Objective White matter hyperintensities (WMH) detectable by magnetic resonance imaging (MRI)are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMH are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified. Methods We performed a meta-analysis of genome-wide association studies (GWAS) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts. Results We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs)in one locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (Pdiscovery= 4.0×10−9; Preplication =1.3×10−7; Pcombined =4.0×10−15). Other SNPs in this region also reaching genome-wide significance are rs9894383 (P=5.3×10−9), rs11869977 (P=5.7×10−9), rs936393 (P=6.8×10−9), rs3744017 (P=7.3×10−9), and rs1055129 (P=4.1×10−8). Variant alleles at these loci conferred a small increase in WMH burden (4–8% of the overall mean WMH burden in the sample). Interpretation This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.

Both atrophic and ischemic imaging changes were driven by altered glycemic and blood pressure control beginning in midlife.

In sedated, unparalyzed children, the narrowest portions of the larynx are the glottic opening (vocal cord level) and the immediate sub-vocal cord level, and there is no change in the relationships of these dimensions relative to cricoid dimensions throughout childhood.

Background and Purpose-Blood pressure (BP) is a predictor of concurrent and subsequently measured white-matter hyperintensity (WMH), but longitudinal studies of WMH changes and data in black participants are lacking. We hypothesized that WMH progression would be (1) strongly related to BP in blacks and whites and (2) predicted more strongly by earlier (midlife) or cumulative BP measurements than by measures at older ages. Methods-Participants were 983 individuals (49% black) from the Atherosclerosis Risk in Communities (ARIC) Study who underwent cerebral magnetic resonance imaging in 1993-1995 and 2004 -2006. Associations between BP (measured at each of 5 visits, in addition to a time-averaged cumulative BP) and progression of WMHs were analyzed and compared. Results-Cumulative systolic BP (SBP) was the strongest BP predictor of WMH progression in adjusted models. Higher cumulative SBP (by 20 mm Hg) was associated with greater progression of WMHs and was similar in blacks (2.5 cm 3 , PϽ0.0001) and whites (2.6 cm 3 , PϽ0.0001). Higher cumulative SBP (per 20 mm Hg) was also associated with being in the top quintile of WMH progression (adjusted odds ratioϭ2.0; 95% CI, 1.6 to 2.6). Earlier SBP measurements were stronger predictors of WMH progression than were later SBP measurements, but in blacks only. Conclusions-In this population-based cohort, cumulative SBP was a stronger predictor of WMH progression than SBP from individual visits, in both blacks and whites. Earlier BPs were stronger predictors than BPs measured at later time points in blacks only. (Stroke. 2010;41:3-8.)

Background and Purpose Immune responses to brain antigens occur after stroke, and experimental studies show that the likelihood of developing a detrimental autoimmune response to these antigens is increased by systemic inflammation at the time of stroke. The aim of this study was to determine if patients who developed infection in the post-stroke period would be similarly predisposed to develop autoimmune responses to central nervous system (CNS) antigens. Methods We enrolled 114 patients within 72 hours of ischemic stroke. Clinical and demographic data were obtained, and cellular immune responses to a panel of CNS antigens were assessed during the initial week and again at day 90. Outcome was assessed using the modified Rankin Scale. Results Patients who developed an infection, especially pneumonia, in the 15 days after stroke were more likely to evidence a TH1(+) response to myelin basic protein (MBP) and glial fibrillary acidic protein (P=0.019 and P=0.039, respectively) at 90 days after stroke. Further, more robust TH1 responses to MBP at 90 days were associated with a decreased likelihood of good outcome, even after adjusting for baseline stroke severity and patient age (Odds Ratio = 0.477, 95% CI = 0.244–0.935; P=0.031). Conclusion This study demonstrates that immune responses to brain antigens occur after stroke. And while these responses are likely to be an epiphenomenon of ischemic brain injury, the response to MBP appears to have clinical consequences. The potential role of post-ischemic autoimmune mediated brain injury deserves further investigation.

Silent brain infarct and white matter lesions are common radiological findings associated with the risk of clinical stroke and dementia; however, our understanding of their underlying pathophysiology and risk factors remains limited. This study aimed to determine whether assessment of retinal microvascular abnormalities could provide prognostic information regarding the risk of brain infarct and white matter lesions on magnetic resonance imaging. This study is based on a subset of 810 middle-aged persons without clinical stroke or baseline magnetic resonance imaging infarct enrolled in the Atherosclerosis Risk in Communities Brain Magnetic Resonance Imaging Study, a prospective, population-based study. Participants had a baseline magnetic resonance imaging brain examination and retinal photography in 1993-1995, and returned for a repeat magnetic resonance imaging examination in 2004-2006. Magnetic resonance images were graded for presence of any cerebral infarct, infarct with lacunar characteristics and white matter lesions according to standardized protocols. Retinal photographs were graded for presence of retinopathy lesions and retinal arteriolar abnormalities following a standardized protocol. Over a median follow-up of 10.5 years, 164 (20.2%) participants developed cerebral infarct, 131 (16.2%) developed lacunar infarct, 182 (24.2%) developed new white matter lesions and 49 (6.1%) had evidence of white matter lesion progression. After adjusting for age, gender, race, cardiovascular risk factors and carotid intima-media thickness, retinopathy was associated with incident cerebral infarct (odds ratio 2.82; 95% confidence interval 1.42-5.60) and lacunar infarct (odds ratio 3.19; 95% confidence interval: 1.56-6.50). Retinal arteriovenous nicking was associated with incident cerebral infarct (odds ratio 2.82; 95% confidence interval: 1.66-4.76), lacunar infarct (odds ratio 2.48; 95% confidence interval: 1.39-4.40) and white matter lesion incidence (odds ratio 2.12; 95% confidence interval: 1.18-3.81) and progression (odds ratio 2.22; 95% confidence interval: 1.00-5.88). In conclusion, retinal microvascular abnormalities are associated with emergence of subclinical magnetic resonance imaging brain infarcts and white matter lesions, independent of shared risk factors. Retinal vascular imaging may offer a non-invasive tool to investigate the pathogenesis and natural history of cerebral small-vessel disease.

Objective: Lacunar infarctions are mainly due to 2 microvascular pathologies: lipohyalinosis and microatheroma. Little is known about risk factor differences for these subtypes. We hypothesized that diabetes and glycated hemoglobin (HbA 1 c) would be related preferentially to the lipohyalinotic subtype.Methods: We performed a cross-section analysis of the brain MRI data from 1,827 participants in the Atherosclerosis Risk in Communities study. We divided subcortical lesions Յ20 mm in diameter into those Յ7 mm (of probable lipohyalinotic etiology) and 8-20 mm (probably due to microatheroma) and used Poisson regression to investigate associations with the number of each type of lesion. Unlike previous studies, we also fitted a model involving lesions Ͻ3 mm.Results: Age (prevalence ratio [PR] 1.11 per year; 95% confidence interval [CI] 1.08-1.14), black ethnicity (vs white, PR 1.66; 95% CI 1.27-2.16), hypertension (PR 2.12; 95% CI 1.61-2.79), diabetes (PR 1.42; 95% CI 1.08-1.87), and ever-smoking (PR 1.34; 95% CI 1.04-1.74) were significantly associated with lesions Յ7 mm. Findings were similar for lesions Ͻ3 mm. HbA 1 c, substituted for diabetes, was also associated with smaller lesions. Significantly associated with 8-20 mm lesions were age (PR 1.14; 95% CI 1.09-1.20), hypertension (PR 1.79; 95% CI 1.14-2.83), ever-smoking (PR 2.66; 95% CI 1.63-4.34), and low-density lipoprotein (LDL) cholesterol (PR 1.27 per SD; 95% CI 1.06-1.52). When we analyzed only participants with lesions, history of smoking (PR 1.99; 95% CI 1.23-3.20) and LDL (PR 1.33 per SD; 95% CI 1.08-1.65) were associated with lesions 8-20 mm. Conclusions:Smaller lacunes (even those Ͻ3 mm) were associated with diabetes and HbA 1 c, and larger lacunes associated with LDL cholesterol, differences which support long-held theories relating to their underlying pathology. The findings may contribute to broader understanding of cerebral microvascular disease. Neurology Lacunar infarcts are small CSF-filled cavities caused by the occlusion of small arteries in the brain. When symptomatic, they may be evident as lacunar strokes. The pathogenesis of lacunes has not been fully clarified, and there is pathologic and clinical evidence of distinct types of lacunar entities. 2-4 Fisher described 2 main vascular culprit lesions: 1) lipohyalinosis, usually with 1 or more small lacunar infarcts (up to 7 mm) and rare symptoms; and 2) microatheromata, usually linked to larger (5-20 mm), more often symptomatic lacunes. 4,5 This pathologic distinction remains unchallenged. Although contemporary authors describe several types of small-vessel disease associated with lacunes, 5-7 we will, for convenience,

Background and Purpose-Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods-Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed crosssectional genome-wide association analysis of MRI infarct using age-and sex-adjusted logistic regression models. 2 Although the majority of these MRI infarcts do not produce acute clinical symptoms leading to a diagnosis of stroke, they cannot be considered benign, silent, or asymptomatic, because they are associated with an increased risk for cognitive deficits, motor impairments, and future stroke. 2 The pathogenesis of these covert brain infarcts remains poorly understood.Whereas several monogenic disorders are known to cause brain infarcts, the genes underlying brain infarcts in the general population remain undetermined. 3 A genetic component is suggested by increased risk of covert MRI infarcts among individuals whose parents or siblings have experienced clinically overt infarcts. 4,5 Previous candidate gene studies of covert MRI infarcts have yielded inconsistent findings. Genome-wide association studies (GWAS) of MRI infarcts are lacking and would permit an unbiased search for genetic variants associated with this phenotype, without relying on a priori hypotheses about underlying pathophysiology. 6 To study genetics of these infarcts, we adapted an analytic approach used in a previous study 7 of stroke from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and combined GWAS from 6 prospective population-based cohort studies: the Aging GeneEnvironment Susceptibility-Reykjavik Study (AGESReykjavik); the Atherosclerosis Risk in Communities (ARIC) Study; the Austrian Stroke Prevention Study (ASPS); the Cardiovascular Health Study (CHS); the Framingham Heart Study (FHS); and the Rotterdam Study. We present results from this meta-analysis that included 9401 stroke-free white participants. Materials and Methods ConsortiumThe CHARGE consortium includes large prospective communitybased cohort studies having genome-wide variation data coupled with extensive data on multiple phenotypes. 8 All participating studies agreed on phenotype harmonization, covariate selection, prespecified analytic plans for within-study analyses, and meta-analysis of results. Each study secured approval from Institutional Review Boards, and all participants provided written informed consent for study participation, MRI scanning, and use of DNA for genetic research. SettingDetails of cohort selection, risk factor assessment, and outcome determination in the 6 studies have been reported previously (supplemental Appendix, section 1, available o...