Neurochemical Aftermath of Repetitive Mild Traumatic Brain Injury

Abstract

IMPORTANCEEvidence is accumulating that repeated mild traumatic brain injury (mTBI) incidents can lead to persistent, long-term debilitating symptoms and in some cases a progressive neurodegenerative condition referred to as chronic traumatic encephalopathy. However, to our knowledge, there are no objective tools to examine to which degree persistent symptoms after mTBI are caused by neuronal injury.OBJECTIVE To determine whether persistent symptoms after mTBI are associated with brain injury as evaluated by cerebrospinal fluid biochemical markers for axonal damage and other aspects of central nervous system injury. DESIGN, SETTINGS, AND PARTICIPANTSA multicenter cross-sectional study involving professional Swedish ice hockey players who have had repeated mTBI, had postconcussion symptoms for more than 3 months, and fulfilled the criteria for postconcussion syndrome (PCS) according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) matched with neurologically healthy control individuals. The participants were enrolled between January 2014 and February 2016. The players were also assessed with Rivermead Post Concussion Symptoms Questionnaire and magnetic resonance imaging. MAIN OUTCOMES AND MEASURESNeurofilament light protein, total tau, glial fibrillary acidic protein, amyloid β, phosphorylated tau, and neurogranin concentrations in cerebrospinal fluid.RESULTS A total of 31 participants (16 men with PCS; median age, 31 years; range, 22-53 years; and 15 control individuals [11 men and 4 women]; median age, 25 years; range, 21-35 years) were assessed. Of 16 players with PCS, 9 had PCS symptoms for more than 1 year, while the remaining 7 returned to play within a year. Neurofilament light proteins were significantly increased in players with PCS for more than 1 year (median, 410 pg/mL; range, 230-1440 pg/mL) compared with players whose PCS resolved within 1 year (median, 210 pg/mL; range, 140-460 pg/mL) as well as control individuals (median 238 pg/mL, range 128-526 pg/mL; P = .04 and P = .02, respectively). Furthermore, neurofilament light protein concentrations correlated with Rivermead Post Concussion Symptoms Questionnaire scores and lifetime concussion events (ρ = 0.58, P = .02 and ρ = 0.52, P = .04, respectively). Overall, players with PCS had significantly lower cerebrospinal fluid amyloid-β levels compared with control individuals (median, 1094 pg/mL; range, 845-1305 pg/mL; P = .05).CONCLUSIONS AND RELEVANCE Increased cerebrospinal fluid neurofilament light proteins and reduced amyloid β were observed in patients with PCS, suggestive of axonal white matter injury and amyloid deposition. Measurement of these biomarkers may be an objective tool to assess the degree of central nervous system injury in individuals with PCS and to distinguish individuals who are at risk of developing chronic traumatic encephalopathy.

Astroglial activation and altered amyloid metabolism in human repetitive concussion

“…In addition, conclusions regarding the precise relationship between rcTBI and PCS cannot be drawn without including a group of concussed athletes who did not develop PCS; a longitudinal study of patients with rcTBI in which PCS is an outcome is warranted. The data from this study suggest that PCS due to rcTBI is associated not only with axonal injury, 21 but also astroglial activation and Ab dysmetabolism, apparent in CSF months to years after the last concussion. Whereas these results might not have any immediate clinical implications, they pinpoint astroglial activation and altered Ab metabolism as being involved in PCS due to rcTBI, which may be relevant to explore further from diagnostic and therapeutic standpoints.…”

“…We have previously measured the neuroaxonal injury marker CSF NFL on most of the study participants. 21 CSF Ab38 and YKL-40 correlated with CSF NFL (figure e-7). Also, there was a borderline significant correlation between CSF:serum albumin ratio and NF-L (figure e-7).…”

“…3,4,12,13 Recently, we showed that PCS due to rcTBI is associated with increased CSF concentrations of neurofilament light (NFL). 14 Considering the literature on disease mechanisms other than axonal injury in cTBI, we tested the following specific hypotheses: (1) PCS due to rcTBI is associated with CSF signs of astroglial activation, (2) PCS due to rcTBI is associated with CSF signs of amyloid burden, and (3) rcTBI is associated with impaired BBB, as reflected by elevated CSF:serum albumin ratio. The study was designed in compliance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement.…”

“…CSF GFAP data for 16 of the 28 patients with PCS due to rcTBI and 15 of the 19 healthy controls were reported in our previous study. 21 Statistical analysis. We used x 2 test to examine differences in categorical variables between the rcTBI vs the control group.…”

“…There are no established objective tools to quantify PCS or identify CTE in living humans, but we recently showed that patients with PCS due to rcTBI had CSF biomarker evidence of axonal injury. 21 Here, we examined CSF biomarkers reflecting astroglial activation, Ab metabolism, and BBB integrity in professional athletes who had rcTBI and fulfilled the criteria for PCS. We found that (1) overall, CSF GFAP concentration was higher in patients with rcTBI compared with controls, (2) CSF YKL-40 showed similar changes as GFAP; however, CSF YKL-40 also correlated with RPQ scores and the lifetime number of concussions, (3) CSF concentrations of Ab40 and Ab42, but not Ab38 or sAPPa/b, were reduced in the rcTBI group, and the lowest concentrations were observed in the subgroup of players with PCS .1 year, and (4) there were no significant changes in the CSF:serum albumin ratio.…”