Subacute cytokine changes after a traumatic brain injury predict chronic brain microstructural alterations on advanced diffusion imaging in the male rat.

INTRODUCTION: The process of neuroinflammation occurring after traumatic brain injury (TBI) has received significant attention as a potential prognostic indicator and interventional target to improve patients' outcomes. Indeed, many of the secondary consequences of TBI have been attributed to neuroinflammation and peripheral inflammatory changes. However, inflammatory biomarkers in blood have not yet emerged as a clinical tool for diagnosis of TBI and predicting outcome. The controlled cortical impact model of TBI in the rodent gives reliable readouts of the dynamics of post-TBI neuroinflammation. We now extend this model to include a panel of plasma cytokine biomarkers measured at different time points post-injury, to test the hypothesis that these markers can predict brain microstructural outcome as quantified by advanced diffusion-weighted magnetic resonance imaging (MRI). METHODS: Fourteen 8-10-week-old male rats were randomly assigned to sham surgery (n = 6) and TBI (n = 8) treatment with a single moderate-severe controlled cortical impact. We collected blood samples for cytokine analysis at days 1, 3, 7, and 60 post-surgery, and carried out standard structural and advanced diffusion-weighted MRI at day 60. We then utilized principal component regression to build an equation predicting different aspects of microstructural changes from the plasma inflammatory marker concentrations measured at different time points. RESULTS: The TBI group had elevated plasma levels of IL-1ß and several neuroprotective cytokines and chemokines (IL-7, CCL3, and GM-CSF) compared to the sham group from days 3 to 60 post-injury. The plasma marker panels obtained at day 7 were significantly associated with the outcome at day 60 of the trans-hemispheric cortical map transfer process that is a frequent finding in unilateral TBI models. DISCUSSION: These results confirm and extend prior studies showing that day 7 post-injury is a critical temporal window for the reorganisation process following TBI. High plasma level of IL-1ß and low plasma levels of the neuroprotective IL-7, CCL3, and GM-CSF of TBI animals at day 60 were associated with greater TBI pathology.

Evidence of Ongoing Cerebral Microstructural Reorganization in Children With Persisting Symptoms Following Mild Traumatic Brain Injury: A NODDI DTI Analysis.

Approximately 300-550 children per 100,000 sustain a mild traumatic brain injury (mTBI) each year, of whom ∼25-30% have long-term cognitive problems. Following mTBI, free water (FW) accumulation occurs in white matter (WM) tracts. Diffusion tensor imaging (DTI) can be used to investigate structural integrity following mTBI. Compared with conventional DTI, neurite orientation dispersion and density imaging (NODDI) orientation dispersion index (ODI) and fraction of isolated free water (FISO) metrics may allow a more advanced insight into microstructural damage following pediatric mTBI. In this longitudinal study, we used NODDI to explore whole-brain and tract-specific differences in ODI and FISO in children with persistent symptoms after mTBI (n = 80) and in children displaying clinical recovery (n = 32) at 1 and 2-3 months post-mTBI compared with healthy controls (HCs) (n = 21). Two-way repeated measures analysis of variance (ANOVA) and voxelwise two-sample t tests were conducted to compare whole-brain and tract-specific diffusion across groups. All results were corrected at positive false discovery rate (pFDR) <0.05. We also examined the association between NODDI metrics and clinical outcomes, using logistical regression to investigate the value of NODDI metrics in predicting future recovery from mTBI. Whole-brain ODI was significantly increased in symptomatic participants compared with HCs at both 1 and 2 months post-injury, where the uncinate fasciculus (UF) and inferior fronto-occipital fasciculus (IFOF) were particularly implicated. Using region of interest (ROI) analysis in significant WM, bilateral IFOF and UF voxels, symptomatic participants had the highest ODI in all ROIs. ODI was lower in asymptomatic participants, and HCs had the lowest ODI in all ROIs. No changes in FISO were found across groups or over time. WM ODI was moderately correlated with a higher youth-reported post-concussion symptom inventory (PCSI) score. With 87% predictive power, ODI (1 month post-injury) and clinical predictors (age, sex, PCSI score, attention scores) were a more sensitive predictor of recovery at 2-3 months post-injury than fractional anisotropy (FA) and clinical predictors, or clinical predictors alone. FISO could not predict recovery at 2-3 months post-injury. Therefore, we found that ODI was significantly increased in symptomatic children following mTBI compared with HCs at 1 month post-injury, and progressively decreased over time alongside clinical recovery. We found no significant differences in FISO between groups or over time. WM ODI at 1 month was a more sensitive predictor of clinical recovery at 2-3 months post-injury than FA, FISO, or clinical measures alone. Our results show evidence of ongoing microstructural reorganization or neuroinflammation between 1 and 2-3 months post-injury, further supporting delayed return to play in children who remain symptomatic. We recommend future research examining the clinical utility of NODDI following mTBI to predict recovery or persistence of post-concussion symptoms and thereby inform management of mTBI.

A cross-comparative analysis of in vivo versus ex vivo MRI indices in a mouse model of concussion.

BACKGROUND: We present a cross-sectional, case-matched, and pair-wise comparison of structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and neurite orientation dispersion and density imaging (NODDI) measures in vivo and ex vivo in a mouse model of concussion, thus aiming to establish the concordance of structural and diffusion imaging findings in living brain and after fixation. METHODS: We allocated 28 male mice aged 3-4 months to sham injury and concussion (CON) groups. CON mice had received a single concussive impact on day 0 and underwent MRI at day 2 (n = 9) or 7 (n = 10) post-impact, and sham control mice likewise underwent imaging at day 2 (n = 5) or 7 (n = 4). Immediately after the final scanning, we collected the perfusion-fixed brains, which were stored for imaging ex vivo 6-12 months later. We then compared the structural imaging, DTI, and NODDI results between different methods. RESULTS: In vivo to ex vivo structural and DTI/NODDI findings were in notably poor agreement regarding the effects of concussion on structural integrity of the brain. COMPARISON WITH EXISTING METHODS: ex vivo imaging was frequently done to study the effects of diseases and treatments, but our results showed that ex vivo and in vivo imaging can detect completely opposite and contradictory results. This is also the first study that compares in vivo and ex vivo NODDI. CONCLUSION: Our findings call for caution in extrapolating translational capabilities obtained ex vivo to physiological measurements in vivo. The divergent findings may reflect fixation artefacts and the contribution of the glymphatic system changes.

Traumatic brain injury alterations in the functional connectome are associated with neuroinflammation but not tau in a P30IL tauopathy mouse model.

INTRODUCTION: Traumatic Brain Injury (TBI) is often associated with long-term cognitive deficits and altered brain networks which have been linked with accumulation of neurofibrillary tau tangles and neuroinflammation. In this work, we investigated the changes in the brain post-TBI in an Alzheimer's disease pR5 tauopathy model and evaluated the contribution of tauopathy and neuroinflammation to connectivity alterations using resting-state functional Magnetic Resonance Imaging (rs-fMRI). METHOD: 26 P301L tau transgenic mice of 8-9 months of age (21-35 g) expressing the human tau isoform carrying the pathogenic P301L mutation were used for the study. Animals were assessed at day 1 and 7 post-injury/craniotomy and were randomly divided into four groups. All animals underwent an MRI scan on a 9.4T Bruker system where rsfMRI was acquired. Following imaging, brains were stained with pSer (396 + 404), glial fibrillary acidic protein (GFAP), and ionised calcium-binding adaptor molecule-1 (Iba-1). Group-information-guided Independent Component Analysis (GIG-ICA) and region-of-interest (ROI)-based network connectivity approaches were applied. Principal Component Regression was applied to predict connectivity network strength from the corresponding ROIs. RESULTS: TBI mice showed decreased functional connectivity in the dentate gyrus, thalamus, and other areas compared to sham animals at day 1 post-injury with the majority of changes resolving at day 7. Principal Component Regression showed only the contralateral CA1 network strength was correlated with the CA1's astrocyte and microglia cell density and the ipsilateral thalamus network strength was correlated with the ipsilateral thalamus' astrocyte and microglia cell density. CONCLUSION: We present the first report on the temporal alterations in functional connectivity in a P30IL mouse model following TBI. Connectivity between key regions known to be affected in Alzheimer's disease were short-term and reversible following injury. Connectivity strength in CA1 and thalamus showed significant correlation with astrocyte and microglial cell density but not tau density.