Brain metabolites measured with magnetic resonance spectroscopy in pediatric concussion and orthopedic injury: An Advancing Concussion Assessment in Pediatrics (A-CAP) study.

Millions of children sustain a concussion annually. Concussion disrupts cellular signaling and neural pathways within the brain but the resulting metabolic disruptions are not well characterized. Magnetic resonance spectroscopy (MRS) can examine key brain metabolites (e.g., N-acetyl Aspartate (tNAA), glutamate (Glx), creatine (tCr), choline (tCho), and myo-Inositol (mI)) to better understand these disruptions. In this study, we used MRS to examine differences in brain metabolites between children and adolescents with concussion versus orthopedic injury. Children and adolescents with concussion (n = 361) or orthopedic injury (OI) (n = 184) aged 8 to 17 years were recruited from five emergency departments across Canada. MRS data were collected from the left dorsolateral prefrontal cortex (L-DLPFC) using point resolved spectroscopy (PRESS) at 3 T at a mean of 12 days post-injury (median 10 days post-injury, range 2-33 days). Univariate analyses for each metabolite found no statistically significant metabolite differences between groups. Within each analysis, several covariates were statistically significant. Follow-up analyses designed to account for possible confounding factors including age, site, scanner, vendor, time since injury, and tissue type (and interactions as appropriate) did not find any metabolite group differences. In the largest sample of pediatric concussion studied with MRS to date, we found no metabolite differences between concussion and OI groups in the L-DLPFC. We suggest that at 2 weeks post-injury in a general pediatric concussion population, brain metabolites in the L-DLPFC are not specifically affected by brain injury.

Characterizing Physical Activity and Sedentary Behavior in Adults With Persistent Postconcussive Symptoms After Mild Traumatic Brain Injury.

OBJECTIVE: To evaluate physical activity (PA) and sedentary behavior and their associations with symptom and quality of life outcomes in adults with persistent postconcussive symptoms (PPCS) after mild traumatic brain injury (mTBI). DESIGN: Cross-sectional cohort study. SETTING: Outpatient brain injury clinic. PARTICIPANTS: Consecutive sample of adults (N=180) with a diagnosis of mTBI and PPCS. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: PA and sedentary behavior were assessed using the Godin Leisure-Time Exercise Questionnaire and Rapid Assessment Disuse Index, respectively. Participants were dichotomized according to whether they completed 150 minutes of moderate-to-vigorous PA per week, based on Canadian guidelines. Postinjury moderate-to-vigorous PA was also analyzed as a continuous variable. RESULTS: Prior to injury, 85% of participants reported meeting PA guidelines, compared with 28% postinjury. Individuals meeting PA guidelines postinjury reported higher quality of life (η2p=0.130; P<.001) and lower scores on measures of functional impact of headache (η2p=0.065; P=.009), fatigue (η2p=0.080; P=.004), depression (η2p=0.085; P=.001), and anxiety (η2p=0.046; P=.031), compared with those not meeting guidelines. Sedentary behavior postinjury was negatively correlated with quality of life (rs[127]=-0.252; P=.004) and positively correlated with symptom burden (rs[167]=0.227; P=.003), fatigue (rs[127]=0.288; P=.001), depression (rs[174]=0.319; P<.001), and anxiety (rs[127]=0.180; P=.042). CONCLUSIONS: PA was significantly decreased in individuals with PPCS compared to preinjury levels. Meeting PA guidelines postinjury was associated with better clinical outcomes, suggesting that returning individuals to PA should be considered in the treatment of this patient population.

The impact of traumatic brain injury on cognitive and neuropsychiatric symptoms of Parkinson's disease.

The objective was to determine whether a history of traumatic brain injury (TBI) was associated with Parkinson's Disease (PD) and specific cognitive, motor, and neuropsychiatric symptoms. A cross-sectional cohort study of 120 participants aged 60-85 years old (48 females) were recruited (69 PD and 51 healthy controls). Assessments included demographic information, neuropsychological tests, a motor evaluation, neuropsychiatric questionnaires, and the Brain Injury Screening Questionnaire. A history of TBI or number of TBIs was not significantly related to an increased risk of developing PD or poorer motor scores on the United Parkinson Disease Rating Scale part 3. There was a significant negative correlation between number of TBI's and mean z-scores of global cognition (rs(69) = -0.338, p = 0.004), executive function (rs(69) = -0.251, p = 0.038), memory (rs(69) = -0.262, p = 0.029), and language (rs(69) = -0.245, p = 0.042), and a significant positive correlation on the Beck Depression Inventory II (rs(69) = 0.285, p = 0.018) and the Patient Health Questionnaire-9 (PHQ-9) (rs(69) = 0.326, p = 0.006) in the PD group only. In conclusion, a history of TBI was negatively associated with cognition and positively associated with depressive symptoms in patients with PD, but not with motor symptoms.

Magnetic Resonance Spectroscopy of Traumatic Brain Injury and Subconcussive Hits: A Systematic Review and Meta-Analysis.

Magnetic resonance spectroscopy (MRS) is a non-invasive technique used to study metabolites in the brain. MRS findings in traumatic brain injury (TBI) and subconcussive hit literature have been mixed. The most common observation is a decrease in N-acetyl-aspartate (NAA), traditionally considered a marker of neuronal integrity. Other metabolites, however, such as creatine (Cr), choline (Cho), glutamate+glutamine (Glx) and myo-inositol (mI) have shown inconsistent changes in these populations. The objective of this systematic review and meta-analysis was to synthesize MRS literature in brain injury and explore factors (biological factors such as brain region, injury severity, time since injury, demographics and technical methodological factors such as field strength, acquisition parameters, analysis approach) that may contribute to differential findings. One hundred and thirty-eight studies met inclusion criteria for the systematic review and of those, 62 NAA, 24 Cr, 49 Cho, 18 Glx, and 21 mI studies met inclusion criteria for meta-analysis. A random effects model was used for meta-analyses with brain region as a subgroup for each of the five metabolites studied. Meta-regression was used to examine the influence of potential moderators including injury severity, time since injury, age, sex, tissue composition, and methodological factors. In this analysis of 1428 unique brain-injured subjects and 1132 controls, the corpus callosum was identified as a brain region highly susceptible to metabolite alteration. NAA was consistently decreased in TBI of all severities, but not in subconcussive hits. Cho and mI were found to be increased in moderate-to-severe TBI but not in mild TBI. Glx and Cr were largely unaffected, but did show alterations in certain conditions.

Balance impairment in patients with moderate-to-severe traumatic brain injury: Which measures are appropriate for assessment?

Left untreated, balance impairment following moderate-to-severe traumatic brain injury (TBI) can be highly debilitating and hinder activities of daily life. To detect impairments, clinicians need appropriate assessment tools. The objective of this study was to evaluate the feasibility and utility of a battery of clinical balance assessments in adults with moderate-to-severe TBI within 6-months of injury. Thirty-seven adults with TBI [Glasgow Coma Scale score ≤ 12 (33 M/4 F) age 18-50 years] participated in balance testing. Assessments included the Balance Error Scoring System (BESS), National Institutes of Health Standing Balance Test (NIH-SBT), Functional Gait Assessment (FGA), Advanced Functional Gait Assessment (FGA-A), Tandem Gait Test (TGT), Berg Balance Scale (BBS), and Walking While Talking Test (WWTT). We identified pronounced ceiling effects on the BBS and FGA, two widely used clinical balance assessments. The NIH-SBT, WWTT, and FGA used in conjunction with the FGA-A, offered versatility in their capacity to assess patients across the balance severity spectrum. This study provides evidence to support a stepwise approach to balance assessment that can be adapted to the broad range of balance ability found in moderate-to-severe TBI.

Glutamate, GABA and glutathione in adults with persistent post-concussive symptoms.

Persistent post-concussive symptoms (PPCS) are debilitating and endure beyond the usual recovery period after mild traumatic brain injury (mTBI). Altered neurotransmission, impaired energy metabolism and oxidative stress have been examined acutely post-injury but have not been explored extensively in those with persistent symptoms. Specifically, the antioxidant glutathione (GSH) and the excitatory and inhibitory metabolites, glutamate (Glu) and γ-aminobutyric acid (GABA), are seldom studied together in the clinical mTBI literature. While Glu can be measured using conventional magnetic resonance spectroscopy (MRS) methods at 3 Tesla, GABA and GSH require the use of advanced MRS methods. Here, we used the recently established Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy (HERMES) to simultaneously measure GSH and GABA and short-echo time point resolved spectroscopy (PRESS) to measure Glu to gain new insight into the pathophysiology of PPCS. Twenty-nine adults with PPCS (mean age: 45.69 years, s.d.: 10.73, 22 females, 7 males) and 29 age- and sex-matched controls (mean age: 43.69 years, s.d.: 11.00) completed magnetic resonance spectroscopy scans with voxels placed in the anterior cingulate and right sensorimotor cortex. Relative to controls, anterior cingulate Glu was significantly reduced in PPCS. Higher anterior cingulate GABA was significantly associated with a higher number of lifetime mTBIs, suggesting GABA may be upregulated with repeated incidence of mTBI. Furthermore, GSH in both regions of interest was positively associated with symptoms of sleepiness and headache burden. Collectively, our findings suggest that the antioxidant defense system is active in participants with PPCS, however this may be at the expense of other glutamatergic functions such as cortical excitation and energy metabolism.

16p13.11 duplication is a risk factor for a wide spectrum of neuropsychiatric disorders.

The chromosome 16p13.11 heterozygous deletion is associated with a diverse array of neuropsychiatric disorders including intellectual disabilities, autism, schizophrenia, epilepsy and attention-deficit hyperactivity disorder. However the clinical significance of its reciprocal duplication is not clearly defined yet. We evaluated 1645 consecutive pediatric patients with various developmental disorders by high-resolution microarray-based comparative genomic hybridization and identified four deletions and eight duplications within the 16p13.11 region, representing ∼0.73% (12/1645) of the patients analyzed. Recurrent clinical features in these patients include mental retardation/intellectual disability, autism, seizure, dysmorphic feature or multiple congenital anomalies. Our data expand the spectrum of the clinical findings in patients with these genomic abnormalities and provide further support for the pathogenic involvement of this duplication in patients who carry them.

Clinical Validation of Somatic Mutation Detection by the OncoScan CNV Plus Assay.

The OncoScan CNV Plus Assay (OS+) is a single-nucleotide polymorphism microarray platform that can detect 74 hotspot somatic mutations (SMs) in nine genes via molecular inversion probes. We report validation of the SM component of OS+ using a cohort of pediatric high-grade brain tumor specimens. SM calls were generated from 46 brain tumor cases, most tested orthogonally via bidirectional Sanger sequencing. The initial calling algorithm result showed that 31 tumors were positive and 15 were negative for SM, with a total of 71 OS+ SM calls [28 high-confidence (HC) and 43 low-confidence (LC)]. Sanger sequencing was performed for 54 of the 71 calls (27 HC and 27 LC), as well as for 21 randomly selected hotspots across the 15 OS+ negative cases. HC calls (except EGFR) Sanger sequencing confirmed positive, negative calls confirmed negative, but none of the LC calls were Sanger-confirmed positive. An update of the OS+ algorithm resolved the LC calls, but of the 11 HC SM EGFR calls, Sanger sequencing confirmed only one. Two PTEN SM calls by OS+ in two separate cases were also negative per Sanger sequencing. We conclude that a majority of HC OS+ SM calls were accurate, except calls identified in EGFR and PTEN. Clinically, we report SMs identified by OS+ only after Sanger sequencing verification.

Cardiac defects are infrequent findings in individuals with 8p23.1 genomic duplications containing GATA4.

BACKGROUND: The GATA4 gene is critical to regulating myocardial differentiation and function. Haploinsufficiency of GATA4 is strongly associated with congenital heart defects (CHD). However, it is inconclusive whether duplicated GATA4 causes CHD. METHODS AND RESULTS: We evaluated 1645 consecutive pediatric patients with various developmental disorders by high-resolution microarray-based comparative genomic hybridization and found 8 probands and 2 relatives with pathogenic genomic imbalances containing GATA4. Four probands contain an ≈4.0-Mb interstitial duplication of 8p23.1 flanked by the 2 olfactory receptor gene clusters REPD and REPP, representing 0.24% (4/1645) of the patients analyzed. None of the 4 patients has CHD or any other heart diseases and 1 mother who transmitted the duplication to her child has a history of aortic stenosis. Two patients who carry multiple genomic abnormalities, including a duplication containing GATA4, have complex CHD. Only 1 of the 3 individuals carrying genomic deletion containing GATA4 has atrial septal and ventricular septal defects. CONCLUSIONS: Cardiac defects are infrequent findings in individuals with 8p23.1 genomic duplications containing GATA4. A 0.24% detection rate of this duplication in this study is significantly higher than previously estimated. Observation in 2 patients with multiple genomic abnormalities and complex CHD is consistent with a 2-hit model that emphasizes accumulative effects of >1 insult to the genome, leading to a visible or more severe clinical manifestation. Haploinsufficient GATA4 may show variable expressivity with a wide spectrum of clinical findings, including CHD.