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Original Investigation |

Neurochemical Aftermath of Repetitive Mild Traumatic Brain Injury ONLINE FIRST

Pashtun Shahim, MD, PhD1; Yelverton Tegner, MD, PhD2; Bengt Gustafsson, MD3; Magnus Gren, MD1; Johan Ärlig, MD1; Martin Olsson, MD1; Niklas Lehto, PhD2; Åsa Engström, PhD2; Kina Höglund, PhD1; Erik Portelius, PhD1; Henrik Zetterberg, MD, PhD1,4; Kaj Blennow, MD, PhD1
[+] Author Affiliations
1Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden
2Division of Medical Sciences, Department of Health Sciences, Luleå University of Technology, Luleå, Sweden
3Capio Artro Clinic, Stockholm, Sweden
4Department of Molecular Neuroscience, University College London Institute of Neurology, London, United Kingdom
JAMA Neurol. Published online September 19, 2016. doi:10.1001/jamaneurol.2016.2038
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Importance  Evidence 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 Participants  A 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 Measures  Neurofilament 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.

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Figure 1.
Cerebrospinal Fluid (CSF) Biomarkers Reflecting Axonal and Astroglial Injury

Concentrations of neurofilament light (NF-L) protein were increased in the postconcussion syndrome (PCS) group vs control group (A). There was no significant difference in the level of total tau (B) and glial fibrillary acidic protein (GFAp) (C). Players with PCS for more than 1 year had increased concentration of NF-L compared with players whose PCS resolved within 1 year after injury as well as control individuals (D). There was no significant difference in the levels of total tau (E) and GFAp (F) at either group or subgroup level as well as compared with control individuals. One of the 15 control participants had increased CSF NF-L concentration (1491 pg/mL) for unknown reasons and was excluded from the statistical analyses. Values are presented as medians; error bars indicate interquartile range.

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Figure 2.
Cerebrospinal Fluid (CSF) Biomarkers Reflecting Amyloid and Tau Pathology and Synaptic Loss

The postconcussion syndrome (PCS) group had significantly (P = .05) lower amyloid β 1-42 (Aβ1-42) than the control group (A). Also, concentrations of Aβ1-42 (C) were lower in players with PCS for more than 1 year vs PCS for less than 1 year; however, this was not significant (P = .09). There was no difference in the phosphorylated tau levels at either group (B) or subgroup level (D). There was also no significant difference in the concentrations of neurogranin at either group (C) or subgroup level (F). Values are presented as medians; error bars indicate interquartile range.

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Figure 3.
Longitudinal Biomarker Changes

One of the players was followed up with repeated lumbar punctures (5, 11, 17, and 23 months after most recent concussion). In this player, the mean concentration of neurofilament light protein was elevated compared with the mean of the control group and remained elevated over time, while the levels of total tau and glial fibrillary acidic protein were unchanged (A). Mean concentrations of amyloid β 1-42 were lower at 2 following times compared with the mean of the control group (B). Also, the mean concentration of neurogranin was elevated compared with the mean of the control group (B). Dashed lines indicate mean (SD) of the control group.

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Figure 4.
Relationship Between Biomarker Levels and Symptom Severity

Concentrations of neurofilament light protein correlated (ρ = 0.58, P = .02) with Rivermead Post Concussion Symptoms Questionnaire (RPQ) score (A). There was no significant correlation between any of the other biomarkers and RPQ score (B-F). Aβ1-42 indicates amyloid β 1-42; CSF indicates cerebrospinal fluid; GFAp indicates glial fibrillary acidic protein; and NF-L indicates neurofilament light protein.

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Figure 5.
Relationship Between Biomarker Concentrations and Lifetime Number of Concussions

Neurofilament light protein correlated (ρ = 0.52; P = .04) with lifetime concussion event (A). There was also a significant correlation between phosphorylated tau and lifetime concussion event (E). There was no significant relationship between the lifetime concussion event and other biomarkers in the study (B-D and F). Aβ1-42 indicates amyloid β 1-42; CSF indicates cerebrospinal fluid; GFAp indicates glial fibrillary acidic protein; and NF-L indicates neurofilament light protein.

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