Post-traumatic brain injury antithrombin III recovers Morris water maze cognitive performance, improving cued and spatial learning.

BACKGROUND: Neuroinflammation and cerebral edema development following severe traumatic brain injury (TBI) affect subsequent cognitive recovery. Independent of its anticoagulant effects, antithrombin III (AT-III) has been shown to block neurovascular inflammation after severe TBI, reduce cerebral endothelial-leukocyte interactions, and decrease blood-brain barrier permeability. We hypothesized that AT-III administration after TBI would improve post-TBI cognitive recovery, specifically enhancing learning, and memory. METHODS: Fifteen CD1 male mice were randomized to undergo severe TBI (controlled cortical impact [CCI]: velocity, 6 m/s; depth, 1 mm; diameter, 3 mm) or sham craniotomy and received either intravenous AT-III (250 IU/kg) or vehicle (VEH/saline) 15 minutes and 24 hours post-TBI. Animals underwent Morris water maze testing from 6 to 14 days postinjury consisting of cued learning trials (platform visible), spatial learning trials (platform invisible, spatial cues present), and probe (memory) trials (platform removed, spatial cues present). Intergroup differences were assessed by the Kruskal-Wallis test (p < 0.05). RESULTS: Morris water maze testing demonstrated that cumulative cued learning (overall mean time in seconds to reach the platform on days 6-8) was worst in CCI-VEH animals (26.1 ± 2.4 seconds) compared with CCI-AT-III counterparts (20.3 ± 2.1 seconds, p < 0.01). Cumulative noncued spatial learning was also worst in the CCI-VEH group (23.4 ± 1.8 seconds) but improved with AT-III (17.6 ± 1.5 seconds, p < 0.01). In probe trials, AT-III failed to significantly improve memory ability. Animals that underwent sham craniotomy demonstrated preserved learning and memory compared with all CCI counterparts (p < 0.05). CONCLUSION: Antithrombin III improves neurocognitive recovery weeks after TBI. This improvement is particularly related to improvement in learning but not memory function. Pharmacologic support of enhanced learning may support new skill acquisition or relearning to improve outcomes after TBI. LEVEL OF EVIDENCE: Therapeutic/care management, level II.

Fluid Biomarkers for Chronic Traumatic Encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neuropathological condition that has been described in individuals who have been exposed to repetitive head impacts, including concussions and subconcussive trauma. Currently, there is no fluid or imaging biomarker for diagnosing CTE during life. Based on retrospective clinical data, symptoms of CTE include changes in behavior, cognition, and mood, and may develop after a latency phase following the injuries. However, these symptoms are often nonspecific, making differential diagnosis based solely on clinical symptoms unreliable. Thus, objective biomarkers for CTE pathophysiology would be helpful in understanding the course of the disease as well as in the development of preventive and therapeutic measures. Herein, we review the literature regarding fluid biomarkers for repetitive concussive and subconcussive head trauma, postconcussive syndrome, as well as potential candidate biomarkers for CTE. We also discuss technical challenges with regard to the current fluid biomarkers and potential pathways to advance the most promising biomarker candidates into clinical routine.

Blood biomarkers for assessment of mild traumatic brain injury and chronic traumatic encephalopathy.

Mild traumatic brain injuries (mTBI) are prevalent and can result in significant debilitation. Current diagnostic methods have implicit limitations, with clinical assessment tools reliant on subjective self-reported symptoms or non-specific clinical observations, and commonly available imaging techniques lacking sufficient sensitivity to detect mTBI. A blood biomarker would provide a readily accessible detector of mTBI to meet the current measurement gap. Suitable options would provide objective and quantifiable information in diagnosing mTBI, in monitoring recovery, and in establishing a prognosis of resultant neurodegenerative disease, such as chronic traumatic encephalopathy (CTE). A biomarker would also assist in progressing research, providing suitable endpoints for testing therapeutic modalities and for further exploring mTBI pathophysiology. This review highlights the most promising blood-based protein candidates that are expressed in the central nervous system (CNS) and released into systemic circulation following mTBI. To date, neurofilament light (NF-L) may be the most suitable candidate for assessing neuronal damage, and glial fibrillary acidic protein (GFAP) for assessing astrocyte activation, although further work is required. Ultimately, the heterogeneity of cells in the brain and each marker's limitations may require a combination of biomarkers, and recent developments in microRNA (miRNA) markers of mTBI show promise and warrant further exploration.

Chronic traumatic encephalopathy: fluid biomarkers.

Chronic traumatic encephalopathy (CTE) is a neuropathologic condition that has been described in individuals who have been exposed to repetitive head impacts, including concussions and subconcussive trauma. CTE cannot currently be diagnosed during life. Clinical symptoms of CTE (including changes in mood, behavior, and cognition) are nonspecific and may develop after a latency phase following the injuries. Differential diagnosis based solely on clinical features is, therefore, difficult. For example, some younger patients who do not experience the latency phase (i.e., symptoms of CTE may begin while still being exposed to the repetitive head impacts) may be clinically diagnosed with postconcussive syndrome, a vaguely defined condition that is described in a minority of concussed patients. Some older patients whose initial features of CTE include memory and executive dysfunction and progress to impaired activities of daily living may be clinically diagnosed with Alzheimer disease or another dementia. Although concussions are common in athletes and nonathletes, contact/collision sport athletes, such as boxers, American football players, and ice hockey players, are at greater risk of exposure to both concussion and repetitive subconcussive head impacts. Biomarkers for CTE pathophysiology would be of great value to study and improve our understanding of when and how the disease process starts and develops, as well as how it can be prevented or treated. Here, we review the literature regarding fluid biomarkers for repetitive subconcussive impacts, concussion, postconcussive syndrome, and CTE. We also discuss technical issues and potential pathways forward regarding how to move the most promising biomarker candidates into clinical laboratory practice.

Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy.

BACKGROUND: Chronic traumatic encephalopathy (CTE) is a tauopathy associated with prior exposure to repetitive head impacts, such as those incurred through American football and other collision sports. Diagnosis is made through neuropathological examination. Many of the clinical features of CTE are common in the general population, with and without a history of head impact exposure, making clinical diagnosis difficult. As is now common in the diagnosis of other neurodegenerative disorders, such as Alzheimer's disease, there is a need for methods to diagnose CTE during life through objective biomarkers. OBJECTIVE: The aim of this study was to examine tau-positive exosomes in plasma as a potential CTE biomarker. METHODS: Subjects were 78 former National Football League (NFL) players and 16 controls. Extracellular vesicles were isolated from plasma. Fluorescent nanoparticle tracking analysis was used to determine the number of vesicles staining positive for tau. RESULTS: The NFL group had higher exosomal tau than the control group (p <  0.0001). Exosomal tau discriminated between the groups, with 82% sensitivity, 100% specificity, 100% positive predictive value, and 53% negative predictive value. Within the NFL group, higher exosomal tau was associated with worse performance on tests of memory (p = 0.0126) and psychomotor speed (p = 0.0093). CONCLUSION: These preliminary findings suggest that exosomal tau in plasma may be an accurate, noninvasive CTE biomarker.