Loss of consciousness at onset of aneurysmal subarachnoid hemorrhage in good-grade patients.

Loss of consciousness (LOC) at presentation with aneurysmal subarachnoid hemorrhage (aSAH) has been associated with early brain injury and poor functional outcome. The impact of LOC on the clinical course after aSAH deserves further exploration. A retrospective analysis of 149 aSAH patients who were prospectively enrolled in the Cerebral Aneurysm Renin Angiotensin Study (CARAS) between 2012 and 2015 was performed. The impact of LOC was analyzed with emphasis on patients presenting in excellent or good neurological condition (Hunt and Hess 1 and 2). A total of 50/149 aSAH patients (33.6%) experienced LOC at presentation. Loss of consciousness was associated with severity of neurological condition upon admission (Hunt and Hess, World Federation of Neurosurgical Societies (WFNS), Glasgow Coma Scale (GCS) grade), hemorrhage burden on initial head CT (Fisher CT grade), acute hydrocephalus, cardiac instability, and nosocomial infection. Of Hunt and Hess grade 1 and 2 patients, 21/84 (25.0%) suffered LOC at presentation. Cardiac instability and nosocomial infection were significantly more frequent in these patients. In multivariable analysis, LOC was the predominant predictor of cardiac instability and nosocomial infection. Loss of consciousness at presentation with aSAH is associated with an increased rate of complications, even in good-grade patients. The presence of LOC may identify good-grade patients at risk for complications such as cardiac instability and nosocomial infection.

The role of endothelial nitric oxide synthase -786 T/C polymorphism in cardiac instability following aneurysmal subarachnoid hemorrhage.

INTRODUCTION: Cardiac abnormalities are observed frequently after aneurysmal subarachnoid hemorrhage (aSAH). A subset of aSAH patients develops neurogenic cardiomyopathy, likely induced by catecholamine excess. Genetic polymorphisms of the endothelial nitric oxide synthase (eNOS) gene have been linked to decreased nitric oxide (NO) levels, coronary artery spasm, and myocardial infarction. The role of the eNOS single nucleotide polymorphism (SNP) -786 T/C in cardiac instability following aSAH has not been previously investigated. METHODS: From 2012 to 2015, aSAH patients were prospectively enrolled in the Cerebral Aneurysm Renin Angiotensin System (CARAS) study at two academic institutions. Blood samples were used to assess the eNOS SNP -786 T/C rs2070744 through 5'exonuclease (Taqman) genotyping assays. Associations between this polymorphism and cardiac instability following aSAH were analyzed. RESULTS: Multivariable analysis demonstrated a dominant effect of the C allele of eNOS SNP -786 T/C on cardiac instability in patients with aSAH. A lower Glasgow Coma Scale score and a history of ischemic vascular disease were also associated with cardiac instability. Furthermore, cardiac instability independently predicted poor functional outcome upon discharge from the hospital. CONCLUSIONS: The C allele of the eNOS SNP -786 T/C was independently associated with an increased risk for cardiac instability following aSAH. Cardiac instability itself was a risk factor for an unfavorable functional outcome upon discharge from the hospital.

Genetic variation in human NPY expression affects stress response and emotion.

Understanding inter-individual differences in stress response requires the explanation of genetic influences at multiple phenotypic levels, including complex behaviours and the metabolic responses of brain regions to emotional stimuli. Neuropeptide Y (NPY) is anxiolytic and its release is induced by stress. NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories. Here we show that haplotype-driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in post-mortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype-driven NPY expression predicted higher emotion-induced activation of the amygdala, as well as diminished resiliency as assessed by pain/stress-induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism (SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic peptide and help to explain inter-individual variation in resiliency to stress, a risk factor for many diseases.

Traumatic brain injury: molecular biomarkers, genetics, secondary consequences, and medical management.

Traumatic brain injury (TBI) has reached epidemic proportions worldwide. The consequences of TBI can be severe even with repetitive mild trauma. If death and coma are avoided, the consequences of TBI in the long term typically involve dizziness, sleep disturbances, headache, seizures, cognitive impairment, focal deficits, depression, and anxiety. The severity of brain injury is a significant predictor of outcome. However, the heterogenous nature of the injury makes prognosis difficult. The present review of the literature focuses on the genetics of TBI including genome wide (GWAS) data and candidate gene associations, among them brain-derived neurotrophic factor (BDNF) with TBI and development of post-traumatic epilepsy (PTE). Molecular biomarkers of TBI are also discussed with a focus on proteins and the inflammatory protein IL1-ß. The secondary medical sequela to TBI of cognitive impairment, PTE, headache and risk for neurodegenerative disorders is also discussed. This overview of TBI concludes with a review and discussion of the medical management of TBI and the medicines used for and being developed at the preclinical and clinical stages for the treatment of TBI and its host of life-debilitating symptoms.

Mechanistic and therapeutic relationships of traumatic brain injury and γ-amino-butyric acid (GABA).

Traumatic brain injury (TBI) is a highly prevalent medical condition for which no medications specific for the prophylaxis or treatment of the condition as a whole exist. The spectrum of symptoms includes coma, headache, seizures, cognitive impairment, depression, and anxiety. Although it has been known for years that the inhibitory neurotransmitter γ-amino-butyric acid (GABA) is involved in TBI, no novel therapeutics based upon this mechanism have been introduced into clinical practice. We review the neuroanatomical, neurophysiological, neurochemical, and neuropharmacological relationships of GABA neurotransmission to TBI with a view toward new potential GABA-based medicines. The long-standing idea that excitatory and inhibitory (GABA and others) balances are disrupted by TBI is supported by the experimental data but has failed to invent novel methods of restoring this balance. The slow progress in advancing new treatments is due to the complexity of the disorder that encompasses multiple dynamically interacting biological processes including hemodynamic and metabolic systems, neurodegeneration and neurogenesis, major disruptions in neural networks and axons, frank brain lesions, and a multitude of symptoms that have differential neuronal and neurohormonal regulatory mechanisms. Although the current and ongoing clinical studies include GABAergic drugs, no novel GABA compounds are being explored. It is suggested that filling the gap in understanding the roles played by specific GABAA receptor configurations within specific neuronal circuits could help define new therapeutic approaches. Further research into the temporal and spatial delivery of GABA modulators should also be useful. Along with GABA modulation, research into the sequencing of GABA and non-GABA treatments will be needed.

BDNF polymorphism-dependent OFC and DLPFC plasticity differentially moderates implicit and explicit bias.

This study examined the role of orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (DLPFC) plasticity in controlling implicit and explicit social biases. Normal controls and patients with varied OFC and DLPFC lesion size and single nucleotide polymorphisms (SNPs) in the brain-derived neurotrophic factor (BDNF) gene, which promotes (methionine-valine [Met/Val] SNP) or stifles (valine-valine [Val/Val] SNP) plasticity in damaged PFC regions, completed measures of implicit and explicit social bias. Patients and controls demonstrated comparable levels of implicit bias, but patients with Met/Val SNPs exhibited less implicit bias when they had smaller OFC lesions compared with Val/Val patients with similar size lesions and those with large OFC lesions. Both patients and controls demonstrated patterns of explicit bias consistent with hypotheses. Patients with Met/Val SNPs exhibited less explicit bias when they had smaller DLPFC lesions sizes compared with Val/Val patients with similar size lesions and those with large DLPFC lesions. OFC lesion size and BDNF SNP type did not moderate explicit bias; DLPFC lesion size and BDNF SNP type did not moderate implicit bias (nor did other medial or lateral regions). Findings suggest that plasticity within specific PFC regions modulates the type and degree of social bias that individuals' exhibit.

The role of the Met66 brain-derived neurotrophic factor allele in the recovery of executive functioning after combat-related traumatic brain injury.

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, promotes survival and synaptic plasticity in the human brain. The Val66Met polymorphism of the BDNF gene interferes with intracellular trafficking, packaging, and regulated secretion of this neurotrophin. The human prefrontal cortex (PFC) shows lifelong neuroplastic adaption implicating the Val66Met BDNF polymorphism in the recovery of higher-order executive functions after traumatic brain injury (TBI). In this study, we examined the effect of this BDNF polymorphism on the recovery of executive functioning after TBI. We genotyped a sample of male Vietnam combat veterans consisting of a frontal lobe lesion group with focal penetrating head injuries and a non-head-injured control group for the Val66Met BDNF polymorphism. The Delis-Kaplan Executive Function System as a standardized psychometric battery was administrated to examine key domains of executive functions. The results revealed that the Met allele but not the hypothesized Val allele promotes recovery of executive functioning. Overall, the Met66 carriers in the lesion group performed as well as the Met66 carriers in the control group. The Met66 allele accounted for 6.2% of variance for executive functioning independently of other significant predictors including preinjury intelligence, left hemisphere volume loss, and dorsolateral PFC volume loss. The findings point to different mechanisms of the Val66Met BDNF gene in complex phenotypes under normal and pathological conditions. A better understanding of these mechanisms could be instrumental in the development and application of effective therapeutic strategies to facilitate recovery from TBI.

Effect of CHRFAM7A Δ2bp gene variant on secondary inflammation after spinal cord injury.

The α7 neuronal nicotinic acetylcholine receptors (α7nAChRs) are essential for anti-inflammatory responses. The human-specific CHRFAM7A gene and its 2bp deletion polymorphism (Δ2bp variant) encodes a structurally-deficient α7nAChRs that may impact the anti-inflammatory function. We studied 45 spinal cord injury (SCI) patients for up to six weeks post SCI to investigate the role of the Δ2bp variant on multiple circulating inflammatory mediators and two outcome measures (neuropathic pain and risk of pressure ulcers). The patient's SCI were classified as either severe or mild. Missing values were imputed. Overall genetic effect was conducted with independent sample t-test and corrected with false discovery rate (FDR). Univariate analysis and regression analysis were applied to evaluate the Δ2bp effects on temporal variation of inflammatory mediators post SCI and their interaction with outcome measures. In severe SCI, the Δ2bp carriers showed higher levels of circulating inflammatory mediators than the Δ2bp non-carriers in TNF-α (FDR = 9.6x10-4), IFN-γ (FDR = 1.3x10-3), IL-13 (FDR = 1.6x10-3), CCL11 (FDR = 2.1x10-3), IL-12p70 (FDR = 2.2x10-3), IL-8 (FDR = 2.2x10-3), CXCL10 (FDR = 3.1x10-3), CCL4 (FDR = 5.7x10-3), IL-12p40 (FDR = 7.1x10-3), IL-1b (FDR = 0.014), IL-15 (FDR = 0.024), and IL-2 (FDR = 0.037). IL-8 and CCL2 were negatively associated with days post injury (DPI) for the Δ2bp carriers (P = 2x10-7 and P = 2x10-8, respectively) and IL-5 was positively associated with DPI for the Δ2bp non-carriers (P = 0.015). Neuropathic pain was marginally positively associated with IL-13 for the Δ2bp carriers (P = 0.056). In mild SCI, the Δ2bp carriers had lower circulating levels of IL-15 (FDR = 0.04) than the Δ2bp non-carriers. Temporal variation of inflammatory mediators post SCI was not associated with the Δ2bp variant. For the mild SCI Δ2bp carriers, risk of pressure ulcers was positively associated with circulating levels of IFN-γ, CXCL10, and CCL4 and negatively associated with circulating levels of IL-12p70. These findings support an important role for the human-specific CHRFAM7A Δ2bp gene variant in modifying anti-inflammatory function of α7nAChRs following SCI.

Early Neurologic Recovery, Practice Pattern Variation, and the Risk of Endotracheal Intubation Following Established Status Epilepticus.

OBJECTIVE: To quantify the association between early neurologic recovery, practice pattern variation, and endotracheal intubation during established status epilepticus, we performed a secondary analysis within the cohort of patients enrolled in the Established Status Epilepticus Treatment Trial (ESETT). METHODS: We evaluated factors associated with the endpoint of endotracheal intubation occurring within 120 minutes of ESETT study drug initiation. We defined a blocked, stepwise multivariate regression, examining 4 phases during status epilepticus management: (1) baseline characteristics, (2) acute treatment, (3) 20-minute neurologic recovery, and (4) 60-minute recovery, including seizure cessation and improving responsiveness. RESULTS: Of 478 patients, 117 (24.5%) were intubated within 120 minutes. Among high-enrolling sites, intubation rates ranged from 4% to 32% at pediatric sites and 19% to 39% at adult sites. Baseline characteristics, including seizure precipitant, benzodiazepine dosing, and admission vital signs, provided limited discrimination for predicting intubation (area under the curve [AUC] 0.63). However, treatment at sites with an intubation rate in the highest (vs lowest) quartile strongly predicted endotracheal intubation independently of other treatment variables (adjusted odds ratio [aOR] 8.12, 95% confidence interval [CI] 3.08-21.4, model AUC 0.70). Site-specific variation was the factor most strongly associated with endotracheal intubation after adjustment for 20-minute (aOR 23.4, 95% CI 6.99-78.3, model AUC 0.88) and 60-minute (aOR 14.7, 95% CI 3.20-67.5, model AUC 0.98) neurologic recovery. CONCLUSIONS: Endotracheal intubation after established status epilepticus is strongly associated with site-specific practice pattern variation, independently of baseline characteristics, and early neurologic recovery and should not alone serve as a clinical trial endpoint in established status epilepticus. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT01960075.

NMDA receptor activation induces differential epigenetic modification of Bdnf promoters in hippocampal neurons.

Transcriptional regulation of the gene encoding brain-derived neurotrophic factor (BDNF) has been widely studied. However, an understanding of mechanisms modifying chromatin, events that are essential for controlling transcription, is rudimentary. We focused on two activation-dependent regions of the Bdnf gene physically linked to known transcription sites for exons 1 and 4. Using chromatin immunoprecipitation assays, we determined that N-methyl-D-aspartate (NMDA) receptor activation derepressed promoters 1 and 4-mediated transcription. This derepression correlated with reduced occupancy by histone deacetylase 1 and methyl cytosine-binding protein 2 of each promoter region near known transcription start sites in cultured hippocampal neurons. These changes did not occur at all sites upstream of transcription initiation. Taken together, these findings suggest that histone and other DNA-binding proteins are involved in remodeling of chromatin at some, but not all sites, within Bdnf promoters 1 and 4 and are associated with NMDA receptor-dependent increases in transcription.

BHLHB2 controls Bdnf promoter 4 activity and neuronal excitability.

Brain-derived neurotrophic factor (BDNF), via activation of TrkB receptors, mediates vital physiological functions in the brain, ranging from neuronal survival to synaptic plasticity, and has been implicated in the pathophysiology of neurodegenerative disorders. Although transcriptional regulation of the BDNF gene (Bdnf) has been extensively studied, much remains to be understood. We discovered a sequence within Bdnf promoter 4 that binds the basic helix-loop-helix protein BHLHB2 and is a target for BHLHB2-mediated transcriptional repression. NMDA receptor activation de-repressed promoter 4-mediated transcription and correlated with reduced occupancy of the promoter by BHLHB2 in cultured hippocampal neurons. Bhlhb2 gene -/- mice showed increased hippocampal exon 4-specific Bdnf mRNA levels compared with +/+ littermates under basal and activity-dependent conditions. Bhlhb2 knock-out mice also showed increased status epilepticus susceptibility, suggesting that BHLHB2 alters neuronal excitability. Together, these results support a role for BHLHB2 as a new modulator of Bdnf transcription and neuronal excitability.

Dynamic chromatin remodeling events in hippocampal neurons are associated with NMDA receptor-mediated activation of Bdnf gene promoter 1.

To determine the epigenetic events associated with NMDA receptor-mediated activation of brain-derived neurotrophic factor gene (Bdnf) promoter 1 by hippocampal neurons in culture, we screened 12 loci across 4.5 kb of genomic DNA 5' of the transcription start site (TSS) of rat Bdnf for specific changes in histone modification and transcription factor binding following NMDA receptor stimulation. Chromatin immunoprecipitation (ChIP) assays showed that NMDA receptor stimulation produced a durable, time-dependent decrease in histone H3 at lysine 9 dimethylation (H3K9me2), within 3 h after NMDA treatment across multiple loci. Concomitant increases in H3K4me2 and H3K9/14 acetylation (H3AcK9/14) were associated with transcriptional activation, but occurred at fewer sites within the promoter. The decrease in H3K9me2 was associated with release of HDAC1, MBD1, MeCP2, and REST from specific locations within promoter 1, although with different kinetics. In addition, occupancy of sites proximal to and distal to the TSS by the transcription factors NF-kappaB, CREB-binding protein (CBP), and cAMP-response element-binding protein were correlated with increased occupancy of RNA polymerase II at two loci proximal to the TSS following NMDA receptor stimulation. These temporal changes in promoter occupancy could occur thousands of base pairs 5' of the TSS, suggesting a mechanism that produces waves of Bdnf transcription.

Molecular differentiation of schizoaffective disorder from schizophrenia using BDNF haplotypes.

BACKGROUND: Allelic variation in the gene encoding brain-derived neurotrophic factor (BDNF) has been associated with affective disorders, but generally not schizophrenia. Brain-derived neurotrophic factor variants may help clarify the status of schizoaffective disorder. AIMS: To test the hypothesis that BDNF haplotypes are associated with psychiatric illness marked by a prominent affective component. METHOD: Frequencies of a 5-marker BDNF haplotype were examined in 600 White participants across four diagnostic categories and healthy controls. RESULTS: Individuals with schizoaffective disorder and other affective disorders were significantly more likely to carry two copies of the most common BDNF haplotype (containing the valine allele of the Val66Met polymorphism) compared with healthy volunteers. Moreover, when compared with people with schizophrenia, individuals with schizoaffective disorder were significantly more likely to carry two copies of the common haplotype. CONCLUSIONS: To our knowledge, this is the first candidate gene study to demonstrate association with schizoaffective disorder but not schizophrenia. Variation in the BDNF gene may be associated with the clinical phenotype of affective dysregulation across several DSM-IV diagnostic categories.

Association of a Functional Polymorphism in the CHRFAM7A Gene with Inflammatory Response Mediators and Neuropathic Pain after Spinal Cord Injury.

The alpha 7 nicotinic acetylcholine receptor, α7 nAChR, plays a central role in regulating inflammatory responses. Previous studies showed that pharmacological inhibitors of α7nAChR have a pro-inflammatory effect, increasing the circulating levels of cytokines such as tumor necrosis factor alpha (TNFα). This study focused on how genetic polymorphisms of the partially duplicated α7nAChR gene (CHRFAM7A), which is highly expressed in peripheral blood cells, contribute to functional outcome after spinal cord injury (SCI). In a cohort of 27 SCI patients and 25 emergency room consented controls (% F/M: 15/85, 24/76; mean ± SE age: 35 ± 1.38 and 35 ± 2.0 respectively), a panel of circulating cytokines, noradrenergic metabolite (normetanephrine [NMN]) levels, and clinical data were available within the first 7 days post-injury (DPI) up to 90 DPI, and were investigated in the acute/subacute (DPI 1-21) and intermediate (DPI 22-90) temporal periods. Cytokine and NMN plasma levels on different DPI were analyzed as a function of CHRFAM7A genotype. TNFα levels, as a representative of some elevated inflammatory mediators, were nearly threefold higher in individuals carrying the del-2bp variant of the CHRFAM7A gene compared with that in the no-deletion genotype (p = 0.001 analysis of variance [ANOVA]) 3 weeks DPI, and twofold higher than genotype-matched acute/subacute non-SCI injury controls within 7 days DPI. In contrast, NMN levels were initially unchanged, although after 3 weeks, NMN levels were significantly decreased in SCI individuals carrying the del-2bp variant compared with non-carriers (p = 0.011 ANOVA). Numerical pain scores over this same period post-injury were significantly elevated in SCI patients carrying the del-2bp variant relative to non-carriers (p = 0.001 ANOVA). Taken together, these data reveal that pro-inflammatory responses associated with CHRFAM7A gene variation may also be associated with differences in pain experience in patients following SCI, at least during the intermediate phase.

Haplotype analysis of SERPINE1 gene: Risk for aneurysmal subarachnoid hemorrhage and clinical outcomes.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) has high fatality and permanent disability rates due to the severe damage to brain cells and inflammation. The SERPINE1 gene that encodes PAI-1 for the regulation of tissue plasminogen activator is considered an important therapeutic target for aSAH. METHODS: Six SNPs in the SERPINE1 gene (in order of rs2227631, rs1799889, rs6092, rs6090, rs2227684, rs7242) were investigated. Blood samples were genotyped with Taqman genotyping assays and pyrosequencing. The experiment-wide statistically significant threshold for single marker analysis was set at p < 0.01 after evaluation of independent markers. Haplotype analysis was performed in Haplo.stats package with permutation tests. Bonferroni correction for multiple comparison in dominant, additive, and recessive model was applied. RESULTS: A total of 146 aSAH patients and 49 control subjects were involved in this study. The rs2227631 G allele is significant (p = 0.01) for aSAH compared to control. In aSAH group, haplotype analysis showed that G5GGGT homozygotes in recessive model were associated with delayed cerebral ischemia (p < 0.01, Odds Ratio = 5.14, 95% CI = 1.45-18.18), clinical vasospasm (p = 0.01, Odds Ratio = 4.58, 95% CI = 1.30-16.13), and longer intensive care unit stay (p = 0.01). By contrast, the G5GGAG carriers were associated with less incidence of cerebral edema (p < 0.01) and higher Glasgow Coma Scale (p < 0.01). The A4GGGT carriers were associated with less incidence of severe hypertension (>140/90) (p < 0.01). CONCLUSION: The results suggested an important regulatory role of the SERPINE1 gene polymorphism in clinical outcomes of aSAH.

Hormesis: a promising strategy to sustain endogenous neuronal survival pathways against neurodegenerative disorders.

The brain developed adaptive mechanisms in the face of changing environments and stresses imposed on the nervous system. The addition of glutamate as the major excitatory amino acid neurotransmitter to the brain's complement of amino acids and peptides dictated a coordinated transcriptional and translational program to meet the demands of excitatory neurotransmission. One such program is the ability of neurons to sustain and maintain their survival given the nature of glutamate-mediated receptor activation. The unique development of endogenous neuronal pathways activated by glutamate receptors transformed neurons and allowed them to survive under conditions of high energy demands. These same endogenous survival pathways also mediate plastic responses to meet another demand of the brain, adaptation. An endogenous protein that plays a central role in glutamate receptor-mediated survival pathways is brain-derived neurotrophic factor (BDNF). Intermittent but frequent synaptic ionotropic glutamate receptor activation ensures neuronal survival through a BDNF autocrine loop. In sharp contrast, overactivation of ionotropic glutamate receptors leads to neuronal cell death. Thus, innovative strategies that induce endogenous neuronal survival pathways through low-level activation of ionotropic glutamate receptors or those that bypass receptor activation but upregulate endogenous survival pathways may not only prevent neurodegenerative disorders that involve glutamate as a final common pathway that kills neurons, but may also provide treatment alternatives critical for neurons to survive stressful conditions such as stroke, status epilepticus and hypoglycemic-induced neuronal cell death.

Association between a functional serotonin transporter promoter polymorphism and citalopram treatment in adult outpatients with major depression.

CONTEXT: The HTTLPR, a functional polymorphism of the serotonin transporter gene solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (SLC6A4), promoter, affects transcription and may be involved in antidepressant drug treatment outcome, although response rates with antidepressants can be lower in patients who experience adverse effects. OBJECTIVE: To test the hypothesis that HTTLPR is associated with treatment outcome to citalopram. DESIGN: A clinical effectiveness trial, Sequenced Treatment Alternatives to Relieve Depression, collected DNA samples from outpatients with nonpsychotic major depressive disorder who received citalopram in the first treatment step. The triallelic HTTLPR locus was genotyped in 1775 samples to discriminate between long (L) and short (S) alleles, followed by the A > G substitution. The low-expression S and L(G) alleles were grouped together compared with the high-expression L(A) allele. SETTING: Eighteen primary care and 23 psychiatric care sites across the United States. PARTICIPANTS: Ages 18 to 75 years, meeting criteria for single or recurrent nonpsychotic major depression. MAIN OUTCOME MEASURES: Categorical response, remission, tolerance, and adverse effect burden. RESULTS: Expression-based grouping produced a significant finding of association between the L(A) allele and adverse effect burden in the entire sample (P = .004 [genotype frequency]; P < .001 [allele frequency]). To control for bias from population stratification, a white American subsample was analyzed. A lesser adverse effect burden was associated with L(A)L(A) genotype frequency (P = .03) or L(A) allele frequency (P = .007). These findings in white patients did not hold when the L allele was undifferentiated. No association was observed between treatment outcome phenotypes and HTTLPR. Development of diarrhea and the presence of the low-expression S or L(G) alleles were the strongest risk factors associated with adverse effect burden. CONCLUSIONS: The HTTLPR polymorphism is associated with citalopram adverse effects. Because the L(A) allele confers increased SLC6A4 transcription, increased serotonin transporter levels in brain and other tissues may lead to fewer adverse effects for antidepressant medications that target the transporter.

PHASES score applied to a prospective cohort of aneurysmal subarachnoid hemorrhage patients.

The treatment of unruptured intracranial aneurysms remains controversial. The PHASES score was developed to predict the 5-year risk of aneurysm rupture. We have assigned PHASES scores to a cohort of aneurysmal subarachnoid hemorrhage (aSAH) patients to assess the distribution of scores and its ability to predict outcome. In this study, the PHASES score was applied to a prospective cohort of aSAH patients that were enrolled in the Cerebral Aneurysm Renin Angiotensin System (CARAS) study. The CARAS study enrolled patients from two academic institutions in the United States from 2012 to 2015. Univariable and multivariable analyses were performed to identify factors predictive of outcome at last follow up. One hundred and forty-nine aSAH patients were included with a mean age of 54.9 ±â€¯12.5 years. Most ruptured aneurysms were <7 mm (62.4%) and located in the anterior circulation (80.5%). Favorable functional outcome (mRS 0-2) at last follow up was achieved in 61.7% of patients. PHASES scores ranged from 0 to 16 with a median of 5; the majority of patients had a score of 4 (20.1%) or 5 (32.2%). Multivariable modeling identified higher PHASES scores (OR 1.235, CI 1.016-1.501, p = 0.034) and higher Hunt and Hess grades (OR 2.224, CI 1.353-3.655, p = 0.002) as independent predictors of poor functional outcome (mRS 3-6) at last follow up. The majority of aSAH patients present with low (≤5) PHASES scores. Elevated PHASES scores are independently associated with poor functional outcome in patients with aSAH.

Mice lacking the transcriptional regulator Bhlhe40 have enhanced neuronal excitability and impaired synaptic plasticity in the hippocampus.

Bhlhe40 is a transcription factor that is highly expressed in the hippocampus; however, its role in neuronal function is not well understood. Here, we used Bhlhe40 null mice on a congenic C57Bl6/J background (Bhlhe40 KO) to investigate the impact of Bhlhe40 on neuronal excitability and synaptic plasticity in the hippocampus. Bhlhe40 KO CA1 neurons had increased miniature excitatory post-synaptic current amplitude and decreased inhibitory post-synaptic current amplitude, indicating CA1 neuronal hyperexcitability. Increased CA1 neuronal excitability was not associated with increased seizure severity as Bhlhe40 KO relative to +/+ (WT) control mice injected with the convulsant kainic acid. However, significant reductions in long term potentiation and long term depression at CA1 synapses were observed in Bhlhe40 KO mice, indicating impaired hippocampal synaptic plasticity. Behavioral testing for spatial learning and memory on the Morris Water Maze (MWM) revealed that while Bhlhe40 KO mice performed similarly to WT controls initially, when the hidden platform was moved to the opposite quadrant Bhlhe40 KO mice showed impairments in relearning, consistent with decreased hippocampal synaptic plasticity. To investigate possible mechanisms for increased neuronal excitability and decreased synaptic plasticity, a whole genome mRNA expression profile of Bhlhe40 KO hippocampus was performed followed by a chromatin immunoprecipitation sequencing (ChIP-Seq) screen of the validated candidate genes for Bhlhe40 protein-DNA interactions consistent with transcriptional regulation. Of the validated genes identified from mRNA expression analysis, insulin degrading enzyme (Ide) had the most significantly altered expression in hippocampus and was significantly downregulated on the RNA and protein levels; although Bhlhe40 did not occupy the Ide gene by ChIP-Seq. Together, these findings support a role for Bhlhe40 in regulating neuronal excitability and synaptic plasticity in the hippocampus and that indirect regulation of Ide transcription may be involved in these phenotypes.

Associations between endothelin polymorphisms and aneurysmal subarachnoid hemorrhage, clinical vasospasm, delayed cerebral ischemia, and functional outcome.

OBJECTIVE Endothelin-1, a potent vasoconstrictor, and its receptors may be involved in the pathogenesis of aneurysmal subarachnoid hemorrhage (aSAH), clinical vasospasm, delayed cerebral ischemia (DCI), and functional outcome following aSAH. In the present study, common endothelin single nucleotide polymorphisms (SNPs) and their relation to aSAH were evaluated. METHODS Blood samples from all patients enrolled in the Cerebral Aneurysm Renin Angiotensin System (CARAS) study were used for genetic evaluation. The CARAS study prospectively enrolled patients with aSAH at 2 academic institutions in the US from 2012 to 2015. Common endothelin SNPs were detected using 5' exonnuclease (TaqMan) genotyping assays. Analysis of associations between endothelin SNPs and aSAH and its clinical sequelae was performed. RESULTS Samples from 149 patients with aSAH and 50 controls were available for analysis. In multivariate logistic regression analysis, the TG (odds ratio [OR] 2.102, 95% confidence interval [CI] 1.048-4.218, p = 0.036) and TT genotypes (OR 7.884, 95% CI 1.003-61.995, p = 0.05) of the endothelin-1 T/G SNP (rs1800541) were significantly associated with aSAH. There was a dominant effect of the G allele (CG/GG genotypes; OR 4.617, 95% CI 1.311-16.262, p = 0.017) of the endothelin receptor A G/C SNP (rs5335) on clinical vasospasm. Endothelin SNPs were not associated with DCI or functional outcome. CONCLUSIONS Common endothelin SNPs were found to be associated with presentation with aSAH and clinical vasospasm. Further studies are required to elucidate the relevant pathophysiology and its potential implications in the treatment of patients with aSAH.