IntroductionSmall vessel disease (SVD) is a common contributor to dementia. Subtle blood-brain barrier (BBB) leakage may be important in SVD-induced brain damage.MethodsWe assessed imaging, clinical variables, and cognition in patients with mild (i.e., nondisabling) ischemic lacunar or cortical stroke. We analyzed BBB leakage, interstitial fluid, and white matter integrity using multimodal tissue-specific spatial analysis around white matter hyperintensities (WMH). We assessed predictors of 1 year cognition, recurrent stroke, and dependency.ResultsIn 201 patients, median age 67 (range 34–97), BBB leakage, and interstitial fluid were higher in WMH than normal-appearing white matter; leakage in normal-appearing white matter increased with proximity to WMH (P < .0001), with WMH severity (P = .033), age (P = .03), and hypertension (P < .0001). BBB leakage in WMH predicted declining cognition at 1 year.DiscussionBBB leakage increases in normal-appearing white matter with WMH and predicts worsening cognition. Interventions to reduce BBB leakage may prevent SVD-associated dementia.

Objective:To assess factors associated with white matter hyperintensity (WMH) change in a large cohort after observing obvious WMH shrinkage 1 year after minor stroke in several participants in a longitudinal study.Methods:We recruited participants with minor ischemic stroke and performed clinical assessments and brain MRI. At 1 year, we assessed recurrent cerebrovascular events and dependency and repeated the MRI. We assessed change in WMH volume from baseline to 1 year (normalized to percent intracranial volume [ICV]) and associations with baseline variables, clinical outcomes, and imaging parameters using multivariable analysis of covariance, model of changes, and multinomial logistic regression.Results:Among 190 participants (mean age 65.3 years, range 34.3–96.9 years, 112 [59%] male), WMH decreased in 71 participants by 1 year. At baseline, participants whose WMH decreased had similar WMH volumes but higher blood pressure (p = 0.0064) compared with participants whose WMH increased. At 1 year, participants with WMH decrease (expressed as percent ICV) had larger reductions in blood pressure (β = 0.0053, 95% confidence interval [CI] 0.00099–0.0097 fewer WMH per 1–mm Hg decrease, p = 0.017) and in mean diffusivity in normal-appearing white matter (β = 0.075, 95% CI 0.0025–0.15 fewer WMH per 1-unit mean diffusivity decrease, p = 0.043) than participants with WMH increase; those with WMH increase experienced more recurrent cerebrovascular events (32%, vs 16% with WMH decrease, β = 0.27, 95% CI 0.047–0.50 more WMH per event, p = 0.018).Conclusions:Some WMH may regress after minor stroke, with potentially better clinical and brain tissue outcomes. The role of risk factor control requires verification. Interstitial fluid alterations may account for some WMH reversibility, offering potential intervention targets.

CT and MR perfusion imaging viability thresholds in stroke are derived from small numbers of patients, variable perfusion analysis methods and definitions of tissue states. Greater consistency of methods would help determine reliable perfusion viability values for wider clinical use of perfusion imaging.

White matter hyperintensities accumulate with age and occur in patients with stroke, but their pathogenesis is poorly understood. We measured multiple magnetic resonance imaging biomarkers of tissue integrity in normal-appearing white matter and white matter hyperintensities in patients with mild stroke, to improve understanding of white matter hyperintensities origins. We classified white matter into white matter hyperintensities and normal-appearing white matter and measured fractional anisotropy, mean diffusivity, water content (T1-relaxation time) and blood-brain barrier leakage (signal enhancement slope from dynamic contrast-enhanced magnetic resonance imaging). We studied the effects of age, white matter hyperintensities burden (Fazekas score) and vascular risk factors on each biomarker, in normalappearing white matter and white matter hyperintensities, and performed receiver-operator characteristic curve analysis. Amongst 204 patients (34.3-90.9 years), all biomarkers differed between normal-appearing white matter and white matter hyperintensities (P < 0.001). In normal-appearing white matter and white matter hyperintensities, mean diffusivity and T1 increased with age (P < 0.001), all biomarkers varied with white matter hyperintensities burden (P < 0.001; P ¼ 0.02 signal enhancement slope), but only signal enhancement slope increased with hypertension (P ¼ 0.028). Fractional anisotropy showed complex age-white matter hyperintensities-tissue interactions; enhancement slope showed white matter hyperintensities-tissue interactions. Mean diffusivity distinguished white matter hyperintensities from normal-appearing white matter best at all ages. Blood-brain barrier leakage increases with hypertension and white matter hyperintensities burden at all ages in normal-appearing white matter and white matter hyperintensities, whereas water mobility and content increase as tissue damage accrues, suggesting that blood-brain barrier leakage mediates small vessel disease-related brain damage.

Background and Purpose Increased blood-brain barrier (BBB) permeability occurs in cerebral small vessel disease (SVD). It is not known if BBB changes predate progression of SVD. Methods We followed up patients with non-disabling lacunar or cortical stroke and BBB permeability MR imaging following their original stroke. About three years later, we assessed functional outcome (Oxford Handicap Score, OHS, poor outcome defined as 3-6), recurrent neurological events and white matter hyperintensity (WMH) progression on MRI. Results Amongst 70 patients, mean age 68 (SD±11) years, median time to clinical follow up was 39 months (IQR 30-45), median OHS was 2 (IQR 1-3); poor functional outcome was associated with higher baseline WMH score (p<0.001) and increased basal ganglia BBB permeability (p=0.046). Amongst 48 patients with follow-up MRI, WMH progression at follow-up was associated with baseline WMH (ANCOVA p<0.0001) and age (ANCOVA p=0.032). Conclusions Further long term studies to evaluate the role of BBB dysfunction in progression of SVD are required in studies that are large enough to account for key prognostic influences such as baseline WMH and age.

ObjectiveMagnetic resonance (MR) diffusion-weighted imaging (DWI) is sensitive to small acute ischemic lesions and might help diagnose transient ischemic attack (TIA). Reclassification of patients with TIA and a DWI lesion as “stroke” is under consideration. We assessed DWI positivity in TIA and implications for reclassification as stroke.MethodsWe searched multiple sources, without language restriction, from January 1995 to July 2012. We used PRISMA guidelines, and included studies that provided data on patients presenting with suspected TIA who underwent MR DWI and reported the proportion with an acute DWI lesion. We performed univariate random effects meta-analysis to determine DWI positive rates and influencing factors.ResultsWe included 47 papers and 9,078 patients (range = 18–1,693). Diagnosis was by a stroke specialist in 26 of 47 studies (55%); all studies excluded TIA mimics. The pooled proportion of TIA patients with an acute DWI lesion was 34.3% (95% confidence interval [CI] = 30.5–38.4, range = 9–67%; I2 = 89.3%). Larger studies (n > 200) had lower DWI-positive rates (29%; 95% CI = 23.2–34.6) than smaller (n < 50) studies (40.1%; 95% CI = 33.5–46.6%; p = 0.035), but no other testable factors, including clinician speciality and time to scanning, reduced or explained the 7-fold DWI-positive variation.InterpretationThe commonest DWI finding in patients with definite TIA is a negative scan. Available data do not explain why ⅔ of patients with definite specialist-confirmed TIA have negative DWI findings. Until these factors are better understood, reclassifying DWI-positive TIAs as strokes is likely to increase variance in estimates of global stroke and TIA burden of disease. ANN NEUROL 2014;75:67–76

RationaleCerebral small vessel disease (SVD) is common in ageing and patients with dementia and stroke. Its manifestations on magnetic resonance imaging (MRI) include white matter hyperintensities, lacunes, microbleeds, perivascular spaces, small subcortical infarcts, and brain atrophy. Many studies focus only on one of these manifestations. A protocol for the differential assessment of all these features is, therefore, needed.AimsTo identify ways of quantifying imaging markers in research of patients with SVD and operationalize the recommendations from the STandards for ReportIng Vascular changes on nEuroimaging guidelines. Here, we report the rationale, design, and methodology of a brain image analysis protocol based on our experience from observational longitudinal studies of patients with nondisabling stroke.DesignThe MRI analysis protocol is designed to provide quantitative and qualitative measures of disease evolution including: acute and old stroke lesions, lacunes, tissue loss due to stroke, perivascular spaces, microbleeds, macrohemorrhages, iron deposition in basal ganglia, substantia nigra and brain stem, brain atrophy, and white matter hyperintensities, with the latter separated into intense and less intense. Quantitative measures of tissue integrity such as diffusion fractional anisotropy, mean diffusivity, and the longitudinal relaxation time are assessed in regions of interest manually placed in anatomically and functionally relevant locations, and in others derived from feature extraction pipelines and tissue segmentation methods. Morphological changes that relate to cognitive deficits after stroke, analyzed through shape models of subcortical structures, complete the multiparametric image analysis protocol.OutcomesFinal outcomes include guidance for identifying ways to minimize bias and confounds in the assessment of SVD and stroke imaging biomarkers. It is intended that this information will inform the design of studies to examine the underlying pathophysiology of SVD and stroke, and to provide reliable, quantitative outcomes in trials of new therapies and preventative strategies.

Background and Purpose-The etiology of cerebral small vessel disease is unknown. An association with endothelial dysfunction has been suggested. We systematically assessed all relevant studies of dynamic endothelial function in patients with lacunar stroke as a marker of small vessel disease. Methods-We searched for studies of cerebral or peripheral vascular reactivity in patients with lacunar or cortical (ie, large artery atheromatous) ischemic stroke or nonstroke control subjects. We calculated standardized mean difference (SMD) in vascular reactivityϮ95% CIs between small vessel disease and control groups. Results-Sixteen publications (974 patients) were included. In lacunar stroke, cerebrovascular reactivity (nϭ534) was reduced compared with age-matched normal (SMD Ϫ0.94, 95% CI Ϫ1.17 to Ϫ0.70), but not ageϩrisk factor-matched control subjects (SMD 0.08, 95% CI Ϫ0.36 to 0.53) or cortical strokes (SMD Ϫ0.29, 95% CI Ϫ0.69 to 0.11); forearm flow-mediated dilatation (nϭ401) was reduced compared with age-matched normal control subjects (SMD Ϫ1.04, 95% CI Ϫ1.33 to Ϫ0.75) and ageϩrisk factor-matched control subjects (SMD Ϫ0.94, 95% CI Ϫ1.26 to Ϫ0.61), but not cortical strokes (SMD Ϫ0.23, 95% CI Ϫ0.55 to 0.08). Conclusions-Endothelial dysfunction is present in patients with lacunar stroke but may simply reflect exposure to vascular risk factors and having a stroke, because a similar degree of dysfunction is found in cortical (large artery atheromatous) stroke. Current data do not confirm that endothelial dysfunction is specific to small vessel stroke. Future studies should include control subjects with nonlacunar stroke. (Stroke. 2010;41:e434-e442.)