Diffuse axonal injury predicts neurodegeneration after moderate-severe traumatic brain injury.

Traumatic brain injury is associated with elevated rates of neurodegenerative diseases such as Alzheimer's disease and chronic traumatic encephalopathy. In experimental models, diffuse axonal injury triggers post-traumatic neurodegeneration, with axonal damage leading to Wallerian degeneration and toxic proteinopathies of amyloid and hyperphosphorylated tau. However, in humans the link between diffuse axonal injury and subsequent neurodegeneration has yet to be established. Here we test the hypothesis that the severity and location of diffuse axonal injury predicts the degree of progressive post-traumatic neurodegeneration. We investigated longitudinal changes in 55 patients in the chronic phase after moderate-severe traumatic brain injury and 19 healthy control subjects. Fractional anisotropy was calculated from diffusion tensor imaging as a measure of diffuse axonal injury. Jacobian determinant atrophy rates were calculated from serial volumetric T1 scans as a measure of measure post-traumatic neurodegeneration. We explored a range of potential predictors of longitudinal post-traumatic neurodegeneration and compared the variance in brain atrophy that they explained. Patients showed widespread evidence of diffuse axonal injury, with reductions of fractional anisotropy at baseline and follow-up in large parts of the white matter. No significant changes in fractional anisotropy over time were observed. In contrast, abnormally high rates of brain atrophy were seen in both the grey and white matter. The location and extent of diffuse axonal injury predicted the degree of brain atrophy: fractional anisotropy predicted progressive atrophy in both whole-brain and voxelwise analyses. The strongest relationships were seen in central white matter tracts, including the body of the corpus callosum, which are most commonly affected by diffuse axonal injury. Diffuse axonal injury predicted substantially more variability in white matter atrophy than other putative clinical or imaging measures, including baseline brain volume, age, clinical measures of injury severity and microbleeds (>50% for fractional anisotropy versus <5% for other measures). Grey matter atrophy was not predicted by diffuse axonal injury at baseline. In summary, diffusion MRI measures of diffuse axonal injury are a strong predictor of post-traumatic neurodegeneration. This supports a causal link between axonal injury and the progressive neurodegeneration that is commonly seen after moderate/severe traumatic brain injury but has been of uncertain aetiology. The assessment of diffuse axonal injury with diffusion MRI is likely to improve prognostic accuracy and help identify those at greatest neurodegenerative risk for inclusion in clinical treatment trials.

Graham NSN ，Jolly A ，Zimmerman K ，Bourke NJ ，Scott G ，Cole JH ，Schott JM ，Sharp DJ ... -  《-》

Distinct patterns of neurodegeneration after TBI and in Alzheimer's disease.

Traumatic brain injury (TBI) is a dementia risk factor, with Alzheimer's disease (AD) more common following injury. Patterns of neurodegeneration produced by TBI can be compared to AD and aging using volumetric MRI. A total of 55 patients after moderate to severe TBI (median age 40), 45 with AD (median age 69), and 61 healthy volunteers underwent magnetic resonance imaging over 2 years. Atrophy patterns were compared. AD patients had markedly lower baseline volumes. TBI was associated with increased white matter (WM) atrophy, particularly involving corticospinal tracts and callosum, whereas AD rates were increased across white and gray matter (GM). Subcortical WM loss was shared in AD/TBI, but deep WM atrophy was TBI-specific and cortical atrophy AD-specific. Post-TBI atrophy patterns were distinct from aging, which resembled AD. Post-traumatic neurodegeneration 1.9-4.0 years (median) following moderate-severe TBI is distinct from aging/AD, predominantly involving central WM. This likely reflects distributions of axonal injury, a neurodegeneration trigger. We compared patterns of brain atrophy longitudinally after moderate to severe TBI in late-onset AD and healthy aging. Patients after TBI had abnormal brain atrophy involving the corpus callosum and other WM tracts, including corticospinal tracts, in a pattern that was specific and distinct from AD and aging. This pattern is reminiscent of axonal injury following TBI, and atrophy rates were predicted by the extent of axonal injury on diffusion tensor imaging, supporting a relationship between early axonal damage and chronic neurodegeneration.

Graham NSN ，Cole JH ，Bourke NJ ，Schott JM ，Sharp DJ ... -  《-》

Spatial patterns of progressive brain volume loss after moderate-severe traumatic brain injury.

Cole JH ，Jolly A ，de Simoni S ，Bourke N ，Patel MC ，Scott G ，Sharp DJ ... -  《-》

Network diffusion modeling predicts neurodegeneration in traumatic brain injury.

Traumatic brain injury (TBI) is a heterogeneous disease with multiple neurological deficits that evolve over time. It is also associated with an increased incidence of neurodegenerative diseases. Accordingly, clinicians need better tools to predict a patient's long-term prognosis. Diffusion-weighted and anatomical MRI data were collected from 17 adolescents (mean age = 15y8mo) with moderate-to-severe TBI and 19 healthy controls. Using a network diffusion model (NDM), we examined the effect of progressive deafferentation and gray matter thinning in young TBI patients. Moreover, using a novel automated inference method, we identified several injury epicenters in order to determine the neural degenerative patterns in each TBI patient. We were able to identify the subject-specific patterns of degeneration in each patient. In particular, the hippocampus, temporal cortices, and striatum were frequently found to be the epicenters of degeneration across the TBI patients. Orthogonal transformation of the predicted degeneration, using principal component analysis, identified distinct spatial components in the temporal-hippocampal network and the cortico-striatal network, confirming the vulnerability of these networks to injury. The NDM model, best predictive of the degeneration, was significantly correlated with time since injury, indicating that NDM can potentially capture the pathological progression in the chronic phase of TBI. These findings suggest that network spread may help explain patterns of distant gray matter thinning, which would be consistent with Wallerian degeneration of the white matter connections (i.e., "diaschisis") from diffuse axonal injuries and multifocal contusive injuries, and the neurodegenerative patterns of abnormal protein aggregation and transmission, which are hallmarks of brain changes in TBI. NDM approaches could provide highly subject-specific biomarkers relevant for disease monitoring and personalized therapies in TBI.

Poudel GR ，Dominguez D JF ，Verhelst H ，Vander Linden C ，Deblaere K ，Jones DK ，Cerin E ，Vingerhoets G ，Caeyenberghs K ... -  《Annals of Clinical and Translational Neurology》

A single closed head injury in male adult mice induces chronic, progressive white matter atrophy and increased phospho-tau expressing oligodendrocytes.

Traumatic brain injury (TBI) acutely damages the brain; this injury can evolve into chronic neurodegeneration. While much is known about the chronic effects arising from multiple mild TBIs, far less is known about the long-term effects of a single moderate to severe TBI. We found that a single moderate closed head injury to mice induces diffuse axonal injury within 1-day post-injury (DPI). At 14 DPI, injured animals have atrophy of ipsilesional cortex, thalamus, and corpus callosum, with bilateral atrophy of the dorsal fornix. Atrophy of the ipsilesional corpus callosum is accompanied by decreased fractional anisotropy and increased mean and radial diffusivity that remains unchanged between 14 and 180 DPI. Injured animals show an increased density of phospho-tau immunoreactive (pTau+) cells in the ipsilesional cortex and thalamus, and bilaterally in corpus callosum. Between 14 and 180 DPI, atrophy occurs in the ipsilesional ventral fornix, contralesional corpus callosum, and bilateral internal capsule. Diffusion tensor MRI parameters remain unchanged in white matter regions with delayed atrophy. Between 14 and 180 DPI, pTau+ cell density increases bilaterally in corpus callosum, but decreases in cortex and thalamus. The location of pTau+ cells within the ipsilesional corpus callosum changes between 14 and 180 DPI; density of all cells increases including pTau+ or pTau- cells. >90% of the pTau+ cells are in the oligodendrocyte lineage in both gray and white matter. Density of thioflavin-S+ cells in thalamus increases by 180 DPI. These data suggest a single closed head impact produces multiple forms of chronic neurodegeneration. Gray and white matter regions proximal to the impact site undergo early atrophy. More distal white matter regions undergo chronic, progressive white matter atrophy with an increasing density of oligodendrocytes containing pTau. These data suggest a complex chronic neurodegenerative process arising from a single moderate closed head injury.

Havlicek DF ，Furhang R ，Nikulina E ，Smith-Salzberg B ，Lawless S ，Severin SA ，Mallaboeva S ，Nayab F ，Seifert AC ，Crary JF ，Bergold PJ ... -  《-》