Qualitative evaluation of enabling factors and barriers to the success and sustainability of national public health institutes in Cambodia, Colombia, Liberia, Mozambique, Nigeria, Rwanda and Zambia.

OBJECTIVES: The success of National Public Health Institutes (NPHIs) in low-income and middle-income countries (LMICs) is critical to countries' ability to deliver public health services to their populations and effectively respond to public health emergencies. However, empirical data are limited on factors that promote or are barriers to the sustainability of NPHIs. This evaluation explored stakeholders' perceptions about enabling factors and barriers to the success and sustainability of NPHIs in seven countries where the U.S. Centers for Disease Control and Prevention (CDC) has supported NPHI development and strengthening. DESIGN: Qualitative study. SETTING: Cambodia, Colombia, Liberia, Mozambique, Nigeria, Rwanda and Zambia. PARTICIPANTS: NPHI staff, non-NPHI government staff, and non-governmental and international organisation staff. METHODS: We conducted semistructured, in-person interviews at a location chosen by the participants in the seven countries. We analysed data using a directed content analysis approach. RESULTS: We interviewed 43 NPHI staff, 29 non-NPHI government staff and 24 staff from non-governmental and international organisations. Participants identified five enabling factors critical to the success and sustainability of NPHIs: (1) strong leadership, (2) financial autonomy, (3) political commitment and country ownership, (4) strengthening capacity of NPHI staff and (5) forming strategic partnerships. Three themes emerged related to major barriers or threats to the sustainability of NPHIs: (1) reliance on partner funding to maintain key activities, (2) changes in NPHI leadership and (3) staff attrition and turnover. CONCLUSIONS: Our findings contribute to the scant literature on sustainability of NPHIs in LMICs by identifying essential components of sustainability and types of support needed from various stakeholders. Integrating these components into each step of NPHI development and ensuring sufficient support will be critical to strengthening public health systems and safeguarding their continuity. Our findings offer potential approaches for country leadership to direct efforts to strengthen and sustain NPHIs.

Stakeholders' assessment of US Centers for Disease Control and Prevention's contributions to the development of National Public Health Institutes in seven countries.

National Public Health Institutes (NPHIs) can strengthen countries' public health capacities to prevent, detect, and respond to public health emergencies. This qualitative evaluation assessed the role of the US Centers for Disease Control and Prevention (CDC) in NPHI development and strengthening of public health functions. We interviewed NPHI staff (N = 43), non-NPHI government staff (N = 29), and non-governmental organization staff (N = 24) in seven countries where CDC has supported NPHI development: Cambodia, Colombia, Liberia, Mozambique, Nigeria, Rwanda, and Zambia. Participants identified four areas of support that were the most important: workforce capacity building, technical assistance for key public health functions, identifying institutional gaps and priorities, and funding to support countries' priorities. Participants underscored the need for capacity building directed toward country-driven priorities during planning and implementation. Continued support for NPHI development from CDC and other partners is vital to building stronger public health systems, improving population health, and strengthening global health security.

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.

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.

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 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.

Genome-wide meta-analysis of cerebral white matter hyperintensities in patients with stroke.

OBJECTIVE: For 3,670 stroke patients from the United Kingdom, United States, Australia, Belgium, and Italy, we performed a genome-wide meta-analysis of white matter hyperintensity volumes (WMHV) on data imputed to the 1000 Genomes reference dataset to provide insights into disease mechanisms. METHODS: We first sought to identify genetic associations with white matter hyperintensities in a stroke population, and then examined whether genetic loci previously linked to WMHV in community populations are also associated in stroke patients. Having established that genetic associations are shared between the 2 populations, we performed a meta-analysis testing which associations with WMHV in stroke-free populations are associated overall when combined with stroke populations. RESULTS: There were no associations at genome-wide significance with WMHV in stroke patients. All previously reported genome-wide significant associations with WMHV in community populations shared direction of effect in stroke patients. In a meta-analysis of the genome-wide significant and suggestive loci (p < 5 × 10(-6)) from community populations (15 single nucleotide polymorphisms in total) and from stroke patients, 6 independent loci were associated with WMHV in both populations. Four of these are novel associations at the genome-wide level (rs72934505 [NBEAL1], p = 2.2 × 10(-8); rs941898 [EVL], p = 4.0 × 10(-8); rs962888 [C1QL1], p = 1.1 × 10(-8); rs9515201 [COL4A2], p = 6.9 × 10(-9)). CONCLUSIONS: Genetic associations with WMHV are shared in otherwise healthy individuals and patients with stroke, indicating common genetic susceptibility in cerebral small vessel disease.

FLAIR Vascular Hyperintensity is a Surrogate of Collateral Flow and Leukoaraiosis in Patients With Acute Stroke Due to Proximal Artery Occlusion.

BACKGROUND: Fluid attenuated inversion recovery (FLAIR) vascular hyperintensity (FVH) is a novel radiographic marker detected in acute ischemic stroke (AIS) patients, which is linked to slow blood flow and potentially salvageable brain tissue. Poor leptomeningeal collateral status in AIS patients with proximal artery occlusion (PAO) is associated with larger final infarct and worse clinical outcomes, which are also affected by severity of white matter hyperintensity (WMH). We sought to evaluate FVH utility as a marker of acute collateral vessel status and its association with WMH burden in AIS patients. METHODS: Consecutive AIS patients with PAO on baseline CT angiography (CTA) were retrospectively selected from a prospectively derived database. FVH was graded by its location, degree, and score on admission MRI obtained immediately after intravenous tissue plasminogen activator administration. Leptomeningeal collateral flow grade was ranked on admission CTA. WMH volume (WMHV) was assessed using a validated volumetric protocol. Relationship between FVH, collateral flow grade, and WMHV were analyzed. RESULTS: Among 39 patients (mean age 70.5 ± 12.7 years; 56% women, mean National Institutes of Health Stroke Scale score 17.2 (± 4.4)), median WMHV was 6.0 cm(3). FVH score and collateral flow grade were significantly correlated (Spearman's ρ = .41, P = .009). In a univariate regression model, FVH degree was inversely associated with WMHV (ß = -.33, P = .04). CONCLUSIONS: FVH score detected on acute MRI can be used as a surrogate of collateral flow grade in AIS patients. FVH degree is inversely associated with WMHV, possibly signifying diffuse disease of cerebral vasculature in patients with severe leukoaraiosis.

Role of Acute Lesion Topography in Initial Ischemic Stroke Severity and Long-Term Functional Outcomes.

BACKGROUND AND PURPOSE: Acute infarct volume, often proposed as a biomarker for evaluating novel interventions for acute ischemic stroke, correlates only moderately with traditional clinical end points, such as the modified Rankin Scale. We hypothesized that the topography of acute stroke lesions on diffusion-weighted magnetic resonance imaging may provide further information with regard to presenting stroke severity and long-term functional outcomes. METHODS: Data from a prospective stroke repository were limited to acute ischemic stroke subjects with magnetic resonance imaging completed within 48 hours from last known well, admission NIH Stroke Scale (NIHSS), and 3-to-6 months modified Rankin Scale scores. Using voxel-based lesion symptom mapping techniques, including age, sex, and diffusion-weighted magnetic resonance imaging lesion volume as covariates, statistical maps were calculated to determine the significance of lesion location for clinical outcome and admission stroke severity. RESULTS: Four hundred ninety subjects were analyzed. Acute stroke lesions in the left hemisphere were associated with more severe NIHSS at admission and poor modified Rankin Scale at 3 to 6 months. Specifically, injury to white matter (corona radiata, internal and external capsules, superior longitudinal fasciculus, and uncinate fasciculus), postcentral gyrus, putamen, and operculum were implicated in poor modified Rankin Scale. More severe NIHSS involved these regions, as well as the amygdala, caudate, pallidum, inferior frontal gyrus, insula, and precentral gyrus. CONCLUSIONS: Acute lesion topography provides important insights into anatomic correlates of admission stroke severity and poststroke outcomes. Future models that account for infarct location in addition to diffusion-weighted magnetic resonance imaging volume may improve stroke outcome prediction and identify patients likely to benefit from aggressive acute intervention and personalized rehabilitation strategies.

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.

Genetic architecture of white matter hyperintensities differs in hypertensive and nonhypertensive ischemic stroke.

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.

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.

Severity of leukoaraiosis, leptomeningeal collaterals, and clinical outcomes after intra-arterial therapy in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: Leukoaraiosis (LA) is defined as ischemic white matter lesions associated with increased stroke risk and poor post-stroke outcomes. These lesions are likely the result of diffuse angiopathic changes affecting the cerebral small vessels. We investigated whether pre-existing LA burden is associated with outcomes in patients with large cerebral artery occlusion undergoing intra-arterial therapy (IAT) for acute ischemic stroke (AIS). METHODS: We analyzed consecutive AIS subjects undergoing IAT from the institutional Get With The Guidelines-Stroke database enrolled between January 1, 2007 and June 30, 2009, who had National Institutes of Health Stroke Scale scores of ≥ 8, baseline diffusion weighted imaging volume ≤ 100 mL, and evidence of proximal artery occlusion (PAO) on pre-IAT computed tomography angiography (CTA). LA volume (LAv) was assessed on fluid attenuated inversion recovery MRI using a validated semi-automated protocol. We used CTA for collateral grade, post-IAT angiogram for recanalization status (Thrombolysis in Cerebral Infarction score ≥ 2b), and the 24 h head CT for symptomatic intracranial hemorrhage. Logistic regression was used to determine independent predictors of 90 day post-stroke good functional outcome (modified Rankin Scale score ≤ 2) and mortality. RESULTS: Increasing LAv independently reduced the odds of good collateral grade (OR 0.85, 95% CI 0.73 to 0.98). Good functional outcome was independently predicted by intravenous tissue plasminogen activator use (OR 12.86, 95% CI 2.20 to 76.28), and recanalization status (OR 6.94, 95% CI 1.56 to 30.86). Mortality was independently associated with recanalization status (OR 0.08, 95% CI 0.01 to 0.51), age (OR 1.08, 95% CI 1.01 to 1.15), and antecedent use of hypoglycemic agents (OR 6.55, 95% CI 1.58 to 54.01). CONCLUSIONS: Severity of LA is linked to poor collateral grade in AIS patients undergoing IAT for PAO; however, greater LAv appears not to be a contraindication for acute intervention.

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.

Determinants of early outcomes in patients with acute ischemic stroke and proximal artery occlusion.

BACKGROUND: Proximal artery occlusions (PAO) recanalize in only a small percentage of acute ischemic stroke (AIS) patients treated with intravenous tissue plasminogen activator (IV tPA) alone, yet the benefits of adjunctive or substitutive intra-arterial therapy (IAT) in this patient subgroup are not well established. We evaluated early poststroke outcomes in a cohort of AIS patients with PAO categorized as "likely to benefit" (LTB) from IAT using prespecified criteria. METHODS: Using a prespecified protocol, 193 patients from our institutional stroke database admitted between January 1, 2007, and December 31, 2011, were prospectively deemed LTB from IAT. Logistic regression was used to determine independent predictors of favorable (discharge to home or acute rehabilitation) versus unfavorable (discharge to skilled nursing facility, hospice, or in-hospital mortality) outcome. RESULTS: Of the patients included, 29.5% received IV tPA only, 11.4% underwent IAT only, and 37.8% had both. Overall in-hospital mortality was 19.2%. In a univariate analysis, age (odds ratio [OR], .95; 95% confidence interval [CI], .93-.98), IV tPA (OR, 2.3; 95% CI, 1.2-4.3), and history of atrial fibrillation (OR, .5; 95% CI, .28-.97) were associated with outcome. Effect of IAT was not statistically significant (OR, 1.3; 95% CI, .7-2.3; P = .4). In multivariate analysis, the only independent predictor of favorable outcome was IV tPA administration (OR, 2.4; 95% CI, 1.2-5.0). The odds of favorable poststroke outcome were significantly lowered (OR, .3; 95% CI, .1-.6; P = .0006) in those receiving neither IV tPA nor IAT. CONCLUSIONS: In AIS patients with PAO thought most likely to benefit from IAT, IV tPA independently predicted favorable outcomes. These data reinforce the recommendation to provide early IV tPA to all eligible patients.

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.

17q25 Locus is associated with white matter hyperintensity volume in ischemic stroke, but not with lacunar stroke status.

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.

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/.

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.

White matter hyperintensity burden and susceptibility to cerebral ischemia.

BACKGROUND AND PURPOSE: White matter hyperintensity (WMH) burden increases risk of ischemic stroke; furthermore, it predicts infarct growth in acute cerebral ischemia. We hypothesized that WMH would be less severe in patients with TIA as compared to those with acute ischemic stroke and completed infarct. METHODS: Cases (TIA, n = 30) and controls (acute ischemic stroke, n = 120) were selected from an ongoing longitudinal cohort study of patients with stroke and matched for age, gender, and race/ethnicity. All subjects had brain MRI within 48 hours of presentation to evaluate for evidence of acute cerebral ischemia. WMH burden on MRI was quantified using a validated computer-assisted program with high inter-rater reliability. RESULTS: Median WMH volume in individuals with TIA was 3.7 cm³ (interquartile range, 1.5 - 8.33 cm³) compared to 6.9 cm³ (interquartile range, 3.1-11.9 cm³) in acute ischemic stroke (P < 0.04). In multivariable analysis, the odds of completed infarct were higher (OR, 2.19; 95% CI, 1.27-3.77; P < 0.005) in subjects with larger volumes of WMH. CONCLUSIONS: WMH burden was significantly less in subjects with TIA as opposed to those with ischemic stroke. These data provide further evidence to support a detrimental role of WMH burden on the capacity of cerebral tissue to survive acute ischemia.