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Subcortical brain structures are involved in developmental, psychiatric and neurological disorders. Here we performed genome-wide association studies meta-analyses of intracranial and nine subcortical brain volumes (brainstem, caudate nucleus, putamen, hippocampus, globus pallidus, thalamus, nucleus accumbens, amygdala and the ventral diencephalon) in 74,898 participants of European ancestry. We identified 254 independent loci associated with these brain volumes, explaining up to 35% of phenotypic variance. We observed gene expression in specific neural cell types across differentiation time points, including genes involved in intracellular signaling and brain aging-related processes. Polygenic scores for brain volumes showed predictive ability when applied to individuals of diverse ancestries. We observed causal genetic effects of brain volumes with Parkinson's disease and attention-deficit/hyperactivity disorder. Findings implicate specific gene expression patterns in brain development and genetic variants in comorbid neuropsychiatric disorders, which could point to a brain substrate and region of action for risk genes implicated in brain diseases., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background and Objectives: Previous studies suggest that lower mitochondrial DNA (mtDNA) copy number (CN) is associated with neurodegenerative diseases. However, whether mtDNA CN in whole blood is related to endophenotypes of Alzheimer disease (AD) and AD-related dementia (AD/ADRD) needs further investigation. We assessed the association of mtDNA CN with cognitive function and MRI measures in community-based samples of middle-aged to older adults., Methods: We included dementia-free participants from 9 diverse community-based cohorts with whole-genome sequencing in the Trans-Omics for Precision Medicine (TOPMed) program. Circulating mtDNA CN was estimated as twice the ratio of the average coverage of mtDNA to nuclear DNA. Brain MRI markers included total brain, hippocampal, and white matter hyperintensity volumes. General cognitive function was derived from distinct cognitive domains. We performed cohort-specific association analyses of mtDNA CN with AD/ADRD endophenotypes assessed within ±5 years (i.e., cross-sectional analyses) or 5-20 years after blood draw (i.e., prospective analyses) adjusting for potential confounders. We further explored associations stratified by sex and age (<60 vs ≥60 years). Fixed-effects or sample size-weighted meta-analyses were performed to combine results. Finally, we performed mendelian randomization (MR) analyses to assess causality., Results: We included up to 19,152 participants (mean age 59 years, 57% women). Higher mtDNA CN was cross-sectionally associated with better general cognitive function (β = 0.04; 95% CI 0.02-0.06) independent of age, sex, batch effects, race/ethnicity, time between blood draw and cognitive evaluation, cohort-specific variables, and education. Additional adjustment for blood cell counts or cardiometabolic traits led to slightly attenuated results. We observed similar significant associations with cognition in prospective analyses, although of reduced magnitude. We found no significant associations between mtDNA CN and brain MRI measures in meta-analyses. MR analyses did not reveal a causal relation between mtDNA CN in blood and cognition., Discussion: Higher mtDNA CN in blood is associated with better current and future general cognitive function in large and diverse communities across the United States. Although MR analyses did not support a causal role, additional research is needed to assess causality. Circulating mtDNA CN could serve nevertheless as a biomarker of current and future cognitive function in the community., (Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Background The periventricular white matter is more sensitive to the systemic hemodynamic alterations than the deep white matter because of differences in its vascular structure and systemic circulation relationship. We hypothesize that periventricular white matter hyperintensity (PVWMH) volume shows greater association than deep white matter hyperintensity (DWMH) volume with vascular properties (VPs) reflecting arterial stiffness and cardiovascular remodeling, indicators of the systemic circulation. Methods and Results A total of 426 participants (age, 59.0±6.1 years; 57.5% women; and 39.7% Black race) in the Genetic Study of Atherosclerosis Risk who were aged ≥50 years and had brain magnetic resonance imaging were studied. VPs included pulse pressure, hypertensive response to exercise, diastolic brachial artery diameter, diastolic common carotid artery diameter, common carotid artery distensibility coefficient, and left ventricular function. The relative associations of VPs with PVWMH and DWMH as multiple measures within the same individual were determined using multilevel linear models. We also determined if age modified the differences in VPs associations with PVWMH and DWMH. Our findings indicated that, within the same subject, PVWMH volume had greater association than DWMH volume with pulse pressure ( P =0.002), hypertensive response to exercise ( P =0.04), diastolic brachial artery diameter ( P =0.012), and diastolic common carotid artery diameter ( P =0.04), independent of age and cardiovascular risk factors. The differences of PVWMH versus DWMH associations with VPs did not differ at any age threshold. Conclusions We show, for the first time, that PVWMH has greater association than DWMH, independent of age, with vascular measurements of arterial stiffness and cardiovascular remodeling suggesting that changes in the systemic circulation affect the PVWMH and DWMH differently.

Efforts to develop effective neuroprotective therapies for ischemic stroke have had little success to date. One promising approach to neuroprotection is ischemic postconditioning, which utilizes brief bouts of ischemia after acute ischemic stroke to elicit neuroprotection, although the mechanism is largely unknown. As the primary components of transient ischemia are local hypoxia and acidosis, and hypoxic postconditioning has had little success, it is possible that the acidosis component may be the primary driver. To address the evidence behind this, we performed a systematic review of preclinical studies focused on the neuroprotective role of transient acidosis after ischemia. Animal studies demonstrated that mild-to-moderate acidosis after ischemic events led to better functional neurologic outcomes with reduced infarct volumes, while severe acidosis often led to cerebral edema and worse functional outcomes. In vitro studies demonstrated that mild-to-moderate acidosis improves neuronal survival largely through two means: (1) inhibition of harmful superoxide formation in the excitotoxic pathway and (2) remodeling neuronal mitochondria to allow for efficient ATP production (i.e., oxidative phosphorylation), even in the absence of oxygen. Similar to the animal studies, acidotic postconditioning in humans would entail short cycles of carbon dioxide inhalation, which has already been demonstrated to be safe as part of a hypercapnic challenge when measuring cerebrovascular reactivity. Due to the preclinical efficacy of acidotic postconditioning, its relatively straightforward translation into humans, and the growing need for neuroprotective therapies, future preclinical studies should focus on filling the current knowledge gaps that are currently restricting the development of phase I/II clinical trials., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: We have demonstrated that asymptomatic cerebral small vessel disease (cSVD) measured by white matter hyperintensity volume is associated with reduced manipulative manual dexterity on the Grooved Peg Board Test (GPBT) in middle-aged healthy individuals with a family history of early coronary artery disease. In this current study, we aim to identify the association of subcortical white matter microstructural impairment measured by diffusion tensor imaging, manual dexterity measured by GPBT and circulating serums ceramide, another marker for white matter injury. We hypothesize that lower regional fractional anisotropy (rFA) is associated with worse performance on GPBT and elevated serum ceramides in the same study population., Methods: rFA of 48 regions representing the subcortical white matters were analyzed in GeneSTAR participants in addition to serum ceramides and GPBT scores. Unadjusted univariable analyses with Bonferroni correction for multiple comparisons were completed using Spearman correlation for testing the associations between ceramides, rFA of subcortical white matter, and GPBT performance. Subsequently, sensitivity analyses were performed after excluding the participants that had any physical limitation that may influence their performance on GPBT. Finally, in the adjusted analysis using generalized estimating equation, linear regression models were performed for the areas that met significance threshold in the unadjusted analyses., Results: 112 subjects (age [49 ± 11], 51% female, 39.3% African American) were included. Adjusted analyses for the significant correlations that met the Bonferroni correction threshold in the unadjusted univariable analyses identified significant negative associations between rFA of the right fornix (RF) and log-GPBT score (β = -0.497, p = 0.037). In addition, rFA of RF negatively correlated with log serum ceramide levels (C18: β = -0.03, p = 0.003, C20: β = -0.0002, p = 0.004) and rFA of left genu of corpus callosum negatively correlated with log C18 level (β = -0.0103, p = 0.027)., Conclusions: These results demonstrate that subcortical microstructural white matter disruption is associated with elevated serum ceramides and reduced manual dexterity in a population with cSVD. These findings suggest that injury to white matter tracts undermines neural networks, with functional consequences in a middle-aged population with cardiovascular risk factors., (© 2020 S. Karger AG, Basel.)

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.

Background and Purpose: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings., Methods: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC., Results: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 ( NBEAL ), 10q23.1 ( TSPAN14/FAM231A ), and 10q24.33 ( SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 ( NOS3 ) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype., Conclusions: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.

Background: With increasing use of direct oral anticoagulants (DOACs) and availability of new reversal agents, the risk of traumatic intracranial hemorrhage (tICH) requires better understanding. We compared hemorrhage expansion rates, mortality, and morbidity following tICH in patients treated with vitamin k antagonists (VKA: warfarin) and DOACs (apixaban, rivaroxaban, dabigatran)., Methods: Retrospective chart review of patients from 2010 to 2017 was performed to identify patients with imaging diagnosis of acute traumatic intraparenchymal, subdural, subarachnoid, and epidural hemorrhage with preadmission use of DOACs or VKAs. We identified 39 patients on DOACs and 97 patients on VKAs. Demographic information, comorbidities, hemorrhage size, and expansion over time, as well as discharge disposition and Glasgow Outcome Scale (GOS) were collected. Primary outcome was development of new or enlargement of tICH within the first 48 h of initial CT imaging., Results: Of 136 patients with mean (SD) age 78.7 (13.2) years, most common tICH subtype was subdural hematoma (N = 102/136; 75%), and most common mechanism was a fall (N = 130/136; 95.6%). Majority of patients in the DOAC group did not receive reversal agents (66.7%). Hemorrhage expansion or new hemorrhage occurred in 11.1% in DOAC group vs. 14.6% in VKA group (p = 0.77) at a median of 8 and 11 h from initial ED admission, respectively (p = 0.82). Patients in the DOAC group compared to VKA group had higher median discharge GOS (4 vs. 3 respectively, p = 0.03), higher percentage of patients with good outcome (GOS 4-5, 66.7% vs. 40.2% respectively, p = 0.005), and higher rate of discharge to home or rehabilitation (p = 0.04)., Conclusions: We report anticoagulation-associated tICH outcomes predominantly due to fall-related subdural hematomas. Patients on DOACs had lower tICH expansion rates although not statistically significantly different from VKA-treated patients. DOAC-treated patients had favorable outcomes versus VKA group following tICH despite low use of reversal strategies. DOAC use may be a safer alternative to VKA in patients at risk of traumatic brain hemorrhage.

Background and Purpose- Patients with active malignancy are at risk for intracerebral hemorrhage (ICH). We aimed to characterize perihematomal edema (PHE) and hematoma volumes after spontaneous nontraumatic ICH in patients with cancer without central nervous system involvement. Methods- Patients with active malignancy who developed ICH were retrospectively identified through automated searches of institutional databases. Control patients were identified with ICH and without active cancer. Demographic and cancer-specific data were obtained by chart review. Hematoma and PHE volumes were determined using semiautomated methodology. Univariate and multivariate linear regression models were created to assess which variables were associated with hematoma and PHE expansion. Results- Patients with cancer (N=80) and controls (N=136) had similar demographics (all P >0.20), although hypertension was more prevalent among controls ( P =0.004). Most patients with cancer had received recent chemotherapy (n=45, 56%) and had recurrence of malignancy (n=43, 54%). Patients with cancer were thrombocytopenic (median platelet count 90 000 [interquartile range, 17 500-211 500]), and most had undergone blood product transfusion (n=41, 51%), predominantly platelets (n=38, 48%). Thirty-day mortality was 36% (n=29). Patients with cancer had significantly increased PHE volumes (23.67 versus 8.61 mL; P =1.88×10 -9 ) and PHE-to-ICH volume ratios (2.26 versus 0.99; P =2.20×10 -16 ). In multivariate analyses, variables associated with PHE growth among patients with cancer were ICH volume (β=1.29 [95% CI, 1.58-1.30] P =1.30×10 -5 ) and platelet transfusion (β=15.67 [95% CI, 3.61-27.74] P =0.014). Variables associated with 30-day mortality were ICH volume (odds ratio, 1.06 [95% CI, 1.03-1.10] P =6.76×10 -5 ), PHE volume (odds ratio, 1.07 [95% CI, 1.04-1.09] P =7.40×10 -6 ), PHE growth (odds ratio, 1.05 [95% CI, 1.01-1.10] P =0.01), and platelet transfusion (odds ratio, 1.48 [95% CI, 1.22-1.79] P =0.0001). Conclusions- Patients with active cancer who develop ICH have increased PHE volumes. PHE growth was independent of thrombocytopenia but associated with blood product transfusion. Thirty-day mortality was associated with PHE and ICH volumes and blood product transfusion.

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Brain lobar volumes are heritable but genetic studies are limited. We performed genome-wide association studies of frontal, occipital, parietal and temporal lobe volumes in 16,016 individuals, and replicated our findings in 8,789 individuals. We identified six genetic loci associated with specific lobar volumes independent of intracranial volume. Two loci, associated with occipital (6q22.32) and temporal lobe volume (12q14.3), were previously reported to associate with intracranial and hippocampal volume, respectively. We identified four loci previously unknown to affect brain volumes: 3q24 for parietal lobe volume, and 1q22, 4p16.3 and 14q23.1 for occipital lobe volume. The associated variants were located in regions enriched for histone modifications ( DAAM1 and THBS3 ), or close to genes causing Mendelian brain-related diseases ( ZIC4 and FGFRL1 ). No genetic overlap between lobar volumes and neurological or psychiatric diseases was observed. Our findings reveal part of the complex genetics underlying brain development and suggest a role for regulatory regions in determining brain volumes., Competing Interests: Competing interestsThe authors declare no competing interests.

Objective: To perform an individual patient-level data (IPLD) analysis and to determine the relationship between haptoglobin ( HP ) genotype and outcomes after aneurysmal subarachnoid hemorrhage (aSAH)., Methods: The primary outcome was favorable outcome on the modified Rankin Scale or Glasgow Outcome Scale up to 12 months after ictus. The secondary outcomes were occurrence of delayed ischemic neurologic deficit, radiologic infarction, angiographic vasospasm, and transcranial Doppler evidence of vasospasm. World Federation of Neurological Surgeons (WFNS) scale, Fisher grade, age, and aneurysmal treatment modality were covariates for both primary and secondary outcomes. As preplanned, a 2-stage IPLD analysis was conducted, followed by these sensitivity analyses: (1) unadjusted; (2) exclusion of unpublished studies; (3) all permutations of HP genotypes; (4) sliding dichotomy; (5) ordinal regression; (6) 1-stage analysis; (7) exclusion of studies not in Hardy-Weinberg equilibrium (HWE); (8) inclusion of studies without the essential covariates; (9) inclusion of additional covariates; and (10) including only covariates significant in univariate analysis., Results: Eleven studies (5 published, 6 unpublished) totaling 939 patients were included. Overall, the study population was in HWE. Follow-up times were 1, 3, and 6 months for 355, 516, and 438 patients. HP genotype was not associated with any primary or secondary outcome. No trends were observed. When taken through the same analysis, higher age and WFNS scale were associated with an unfavorable outcome as expected., Conclusion: This comprehensive IPLD analysis, carefully controlling for covariates, refutes previous studies showing that HP1-1 associates with better outcome after aSAH., (© 2019 American Academy of Neurology.)

Background: Readmission for ventilator support in tracheostomy patients with primary brain injury is often attributed to failure of airway protection and aspiration pneumonia. Data regarding the incidence of intensive care unit readmissions and associated factors in these patients are limited., Objectives: To determine the factors associated with intensive care unit readmission among tracheostomy patients with primary brain injury, as compared with tracheostomy patients without primary brain injury., Methods: Prospectively acquired data from an ongoing tracheostomy registry at an academic health center were reviewed retrospectively. A total of 164 patients more than 18 years of age who received an elective tracheostomy and had at least 1 readmission to the intensive care unit between 2007 and 2013 were included., Results: The incidence of mechanical ventilation resumption and readmission was significantly higher in patients with than without primary brain injury ( P = .005). Patients requiring tracheostomy for airway protection were at a higher risk for atelectasis (odds ratio, 8.23; P = .05). In patients with primary brain injury, a higher Glasgow Coma Scale score was associated with a lower risk for atelectasis (odds ratio, 0.84; P = .04). Mean (SD) Glasgow Coma Scale score was higher in patients without primary brain injury (10.64 [3.98]) than in patients with primary brain injury (8.62 [4.57]; P = .006)., Conclusions: Tracheostomy patients with primary brain injury may have central nervous system-mediated respiratory compromise associated with reduced Glasgow Coma Scale score, increased atelectasis, and shorter duration of ventilator dependency., (©2019 American Association of Critical-Care Nurses.)

Background and Purpose: Traditional cardiovascular risk factors have been associated with white matter disease. Because hypertension results in vascular stiffness and impaired cerebral perfusion, we hypothesized that it would be the most relevant risk factor for microstructural white matter disruption in apparently healthy middle-aged individuals with a family history of early-onset coronary artery disease., Materials and Methods: This was a cross-sectional analysis of participants in the Genetic Study of Atherosclerosis Risk with DTI. Regional fractional anisotropy of 181 segmented brain regions was measured using Eve WM Atlas. Risk factors were examined using univariate analysis for 48 regions representing deep WM structures. Minimal multivariable linear regression models adjusting for age, sex, and race and maximal linear regression models adjusting for cardiovascular risk factors were performed for regions meeting the Bonferroni threshold in the initial analysis., Results: Included were 116 subjects (mean age, 49 ± 11 years; 57% men) with a moderate load of cardiovascular risk factors. Subjects with hypertension had significantly lower regional fractional anisotropy in the right cingulum and left stria terminalis in the minimal and maximal regression models. Additionally, there was lower regional fractional anisotropy in the left fornix in the maximal model and right sagittal stratum in the minimal model. Systolic blood pressure values were significantly associated with regional fractional anisotropy in the left superior longitudinal fasciculus in the maximal model. There were no significant differences among regional fractional anisotropy values for other cardiovascular risk factors., Conclusions: In middle-aged apparently healthy individuals with susceptibility to vascular disease, among all known cardiovascular risk factors, hypertension was associated with microstructural WM disruption., (© 2018 by American Journal of Neuroradiology.)

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρ genetic  = -0.59, p-value = 3.14 × 10 -6 ), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.

Background and Purpose- White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods- In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results- At 17q25, we confirmed the association of multiple common variants in TRIM65, FBF1, and ACOX1 ( P<6×10 -7 ). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; P EA =4.5×10 -8 ) partially independent of known common signal ( P EA(conditional) =1.4×10 -3 ). We further identified a locus at 2q33 containing common variants in NBEAL1, CARF, and WDR12 (lead, rs2351524; P all =1.9×10 -10 ). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants ( P rs34136221 =2.8×10 -8 ). Conclusions- Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρ genetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N combined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.

Background: Haptoglobin (Hp) genotype has been shown to be a predictor of clinical outcomes in subarachnoid hemorrhage. Cerebral salt wasting (CSW) has been suggested to precede the development of symptomatic vasospasm., Objective: To determine if Hp genotype was associated with CSW and subsequent vasospasm after aneurysmal subarachnoid hemorrhage., Methods: Hp genotypic determination was done for patients admitted with a diagnosis of subarachnoid hemorrhage. Outcome measures included CSW, delayed cerebral infarction, and Glasgow Outcome Score of 4 to 5 at 30 days. Criteria for CSW included hyponatremia <135 mEq/L, and urine output >4 L in 12 hours with urine sodium >40 mEq/L., Results: A total of 133 patients were included in the study. The 3 Hp subgroups did not differ in terms of baseline characteristics. CSW occurred in 1 patient (3.4%) with Hp 1-1, 8 (14.0%) patients with Hp 2-1, and 15 (31.9%) patients with Hp 2-2 (P = .004). In the multivariate regression model, Hp 2-2 was associated with CSW (odds ratio [OR]: 4.94; CI: 1.78-17.43; P = .01), but Hp 2-1 was not (OR: 2.92; CI: 0.56-4.95; P = .15) compared with Hp 1-1. There were no associations between Hp genotypes and functional outcome or delayed cerebral infarction. CSW was associated with delayed cerebral infarction (OR: 7.46; 95% CI: 2.54-21.9; P < .001)., Conclusion: Hp 2-2 genotype was an independent predictor of CSW after subarachnoid hemorrhage. Because CSW is strongly associated with delayed cerebral infarction, the use of Hp genotype testing requires more investigation, and larger prospective confirmation is warranted. Additionally, a more objective definition of CSW needs to be delineated.

Objectives: We hypothesized that integrated motor-visual functions measured by manipulative manual dexterity are affected by white matter lesion (WML) burden as measured on cranial MRI across relevant brain regions in subjects at risk of preclinical occult vascular disease., Methods: A real-time cross-sectional study of healthy subjects aged 29 to 74 years with a family history of early-onset coronary artery disease (n = 714; mean age, 51 ± 11 years; mean education, 14 ± 3 years; 42% male; 38% black) were identified from probands with coronary artery disease diagnosed before age 60 years. WMLs on 3-tesla brain MRI and Grooved Pegboard scores were measured., Results: WMLs were observed at all ages. Mean pegboard scores were 108 ± 18, similar to normal populations. In unadjusted analysis, WMLs and pegboard scores were significantly correlated by region (total WMLs, r = 0.34, p = 0.0001; frontal [r = 0.34, p < 0.0001], insula [r = 0.31, p < 0.0001], parietal [r = 0.31, p < 0.0001], and temporal [r = 0.17, p < 0.0001]). In multivariate analysis predicting (log) pegboard score adjusted for age, sex, race, education, regional or total volumes, and familial non-independence, total WML volume (p = 5.79E - 05) and regional WML volumes (p < 0.01) retained statistical significance in all but the youngest age quartile (29-43 years)., Conclusions: Greater WML volumes in different brain regions are associated with higher pegboard scores (worse performance) independent of age, sex, race, education, and total or regional volumes. This suggests that small vessel cerebrovascular disease may be present in healthy individuals in a preclinical state with measurable impact on complex integrative functions in individuals with excess risk of clinical vascular disease., (© 2015 American Academy of Neurology.)

Objective: To determine if the haptoglobin (Hp) phenotype, which has been shown to be a predictor of clinical outcomes in cerebrovascular disorders, particularly subarachnoid hemorrhage, was predictive of functional outcomes after spontaneous intracerebral hemorrhage (ICH)., Methods: Patients admitted with a diagnosis of ICH were prospectively included and divided into 3 groups based on their genetically determined Hp phenotype: 1-1, 2-1, and 2-2. Outcome measures included mortality and 30-day modified Rankin Scale scores. Demographics and outcomes were compared for each phenotype using multivariate linear regression analysis., Results: The study included 94 patients. The distribution of Hp phenotype was Hp 1-1, 12 (13%); Hp 2-1, 46 (49%); and Hp 2-2, 36 (38%). The 3 Hp subgroups did not differ in terms of demographic variables, comorbidities, or ICH characteristics. There was a nonsignificant trend toward increased mortality in Hp 2-1 and Hp 2-2 compared with Hp 1-1, with mortality of 8% in Hp 1-1, 17% in Hp 2-1, and 25% in Hp 2-2 (P = 0.408). In the regression model adjusted for confounders, Hp 2-1 (odds ratio = 0.05, 95% confidence interval = 0.01-0.47, P < 0.001) and Hp 2-2 phenotypes (odds ratio = 0.14, 95% confidence interval = 0.02-0.86, P = 0.045) had significantly lower odds of modified Rankin Scale scores 0-2 compared with Hp 1-1., Conclusions: After ICH, individuals with the Hp-2 allele (2-1 and 2-2) had worse functional outcomes than individuals with the Hp-1 allele (Hp 1-1). There was a nonsignificant association between Hp phenotype and mortality. Larger prospective studies with better surrogates of ICH outcomes are warranted., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Deep white matter hyperintensity (DWMH) and periventricular (PV) white matter lesion volumes are associated with age and subsequent stroke. We studied age differences in these volumes accounting for collinearity and risk factors. Subjects were 563 healthy family members of early-onset coronary artery disease patients. Using 3T magnetic resonance imaging, lesions were classified as DWMH or PV. Age association with lesion classification was analyzed using random effects Tobit regression, adjusting for intracranial volume (ICV) and risk factors. Subjects were 60% women, 36% African-American, mean age 51 ± 11 years. In multivariable analysis adjusted for PV and ICV, DWMH was associated with age (p < 0.001) and female sex (p = 0.003). PV, adjusted for DWMH and ICV, was age associated (p < 0.001). For each age decade, DWMH showed 0.07 log units/decade greater volume (95% CI = 0.04-0.11); PV was 0.18 log units/decade greater (95% CI = 0.14-0.23); slope differences (p < 0.001). In people with a family history of coronary artery disease, PV and DWMH are independently and differentially associated with age controlling for traditional risk factors., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Intraventricular hemorrhage (IVH) frequently complicates intracranial hemorrhage (ICH) and is a significant independent contributor to morbidity and mortality, yet therapy directed at ameliorating intraventricular clotting has been limited and until recently, has not been subject to systematic evaluation. Thrombolytic therapy with placement of an external ventricular drain for management of severe IVH secondary to ICH has been investigated in multiple observational studies, small randomized controlled trials and several meta-analyses, soon to culminate with the completion of the 500 patient CLEAR IVH randomized controlled trial. We review conventional and lytic therapeutic approaches to severe IVH in the setting of small ICH, articulating the scope of the problem, management issues, and relevant questions for future research., (© 2016 S. Karger AG, Basel.)

Background: African Americans (AAs) have a higher prevalence of extreme ischemic white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) than do European Americans (EAs) based on the Cardiovascular Health Study (CHS) score. Ischemic white matter disease, limited to the deep white matter, may be biologically distinct from disease in other regions and may reflect a previously observed trend toward an increased risk of subcortical lacunar infarcts in AAs. We hypothesized that extreme deep WMH volume (DWMV) or periventricular volume (PV) may also have a higher prevalence in AAs. Thus, we studied extreme CHS scores and extreme DWMV and PV in a healthy population enriched for cardiovascular disease risk factors., Methods: We imaged the brains of 593 subjects who were first-degree relatives of probands with early onset coronary disease prior to 60 years of age. WMHs were manually delineated on 3-tesla cranial MRI by a trained radiology reader; the location and volume of lesions were characterized using automated software. DWMV and PV were measured directly with automated software, and the CHS score was determined by a neuroradiologist. Volumes were characterized as being in the upper 25% versus lower 75% of total lesion volume. Volumes in the upper versus the remaining quartiles were examined for AA versus EA race using multiple logistic regression (generalized estimating equations adjusted for family relatedness) and adjusted for major vascular disease risk factors including age ≥55 years versus <55, sex, current smoking, obesity, hypertension, diabetes and low-density lipoprotein >160 mg/dl., Results: Participants were 58% women and 37% AAs, with a mean age of 51.5 ± 11.0 years (range, 29-74 years). AAs had significantly higher odds of having extreme DWMVs (odds ratio, OR, 1.8; 95% confidence interval, CI, 1.2-2.9; p = 0.0076) independently of age, sex, hypertension and all other risk factors. AAs also had significantly higher odds of having extreme CHS scores ≥3 (OR, 1.3; 95% CI, 1.1-3.6; p = 0.025). Extreme PV was not significantly associated with AA race (OR, 1.3; 95% CI, 0.81-2.1; p = 0.26)., Conclusions: AAs from families with early-onset cardiovascular disease are more likely to have extreme DWMVs (a subclinical form of cerebrovascular disease) and an extreme CHS score, but not extreme PV, independently of age and other cardiovascular disease risk factors. These findings suggest that this AA population is at an increased risk for DWMV and may be at an increased risk for future subcortical stroke. Longitudinal studies are required to see if DWMV is predictive of symptomatic subcortical strokes in this population., (© 2014 S. Karger AG, Basel.)

Transcranial Doppler (TCD) is a portable device that uses a handheld 2-MHz transducer. It is most commonly used in subarachnoid hemorrhage where cerebral blood flow velocities in major intracranial blood vessels are measured to detect vasospasm in the first 2 to 3 weeks. TCD is used to detect vasospasm in traumatic brain injury and post-tumor resection, measurement of cerebral autoregulation and cerebrovascular reactivity, diagnosis of acute arterial occlusions in stroke, screening for patent foramen ovale and monitoring of emboli. It can be used to detect abnormally high intracranial pressure and for confirmation of total cerebral circulatory arrest in brain death., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Mechanical ventilation in neurologically injured patients presents unique challenges. Patients with acute neurologic injuries may require mechanical ventilation for reasons beyond respiratory failure. There is also a subset of pulmonary pathologic abnormality directly associated with neurologic injuries. Balancing the need to maintain brain oxygenation, cerebral perfusion, and control of intracranial pressure can be in conflict with concurrent ventilator strategies aimed at lung protection. Weaning and liberation from mechanical ventilation also require special considerations. These issues are examined in the ventilator management of the neurologically injured patient., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Management of intracranial pressure in neurocritical care remains a potentially valuable target for improvements in therapy and patient outcomes. Surrogate markers of increased intracranial pressure, invasive monitors, and standard therapy, as well as promising new approaches to improve cerebral compliance are discussed, and a current review of the literature addressing this metric in neuroscience critical care is provided., (Published by Elsevier Inc.)

Labeling of cerebral vasculature is important for characterization of anatomical variation, quantification of brain morphology with respect to specific vessels, and inter-subject comparisons of vessel properties and abnormalities. We propose an automated method to label the anterior portion of cerebral arteries using a statistical inference method on the Bayesian network representation of the vessel tree. Our approach combines the likelihoods obtained from a random forest classifier trained using vessel centerline features with a belief propagation method integrating the connection probabilities of the cerebral artery network. We evaluate our method on 30 subjects using a leave-one-out validation, and show that it achieves an average correct vessel labeling rate of over 92%.

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating neurological disease. It has many sequelae, including vasospasm and delayed ischemic neurological deficits (DINDs). We explored the blood proteome in patients with aSAH using transcranial Doppler (TCD) velocity as a guide to patients who are at risk for symptomatic vasospasm and DIND. Blood was drawn on all days that patients were observed in the neurocritical care unit (NCCU) after aSAH. A team of neurologists and neurosurgeons identified patients with clinical evidence of vasospasm and DIND. Serum was fractionated using protein chips and surface-enhanced laser desorption and ionization time-of-flight mass spectrometry (SELDI-TOF MS). We detected a pattern of protein expression associated with those at risk for elevated TCD velocities by day 8, compared with blood collected in the presymptomatic stage (days 1-3). We further analyzed serum using pooled samples from study entry to the time of elevated TCD velocities using a protein microarray that analyzed 500 human proteins thematically oriented toward inflammation. After identifying several candidates with elevated concentrations in the pooled samples, we then used reverse protein arrays to quantitate the concentration of potential candidate proteins in the individual samples. Proteins with significantly elevated concentrations included apolipoprotein-E, apolipoprotein-A, serum amyloid protein-4, and serum amyloid protein-P. Future studies in larger sample populations are needed to evaluate these biomarkers further as representative of biosystems involved in vasospasm and DIND or as potential biomarkers predictive of risk associated with disease.

Purpose: African Americans (AA) have been shown to have lower exercise capacities and a higher prevalence of related risk for cardiovascular disease (CVD) compared to European Americans (EA). Broad biopsychosocial models that may inform the design of ethnic-specific exercise programs have not been well examined. We thus examined exercise capacity and its biopsychosocial correlates in a healthy population of AA and EA at increased risk of CVD., Methods: Subjects underwent maximal graded treadmill testing with gated single-photon emission computed tomography (SPECT); exercise capacity was expressed in MET-minutes. Medical history, psychosocial variables, general well-being, physical activity, and anthropometrics were assessed. Peak filling rate, a measure of left ventricular function, and ejection fraction were obtained from SPECT imaging, and the presence of silent ischemia was determined from the treadmill and SPECT imaging., Results: The sample (N = 1054) was 47% AA and 60% female. Mean age was 52.1 ± 9 yr for AA and 49.9 ± 10 yr for EA. Body mass index (BMI) was 32.5 ± 6.7 kg·m(-2) for AA and 29 ± 5.3 kg·m(-2) for EA. AA achieved a mean maximal exercise level of 31 MET·min less than EA did. In separate regression models by race, BMI (r(2) = 0 .30), age (r(2) = 0 .07), and sex (r(2) = 0 .03) explained 40% of the variance in MET-minutes in AA and 36% in EA, with a similar hierarchy of associated variables. The remaining variables had minimal effect on exercise capacity in either group., Conclusions: BMI, older age, and female sex together contribute most to exercise capacity in both ethnicities. Hypothetically important biopsychosocial variables that may help shape ethnic-specific exercise programs add little to the prediction of exercise capacity. Thus, programs designed to reduce disparities in exercise capacity still need to first and foremost be geared to the age and sex demographics and address obesity.

Background: Neurocritical care is a new subspecialty field in medicine that intersects with many of the neuroscience and critical care specialties, and continues to evolve in its scope of practice and practitioners. The objective of this study was to assess the perceived need for and roles of neurocritical care intensivists and neurointensive care units among physicians involved with intensive care and the neurosciences., Methods: An online survey of physicians practicing critical care medicine, and neurology was performed during the 2008 Leapfrog initiative to formally recognize neurocritical care training., Results: The survey closed in July 2009 and achieved a 13% response rate (980/7524 physicians surveyed). Survey respondents (mostly from North America) included 362 (41.4%) neurologists, 164 (18.8%) internists, 104 (11.9%) pediatric intensivists, 82 (9.4%) anesthesiologists, and 162 (18.5%) from other specialties. Over 70% of respondents reported that the availability of neurocritical care units staffed with neurointensivists would improve the quality of care of critically ill neurological/neurosurgical patients. Neurologists were reported as the most appropriate specialty for training in neurointensive care by 53.3%, and 57% of respondents responded positively that neurology residency programs should offer a separate training track for those interested in neurocritical care., Conclusion: Broad level of support exists among the survey respondents (mostly neurologists and intensivists) for the establishment of neurological critical care units. Since neurology remains the predominant career path from which to draw neurointensivists, there may be a role for more comprehensive neurointensive care training within neurology residencies or an alternative training track for interested residents.

Background: Blood-based biomarkers of atherosclerosis have been used to identify patients at high risk for developing stroke. We hypothesized that patients with carotid artery disease would have a distinctive proteomic signature in blood as compared to a healthy control population without carotid artery disease. In order to discover protein biomarkers associated with increased atherosclerotic risk, we used two different strategies to identify biomarkers from patients with clinically defined atherosclerosis who were undergoing endarterectomy for atherosclerotic carotid artery disease. These patients were compared with healthy matched controls., Methods: Serum was obtained from patients undergoing endarterectomy (EA; n = 38) and compared to a group of age-matched healthy controls (n = 40). Serum was fractionated using anion exchange chromatography and three different surface-enhanced laser desorption/ionization (SELDI) chip surfaces and then evaluated with mass spectrometry (MS) and two-dimensional difference gel electrophoresis (2D-DIGE)., Results: A random forest (RF) analysis of the SELDI-MS protein peak data distinguished these two groups with 69.2% sensitivity and 73.2% specificity. Four unique SELDI peaks (4.2, 4.4, 16.7 and 28 kDa, all p< 0.01) showed the greatest influence in the RF model. The EA patients with a history of prior clinical atherosclerotic plaque rupture manifested as either stroke or transient ischemic attack (symptomatic; n = 16) were compared to patients with carotid atherosclerosis but no clinical evidence of plaque rupture (asymptomatic; n = 22). Analysis of the SELDI spectra did not separate these two patient subgroups. A subgroup analysis using 2D-DIGE images obtained from albumin-depleted serum comparing symptomatic (n = 10) to asymptomatic EA patients (n = 10) found 4 proteins that were differentially expressed (p < 0.01) in the symptomatic patients. These proteins were identified as α(1)-antitrypsin, haptoglobin and vitamin D binding protein that were downregulated and α(2)-glycoprotein precursor that was upregulated in the symptomatic EA group., Conclusions: SELDI-MS data analysis of fractionated serum suggests that a distinct protein signature exists in patients with carotid atherosclerosis compared to age-matched healthy controls. Identification of 4 proteins in a subset of patients with symptomatic and asymptomatic carotid atherosclerosis suggests that these and other protein biomarkers may assist in identifying high-risk patients with carotid atherosclerosis.

Background: The management of symptomatic cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH) can be often complicated by the presence of stunned myocardium and left ventricular failure. Vasopressors and inotropes are commonly used to optimize mean arterial pressure (MAP) and cerebral perfusion pressure (CPP). Intra-aortic balloon counterpulsation pump (IABP) may be indicated in the management of these patients., Methods: We report the case of a 55-year-old patient who suffered an aSAH complicated by severe left ventricular failure, who subsequently developed symptomatic cerebral vasospasm. Left ventricular failure precluded traditional hemodynamic augmentation, and IABP was successfully used instead, which allowed for reinstitution of hypertensive hypervolemic therapy and prevented delayed cerebral ischemia., Results: A review of the literature conducted on symptomatic cerebral vasospasm after aSAH and severe left ventricular failure revealed seven publications describing 14 patients with aSAH treated with an IABP during the period of vasospasm., Conclusions: Intra-aortic balloon counterpulsation pump (IABP) is used for hemodynamic support of patients in cardiogenic shock and its use in the setting of aSAH, cardiomyopathy, and cerebral vasospasm can be beneficial in preventing delayed ischemic deficits.