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The purpose of the study was to test the utility of unique panel of blood biomarkers as a means to reflect one’s recovery process after sport-related neurotrauma. We established a panel of biomarkers that reacted positive with CD81 (extracellular vesicle marker) and various neuron- and glia-specific antigens [e.g., neurofilament light polypeptide (NF-L), tau, synaptosome-associated protein 25 (SNAP25), glial fibrillary acidic protein, and myelin basic protein]. We first evaluated test–retest reliabilities of brain-derived exosome markers, followed by an application of these markers in eight professional ice hockey players to detect cumulative neuronal burden from a single ice hockey season. During the season, two players were diagnosed with concussions by team physician based on an exhibition of symptoms as well as abnormality in balance and ocular motor testing. One player reached symptom-free status 7 days after the concussion, while the other player required 36 days for symptoms to completely resolve. Blood samples and clinical assessments including balance error scoring system and near point of convergence throughout recovery process were obtained. Biomarkers indicative of axonal damage, neuronal inflammation, and glial activation showed excellent test–retest reliabilities (intraclass correlation coefficient: 0.713–0.998, p’s < 0.01). There was a statistically significant increase in the NF-L marker at post-season follow-up compared to pre-season baseline (Z = −2.100, P = 0.036); however the statistical significance did not withstand Bonferroni correction for multiple comparisons. In concussion cases, neuronal and microglia markers notably increased after concussions, with the unique expression patterns being similar to that of concussion recovery process. These longitudinal data coupled with excellent test–retest reliabilities of novel array of blood biomarkers potentially reflect the damage in neural cell structures and metabolic crisis due to concussion. However, future studies with larger sample size and appropriate control groups to evaluate sensitivity and specificity of these markers are needed. This preliminary case report suggests the potential utility of multimodal blood biomarkers for concussion prognosis and recovery assessment.

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Background: Extracellular vesicles (EV) released from neurons into the blood can reflect the state of nervous tissue. Measurement of neuron derived EV (NDE) may serve as an indicator of brain injury. Methods: A sandwich immunoassay was established to measure plasma NDE using anti-neuron CD171 and anti-EV CD9 ([CD171 + CD9+]). Plasma samples were obtained from commercial sources, cross-country (n = 9), football (n = 22), soccer (n = 19), and rugby (n = 18) athletes over time. Plasma was also collected from patients undergoing total aortic arch replacement (TAR) with selective cerebral perfusion during cardiopulmonary bypass before and after surgery (n = 36). Results: The specificity, linearity, and reproducibility of NDE assay (measurement of [CD171 + CD9+]) were confirmed. By scanning electron microscopy and nanoparticle tracking, spherical vesicles ranging in size from 150 to 300 nm were confirmed. Plasma levels of NDE were widely spread over 2 to 3 logs in different individuals with a significant age-dependent decrease. However, NDE were very stable in each individual within a ± 50% change over time (cross-country, football, soccer), whereas rugby players were more variable over 4 years. In patients undergoing TAR, NDE increased rapidly in days post-surgery and were significantly ( P = .0004) higher in those developing postoperative delirium (POD) (n = 13) than non-delirium patients (n = 23). Conclusions: The blood test to determine plasma levels of NDE was established by a sandwich immunoassay using 2 antibodies against neuron (CD171) and exosomes (CD9). NDE levels varied widely in different individuals and decreased with age, indicating that NDE levels should be considered as a normalizer of NDE biomarker studies. However, NDE levels were stable over time in each individual, and increased rapidly after TAR with greater increases associated with patients developing POD. This assay may serve as a surrogate for evaluating and monitoring brain injuries.

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