Department of Brain Sciences, Division of Medicine, Imperial College London, London, UK.
UK Dementia Research Institute, Centre for Care, Research and Technology, London, UK.
Brain. 2020 Dec 1;143(12):3685-3698. doi: 10.1093/brain/awaa316.
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.
创伤性脑损伤与神经退行性疾病（如阿尔茨海默病和慢性创伤性脑病）的发病率升高有关。在实验模型中，弥漫性轴索损伤引发创伤后神经退行性变，轴突损伤导致沃勒变性和淀粉样蛋白和过度磷酸化 tau 的毒性蛋白病。然而，在人类中，弥漫性轴索损伤与随后的神经退行性变之间的联系尚未建立。在这里，我们测试了这样一个假设，即弥漫性轴索损伤的严重程度和位置预测进行性创伤后神经退行性变的程度。我们研究了 55 例中度至重度创伤性脑损伤慢性期患者和 19 例健康对照者的纵向变化。各向异性分数从弥散张量成像中计算出来，作为弥漫性轴索损伤的测量指标。雅可比行列式萎缩率从连续容积 T1 扫描中计算出来，作为创伤后神经退行性变的测量指标。我们探索了一系列潜在的预测因素来预测纵向创伤后神经退行性变，并比较了它们解释的脑萎缩的方差。患者表现出广泛的弥漫性轴索损伤证据，基线和随访时在大部分白质中出现各向异性分数降低。未观察到各向异性分数随时间的显著变化。相比之下，在灰质和白质中都观察到异常高的脑萎缩率。弥漫性轴索损伤的位置和程度预测了脑萎缩的程度：各向异性分数预测了全脑和体素分析中的进行性萎缩。在中央白质束中观察到最强的关系，包括胼胝体体部，这是最常受弥漫性轴索损伤影响的部位。与其他潜在的临床或影像学指标（包括基线脑容量、年龄、损伤严重程度的临床指标和微出血（各向异性分数 >50%，而其他指标 <5%）相比，弥漫性轴索损伤预测了白质萎缩更大的变异性。基线时弥漫性轴索损伤不能预测灰质萎缩。总之，弥散 MRI 测量的弥漫性轴索损伤是创伤后神经退行性变的一个强有力的预测指标。这支持了轴突损伤与中度/重度创伤性脑损伤后常见的进行性神经退行性变之间的因果关系，但病因尚不确定。弥散 MRI 对弥漫性轴索损伤的评估可能会提高预后的准确性，并有助于识别那些处于最大神经退行性风险的患者，以便纳入临床试验治疗。
