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B r i e f r e p o r t4 IntroductionStroke is a leading cause of morbidity and mortality, whose prevalence increases dramatically with age. Despite its substantial heritable basis, only a small number of causative genes have so far been identified, generally for severe early-onset phenotypes (cerebral autosomal dominant or recessive arteriopathy with subcortical infarcts and leukoencephalopathy: CADASIL [NOTCH3], CARASIL [HTRA1], and porencephaly [COL4A1]) (1-3). Such cases have revealed important pathways that contribute to stroke, including the roles of Notch and TGF-β signaling.In the same way, the vascular basement membrane's contribution (COL4A1 and COL4A2) (3, 4) to juvenile stroke phenotypes further stimulated investigation of the cellular components (endothelial and mural cells) upon which brain vascular integrity depends. The demonstration that Notch signaling regulates pericyte numbers (5, 6) has in turn provided a mechanistic explanation for disorders such as CADASIL. These examples of juvenile stroke resulting from severe alterations in brain vascular development raise the intriguing possibility that milder changes contribute to late-onset disease and that a larger proportion of strokes have embryonic origins. It is therefore notable that the same genes regulate cerebral structural development and angiogenesis (7) and that the cell populations essential for cerebral vascular homeostasis (pericytes and vascular smooth muscle) are predominantly derived from the neural crest (8, 9). The increasing prevalence of stroke exerts disproportionately severe effects on the quality of life of affected individuals and their families. Consequently, phenotypes predictive of future stroke merit investigation, with the goal of developing treatments targeting causative pathways and preventing a frequently preterminal disease. One such phenotype is cerebral small-vessel disease (CSVD), which represents a major risk factor for both ischemic and hemorrhagic stroke (10-13). Characterized by perturbed perforating end-artery function, CSVD results in lesions apparent on MRI that encompass white matter hyperintensities (WMHs), dilated perivascular spaces, microbleeds, and lacunar infarcts. These markers of cerebrovascular pathology provide opportunities for gene discovery and for defining the mechanisms that contribute to subsequent stroke.Our study evaluated the hypothesis that the forkhead box transcription factor FOXC1, which patterns multiple organs including the CNS, contributes to CSVD. It was prompted by a higher incidence of self-reported stroke in some of our local pedigrees with FOXC1 mutations and supported experimentally by: (a) blood-stained hydrocephalus in murine Foxc1 -/-mutants, (b) related zebrafish foxc1 morphant phenotypes, and (c) the extenPatients with cerebral small-vessel disease (CSVD) exhibit perturbed end-artery function and have an increased risk for stroke and age-related cognitive decline. Here, we used targeted genome-wide association (GWA) analysis and defined a CSVD locus adjacent to the forkh...

Background and Purpose— Acute blood pressure (BP) reduction aimed at attenuation of intracerebral hemorrhage (ICH) expansion might also compromise cerebral blood flow (CBF). We tested the hypothesis that CBF in acute ICH patients is unaffected by BP reduction. Methods— Patients with spontaneous ICH <24 hours after onset and systolic BP > 150 mm Hg were randomly assigned to an intravenous antihypertensive treatment protocol targeting a systolic BP of <150 mm Hg (n=39) or <180 mm Hg (n=36). Patients underwent computed tomography perfusion imaging 2 hours postrandomization. The primary end point was perihematoma relative (relative CBF). Results— Treatment groups were balanced with respect to baseline systolic BP: 182±20 mm Hg (<150 mm Hg target group) versus 184±25 mm Hg (<180 mm Hg target group; P =0.60), and for hematoma volume: 25.6±30.8 versus 26.9±25.2 mL ( P =0.66). Mean systolic BP 2 hours after randomization was significantly lower in the <150 mm Hg target group (140±19 vs 162±12 mm Hg; P <0.001). Perihematoma CBF (38.7±11.9 mL/100 g per minute) was lower than in contralateral homologous regions (44.1±11.1 mL/100 g per minute; P <0.001) in all patients. The primary end point of perihematoma relative CBF in the <150 mm Hg target group (0.86±0.12) was not significantly lower than that in the <180 mm Hg group (0.89±0.09; P =0.19; absolute difference, 0.03; 95% confidence interval −0.018 to 0.078). There was no relationship between the magnitude of BP change and perihematoma relative CBF in the <150 mm Hg ( R =0.00005; 95% confidence interval, −0.001 to 0.001) or <180 mm Hg target groups ( R =0.000; 95% confidence interval, −0.001 to 0.001). Conclusions— Rapid BP lowering after a moderate volume of ICH does not reduce perihematoma CBF. These physiological data indicate that acute BP reduction does not precipitate cerebral ischemia in ICH patients. Clinical Trial Registration Information— URL: http://clinicaltrials.gov . Unique Identifier: NCT00963976.