Structural Integrity of Normal Appearing White Matter and Sex-Specific Outcomes After Acute Ischemic Stroke.

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 <2: 49.6% versus 67.0%; 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.

Antecedent Aspirin Use Is Associated with Less Severe Symptoms on Admission for Ischemic Stroke.

BACKGROUND: Aspirin is known to reduce stroke risk; however, its role in reducing severity of ischemic syndrome is not clear. We sought to investigate the relationship between antecedent aspirin use and stroke severity in patients presenting with acute ischemic stroke (AIS). METHODS: We retrospectively analyzed a prospectively collected database of consecutive AIS patients presenting to our center. Clinical characteristics (including antecedent aspirin use), imaging findings, and laboratory data were assessed in association with presenting stroke severity, as measured by the National Institutes of Health Stroke Scale (NIHSS). Logistic regression models were used to determine univariate and multivariate predictors of baseline NIHSS. RESULTS: Of the 610 AIS patients with admission brain magnetic resonance imaging available for volumetric analysis of acute infarct size, 241 (39.5%) used aspirin prior to stroke onset. Antecedent aspirin use (P = .0005), history of atrial fibrillation (P < .0001), acute infarct volume (P < .0001), initial systolic blood pressure (P = .041), admission glucose level (P = .0027), and stroke subtype (P < .0001) were associated with presenting stroke severity in univariate analysis. Antecedent aspirin use (P < .0001), history of atrial fibrillation (P < .0002), acute infarct volume (P < .0001), systolic blood pressure (P = .038), and glucose level (P = .0095) remained independent predictors of NIHSS in multivariable analysis. CONCLUSIONS: Antecedent aspirin use was independently associated with milder presenting stroke severity, even after accounting for acute infarct volume. While the underlying biology of this apparent protective relationship requires further study, patients at high risk of stroke may benefit from routine aspirin use.

Determinants of white matter hyperintensity burden differ at the extremes of ages of ischemic stroke onset.

BACKGROUND: Age is a well-known risk factor for both stroke and increased burden of white matter hyperintensity (WMH), as detected on magnetic resonance imaging (MRI) scans. However, in patients diagnosed with ischemic stroke (IS), WMH volume (WMHv) varies significantly across age groups. We sought to examine the determinants of WMH burden across the ages of stroke onset with the goal to uncover potential age-specific stroke prevention targets. METHODS: Adult subjects from an ongoing hospital-based cohort study of IS patients with admission brain MRI were categorized as having early (<55 years), late (>75 years), or average (55-75 years) age of stroke onset. WMHv was measured using a previously validated, MRI-based semi-automated method and normalized for linear regression analyses. RESULTS: Of 1008 IS subjects, 249 had early-onset stroke (24.7%), and 311 had late-onset stroke (30.9%). In multivariable analysis of WMHv using backward stepwise selection, only age (ß = .02, P = .018), hypertension (ß = .24, P = .049), and history of tobacco use (ß = .38, P = .001) were independently associated with WMHv in patients with early-onset stroke, whereas male sex (ß = -.30, P = .007), hyperlipidemia (ß = -.27, P = .015), and current alcohol use (ß = .23, P = .034) were independently associated with WMHv in patients with late-onset stroke. CONCLUSIONS: History of tobacco use is a strong independent predictor of WMH burden in patients with early-onset stroke, whereas age is no longer associated with WMHv in IS patients older than 75 years of age. These findings suggest that the major risk factors to target for stroke prevention differ across age groups and may be modifiable.

Integrity of normal-appearing white matter and functional outcomes after acute ischemic stroke.

OBJECTIVE: To characterize the effect of white matter microstructural integrity on cerebral tissue and long-term functional outcomes after acute ischemic stroke (AIS). METHODS: Consecutive AIS patients with brain MRI acquired within 48 hours of symptom onset and 90-day modified Rankin Scale (mRS) score were included. Acute infarct volume on diffusion-weighted imaging (DWIv) and white matter hyperintensity volume (WMHv) on T2 fluid-attenuated inversion recovery MRI were measured. Median fractional anisotropy (FA), mean diffusivity, radial diffusivity, and axial diffusivity values were calculated within normal-appearing white matter (NAWM) in the hemisphere contralateral to the acute lesion. Regression models were used to assess the association between diffusivity metrics and acute cerebral tissue and long-term functional outcomes in AIS. Level of significance was set at p < 0.05 for all analyses. RESULTS: Among 305 AIS patients with DWIv and mRS score, mean age was 64.4 ± 15.9 years, and 183 participants (60%) were male. Median NIH Stroke Scale (NIHSS) score was 3 (interquartile range [IQR] 1-8), and median normalized WMHv was 6.19 cm3 (IQR 3.0-12.6 cm3). Admission stroke severity (ß = 0.16, p < 0.0001) and small vessel stroke subtype (ß = -1.53, p < 0.0001), but not diffusivity metrics, were independently associated with DWIv. However, median FA in contralesional NAWM was independently associated with mRS score (ß = -9.74, p = 0.02), along with age, female sex, NIHSS score, and DWIv. CONCLUSIONS: FA decrease in NAWM contralateral to the acute infarct is associated with worse mRS category at 90 days after stroke. These data suggest that white matter integrity may contribute to functional recovery after stroke.

Determinants of white matter hyperintensity burden in patients with Fabry disease.

OBJECTIVE: Using a semiautomated volumetric MRI assessment method, we aimed to identify determinants of white matter hyperintensity (WMH) burden in patients with Fabry disease (FD). METHODS: Patients with confirmed FD and brain MRI available for this analysis were eligible for this protocol after written consent. Clinical characteristics were abstracted from medical records. T2 fluid-attenuated inversion recovery MRI were transferred in electronic format and analyzed for WMH volume (WMHV) using a validated, computer-assisted method. WMHV was normalized for head size (nWMHV) and natural log-transformed (lnWMHV) for univariate and multivariate linear regression analyses. Level of significance was set at p < 0.05 for all analyses. RESULTS: Of 223 patients with FD and WMHV analyzed, 132 (59%) were female. Mean age at MRI was 39.2 ± 14.9 (range 9.6-72.7) years, and 136 (61%) patients received enzyme replacement therapy prior to enrollment. Median nWMHV was 2.7 cm(3) (interquartile range 1.8-4.0). Age (ß 0.02, p = 0.008) and history of stroke (ß 1.13, p = 0.02) were independently associated with lnWMHV. However, WMH burden-as well as WMHV predictors-varied by decade of life in this cohort of patients with FD (p < 0.0001). CONCLUSIONS: In this largest-to-date cohort of patients with FD who had volumetric analysis of MRI, age and prior stroke independently predicted the burden of WMH. The 4th decade of life appears to be critical in progression of WMH burden, as novel predictors of WMHV emerged in patients aged 31-40 years. Future studies to elucidate the biology of WMH in FD and its role as potential MRI marker of disease progression are needed.

Metabolic determinants of white matter hyperintensity burden in patients with ischemic stroke.

OBJECTIVE: Increasing white matter hyperintensity (WMH) burden is linked to risk of stroke and poor post-stroke outcomes. While the biology of WMH remains ill-defined, several lines of evidence implicate endothelial dysfunction. In this study, we sought to assess the association between metabolic markers of endothelial dysfunction and WMH severity in patients with acute ischemic stroke (AIS). METHODS: In this retrospective study, consecutive subjects, ≥18 years of age, admitted to our ED with AIS, brain MRI, and blood homocysteine (Hcy) and hemoglobin A1c (HgbA1c) measurements were eligible for this analysis. WMH volume (WMHV) was quantified using a validated semi-automated algorithm and log-transformed for linear regression analyses. RESULTS: There were 809 AIS subjects included (mean age 65.57±14.7, median WMHV 6.25 cm3 (IQR 2.8-13.1)). In univariate analysis, age, female gender, race, ethnicity, systolic blood pressure, history of hypertension, atrial fibrillation, coronary artery disease, prior stroke, and current alcohol and tobacco use (all p<0.05), as well as Hcy (p<0.0001) and HgbA1c levels (p=0.0005) were associated with WMHV. However, only Hcy (ß=0.11, p=0.003) and HgbA1c levels (ß=0.1, p=0.008) independently predicted WMHV in the multivariate model, along with age (ß=0.03, p<0.0001), race (ß=0.39, p=0.01), ethnicity (ß=-0.11, p=0.03), and current alcohol use (ß=0.26, p=0.002). CONCLUSIONS: Elevated levels of Hcy and HgbA1c have been previously linked to endothelial dysfunction related to oxidative stress. The association between Hcy and HgbA1c and WMH burden in AIS suggests that the degree of endothelial dysfunction may be greater in patients with increased WMHV, and may in part explain the relationship between WMHV and poor post-stroke outcomes.

Setting a gold standard for quantification of leukoaraiosis burden in patients with ischemic stroke: the Atherosclerosis Risk in Communities Study.

BACKGROUND: Accurate and reliable measurement of leukoaraiosis, or MR-detected white, matter hyper-intensity (WMH) burden in subjects with acute ischemic stroke (AIS) is important for, ongoing research studies and future models of risk and outcome prediction, but the presence of a, cerebral infarct may complicate measurement. We sought to assess accuracy of a volumetric method, designed to measure WMH in AIS subjects as compared to the previously validated protocol. NEW METHOD: We randomly selected and equally sampled 120 brain scans from the Atherosclerosis, Risk in Communities (ARIC) MRI Study individuals within designated mild, moderate, and severe, tertiles of WMH volume (WMHV). T2 FLAIR axial images were analyzed using the AIS WMH volumetric, protocol and compared with the ARIC (gold standard) method. Pearson correlation coefficients, linear, concordance correlation coefficient, and Blant­Altman procedures were used to assess measurement, agreements between the two procedures. RESULTS: Median WMHV determined by using the ARIC method was 7.8 cm3 (IQR 5.7­13.55) vs. 3.54 cm3, (IQR 2.1­7.2) using the AIS WMH method. There was good correlation between the two measurements, (r = 0.52, 0.67, and 0.9 for tertiles 1, 2, and 3 respectively) (p < 0.001). COMPARISON WITH EXISTING METHOD: The AIS WMH protocol was specific for leukoaraiosis in ischemic, stroke, but it appeared to underestimate WMHV compared to the gold standard method. CONCLUSIONS: Estimates of MR-detectable WMH burden using a volumetric protocol designed for, analysis of clinical scans correlate strongly with gold standard measurements. These findings will, facilitate future studies of WMH in normal aging and in patients with stroke and other cerebrovascular, disease.

Segmentation of cerebrovascular pathologies in stroke patients with spatial and shape priors.

We propose and demonstrate an inference algorithm for the automatic segmentation of cerebrovascular pathologies in clinical MR images of the brain. Identifying and differentiating pathologies is important for understanding the underlying mechanisms and clinical outcomes of cerebral ischemia. Manual delineation of separate pathologies is infeasible in large studies of stroke that include thousands of patients. Unlike normal brain tissues and structures, the location and shape of the lesions vary across patients, presenting serious challenges for prior-driven segmentation. Our generative model captures spatial patterns and intensity properties associated with different cerebrovascular pathologies in stroke patients. We demonstrate the resulting segmentation algorithm on clinical images of a stroke patient cohort.

Implementation of a patient selection protocol for intra-arterial therapy increases treatment rates in patients with acute ischemic stroke.

BACKGROUND: Strategies for patient selection for intra-arterial therapy (IAT) in acute ischemic stroke (AIS) are highly variable. The degree of protocol adoption and treatment rates associated with implementation of a service-wide patient selection IAT protocol were assessed. METHODS: All patients with AIS prospectively recorded in our stroke database from January 2007 to June 2009 were reviewed. The IAT patient selection protocol was implemented in March 2008. Patients were defined as likely to benefit (LTB) from IAT if they had brain imaging completed within 6 h from last known well time, NIH Stroke Scale score ≥ 8, infarct volume ≤ 100 ml and evidence of proximal artery occlusion. RESULTS: Of 1348 subjects identified, 118 (8.7%) met the criteria for LTB and 62 (52%) underwent IAT. There was a significant increase in rates of IAT among LTB patients after protocol implementation (61% vs 40%, p<0.02). In LTB patients, factors associated with IAT were stroke duration (OR 0.78, 95% CI 0.6 to 0.9 per hour), arrival within later calendar months during study period (OR 1.1, 95% CI 1.02 to 1.2 per month), intravenous tissue plasminogen activator (OR 0.6, 95% CI 0.4 to 0.9) and age (OR 0.98, 95% CI 0.95 to 1.02 per year). After multivariable adjustment, only stroke duration (OR 0.65, 95% CI 0.5 to 0.8 per hour) remained an independent predictor of IAT. CONCLUSIONS: Most patients with AIS did not meet our criteria for LTB and only 52% of those defined as LTB received IAT. Protocol adoption increased the use of IAT over time; however, further exploration of factors associated with the reasons for non-treatment and the impact of IAT on outcomes is necessary.

Quantification and Analysis of Large Multimodal Clinical Image Studies: Application to Stroke.

We present an analysis framework for large studies of multimodal clinical quality brain image collections. Processing and analysis of such datasets is challenging due to low resolution, poor contrast, mis-aligned images, and restricted field of view. We adapt existing registration and segmentation methods and build a computational pipeline for spatial normalization and feature extraction. The resulting aligned dataset enables clinically meaningful analysis of spatial distributions of relevant anatomical features and of their evolution with age and disease progression. We demonstrate the approach on a neuroimaging study of stroke with more than 800 patients. We show that by combining data from several modalities, we can automatically segment important biomarkers such as white matter hyperintensity and characterize pathology evolution in this heterogeneous cohort. Specifically, we examine two sub-populations with different dynamics of white matter hyperintensity changes as a function of patients' age. Pipeline and analysis code is available at http://groups.csail.mit.edu/vision/medical-vision/stroke/.