RESUMO
OBJECTIVE: Identifying factors that moderate cognitive outcomes following mild traumatic brain injury (mTBI) is crucial. Prospective memory (PM) is a cognitive domain of interest in mTBI recovery as it may be especially sensitive to TBI-related changes. Since studies show that genetic status - particularly possession of the apolipoprotein E (APOE) ε4 allele - can modify PM performance, we investigated associations between mTBI status and APOE-ε4 genotype on PM performance in a well-characterized sample of Veterans with neurotrauma histories. METHODS: 59 Veterans (mTBI = 33, Military Controls [MCs] = 26; age range: 24-50; average years post-injury = 10.41) underwent a structured clinical interview, neuropsychological assessment, and genotyping. The Memory for Intentions Test (MIST) measured PM across multiple subscales. ANCOVAs, adjusting for age and posttraumatic stress symptoms, tested the effects of mTBI status (mTBI vs. MC) and ε4 status (ε4+ vs. ε4-) on MIST scores. RESULTS: Veterans with mTBI history performed more poorly compared to MCs on the MIST 15-min delay (p=.002, ηp2 =.160), Time Cue (p = .003, ηp2 =.157), and PM Total (p = .016, ηp2 =.102). Those with at least one copy of the ε4 allele performed more poorly compared to ε4- Veterans on the MIST 15-min delay (p = .011, ηp2 =.113) and PM Total (p = .048, ηp2 = .071). No significant interactions were observed between mTBI and APOE-ε4 status on MIST outcomes (ps>.25). Within the mTBI group, APOE-ε4+ Veterans performed worse than APOE-ε4- Veterans on the MIST 15-min delay subscale (p = .031, ηp2 = .150). CONCLUSIONS: mTBI history and APOE-ε4 genotype status were independently associated with worse PM performance compared to those without head injury histories or possession of the APOE-e4 genotype. Performance on the MIST 15-min delay was worse in Veterans with both risk factors (mTBI history and APOE-ε4 positivity). Findings suggest that genetic status may modify outcomes even in relatively young Veterans with mTBI histories. Future research examining longitudinal associations and links to neuroimaging and biomarker data are needed.
Assuntos
Apolipoproteína E4 , Concussão Encefálica , Memória Episódica , Veteranos , Humanos , Masculino , Apolipoproteína E4/genética , Adulto , Feminino , Concussão Encefálica/genética , Concussão Encefálica/complicações , Concussão Encefálica/fisiopatologia , Pessoa de Meia-Idade , Adulto Jovem , Genótipo , Testes Neuropsicológicos/estatística & dados numéricosRESUMO
More than 75% of traumatic brain injuries (TBIs) are mild (mTBI) and military service members often experience repeated combat-related mTBI. The chronic comorbidities concomitant with repetitive mTBI (rmTBI) include depression, post-traumatic stress disorder or neurological dysfunction. This study sought to determine a long noncoding RNA (lncRNA) expression signature in serum samples that correlated with rmTBI years after the incidences. Serum samples were obtained from Long-Term Impact of Military-Relevant Brain-Injury Consortium Chronic Effects of Neurotrauma Consortium (LIMBIC CENC) repository, from participants unexposed to TBI or who had rmTBI. Four lncRNAs were identified as consistently present in all samples, as detected via droplet digital PCR and packaged in exosomes enriched for CNS origin. The results, using qPCR, demonstrated that the lncRNA VLDLR-AS1 levels were significantly lower among individuals with rmTBI compared to those with no lifetime TBI. ROC analysis determined an AUC of 0.74 (95% CI: 0.6124 to 0.8741; p = 0.0012). The optimal cutoff for VLDLR-AS1 was ≤153.8 ng. A secondary analysis of clinical data from LIMBIC CENC was conducted to evaluate the psychological symptom burden, and the results show that lncRNAs VLDLR-AS1 and MALAT1 are correlated with symptoms of depression. In conclusion, lncRNA VLDLR-AS1 may serve as a blood biomarker for identifying chronic rmTBI and depression in patients.
Assuntos
Concussão Encefálica , Lesões Encefálicas Traumáticas , RNA Longo não Codificante , Veteranos , Humanos , Veteranos/psicologia , Concussão Encefálica/epidemiologia , Concussão Encefálica/genética , Concussão Encefálica/complicações , RNA Longo não Codificante/genética , Depressão/genética , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/complicaçõesRESUMO
MicroRNAs (miRNAs) are non-coding RNA molecules that function in RNA silencing and post-transcriptional regulation of gene expression. They are profound mediators of molecular and cellular changes in several pathophysiological conditions. Since miRNAs play major roles in regulating gene expression after traumatic brain injury (TBI), their possible role in diagnosis, prognosis, and therapy is not much explored. In this study, we aimed to identify specific miRNAs that are involved in the pathophysiological conditions in the first 24 h after mild TBI (mTBI). The genome-wide expression of miRNAs was evaluated by applying RNA sequence in the injury area of the cerebral cortex 24 after inflicting the injury using a mouse model of mild fluid percussion injury (FPI; 10 psi). Here, we identified different annotated, conserved, and novel miRNAs. A total of 978 miRNAs after 24 h of TBI were identified, and among these, 906 miRNAs were differentially expressed between control and mTBI groups. In this study, 146 miRNAs were identified as novel to mTBI and among them, 21 miRNAs were significant (p < 0.05). Using q-RT-PCR, we validated 10 differentially and significantly expressed novel miRNAs. Further, we filtered the differentially expressed miRNAs that were linked with proinflammatory cytokines, apoptosis, matrix metalloproteinases (MMPs), and tight junction and junctional adhesion molecule genes. Overall, this work shows that mTBI induces widespread changes in the expression of miRNAs that may underlie the progression of the TBI pathophysiology. The detection of several novel TBI-responsive miRNAs and their solid link with pathophysiological genes may help in identifying novel therapeutic targets.
Assuntos
Concussão Encefálica , Lesões Encefálicas Traumáticas , MicroRNAs , Humanos , Concussão Encefálica/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/metabolismo , Regulação da Expressão Gênica , Córtex Cerebral/patologiaRESUMO
We have previously reported that pathogenic variants in a key metabolite repair enzyme NAXD cause a lethal neurodegenerative condition triggered by episodes of fever in young children. However, the clinical and genetic spectrum of NAXD deficiency is broadening as our understanding of the disease expands and as more cases are identified. Here, we report the oldest known individual succumbing to NAXD-related neurometabolic crisis, at 32 years of age. The clinical deterioration and demise of this individual were likely triggered by mild head trauma. This patient had a novel homozygous NAXD variant [NM_001242882.1:c.441+3A>G:p.?] that induces the mis-splicing of the majority of NAXD transcripts, leaving only trace levels of canonically spliced NAXD mRNA, and protein levels below the detection threshold by proteomic analysis. Accumulation of damaged NADH, the substrate of NAXD, could be detected in the fibroblasts of the patient. In agreement with prior anecdotal reports in paediatric patients, niacin-based treatment also partly alleviated some clinical symptoms in this adult patient. The present study extends our understanding of NAXD deficiency by uncovering shared mitochondrial proteomic signatures between the adult and our previously reported paediatric NAXD cases, with reduced levels of respiratory complexes I and IV as well as the mitoribosome, and the upregulation of mitochondrial apoptotic pathways. Importantly, we highlight that head trauma in adults, in addition to paediatric fever or illness, may precipitate neurometabolic crises associated with pathogenic NAXD variants.
Assuntos
Concussão Encefálica , Encefalopatias Metabólicas , Hidroliases , Adulto , Criança , Pré-Escolar , Humanos , Hidroliases/metabolismo , Mitocôndrias/metabolismo , NAD/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Proteômica , Concussão Encefálica/complicações , Concussão Encefálica/genética , Encefalopatias Metabólicas/etiologia , Encefalopatias Metabólicas/genéticaRESUMO
OBJECTIVE: Concussions are common match injuries in elite rugby, and reports exist of reduced cognitive function and long-term health consequences that can interrupt or end a playing career and produce continued ill health. The aim of this study was to investigate the association between elite rugby status and 8 concussion-associated risk polymorphisms. We hypothesized that concussion-associated risk genotypes and alleles would be underrepresented in elite rugby athletes compared with nonathletes. DESIGN: A case-control genetic association study. SETTING: Institutional (university). PARTICIPANTS: Elite White male rugby athletes [n = 668, mean (SD) height 1.85 (0.07) m, mass 102 (12) kg, and age 29 (7) years] and 1015 nonathlete White men and women (48% men). INTERVENTIONS: Genotype was the independent variable, obtained by PCR of genomic DNA using TaqMan probes. MAIN OUTCOME MEASURE: Elite athlete status with groups compared using χ 2 and odds ratio (OR). RESULTS: The COMT rs4680 Met/Met (AA) genotype, Met allele possession, and Met allele frequency were lower in rugby athletes (24.8%, 74.6%, and 49.7%, respectively) than nonathletes (30.2%, 77.6%, and 54.0%; P < 0.05). The Val/Val (GG) genotype was more common in elite rugby athletes than nonathletes (OR 1.39, 95% confidence interval 1.04-1.86). No other polymorphism was associated with elite athlete status. CONCLUSIONS: Elite rugby athlete status is associated with COMT rs4680 genotype that, acting pleiotropically, could affect stress resilience and behavioral traits during competition, concussion risk, and/or recovery from concussion. Consequently, assessing COMT rs4680 genotype might aid future individualized management of concussion risk among athletes.
Assuntos
Concussão Encefálica , Futebol Americano , Humanos , Masculino , Feminino , Adulto , Rugby , Futebol Americano/lesões , Concussão Encefálica/genética , Concussão Encefálica/psicologia , Polimorfismo Genético , Atletas , Catecol O-Metiltransferase/genéticaRESUMO
Due to the high-velocity collision-based nature of elite rugby league and union, the risk of sustaining a concussion is high. Occurrence of and outcomes following a concussion are probably affected by the interaction of multiple genes in a polygenic manner. This study investigated whether suspected concussion-associated polygenic profiles of elite rugby athletes differed from non-athletes and between rugby union forwards and backs. We hypothesised that a total genotype score (TGS) using eight concussion-associated polymorphisms would be higher in elite rugby athletes than non-athletes, indicating selection for protection against incurring or suffering prolonged effects of, concussion in the relatively high-risk environment of competitive rugby. In addition, multifactor dimensionality reduction was used to identify genetic interactions. Contrary to our hypothesis, TGS did not differ between elite rugby athletes and non-athletes (p ≥ 0.065), nor between rugby union forwards and backs (p = 0.668). Accordingly, the TGS could not discriminate between elite rugby athletes and non-athletes (AUC ~0.5), suggesting that, for the eight polymorphisms investigated, elite rugby athletes do not have a more 'preferable' concussion-associated polygenic profile than non-athletes. However, the COMT (rs4680) and MAPT (rs10445337) GC allele combination was more common in rugby athletes (31.7%; p < 0.001) and rugby union athletes (31.8%; p < 0.001) than non-athletes (24.5%). Our results thus suggest a genetic interaction between COMT (rs4680) and MAPT (rs10445337) assists rugby athletes in achieving elite status. These findings need exploration vis-à-vis sport-related concussion injury data and could have implications for the management of inter-individual differences in concussion risk.
Assuntos
Traumatismos em Atletas , Concussão Encefálica , Herança Multifatorial , Rugby , Atletas , Traumatismos em Atletas/genética , Concussão Encefálica/genética , Humanos , Masculino , Rugby/lesõesRESUMO
AIM: To explore the short-term effects of accidental head impacts and repetitive headers on circulating microRNAs, accounting for the effects of high-intensity exercise alone. METHODS: Blood samples were collected from professional soccer players at rest. Repeat samples were drawn 1 h and 12 h after three conditions: (1) accidental head impacts in a match, (2) repetitive headers during training, and (3) high-intensity exercise. 89 samples were screened to detect microRNAs expressed after each exposure. Identified microRNAs were then validated in 98 samples to determine consistently deregulated microRNAs. Deregulated microRNAs were further explored using bioinformatics to identify target genes and characterize their involvement in biological pathways. RESULTS: Accidental head impacts led to deregulation of eight microRNAs that were unaffected by high-intensity exercise; target genes were linked to 12 specific signaling pathways, primarily regulating chromatin organization, Hedgehog and Wnt signaling. Repetitive headers led to deregulation of six microRNAs that were unaffected by high-intensity exercise; target genes were linked to one specific signaling pathway (TGF-ß). High-intensity exercise led to deregulation of seven microRNAs; target genes were linked to 31 specific signaling pathways. CONCLUSION: We identified microRNAs specific to accidental head impacts and repetitive headers in soccer, potentially being useful as brain injury biomarkers.
Assuntos
Concussão Encefálica , MicroRNA Circulante , MicroRNAs , Futebol , Biomarcadores , Concussão Encefálica/genética , MicroRNA Circulante/genética , Cabeça , Humanos , MicroRNAs/genética , Futebol/lesõesAssuntos
Traumatismos em Atletas/epidemiologia , Concussão Encefálica/epidemiologia , Suscetibilidade a Doenças , Caracteres Sexuais , Esportes , Aceleração , Animais , Traumatismos em Atletas/diagnóstico , Traumatismos em Atletas/genética , Traumatismos em Atletas/patologia , Axônios/patologia , Concussão Encefálica/diagnóstico , Concussão Encefálica/genética , Concussão Encefálica/patologia , Estudos de Coortes , Feminino , Futebol Americano , Inquéritos Epidemiológicos , Humanos , Masculino , Doenças Neurodegenerativas/epidemiologia , Doenças Neurodegenerativas/genética , Progesterona/metabolismo , Prognóstico , Ratos , Medicina Esportiva/economia , Medicina Esportiva/tendências , Traumatismos em Chicotada/epidemiologia , Traumatismos em Chicotada/patologiaRESUMO
Past research has found a relationship between the apolipoprotein E (APOE) e4 allele and worse neurobehavioral functioning following mild traumatic brain injury (MTBI) in civilian populations. The purpose of this study was to examine this relationship in service members and veterans (SMVs) following MTBI. Participants were 151 SMVs (103 uncomplicated MTBI; 48 Injured Controls [IC]) prospectively enrolled in the DVBIC-TBICoE 15-Year Longitudinal TBI Study. Participants completed a battery of self-reported neurobehavioral symptom measures on average 76.2 months post-injury (SD = 31.8). APOE genotyping was undertaken using non-fasting blood samples. Participants were classified into four subgroups based on injury (MTBI vs. IC) and APOE e4 allele status (e4 present/absent). In the IC group, there were no significant differences across APOE e4 status subgroups for all measures. In the MTBI group, participants with the APOE e4 allele had significantly worse scores on measures of depression, pain, anxiety, grief, positive well-being, social participation, and resilience compared to those without the e4 allele (d = .44 to d = .69). When comparing the number of 'clinically elevated' neurobehavioral measures simultaneously, the MTBI/e4 present subgroup consistently had a higher number of elevated measures compared to the MTBI/e4 absent, IC/e4 present, and IC/e4 absent subgroups. The APOE e4 allele was associated with poorer neurobehavioral outcome in SMVs in the chronic phase of recovery following MTBI. APOE e4 could be incorporated into screening tools to predict SMVs at risk for poor long-term neurobehavioral outcome in an effort to provide early intervention to improve long-term clinical outcome.
Assuntos
Apolipoproteína E4/genética , Sintomas Comportamentais/fisiopatologia , Concussão Encefálica/genética , Concussão Encefálica/fisiopatologia , Militares , Adulto , Idoso , Sintomas Comportamentais/etiologia , Concussão Encefálica/complicações , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Autorrelato , Estados Unidos , VeteranosRESUMO
BACKGROUND: Major depression has been recognized as the most commonly diagnosed psychiatric complication of mild traumatic brain injury (mTBI). Moreover, major depression is associated with poor outcomes following mTBI; however, the underlying biological mechanisms of this are largely unknown. Recently, genomic and epigenetic factors have been increasingly implicated in the recovery following TBI. RESULTS: This study leveraged DNA methylation within the major depression pathway, along with demographic and behavior measures (features used in the clinical model) to predict post-concussive symptom burden and quality of life four-month post-injury in a cohort of 110 pediatric mTBI patients and 87 age-matched healthy controls. The results demonstrated that including DNA methylation markers in the major depression pathway improved the prediction accuracy for quality of life but not persistent post-concussive symptom burden. Specifically, the prediction accuracy (i.e., the correlation between the predicted value and observed value) of quality of life was improved from 0.59 (p = 1.20 × 10-3) (clinical model) to 0.71 (p = 3.89 × 10-5); the identified cytosine-phosphate-guanine sites were mainly in the open sea regions and the mapped genes were related to TBI in several molecular studies. Moreover, depression symptoms were a strong predictor (with large weights) for both post-concussive symptom burden and pediatric quality of life. CONCLUSION: This study emphasized that both molecular and behavioral manifestations of depression symptoms played a prominent role in predicting the recovery process following pediatric mTBI, suggesting the urgent need to further study TBI-caused depression symptoms for better recovery outcome.
Assuntos
Concussão Encefálica/complicações , Transtorno Depressivo Maior/etiologia , Qualidade de Vida/psicologia , Adolescente , Concussão Encefálica/epidemiologia , Concussão Encefálica/genética , Criança , Estudos de Coortes , Metilação de DNA/genética , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Maior/psicologia , Feminino , Humanos , Masculino , Suíça/epidemiologiaRESUMO
Mild traumatic brain injury (mTBI) results in broad neurological symptoms and an increased risk of being diagnosed with a neurodegenerative disease later in life. While the immediate oxidative stress response and post-mortem pathology of the injured brain has been well studied, it remains unclear how early pathogenic changes may drive persistent symptoms and confer susceptibility to neurodegeneration. In this study we have used a mouse model of repeated mTBI (rmTBI) to identify early gene expression changes at 24 h or 7 days post-injury (7 dpi). At 24 h post-injury, gene expression of rmTBI mice shows activation of the DNA damage response (DDR) towards double strand DNA breaks, altered calcium and cell-cell signalling, and inhibition of cell death pathways. By 7 dpi, rmTBI mice had a gene expression signature consistent with induction of cellular senescence, activation of neurodegenerative processes, and inhibition of the DDR. At both timepoints gliosis, microgliosis, and axonal damage were evident in the absence of any gross lesion, and by 7 dpi rmTBI also mice had elevated levels of IL1ß, p21, 53BP1, DNA2, and p53, supportive of DNA damage-induced cellular senescence. These gene expression changes reflect establishment of processes usually linked to brain aging and suggests that cellular senescence occurs early and most likely prior to the accumulation of toxic proteins. These molecular changes were accompanied by spatial learning and memory deficits in the Morris water maze. To conclude, we have identified DNA damage-induced cellular senescence as a repercussion of repeated mild traumatic brain injury which correlates with cognitive impairment. Pathways involved in senescence may represent viable treatment targets of post-concussive syndrome. Senescence has been proposed to promote neurodegeneration and appears as an effective target to prevent long-term complications of mTBI, such as chronic traumatic encephalopathy and other related neurodegenerative pathologies.
Assuntos
Envelhecimento/patologia , Concussão Encefálica/patologia , Disfunção Cognitiva/patologia , Dano ao DNA/fisiologia , Modelos Animais de Doenças , Idade de Início , Envelhecimento/genética , Envelhecimento/psicologia , Animais , Concussão Encefálica/genética , Concussão Encefálica/psicologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/psicologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The cumulative effect of mild traumatic brain injuries (mTBI) can result in chronic neurological damage, however the molecular mechanisms underpinning this detriment require further investigation. A closed head weight drop model that replicates the biomechanics and head acceleration forces of human mTBI was used to provide an exploration of the acute and chronic outcomes following single and repeated impacts. Adult male C57BL/6J mice were randomly assigned into one of four impact groups (control; one, five and 15 impacts) which were delivered over 23 days. Outcomes were assessed 48 hours and 3 months following the final mTBI. Hippocampal spatial learning and memory assessment revealed impaired performance in the 15-impact group compared with control in the acute phase that persisted at chronic measurement. mRNA analyses were performed on brain tissue samples of the cortex and hippocampus using quantitative RT-PCR. Eight genes were assessed, namely MAPT, GFAP, AIF1, GRIA1, CCL11, TARDBP, TNF, and NEFL, with expression changes observed based on location and follow-up duration. The cortex and hippocampus showed vulnerability to insult, displaying upregulation of key excitotoxicity and inflammation genes. Serum samples showed no difference between groups for proteins phosphorylated tau and GFAP. These data suggest that the cumulative effect of the impacts was sufficient to induce mTBI pathophysiology and clinical features. The genes investigated in this study provide opportunity for further investigation of mTBI-related neuropathology and may provide targets in the development of therapies that help mitigate the effects of mTBI.
Assuntos
Concussão Encefálica/genética , Encéfalo/metabolismo , Inflamação/genética , Animais , Encéfalo/patologia , Concussão Encefálica/metabolismo , Concussão Encefálica/patologia , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Quimiocina CCL11/genética , Quimiocina CCL11/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Proteínas de Neurofilamentos/genética , Proteínas de Neurofilamentos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de AMPA/genética , Receptores de AMPA/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
INTRODUCTION: Traumatic brain injury (TBI) is considered as the most robust environmental risk factor for Alzheimer's disease (AD). Besides direct neuronal injury and neuroinflammation, vascular impairment is also a hallmark event of the pathological cascade after TBI. However, the vascular connection between TBI and subsequent AD pathogenesis remains underexplored. METHODS: In a closed-head mild TBI (mTBI) model in mice with controlled cortical impact, we examined the time courses of microvascular injury, blood-brain barrier (BBB) dysfunction, gliosis and motor function impairment in wild type C57BL/6 mice. We also evaluated the BBB integrity, amyloid pathology as well as cognitive functions after mTBI in the 5xFAD mouse model of AD. RESULTS: mTBI induced microvascular injury with BBB breakdown, pericyte loss, basement membrane alteration and cerebral blood flow reduction in mice, in which BBB breakdown preceded gliosis. More importantly, mTBI accelerated BBB leakage, amyloid pathology and cognitive impairment in the 5xFAD mice. DISCUSSION: Our data demonstrated that microvascular injury plays a key role in the pathogenesis of AD after mTBI. Therefore, restoring vascular functions might be beneficial for patients with mTBI, and potentially reduce the risk of developing AD.
Assuntos
Doença de Alzheimer/patologia , Concussão Encefálica/patologia , Disfunção Cognitiva/patologia , Progressão da Doença , Microvasos/patologia , Doença de Alzheimer/etiologia , Doença de Alzheimer/genética , Animais , Concussão Encefálica/complicações , Concussão Encefálica/genética , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
PURPOSE: This study aimed to screen the entire genome for genetic markers associated with risk for concussion. METHODS: A genome-wide association analyses was performed using data from the Kaiser Permanente Research Bank and the UK Biobank. Concussion cases were identified based on electronic health records from the Kaiser Permanente Research Bank and the UK Biobank from individuals of European ancestry. Genome-wide association analyses from both cohorts were tested for concussion using a logistic regression model adjusting for sex, height, weight, and race/ethnicity using allele counts for single nucleotide polymorphisms. Previously identified genes within the literature were also tested for association with concussion. RESULTS: There were a total of 4064 cases of concussion and 291,472 controls within the databases, with two single nucleotide polymorphisms demonstrating a genome-wide significant association with concussion. The first polymorphism, rs144663795 (P = 9.7 × 10-11; OR = 2.91 per allele copy), is located within the intron of SPATA5. Strong, deleterious mutations in SPATA5 cause intellectual disability, hearing loss, and vision loss. The second polymorphism, rs117985931 (P = 3.97 × 10-9; OR = 3.59 per allele copy), is located within PLXNA4. PLXNA4 plays a key role is axon outgrowth during neural development, and DNA variants in PLXNA4 are associated with risk for Alzheimer's disease. Previous investigations have identified five candidate genes that may be associated with concussion, but none showed a significant association in the current model (P < 0.05). CONCLUSION: Two genetic markers were identified as potential risk factors for concussion and deserve further validation and investigation of molecular mechanisms.
Assuntos
ATPases Associadas a Diversas Atividades Celulares/genética , Concussão Encefálica/genética , Estudo de Associação Genômica Ampla , Receptores de Superfície Celular/genética , Alelos , Estatura , Peso Corporal , Concussão Encefálica/epidemiologia , Concussão Encefálica/etnologia , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Marcadores Genéticos , Humanos , Modelos Logísticos , Masculino , Mutação , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Fatores SexuaisRESUMO
Pediatric traumatic brain injury (TBI) can lead to adverse emotional, social, and behavioral consequences. However, outcome is difficult to predict due to significant individual variability, likely reflecting a complex interaction between injury- and child-related variables. Among these variables are genetically determined individual differences, which can modulate TBI outcome through their influence on neuroplasticity mechanisms. In this study, we examined the effect of Val66Met, a common polymorphism of the brain-derived neurotrophic factor gene known to be involved in neuroplasticity mechanisms, on behavioral symptoms of mild TBI (mTBI) sustained in early childhood. This work is part of a prospective, longitudinal cohort study of early TBI. The current sample consisted of 145 children between ages 18 and 60 months assigned to one of three participant groups: mild TBI, orthopedic injury, or typically developing children. Participants provided a saliva sample to detect the presence of the Val66Met polymorphism, and the Child Behavior Checklist was used to document the presence of behavioral symptoms at 6- and 18-months post-injury. Contrary to our initial hypothesis, at 6 months post-injury, non-carriers of the Val66Met polymorphism in the mTBI group presented significantly more internalizing symptoms (e.g., anxiety/depression and somatic complaints) than Val66Met carriers, who were similar to orthopedically injured and typically developing children. However, at 18 months post-injury, all children with mTBI presented more internalizing symptoms, independent of genotype. The results of the study provide evidence for a protective effect of the Val66Met polymorphism on internalizing behavior symptoms 6 months after early childhood mTBI.
Assuntos
Ansiedade/etiologia , Concussão Encefálica/complicações , Fator Neurotrófico Derivado do Encéfalo/genética , Depressão/etiologia , Polimorfismo de Nucleotídeo Único , Adolescente , Alelos , Ansiedade/genética , Concussão Encefálica/genética , Criança , Pré-Escolar , Depressão/genética , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Estudos ProspectivosRESUMO
Recurrent concussions increase risk for persistent post-concussion symptoms, and may lead to chronic neurocognitive deficits. Little is known about the molecular pathways that contribute to persistent concussion symptoms. We hypothesized that salivary measurement of microribonucleic acids (miRNAs), a class of epitranscriptional molecules implicated in concussion pathophysiology, would provide insights about the molecular cascade resulting from recurrent concussions. This hypothesis was tested in a case-control study involving 13 former professional football athletes with a history of recurrent concussion, and 18 age/sex-matched peers. Molecules of interest were further validated in a cross-sectional study of 310 younger individuals with a history of no concussion (n = 230), a single concussion (n = 56), or recurrent concussions (n = 24). There was no difference in neurocognitive performance between the former professional athletes and their peers, or among younger individuals with varying concussion exposures. However, younger individuals without prior concussion outperformed peers with prior concussion on three balance assessments. Twenty salivary miRNAs differed (adj. p < 0.05) between former professional athletes and their peers. Two of these (miR-28-3p and miR-339-3p) demonstrated relationships (p < 0.05) with the number of prior concussions reported by younger individuals. miR-28-3p and miR-339-5p may play a role in the pathophysiologic mechanism involved in cumulative concussion effects.
Assuntos
Biomarcadores/metabolismo , Concussão Encefálica/genética , MicroRNAs/genética , Saliva/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Atletas/estatística & dados numéricos , Estudos de Casos e Controles , Criança , Estudos Transversais , Futebol Americano , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Mild traumatic brain injury (mTBI) in early childhood is prevalent, and some children may be at risk for short- and long-term difficulties that could affect quality of life (QoL). Despite growing efforts to understand associations between potential risk factors and outcomes after injury, prognosis is elusive and lacks the inclusion of genetic variables which may convey additional predictive power. This study assessed which factors contribute to pediatric QoL 6 and 18 months post-recruitment in 159 participants (mTBI = 52; orthopedic injury [OI] = 43; typically developing controls [TDC] = 64) aged 18 to 60 months at the time of injury (M = 37.50, SD = 11.69). Family environment, injury characteristics, and child cognitive-behavioral functioning were assessed at 6 months via parent questionnaires and socio-cognitive assessment. QoL was determined using the Pediatric Quality of Life Inventory at both time points. Genetic information (Brain-derived neurotrophic factor [BDNF] genotype) was collected using saliva samples. Hierarchical regression analyses testing biological, family-environmental, injury and cognitive-behavioral factors revealed that the BDNF Val66Met polymorphism was a significant independent predictor of better QoL 6 months post-injury in the mTBI group. Lower parental distress significantly and independently predicted higher QoL 18 months after mTBI, and 6 months post-recruitment in the TDC group. At 18 months, models were non-significant for both control groups. Genetic factors involved in neuroplasticity may play an important role in recovery 6 months after mTBI and contribute to outcome via their interplay with environmental factors. Over time, family factors appear to become the primary determinants of post-mTBI outcome.
Assuntos
Concussão Encefálica/psicologia , Cognição/fisiologia , Qualidade de Vida/psicologia , Concussão Encefálica/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Testes NeuropsicológicosRESUMO
PRIMARY OBJECTIVE: This study determined whether initial GCS score, head CT results, cognitive performance on IMPACT testing, or APOE genotype most effectively predicted 1-month functional outcome after mild traumatic brain injury (mTBI). This study tested the hypotheses that participants with poor performance on initial cognitive testing and those with an APOEe4 genotype would exhibit a poorer 1-month recovery after mTBI. RESEARCH DESIGN: Regression analysis determined which independent variables were most effective in predicting 1-month GOS-E or DRS score. Independent t-test procedures determined whether cognitive recovery varied across APOEe4 carriers. METHODS AND PROCEDURES: 49 participants admitted to the hospital with mTBI received cognitive evaluation within 48 hours after injury and again one month later. DNA analysis provided participant APOE genotype. MAIN OUTCOMES AND RESULTS: Results showed that no study variables significantly predicted GOS-E or DRS scores, however, differences were identified when APOE groups were compared. Participants who were noncarriers of APOEe4 had significantly slower reaction times compared to APOEe4 carriers. Participants who were homozygous APOEe4 carriers had significantly lower instances of impulsivity than noncarriers. CONCLUSIONS: Further research is needed to understand how APOE allele status and performance on initial cognitive testing may influence short-term recovery after mTBI.
Assuntos
Concussão Encefálica , Concussão Encefálica/genética , Genótipo , Humanos , Testes Neuropsicológicos , Análise de Regressão , Tomografia Computadorizada por Raios XRESUMO
The worldwide incidence of traumatic brain injury (TBI) is â¼0.5% per year and the frequency is significantly higher among military personnel and athletes. Repetitive TBIs are associated with military and athletic activities, and typically involve more severe consequences. The majority of TBIs are mild; however, these still can result in long-term cognitive deficits, and there is currently no effective treatment. tert-Butylhydroquinone (tBHQ) and pioglitazone can activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and peroxisome proliferator-activated receptor-gamma (PPAR-γ) transcription factors, respectively, and each has been shown to be neuroprotective in various model systems. We examined behavioral and gene expression changes after repetitive mild TBI followed by simultaneous treatment with both factors. We used a repetitive closed head injury of mice involving five injuries with a 1-week interval between each TBI. We found that memory performance was significantly reduced by the injuries, unless the TBIs were followed by the tBHQ and pioglitazone administrations. Certain genes; for example, growth hormone and osteopontin, were downregulated by the injury, and this was reversed by the treatment, whereas other genes; for example, a tumor necrosis factor receptor, were upregulated by the injury and restored if the post-injury treatment was administered. Analysis of gene expression levels affected by the injury and/or the treatment point to potential mechanisms that could be exploited therapeutically.