Allison Kanakis

White matter hyperintensity volume is increased in small vessel stroke subtypes.

Objective: White matter hyperintensity (WMH) may be a marker of an underlying cerebral microangiopathy. Therefore, we hypothesized that WMH would be most severe in patients with lacunar stroke and intracerebral hemorrhage (ICH), 2 types of stroke in which cerebral small vessel (SV) changes are pathophysiologically relevant. Methods: We determined WMH volume (WMHV) in cohorts of prospectively ascertained patients with acute ischemic stroke (AIS) (Massachusetts General Hospital [MGH], n = 628, and the Ischemic Stroke Genetics Study [ISGS], n = 263) and ICH (MGH, n = 122). Results: Median WMHV was 7.5 cm3 (interquartile range 3.4–14.7 cm3) in the MGH AIS cohort (mean age 65 ± 15 years). MGH patients with larger WMHV were more likely to have lacunar stroke compared with cardioembolic (odds ratio [OR] = 1.87 per SD normally transformed WMHV), large artery (OR = 2.25), undetermined (OR = 1.87), or other (OR = 1.85) stroke subtypes (p < 0.03). These associations were replicated in the ISGS cohort (p = 0.03). In a separate analysis, greater WMHV was seen in ICH compared with lacunar stroke (OR = 1.2, p < 0.02) and in ICH compared with all ischemic stroke subtypes combined (OR = 1.34, p < 0.007). Conclusions: Greater WMH burden was associated with SV stroke compared with other ischemic stroke subtypes and, even more strongly, with ICH. These data, from 2 independent samples, support the model that increasing WMHV is a marker of more severe cerebral SV disease and provide further evidence for links between the biology of WMH and SV stroke.

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.

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.

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.

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.

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.

Severity of Leukoaraiosis in Large Vessel Atherosclerotic Disease

BACKGROUND AND PURPOSE: The severity of white matter hyperintensity, or leukoaraiosis, is a marker of cerebrovascular disease. In stroke, WMH burden is strongly linked to lacunar infarction; however, impaired cerebral perfusion due to extracranial or intracranial atherosclerosis may also contribute to WMH burden. We sought to determine whether WMH burden is associated with extracranial or intracranial stenosis in patients with AIS. MATERIALS AND METHODS: Patients with AIS with admission head/neck CTA and brain MR imaging were included in this analysis. “Extracranial stenosis” was defined as >50% stenosis in the extracranial ICA, and “intracranial,” as >50% stenosis in either the middle, anterior, or posterior cerebral arteries on CTA, on either side. WMHV was determined by using a validated semiautomated protocol. Multiple regression was used to assess the relationship between WMHV and extracranial/intracranial atherosclerosis. RESULTS: Of 201 subjects, 51 (25.4%) had extracranial and 63 (31.5%) had intracranial stenosis. Mean age was 62 ± 15 years; 36% were women. Mean WMHV was 12.87 cm3 in the extracranial and 8.59 cm3 in the intracranial stenosis groups. In univariate analysis, age (P < .0001), SBP and DBP (P = .004), and HTN (P = .0003) were associated with WMHV. Extracranial stenosis was associated with greater WMHV after adjustment for intracranial stenosis (P = .04). In multivariate analysis including extracranial stenosis, only age (P < .0001) and HTN (P = .03) demonstrated independent effects on WMHV. CONCLUSIONS: In our cohort of patients with AIS, age and HTN were the strongest determinants of the WMHV severity. Future studies are warranted to unravel further association between WMHV and cerebral vessel atherosclerosis.

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.

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 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 cm3 (interquartile range 1.8–4.0). Age (β 0.02, p = 0.008) and history of stroke (β 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.