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Treatment of youth concussion during the acute phase continues to evolve, and this has led to the emergence of guidelines to direct care. While symptoms after concussion typically resolve in 14-28 days, a portion (∼20%) of adolescents endorse persistent post-concussive symptoms (PPCS) beyond normal resolution. This report outlines a study implemented in response to the National Institute of Neurological Diseases and Stroke call for the development and initial clinical validation of objective biological measures to predict risk of PPCS in adolescents. We describe our plans for recruitment of a Development cohort of 11- to 17-year-old youth with concussion, and collection of autonomic, neurocognitive, biofluid, and imaging biomarkers. The most promising of these measures will then be validated in a separate Validation cohort of youth with concussion, and a final, clinically useful algorithm will be developed and disseminated. Upon completion of this study, we will have generated a battery of measures predictive of high risk for PPCS, which will allow for identification and testing of interventions to prevent PPCS in the most high-risk youth.

BACKGROUND AND OBJECTIVES: To study longitudinal associations between blood-based neural biomarkers (including total tau, neurofilament light [NfL], glial fibrillary acidic protein [GFAP], and ubiquitin C-terminal hydrolase-L1) and white matter neuroimaging biomarkers in collegiate athletes with sport-related concussion (SRC) from 24 hours postinjury to 1 week after return to play. METHODS: We analyzed clinical and imaging data of concussed collegiate athletes in the Concussion Assessment, Research, and Education (CARE) Consortium. The CARE participants completed same-day clinical assessments, blood draws, and diffusion tensor imaging (DTI) at 3 time points: 24-48 hours postinjury, point of becoming asymptomatic, and 7 days after return to play. DTI probabilistic tractography was performed for each participant at each time point to render 27 participant-specific major white matter tracts. The microstructural organization of these tracts was characterized by 4 DTI metrics. Mixed-effects models with random intercepts were applied to test whether white matter microstructural abnormalities are associated with the blood-based biomarkers at the same time point. An interaction model was used to test whether the association varies across time points. A lagged model was used to test whether early blood-based biomarkers predict later microstructural changes. RESULTS: Data from 77 collegiate athletes were included in the following analyses. Among the 4 blood-based biomarkers, total tau had significant associations with the DTI metrics across the 3 time points. In particular, high tau level was associated with high radial diffusivity (RD) in the right corticospinal tract (β = 0.25, SE = 0.07, p FDR-adjusted = 0.016) and superior thalamic radiation (β = 0.21, SE = 0.07, p FDR-adjusted = 0.042). NfL and GFAP had time-dependent associations with the DTI metrics. NfL showed significant associations only at the asymptomatic time point (|β|s > 0.12, SEs 0.14, SEs

Concussion or mild traumatic brain injury (mTBI) is a common phenomenon in the United States, with up to 3.6 million sport-related mTBIs diagnosed annually. Return to learn protocols have been developed to facilitate the reintegration of students into school after mTBI, however, the implementation of return to learn protocols varies significantly across geographic regions and school districts. An integrative review of the literature was performed using Whittemore and Knalf's methodology. A search of published literature was conducted using the PRISMA checklist. Database searches were conducted from March 2,019 to October 2,021 using the terms "mild traumatic brain injury" and "return to learn." Twenty-eight publications were included. Three themes were derived from this review: lack of policy, poor staff education on concussion symptoms and stakeholder communication breakdown. The development of communication patterns and use of a return to learn protocol could facilitate a gradual return to full academic workload after concussion.

ObjectiveTo determine whether blood-based biomarkers can differentiate older veterans with and without traumatic brain injury (TBI) and cognitive impairment (CogI).MethodsWe enrolled 155 veterans from 2 veterans' retirement homes: 90 without TBI and 65 with TBI history. Participants were further separated into CogI groups: controls (no TBI, no CogI), n = 60; no TBI with CogI, n = 30; TBI without CogI, n = 30; and TBI with CogI, n = 35. TBI was determined by the Ohio State University TBI Identification Method. CogI was defined as impaired cognitive testing, dementia diagnosis, or use of dementia medication. Blood specimens were enriched for CNS-derived exosomes. Proteins (neurofilament light [NfL], total tau, glial fibrillary acidic protein [GFAP], α-synuclein, β-amyloid 42 [Aβ42], and phosphorylated tau [p-tau]) and cytokines (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], and interleukin-10) were measured using ultrasensitive immunoassays.ResultsVeterans were, on average, 79 years old. In participants with TBI history, 65% had mild TBI; average time from most recent TBI was 37 years. In adjusted analyses, the TBI and CogI groups differed on CNS-enriched exosome concentration of p-tau, NfL, IL-6, TNF-α (all p < 0.05), and GFAP (p = 0.06), but not on Aβ42 or other markers. Adjusted area under the curve (AUC) analyses found that all significantly associated biomarkers combined separated TBI with/without CogI (AUC, 0.85; 95% confidence interval [CI], 0.74-0.95) and CogI with/without TBI (AUC, 0.88; 95% CI, 0.77-0.99).ConclusionsIncreased levels of blood-based, CNS-enriched exosomal biomarkers associated with TBI and CogI can be detected even decades after TBI.Classification of evidenceThis study provides Class II evidence that in veterans with a history of TBI, CNS-enriched exosome concentration of p-tau, NfL, IL-6, and TNF-α are associated with CogI.

Objective: Blood-based biomarkers have received considerable attention for their diagnostic and prognostic value in the acute and postacute period following traumatic brain injury (TBI). The purpose of this study was to examine whether blood-based biomarker concentrations within the first 12 months of TBI can predict neurobehavioral outcome in the chronic phase of the recovery trajectory. Setting: Inpatient and outpatient wards from 3 military medical treatment facilities. Participants: A total of 161 service members and veterans classified into 3 groups: (a) uncomplicated mild TBI (MTBI; n = 37), (b) complicated mild, moderate, severe, penetrating TBI combined (STBI; n = 46), and (c) controls (CTRL; n = 78). Design: Prospective longitudinal. Main Measures: Participants completed 6 scales from the Traumatic Brain Injury Quality of Life (ie, Anger, Anxiety, Depression, Fatigue, Headaches, and Cognitive Concerns) within 12 months (baseline) and at 2 or more years (follow-up) post-injury. Serum concentrations of tau, neurofilament light, glial fibrillary acidic protein, and UCHL-1 at baseline were measured using SIMOA. Results: Baseline tau was associated with worse anger, anxiety, and depression in the STBI group at follow-up (R 2 = 0.101-0.127), and worse anxiety in the MTBI group (R 2 = 0.210). Baseline ubiquitin carboxyl-terminal hydrolase L1 (UCHL-1) was associated with worse anxiety and depression at follow-up in both the MTBI and STBI groups (R 2Δ = 0.143-0.207), and worse cognitive concerns in the MTBI group (R 2Δ = 0.223). Conclusions: A blood-based panel including these biomarkers could be a useful tool for identifying individuals at risk of poor outcome following TBI. [ABSTRACT FROM AUTHOR]