Dean Shibata

Genome-wide association studies of cerebral white matter lesion burden

White matter hyperintensities (WMHs) detectable by magnetic resonance imaging 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. WMHs 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.

Developmental changes of laryngeal dimensions in unparalyzed, sedated children.

Background Knowledge of the influence of age on laryngeal dimensions is essential for all practitioners whose interest is the pediatric airway. Early cadaver studies documented that the larynx is conically shaped, with the apex of the cone caudally positioned at the nondistensible cricoid cartilage. These dimensions change during childhood, as the larynx assumes a more cylindrical shape. The authors analyzed laryngeal dimensions during development to determine if this relationship continues in unparalyzed children in whom laryngeal muscles are tonically active. The authors determined the relationships between the vocal cord, sub–vocal cord, and cricoid ring dimensions and the influence of age on these relationships. Methods Infants and children undergoing magnetic resonance imaging with propofol sedation had determinations of the transverse and anterior–posterior (AP) dimensions of the larynx at the most cephalad level of the larynx (vocal cords) and the most caudad level (cricoid). Most patients had an additional measurement (sub–vocal cord) at a level between the vocal cords and the cricoid ring. Relationships were obtained by plotting age against laryngeal dimensions and the ratio of laryngeal dimensions at different levels within the larynx. Results The authors measured transverse and AP laryngeal dimensions in 99 children, aged 2 months–13 yr. The relationship between the transverse and AP dimensions at all levels of the larynx did not change during development. Transverse and AP dimensions increased linearly with age at all levels of the larynx. In all children studied, the narrowest portion of the larynx was the transverse dimension at the level of the vocal cords. Transverse dimensions increased linearly in a caudad direction through the larynx (P < 0.001), while AP dimensions did not change relative to laryngeal level. The shape of the cricoid ring did not change throughout childhood. Conclusions 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.

Vascular risk factors and longitudinal changes on brain MRI: The ARIC study

Objective: To evaluate associations between vascular risk factors and changes in burden of infarcts, ventricular size (VS), sulcal widening (SW), and white matter hyperintensities (WMH) in an initially middle-aged, biracial cohort from the Atherosclerosis Risk in Communities (ARIC) study. Methods: Initial brain magnetic resonance (MR) scans and evaluations for vascular risk factors were performed in 1,812 ARIC participants in 1994–1995. In 2004–2006, 1,130 ARIC participants underwent repeat MR scans. MR scans were rated using a validated 9-point scale for VS, SW, and WMH. Infarcts were recorded. Multiple logistic regression analysis was used to assess associations between vascular risk factors and change between MR scans of one or more grades in VS, SW, WMH, or appearance of new infarcts, controlling for age, sex, and race. Results: At baseline, the 1,112 participants with usable scans (385 black women, 200 black men, 304 white women, 223 white men) had a mean age of 61.7 ± 4.3 years. In adjusted models, diabetes at baseline was associated with incident infarcts (odds ratio [OR] 1.95, 95% confidence interval [CI] 1.29–2.95) and worsening SW (OR 2.10, 95% CI 1.36–3.24). Hypertension at baseline was associated with incident infarcts (OR 1.73, 95% CI 1.23–2.42). In subjects with the highest tertile of fasting blood sugar and systolic blood pressure at baseline, the risk of incident infarcts was 3.68 times higher (95% CI 1.89–7.19) than those in the lowest tertile for both. Conclusion: Both atrophic and ischemic imaging changes were driven by altered glycemic and blood pressure control beginning in midlife.

Blood Pressure and White-Matter Disease Progression in a Biethnic Cohort Atherosclerosis Risk in Communities (ARIC) Study

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 cm3, P<0.0001) and whites (2.6 cm3, P<0.0001). Higher cumulative SBP (per 20 mm Hg) was also associated with being in the top quintile of WMH progression (adjusted odds ratio=2.0; 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.

Retinal microvascular abnormalities and subclinical magnetic resonance imaging brain infarct: A prospective study

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.

Genome-Wide Association Studies of MRI-Defined Brain Infarcts Meta-Analysis From the CHARGE Consortium

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 cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had ≥1 MRI infarct). Results— The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68–0.84; P=4.64×10−7). Highly suggestive associations (P<1.0×10−5) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r2>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample. Conclusions— This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.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 cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had ≥1 MRI infarct). Results— The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68–0.84; P =4.64×10−7). Highly suggestive associations ( P 0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample. Conclusions— This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed. # Supplemental Appendix {#article-title-2}

Autoimmune Responses to the Brain After Stroke Are Associated With Worse Outcome

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 poststroke period would be similarly predisposed to develop autoimmune responses to central nervous system 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 central nervous system 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 and glial fibrillary acidic protein (P=0.019 and P=0.039, respectively) at 90 days after stroke. Further, more robust Th1 responses to myelin basic protein at 90 days were associated with a decreased likelihood of good outcome, even after adjusting for baseline stroke severity and patient age (OR, 0.477; 95% CI, 0.244 to 0.935; P=0.031). Conclusions— This study demonstrates that immune responses to brain antigens occur after stroke. Although these responses are likely to be an epiphenomenon of ischemic brain injury, the response to myelin basic protein appears to have clinical consequences. The potential role of postischemic autoimmune-mediated brain injury deserves further investigation.

Risk factors for lacune subtypes in the Atherosclerosis Risk in Communities (ARIC) Study

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 (HbA1c) 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 ≤20 mm in diameter into those ≤7 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 <3 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 ≤7 mm. Findings were similar for lesions <3 mm. HbA1c, 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 <3 mm) were associated with diabetes and HbA1c, 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.

Retinal Microvascular Signs and 10-Year Risk of Cerebral Atrophy The Atherosclerosis Risk in Communities (ARIC) Study

Background and Purpose— Cerebral atrophy, detected as ventricular enlargement or sulcal widening on MRI, is recognized as a risk factor for vascular dementia or Alzheimer disease. However, its underlying pathophysiology is not known. We examined whether retinal microvascular assessment could provide predictive information on the risk of ventricular enlargement and sulcal widening on MRI. Methods— A prospective, population-based study was conducted of 810 middle-aged persons without clinical stroke or MRI infarcts. All participants had a first cranial MRI and retinal photography in 1993 to 1995 and returned for a repeated MRI in 2004 to 2006 (median follow-up of 10.5 years). Retinal photographs were graded for presence of retinopathy and retinal microvascular abnormalities, and MRI images were graded for ventricular size and sulcal size according to standardized protocols. Ventricular enlargement and sulcal widening were defined as an increase in ventricular size or sulcal size of ≥3 of 10 grades between baseline and follow-up. Results— After adjusting for age, gender, and cardiovascular risk factors, retinopathy and arteriovenous nicking at baseline were associated with 10-year ventricular enlargement (OR and 95% CI: 2.03, 1.20 to 4.42 for retinopathy and 2.19, 1.23 to 3.90 for arteriovenous nicking). Retinal signs were not associated with 10-year sulcal widening. Conclusions— Retinopathy and arteriovenous nicking are predictive of long-term risk of ventricular enlargement, but not of sulcal widening, independent of cardiovascular risk factors. These data support a microvascular etiology for subcortical but not cortical cerebral atrophy.Cerebral atrophy, detected on magnetic resonance imaging (MRI) as ventricular enlargement (VE) or sulcal widening (SW),1 has been shown to be associated with cognitive impairment.2 Semi-quantitative assessment of ventricular size based on MRI is recognized as a risk marker for dementia3 and Alzheimer’s disease (AD)4, and it accelerates during the pre-AD stage of amnestic mild cognitive impairment5, thus providing complementary information for diagnosis and monitoring of neurodegenerative diseases.4, 6 While neurodegenerative processes clearly play an essential role in the pathophysiology of cerebral atrophy,7 reduced cerebral perfusion due to microvascular disease may also contribute to the development of cerebral atrophy.8 The retina provides a non-invasive window to study microvascular etiology of cerebrovascular disease.9 Pathologic retinal changes may reflect micro-angiopathic processes in the brain. In the Atherosclerosis Risk in Communities (ARIC) study, we have previously demonstrated cross-sectional associations between retinal signs and VE and SW.10 and both cross-sectional and longitudinal associations with cognitive decline10, 11 In this study, we examine the prospective relationship of retinal microvascular abnormalities to the 10- year incidence of VE and SW in the ARIC cohort.

Severe Stroke Induces Long-Lasting Alterations of High-Mobility Group Box 1

Background and Purpose— The signals that initiate the poststroke inflammatory response are unknown. High-mobility group box (HMGB) 1 protein is a nuclear protein that is passively released from necrotic tissue and is able to activate leukocytes, which in turn secrete HMGB1. HMGB1 is also able to activate antigen-presenting cells and therefore stands at the crossroads of innate and adaptive immunity. Methods— Plasma HMGB1 concentrations were determined at multiple time points after ischemic stroke (N=110) and correlated to stroke severity and biomarkers of inflammation. The relationships between HMGB1, stroke outcome, and autoimmune responses to brain antigens were also assessed. Results— Stroke resulted in an increase in HMGB1 that persisted for 30 days. Plasma HMGB1 was correlated with the number of circulating leukocytes but was not predictive of either stroke outcome or the development of autoimmune responses to brain antigens. Patients with a TH1(+) response to myelin basic protein at 90 days after stroke, however, had higher plasma HMGB1. Conclusions— HMGB1 appears to be involved in the postischemic inflammatory response, but it remains unclear whether HMGB1 initiates this response or merely reflects activation of leukocytes by another signal.