Natural course of pain in chronic pancreatitis is independent of disease duration.

OBJECTIVES: Pain burn-out during the course of chronic pancreatitis (CP), proposed in the 1980s, remains controversial, and has clinical implications. We aimed to describe the natural course of pain in a well-characterized cohort. METHODS: We constructed the clinical course of 279 C P patients enrolled from 2000 to 2014 in the North American Pancreatitis Studies from UPMC by retrospectively reviewing their medical records (median observation period, 12.4 years). We assessed abdominal pain at different time points, characterized pain pattern (Type A [short-lived pain episodes] or B [persistent pain and/or clusters of recurrent severe pain]) and recorded information on relevant covariates. RESULTS: Pain at any time, at the end of follow-up, Type A pain pattern or B pain pattern was reported by 89.6%, 46.6%, 34% and 66% patients, respectively. In multivariable analyses, disease duration (time from first diagnosis of pancreatitis to end of observation) did not associate with pain - at last clinical contact (OR, 1.0, 95% CI 0.96-1.03), at NAPS2 enrollment (OR 1.02, 95% CI 0.96-1.07) or Type B pain pattern (OR 1.01, 95% CI 0.97-1.04). Patients needing endoscopic or surgical therapy (97.8 vs. 75.2%, p < 0.001) and those with alcohol etiology (94.7 vs. 84.9%, p = 0.007) had a higher prevalence of pain. In multivariable analyses, invasive therapy associated with Type B pain and pain at last clinical contact. CONCLUSIONS: Only a subset of CP patients achieve durable pain relief. There is urgent need to develop new strategies to evaluate and manage pain, and to identify predictors of response to pain therapies for CP.

Bone health assessment in clinical practice is infrequenty performed in patients with chronic pancreatitis.

BACKGROUND: Chronic pancreatitis (CP) patients have a high prevalence of osteoporotic fractures. In addition to prevalence of osteoporotic fractures, we evaluated how often bone health is assessed by dual-energy x-ray absorptiometry (DXA) in clinical practice, and the performance of Fracture Risk Assessment Tool (FRAX®) in predicting fracture risk in CP patients. METHODS: Medical records of CP patients age ≥40 years prospectively enrolled in the North American Pancreatitis Study 2 (NAPS2) from the University of Pittsburgh Medical Center from 2000 to 2014 were retrospectively reviewed to gather additional relevant data before, at, and after enrollment until December 2016. We determined if patients underwent DXA, compared their observed prevalence of fractures with published data from two large US studies based on administrative data, and their predicted fracture risk with US population based on FRAX®. RESULTS: Only 21% (49/239) patients were evaluated by DXA during their care. The observed cumulative prevalence of fragility fractures in NAPS2 CP patients (9.2%, 95% confidence interval 5.9-13.6) was significantly greater than in controls (1.46% and 2.16%, p ≤ 0.001 for each comparison) and CP patients (4.66%, and 5.13%, p < 0.005 for each comparison) in the two US administrative data studies. The FRAX® 10-year probability of major osteoporotic fracture of ≥20% (5.1% vs. 8.3%, p > 0.05) and for hip fracture of ≥3% (19.6% vs. 18.9%, p > 0.05) in NAPS2 CP patients did not differ from the US population. CONCLUSIONS: Despite their high risk of fragility fractures, bone health is infrequently assessed in CP patients. FRAX® may not adequately predict fracture risk in CP patients.

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.

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.

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.

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.

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.

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.

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.

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/.

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.

Determinants of white matter hyperintensity volume in patients with acute ischemic stroke.

BACKGROUND: White matter hyperintensity (WMH) is a common radiographic finding in the aging population and a potent risk factor for symptomatic cerebrovascular disease. It is unclear whether WMH represents a single or multiple biological processes. We sought to investigate the extent and determinants of WMH in patients with acute ischemic stroke (AIS). METHODS: We retrospectively analyzed a prospectively enrolled hospital-based cohort of patients with AIS. WMH volume (WMHV) was measured using a previously published method with high interrater reliability based on a semiautomated image analysis program. RESULTS: WMHV was measured in 523 consecutive patients with stroke (mean age 65.2 years, median WMHV 8.2 cm(3)). In univariate linear regression analyses, individuals who were older, had elevated homocysteine (HCY) level or systolic blood pressure, or history of hypertension (all P < .0001), decreased glomerular filtration rate (P < .0002), atrial fibrillation (P < .0008), or coronary artery disease (P < .03) had significantly greater WMHV. After multivariable adjustment, only age (P < .0001) and HCY levels greater than 9 mumol/L (P < .003) remained independently associated with WMHV. CONCLUSIONS: In patients with AIS, risk factors for WMH severity do not appear to overlap with those previously reported for population-based cohorts. Only age and higher HCY levels were independently associated with more severe WMH in patients with stroke. This suggests that some of the processes underlying WMH burden accumulation in patients with stroke may differ from those in the general population and are not simply mediated by traditional vascular risk factors.

Hyperlipidemia and reduced white matter hyperintensity volume in patients with ischemic stroke.

BACKGROUND AND PURPOSE: White matter hyperintensity (WMH), or leukoaraiosis, is a radiologic finding generally assumed to reflect diseased small cerebral vasculature. WMH has significant functional impact through its relation to cognitive decline and risk of ischemic and hemorrhagic stroke. Accumulating evidence suggests that some manifestations of small-vessel disease such as intracerebral hemorrhage are associated with low levels of cholesterol. We sought to determine the relation between hyperlipidemia and WMH severity in patients with acute ischemic stroke (AIS). METHODS: We analyzed 2 independent, hospital-based AIS cohorts. Demographic and clinical data were collected prospectively. WMH was measured using semiautomated volumetric image analysis and a semiquantitative visual grading scale. Univariate and multivariable regression analyses were used to assess the relation between WMH severity and study variables. RESULTS: A total of 631 and 504 subjects in the first and second cohorts, respectively, were included. In univariate analyses, advancing age and hypertension were associated with severity of WMH (P<0.001) in both cohorts. In the multivariable analysis, after controlling for age, sex, and significant risk factors in the univariate and age-adjusted analyses, patients with a history of hyperlipidemia had less severe WMH in both cohorts (P<0.01). CONCLUSIONS: Results from 2 independent cohorts demonstrate that AIS patients with a history of hyperlipidemia have less severe WMH at the time of stroke. These data support the hypothesis that hyperlipidemia may play a relatively protective role in cerebral small-vessel disease.