessing small vessel function in vivo. We developed a method to measure blood flow velocity pulsatility in perforating arteries in the basal ganglia and semioval center. We aimed to determine whether this novel method could detect functional abnormalities at the level of the small vessels in patients with stroke attributable to SVD. Methods- We investigated 10 patients with lacunar infarction (mean age 61 years, 80% men), 11 patients with deep intracerebral hemorrhage (ICH) considered to be caused by SVD (ICH, mean age 58 years, 82% men) and 18 healthy controls that were age- and sex-matched. We performed 2-dimensional phase contrast magnetic resonance imaging at 7 T to measure time-resolved blood flow velocity in cerebral perforating arteries of the semioval center and the basal ganglia. We compared the number of detected arteries, pulsatility index and mean velocity between the patient groups and controls. Results- In the basal ganglia, the number of detected perforators was lower in lacunar infarction (26±9, P=0.01) and deep ICH patients (28±6, P=0.02) than in controls (35±7). The pulsatility index in the basal ganglia was higher in lacunar infarction (1.07±0.13, P=0.03), and deep ICH patients (1.02±0.11, P=0.11), than in controls (0.94±0.10). Observations in the semioval center were similar. Number of detected perforators was lower in lacunar infarction (32±18, P=0.06), and deep ICH patients (28±18, P=0.02), than in controls (45±16). The pulsatility index was higher in lacunar infarction (1.18±0.15, P=0.02), and deep ICH patients (1.17±0.14, P=0.045) than in controls (1.08±0.07). No velocity differences were detected. Conclusions- This exploratory study shows that SVD can be expressed in terms of functional measures, such as pulsatility index, which are derived directly from the small vessels themselves. Future studies may use this technique to further unravel the mechanisms underlying SVD.

Patterns of pontine strokes mimicking Bell's palsy.

BACKGROUND: Peripheral-type facial palsy very rarely arises from pontine stroke. We attempted to identify unique clinico-radiologic patterns associated with this condition. CASE PRESENTATION: Patients with pontine tegmentum stroke and acute onset of peripheral-type facial weakness were reviewed from the acute stroke registry of a tertiary hospital. The clinico-radiologic patterns of 10 patients were classified into one of three types based on the respective stroke mechanism. Type A (n = 5) was characterized by relatively diverse clinical presentations and larger, multiple infarctions resulting from large-artery atherosclerosis. Three cases with small lacunar infarcts were classified to type B (small vessel occlusion), and they showed only limited symptoms including horizontal gaze disturbance and facial paralysis. The two hemorrhagic cases (type C) presented with a focal pontine hemorrhage, likely due to a cavernous hemangioma. CONCLUSIONS: Peripheral-type facial palsy often occurs in pontine stroke with specific patterns. Type recognition helps to determine the underlying mechanism and the appropriate clinical approach. In particular, focal pontine tegmental infarctions showing stereotypic combinations of ophthalmoplegia and peripheral-type facial weakness (type B) might be recognized as a new type of lacunar syndrome.

Lacunar Stroke in Cryptococcal Meningitis: Clinical and Radiographic Features.

OBJECTIVE: Cryptococcal meningitis carries a high mortality, and survivors are left with considerable neurologic sequelae and marked disability. We lack a clear understanding of the pathogenesis of neurologic sequelae and description of stroke features in this population. We aim to describe clinical and radiographic features and predictors of stroke in a cohort of patients with cryptococcal meningitis. METHODS: We collected key information on patients diagnosed with cryptococcal meningitis at the University of Colorado Hospital between 2000 and 2018 (n = 42). Of those, 32 had neuroimaging studies available. Bivariate and risk ratio estimates regression models were performed to identify predictors of stroke. RESULTS: We found a 26% ischemic stroke complication rate in individuals with cryptococcal meningitis. Most strokes were acute (75%), lacunar (100%), multiple (88%), bilateral (63%), and involving the basal ganglia (75%). Presence of malignancy (38% versus 8%, P = .085) was higher in stroke in individuals with cryptococcal meningitis, although not statistically significant. Every unit decrease in hemoglobin and serum sodium were predictors for 1.35 and 1.14 times increase in the risk of ischemic stroke, respectively. The presence of hyponatremia carried a RR of 5.7 (95% confidence interval, 1.7-34, P = .005). Cryptococcal meningitis lead to death in 19% of patients and a considerable rate of neurologic sequela among survivors. CONCLUSIONS: Cryptococcal meningitis carries a high risk of lacunar stroke, particularly in the basal ganglia. Cryptococcal meningitis-associated stroke is common and frequently associated with neurologic disability among survivors. We need to understand the possible role of malignancy, anemia, and hyponatremia in the onset of ischemic stroke.

Causal Impact of Type 2 Diabetes Mellitus on Cerebral Small Vessel Disease: A Mendelian Randomization Analysis.

BACKGROUND AND PURPOSE: The relationship between type 2 diabetes mellitus (T2D) and cerebral small vessel disease (CSVD) is unclear. We aimed to examine the causal effect of T2D, fasting glucose levels, and higher insulin resistance on CSVD using Mendelian randomization. METHODS: Five CSVD phenotypes were studied; 2 were clinical outcomes associated with CSVD (lacunar stroke: n=2191/27 297 and intracerebral hemorrhage [ICH]: n=2254/8195 [deep and lobar ICH]), whereas 3 were radiological markers of CSVD (white matter hyperintensities: n=8429; fractional anisotropy [FA]: n=8357; and mean diffusivity: n=8357). We applied 2 complementary analyses to evaluate the association of T2D with CSVD. First, we used summarized data from genome-wide association study to calculate the effects of T2D-related variants on CSVD with inverse-variance weighted and weighted median approaches. Second, we performed a genetic risk score approach to test the effects of T2D-associated variants on white matter hyperintensities, FA, and mean diffusivity using individual-level data in UK Biobank. RESULTS: T2D was associated with higher risk of lacunar stroke (odds ratio [OR], 1.15; 95% confidence interval [CI], 1.04-1.28; P=0.007) and lower mean FA (OR, 0.78; 95% CI, 0.66-0.92; P=0.004) but not white matter hyperintensities volume (OR, 1.01; 95% CI, 0.97-1.04; P=0.626), higher mean diffusivity (OR, 1.04; 95% CI, 0.89-1.23; P=0.612), ICH (OR, 1.07; 95% CI, 0.95-1.20; P=0.269), lobar ICH (OR, 1.07; 95% CI, 0.89-1.28; P=0.466), or deep ICH (OR, 1.16; 95% CI, 0.99-1.36; P=0.074). Weighted median and penalized median weighted analysis showed similar effect estimates of T2D on lacunar stroke and FA, but with wider CIs, meaning they were not significant. The genetic score on individual-level data was significantly associated with FA (OR, 0.63; 95% CI, 0.45-0.89; P=0.008) after adjusting for potential confounders. CONCLUSIONS: Our Mendelian randomization study provides evidence to suggest that T2D may be causally associated with CSVD, in particular with lacunar stroke and FA.

Doppler Resistivity and Cerebral Small Vessel Disease: Hemodynamic Structural Correlation and Usefulness for the Etiological Classification of Acute Ischemic Stroke.

INTRODUCTION AND GOAL: Lacunar stroke is defined as an <1.5 cm diameter infarct located in the territory of a perforating artery, that is not accessible for direct study using conventional imaging techniques. Diagnosis requires exclusion of other causes. It usually occurs in the context of chronic cerebral small vessel disease, which can be suspected during the neurosonography study in the form of high pulsatility [PI] or resistance index [RI]. Clinical research was performed to confirm that PI and RI correlate with cerebral small vessel lesion burden and to determine whether these parameters are useful for supporting a lacunar origin (LO) in acute stroke. MATERIAL AND METHODS: We prospectively recorded internal carotid artery resistivity and the Fazekas score for all patients with acute ischemic stroke who met inclusion but not exclusion criteria over a 6-month period. RESULTS: The study population comprised 74 patients. A correlation was observed between the Fazekas score and resistivity. Both parameters predicted a LO, with an area under the curve of .78 and .696, respectively. The optimal cut-offs were PI = .96/RI = .58 for screening (sensitivity, 96%) and PI = 1.46/RI = .83 for confirmation (specificity, 89%). CONCLUSIONS: Doppler ultrasound is a useful technique for determining the LO of acute stroke.

Human Muse Cells Reconstruct Neuronal Circuitry in Subacute Lacunar Stroke Model.

BACKGROUND AND PURPOSE: Multilineage-differentiating stress-enduring (muse) cells are endogenous nontumorigenic stem cells with pluripotency harvestable as pluripotent marker SSEA-3+ cells from the bone marrow from cultured bone marrow-mesenchymal stem cells. After transplantation into neurological disease models, muse cells exert repair effects, but the exact mechanism remains inconclusive. METHODS: We conducted mechanism-based experiments by transplanting serum/xeno-free cultured-human bone marrow-muse cells into the perilesion brain at 2 weeks after lacunar infarction in immunodeficient mice. RESULTS: Approximately 28% of initially transplanted muse cells remained in the host brain at 8 weeks, spontaneously differentiated into cells expressing NeuN (≈62%), MAP2 (≈30%), and GST-pi (≈12%). Dextran tracing revealed connections between host neurons and muse cells at the lesioned motor cortex and the anterior horn. Muse cells extended neurites through the ipsilateral pyramidal tract, crossed to contralateral side, and reached to the pyramidal tract in the dorsal funiculus of spinal cord. Muse-transplanted stroke mice displayed significant recovery in cylinder tests, which was reverted by the human-selective diphtheria toxin. At 10 months post-transplantation, human-specific Alu sequence was detected only in the brain but not in other organs, with no evidence of tumor formation. CONCLUSIONS: Transplantation at the delayed subacute phase showed muse cells differentiated into neural cells, facilitated neural reconstruction, improved functions, and displayed solid safety outcomes over prolonged graft maturation period, indicating their therapeutic potential for lacunar stroke.

Frequency and Predictors of Dysphagia in Patients With Recent Small Subcortical Infarcts.

BACKGROUND AND PURPOSE: Detailed data on the occurrence of swallowing dysfunction in patients with recent small subcortical infarcts (RSSI) in the context of cerebral small vessel disease are lacking. This prompted us to assess the frequency of and risk factors for dysphagia in RSSI patients. METHODS: We identified all inpatients with magnetic resonance imaging-confirmed RSSI between January 2008 and February 2013. Demographic and clinical data were extracted from our stroke database, and magnetic resonance imaging scans were reviewed for morphological changes. Dysphagia was determined according to the Gugging Swallowing Screen. RESULTS: We identified 332 patients with RSSI (mean age, 67.7±11.9 years; 64.5% male). Overall, 83 patients (25%) had dysphagia, which was mild in 46 (55.4%), moderate in 26 (31.3%), and severe in 11 patients (13.3%). The rate of dysphagia in patients with supratentorial RSSI was 20%. Multivariate analysis identified a higher National Institutes of Health Stroke Scale score (P<0.001), pontine infarction (P<0.01), and more severe white matter hyperintensities (Fazekas grades 2 and 3, P=0.03) as risk factors for swallowing dysfunction. CONCLUSIONS: Dysphagia is present in a quarter of patients with RSSI and has to be expected especially in those with higher stroke severity, pontine infarction, and severe white matter hyperintensities.

Genetic Associations With White Matter Hyperintensities Confer Risk of Lacunar Stroke.

BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) are increased in patients with lacunar stroke. Whether this is because of shared pathogenesis remains unknown. Using genetic data, we evaluated whether WMH-associated genetic susceptibility factors confer risk of lacunar stroke, and therefore whether they share pathogenesis. METHODS: We used a genetic risk score approach to test whether single nucleotide polymorphisms associated with WMH in community populations were associated with magnetic resonance imaging-confirmed lacunar stroke (n=1,373), as well as cardioembolic (n=1,331) and large vessel (n=1,472) Trial of Org 10172 in Acute Stroke Treatment subtypes, against 9,053 controls. Second, we separated lacunar strokes into those with WMH (n=568) and those without (n=787) and tested for association with the risk score in these 2 groups. In addition, we evaluated whether WMH-associated single nucleotide polymorphisms are associated with lacunar stroke, or in the 2 groups. RESULTS: The WMH genetic risk score was associated with lacunar stroke (odds ratio [OR; 95% confidence interval [CI]]=1.14 [1.06-1.22]; P=0.0003), in patients both with and without WMH (WMH: OR [95% CI]=1.15 [1.05-1.26]; P=0.003 and no WMH: OR [95% CI]=1.11 [1.02-1.21]; P=0.019). Conversely, the risk score was not associated with cardioembolic stroke (OR [95% CI]=1.03 [0.97-1.09]; P=0.63) or large vessel stroke (OR [95% CI]=0.99 [0.93,1.04]; P=0.39). However, none of the WMH-associated single nucleotide polymorphisms passed Bonferroni-corrected significance for association with lacunar stroke. CONCLUSIONS: Genetic variants that influence WMH are associated with an increased risk of lacunar stroke but not cardioembolic or large vessel stroke. Some genetic susceptibility factors seem to be shared across different radiological manifestations of small vessel disease.

Common NOTCH3 Variants and Cerebral Small-Vessel Disease.

BACKGROUND AND PURPOSE: The most common monogenic cause of cerebral small-vessel disease is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, caused by NOTCH3 gene mutations. It has been hypothesized that more common variants in NOTCH3 may also contribute to the risk of sporadic small-vessel disease. Previously, 4 common variants (rs10404382, rs1043994, rs10423702, and rs1043997) were found to be associated with the presence of white matter hyperintensity in hypertensive community-dwelling elderly. METHODS: We investigated the association of common single nucleotide polymorphisms (SNPs) in NOTCH3 in 1350 patients with MRI-confirmed lacunar stroke and 7397 controls, by meta-analysis of genome-wide association study data sets. In addition, we investigated the association of common SNPs in NOTCH3 with MRI white matter hyperintensity volumes in 3670 white patients with ischemic stroke. In each analysis, we considered all SNPs within the NOTCH3 gene, and within 50-kb upstream and downstream of the coding region. A total of 381 SNPs from the 1000 genome population with a mean allele frequency>0.01 were included in the analysis. A significance level of P<0.0015 was used, adjusted for the effective number of independent SNPs in the region using the Galwey method. RESULTS: We found no association of any common variants in NOTCH3 (including rs10404382, rs1043994, rs10423702, and rs1043997) with lacunar stroke or white matter hyperintensity volume. We repeated our analysis stratified for hypertension but again found no association. CONCLUSIONS: Our study does not support a role for common NOTCH3 variation in the risk of sporadic small-vessel disease.

Genetic Architecture of Lacunar Stroke.

BACKGROUND AND PURPOSE: Lacunar strokes comprise ≈20% of all strokes. Despite this frequency, their pathogenesis is poorly understood. Previous genome-wide association studies in lacunar stroke have been disappointing, which may be because of phenotypic heterogeneity. Pathological and radiological studies suggest that there may be different pathologies underlying lacunar strokes. This has led to the suggestion of 2 subtypes: isolated lacunar infarcts and multiple lacunar infarcts and leukoaraiosis. METHODS: We performed genome-wide analyses in a magnetic resonance imaging-verified cohort of 1012 younger onset lacunar stroke cases and 964 controls. Using these data, we first estimated the heritability of lacunar stroke and its 2 hypothesized subtypes, and secondly, we determined whether this is enriched for regulatory regions in the genome, as defined by data from Encyclopedia of DNA Elements (ENCODE) and other sources. Finally, we determine the evidence for a polygenic contribution from rare variation to lacunar stroke and its subtypes. RESULTS: Our results indicate a substantial heritable component to magnetic resonance imaging-verified lacunar stroke (20%-25%) and its 2 subtypes (isolated lacunar infarct, 15%-18%; multiple lacunar infarcts/leukoaraiosis, 23%-28%). This heritable component is significantly enriched for sites affecting expression of genes. In addition, we show that the risk of the 2 subtypes of lacunar stroke in isolation, but not in combination, is associated with rare variation in the genome. CONCLUSIONS: Lacunar stroke, when defined on magnetic resonance imaging, is a highly heritable complex disease. Much of this heritability arises from regions of the genome affecting gene regulation. Rare variation affects 2 subtypes of lacunar in isolation, suggesting that they may have distinct genetic susceptibility factors.

Predictors of mortality in patients with lacunar stroke in the secondary prevention of small subcortical strokes trial.

BACKGROUND AND PURPOSE: The Secondary Prevention of Small Subcortical Stroke trial (SPS3) recruited participants meeting clinical and radiological criteria for symptomatic lacunes. Individuals randomized to dual antiplatelet therapy with clopidogrel and aspirin had an unanticipated increase in all-cause mortality compared with those assigned to aspirin. We investigated the factors associated with mortality in this well-characterized population. METHODS: We identified independent predictors of mortality among baseline demographic and clinical factors by Cox regression analysis in participants of the SPS3 trial. Separately, we examined the effect on mortality of nonfatal bleeding during the trial. RESULTS: During a mean follow-up of 3.6 years, the mortality rate was 1.78% per year for the 3020 participants (mean age, 63 years). Significant independent predictors of mortality at study entry were age, diabetes mellitus, history of hypertension, systolic blood pressure (hazard ratio [HR], 1.3 per 20 mm Hg increase), serum hemoglobin<13 g/dL (HR, 1.6), renal function (HR, 1.3 per estimated glomerular filtration rate decrease of 20 mL/min), and body mass index (HR, 1.8 per 10 kg/m2 decrease). Participants with ischemic heart disease (P=0.01 for interaction) and normotensive/prehypertensive participants (P=0.03 for interaction) were at increased risk if assigned to dual antiplatelet therapy. Nonfatal major hemorrhage increased mortality in both treatment arms (HR, 4.5; 95% confidence interval, 3.1-6.6; P<0.001). CONCLUSIONS: Unexpected interactions between assigned antiplatelet therapy and each of ischemic heart disease and normal/prehypertensive status accounted for increased mortality among patients with recent lacunar stroke given dual antiplatelet therapy. Despite extensive exploratory analyses, the mechanisms underlying these interactions are uncertain. CLINICAL TRIAL REGISTRATION URL: http://www.SPS3ClinicalTrials.gov. Unique identifier: NCT00059306.

Lacunar strokes in patients with diabetes mellitus: risk factors, infarct location, and prognosis: the secondary prevention of small subcortical strokes study.

BACKGROUND AND PURPOSE: Diabetes mellitus is an independent risk factor for lacunar strokes. Few data are available regarding patient features, infarct location, and recurrent vascular events for patients with diabetes mellitus with lacunar stroke. METHODS: We compared features at study entry and prognosis during 3.6 years of follow-up of patients with diabetes mellitus versus patients without diabetes mellitus with recent lacunar stroke participating in the Secondary Prevention of Small Subcortical Strokes (SPS3) randomized trial. RESULTS: Among the 3020 participants, the prevalence of diabetes mellitus was 37% with a mean duration of 11 years. Diabetes mellitus was independently associated with slightly younger age (63 versus 64 years; P<0.001), Hispanic ethnicity (36% versus 28%; P<0.0001), ischemic heart disease (11% versus 6%; P=0.002), and peripheral vascular disease (5% versus 2%; P<0.001). Patients with diabetes mellitus more frequently had intracranial stenosis ≥50% (P<0.001), infarcts involving the brain stem or cerebellum (P<0.001), and more extensive white matter abnormalities (P<0.001). Patients with diabetes mellitus were almost twice as likely to have a recurrent stroke (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.4-2.3), recurrent ischemic stroke (HR, 1.8; 95% CI, 1.4-2.4), disabling/fatal stroke (HR, 1.8; 95% CI, 1.2-2.9), myocardial infarction (HR, 1.7; 95% CI, 1.0-2.8), and death (HR, 2.1 95% CI, 1.6-2.8) compared with patients without diabetes mellitus. CONCLUSIONS: Patients with diabetes mellitus with lacunar stroke have a distinctive clinical profile that includes double the prevalence of systemic and intracranial atherosclerosis, preferential involvement of the posterior circulation, and a poor prognosis for recurrent stroke and death. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059306.

Association between arterial calcifications and nonlacunar and lacunar ischemic strokes.

BACKGROUND AND PURPOSE: Nonlacunar cerebral infarcts are presumed to be caused by thromboembolism from the heart or extracranial arteries, whereas lacunar infarcts are thought to be caused by small vessel disease. We investigated to what extent arterial calcifications differ between nonlacunar and lacunar ischemic strokes. METHODS: We studied 820 consecutive patients with transient ischemic attack or ischemic stroke in the anterior circulation who underwent multidetector computed tomography angiography and had no rare cause of stroke. The presence of likely cardioembolic pathogenesis was determined according to the Trial of Org 10172 in Acute Stroke Treatment criteria. The remaining 708 patients were categorized as nonlacunar or lacunar strokes, either transient ischemic attacks or strokes, based on clinical symptoms corrected by brain imaging results. We measured volume of calcifications in the aortic arch, symptomatic extracranial and intracranial carotid artery using multidetector computed tomography angiography. The difference in calcifications between nonlacunar and lacunar strokes was assessed with a multivariable logistic regression analysis. We adjusted for degree of symptomatic carotid artery stenosis and cardiovascular risk factors. RESULTS: We found an independent association between volume of aortic arch calcifications and nonlacunar ischemic strokes (adjusted odds ratio [95% confidence interval], 1.11 [1.02-1.21]). No independent associations between extracranial and intracranial carotid artery calcifications and nonlacunar strokes were present. CONCLUSIONS: The only difference we found between nonlacunar and lacunar strokes was a higher calcification volume in the aortic arch in nonlacunar strokes. Our findings only partially confirm the notion of distinct etiologies and suggest that the potential role of other plaque components, plaque morphology, and aortic arch calcifications in ischemic stroke subtypes awaits further evaluation.

Recognition memory impairments after subcortical white matter stroke in mice.

BACKGROUND AND PURPOSE: Small subcortical white matter infarcts are a common stroke subtype often associated with cognitive deficits. The lack of relevant models confined to white matter has limited the investigation of its pathophysiology. Here, we examine tissue and functional outcome after an ischemic lesion within corpus callosum in wild-type (WT) mice and in mice null for a gene, NOTCH3, linked to white matter ischemic injury in patients. METHODS: WT and NOTCH3 knockout mice were subjected to stereotactic microinjections of the potent vasoconstrictor endothelin-1 at the level of periventricular white matter to induce a focal ischemic lesion. Infarct location was confirmed by MRI, and brains were examined for lesion size and histology; behavioral deficits were assessed ≤1 month in WT mice. RESULTS: Ischemic damage featured an early cerebral blood flow deficit, blood-brain barrier opening, and a lesion largely confined to white matter. At later stages, myelin and axonal degeneration and microglial/macrophage infiltration were found. WT mice displayed prolonged cognitive deficit when tested using a novel object recognition task. NOTCH3 mutants showed larger infarcts and greater cognitive deficit at 7 days post stroke. CONCLUSIONS: Taken together, these data show the usefulness of microinjections of endothelin-1 into periventricular white matter to study focal infarcts and cognitive deficit in WT mice. In short-term studies, stroke outcome was worse in NOTCH3 null mice, consistent with the notion that the lack of the NOTCH3 receptor affects white matter stroke susceptibility.

Leukoaraiosis predicts cortical infarct volume after distal middle cerebral artery occlusion.

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<0.001) were independent predictors of a poor 90-day outcome (modified Rankin Scale, 3-6). 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.