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Axonal injury following mild traumatic brain injury is exacerbated by repetitive insult and is linked to the delayed attenuation of NeuN expression without concomitant neuronal death in the mouse.

ABSTRACT: Mild traumatic brain injury (mTBI) affects brain structure and function and can lead to persistent abnormalities. Repetitive mTBI exacerbates the acute phase response to injury. Nonetheless, its long-term implications remain poorly understood, particularly in the context of traumatic axonal injury (TAI), a player in TBI morbidity via axonal disconnection, synaptic loss and retrograde neuronal perturbation. In contrast to the examination of these processes in the acute phase of injury, the chronic-phase burden of TAI and/or its implications for retrograde neuronal perturbation or death have received little consideration. To critically assess this issue, murine neocortical tissue was investigated at acute (24-h postinjury, 24hpi) and chronic time points (28-days postinjury, 28dpi) after singular or repetitive mTBI induced by central fluid percussion injury (cFPI). Neurons were immunofluorescently labeled for NeuroTrace and NeuN (all neurons), p-c-Jun (axotomized neurons) and DRAQ5 (cell nuclei), imaged in 3D and quantified in automated manner. Single mTBI produced axotomy in 10% of neurons at 24hpi and the percentage increased after repetitive injury. The fraction of p-c-Jun+ neurons decreased at 28dpi but without neuronal loss (NeuroTrace), suggesting their reorganization and/or repair following TAI. In contrast, NeuN+ neurons decreased with repetitive injury at 24hpi while the corresponding fraction of NeuroTrace+ neurons decreased over 28dpi. Attenuated NeuN expression was linked exclusively to non-axotomized neurons at 24hpi which extended to the axotomized at 28dpi, revealing a delayed response of the axotomized neurons. Collectively, we demonstrate an increased burden of TAI after repetitive mTBI, which is most striking in the acute phase response to the injury. Our finding of widespread axotomy in large fields of intact neurons contradicts the notion that repetitive mTBI elicits progressive neuronal death, rather, emphasizing the importance of axotomy-mediated change.

SUBMITTER: Ogino Y

PROVIDER: S-EPMC8877729 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceOne traumatic brain injury (TBI) increases the risk of subsequent TBIs. Research on longitudinal outcomes of civilian repetitive TBIs is limited.ObjectiveTo investigate associations between sustaining 1 or more TBIs (ie, postindex TBIs) after study enrollment (ie, index TBIs) and multidimensional outcomes at 1 year and 3 to 7 years.Design, setting, and participantsThis cohort study included participants presenting to emergency departments enrolled within 24 hours of TBI in the prospective, 18-center Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study (enrollment years, February 2014 to July 2020). Participants who completed outcome assessments at 1 year and 3 to 7 years were included. Data were analyzed from September 2022 to August 2023.ExposuresPostindex TBI(s).Main outcomes and measuresDemographic and clinical factors, prior TBI (ie, preindex TBI), and functional (Glasgow Outcome Scale-Extended [GOSE]), postconcussive (Rivermead Post-Concussion Symptoms Questionnaire [RPQ]), psychological distress (Brief Symptom Inventory-18 [BSI-18]), depressive (Patient Health Questionnaire-9 [PHQ-9]), posttraumatic stress disorder (PTSD; PTSD Checklist for DSM-5 [PCL-5]), and health-related quality-of-life (Quality of Life After Brain Injury-Overall Scale [QOLIBRI-OS]) outcomes were assessed. Adjusted mean differences (aMDs) and adjusted relative risks are reported with 95% CIs.ResultsOf 2417 TRACK-TBI participants, 1572 completed the outcomes assessment at 1 year (1049 [66.7%] male; mean [SD] age, 41.6 [17.5] years) and 1084 completed the outcomes assessment at 3 to 7 years (714 [65.9%] male; mean [SD] age, 40.6 [17.0] years). At 1 year, a total of 60 participants (4%) were Asian, 255 (16%) were Black, 1213 (77%) were White, 39 (2%) were another race, and 5 (0.3%) had unknown race. At 3 to 7 years, 39 (4%) were Asian, 149 (14%) were Black, 868 (80%) were White, 26 (2%) had another race, and 2 (0.2%) had unknown race. A total of 50 (3.2%) and 132 (12.2%) reported 1 or more postindex TBIs at 1 year and 3 to 7 years, respectively. Risk factors for postindex TBI were psychiatric history, preindex TBI, and extracranial injury severity. At 1 year, compared with those without postindex TBI, participants with postindex TBI had worse functional recovery (GOSE score of 8: adjusted relative risk, 0.57; 95% CI, 0.34-0.96) and health-related quality of life (QOLIBRI-OS: aMD, -15.9; 95% CI, -22.6 to -9.1), and greater postconcussive symptoms (RPQ: aMD, 8.1; 95% CI, 4.2-11.9), psychological distress symptoms (BSI-18: aMD, 5.3; 95% CI, 2.1-8.6), depression symptoms (PHQ-9: aMD, 3.0; 95% CI, 1.5-4.4), and PTSD symptoms (PCL-5: aMD, 7.8; 95% CI, 3.2-12.4). At 3 to 7 years, these associations remained statistically significant. Multiple (2 or more) postindex TBIs were associated with poorer outcomes across all domains.Conclusions and relevanceIn this cohort study of patients with acute TBI, postindex TBI was associated with worse symptomatology across outcome domains at 1 year and 3 to 7 years postinjury, and there was a dose-dependent response with multiple postindex TBIs. These results underscore the critical need to provide TBI prevention, education, counseling, and follow-up care to at-risk patients.

Project description:Poor outcomes after traumatic brain injury (TBI) are common yet remain difficult to predict. Diffuse axonal injury is important for outcomes, but its assessment remains limited in the clinical setting. Currently, axonal injury is diagnosed based on clinical presentation, visible damage to the white matter or via surrogate markers of axonal injury such as microbleeds. These do not accurately quantify axonal injury leading to misdiagnosis in a proportion of patients. Diffusion tensor imaging provides a quantitative measure of axonal injury in vivo, with fractional anisotropy often used as a proxy for white matter damage. Diffusion imaging has been widely used in TBI but is not routinely applied clinically. This is in part because robust analysis methods to diagnose axonal injury at the individual level have not yet been developed. Here, we present a pipeline for diffusion imaging analysis designed to accurately assess the presence of axonal injury in large white matter tracts in individuals. Average fractional anisotropy is calculated from tracts selected on the basis of high test-retest reliability, good anatomical coverage and their association to cognitive and clinical impairments after TBI. We test our pipeline for common methodological issues such as the impact of varying control sample sizes, focal lesions and age-related changes to demonstrate high specificity, sensitivity and test-retest reliability. We assess 92 patients with moderate-severe TBI in the chronic phase (≥6 months post-injury), 25 patients in the subacute phase (10 days to 6 weeks post-injury) with 6-month follow-up and a large control cohort (n = 103). Evidence of axonal injury is identified in 52% of chronic and 28% of subacute patients. Those classified with axonal injury had significantly poorer cognitive and functional outcomes than those without, a difference not seen for focal lesions or microbleeds. Almost a third of patients with unremarkable standard MRIs had evidence of axonal injury, whilst 40% of patients with visible microbleeds had no diffusion evidence of axonal injury. More diffusion abnormality was seen with greater time since injury, across individuals at various chronic injury times and within individuals between subacute and 6-month scans. We provide evidence that this pipeline can be used to diagnose axonal injury in individual patients at subacute and chronic time points, and that diffusion MRI provides a sensitive and complementary measure when compared to susceptibility weighted imaging, which measures diffuse vascular injury. Guidelines for the implementation of this pipeline in a clinical setting are discussed.

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Axonal injury following mild traumatic brain injury is exacerbated by repetitive insult and is linked to the delayed attenuation of NeuN expression without concomitant neuronal death in the mouse.

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