Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO, USA.
Acta Neuropathol. 2017 Mar;133(3):367-380. doi: 10.1007/s00401-017-1686-x. Epub 2017 Feb 18.
Chronic traumatic encephalopathy (CTE) is a progressive degenerative disorder associated with repetitive traumatic brain injury. One of the primary defining neuropathological lesions in CTE, based on the first consensus conference, is the accumulation of hyperphosphorylated tau in gray matter sulcal depths. Post-mortem CTE studies have also reported myelin loss, axonal injury and white matter degeneration. Currently, the diagnosis of CTE is restricted to post-mortem neuropathological analysis. We hypothesized that high spatial resolution advanced diffusion MRI might be useful for detecting white matter microstructural changes directly adjacent to gray matter tau pathology. To test this hypothesis, formalin-fixed post-mortem tissue blocks from the superior frontal cortex of ten individuals with an established diagnosis of CTE were obtained from the Veterans Affairs-Boston University-Concussion Legacy Foundation brain bank. Advanced diffusion MRI data was acquired using an 11.74 T MRI scanner at Washington University with 250 × 250 × 500 µm spatial resolution. Diffusion tensor imaging, diffusion kurtosis imaging and generalized q-sampling imaging analyses were performed in a blinded fashion. Following MRI acquisition, tissue sections were tested for phosphorylated tau immunoreactivity in gray matter sulcal depths. Axonal disruption in underlying white matter was assessed using two-dimensional Fourier transform analysis of myelin black gold staining. A robust image co-registration method was applied to accurately quantify the relationship between diffusion MRI parameters and histopathology. We found that white matter underlying sulci with high levels of tau pathology had substantially impaired myelin black gold Fourier transform power coherence, indicating axonal microstructural disruption (r = -0.55, p = 0.0015). Using diffusion tensor MRI, we found that fractional anisotropy (FA) was modestly (r = 0.53) but significantly (p = 0.0012) correlated with axonal disruption, where lower FA was associated with greater axonal disruption in white matter directly adjacent to hyperphosphorylated tau positive sulci. In summary, our findings indicate that axonal disruption and tau pathology are closely associated, and high spatial resolution ex vivo diffusion MRI has the potential to detect microstructural alterations observed in CTE tissue. Future studies will be required to determine whether this approach can be applied to living people.
慢性创伤性脑病（CTE）是一种与重复创伤性脑损伤相关的进行性退行性疾病。根据第一次共识会议，CTE 的主要神经病理学病变之一是在灰质脑沟深处积累过度磷酸化的 tau。尸检 CTE 研究还报告了髓鞘丢失、轴突损伤和白质退化。目前，CTE 的诊断仅限于死后神经病理学分析。我们假设高空间分辨率的高级扩散 MRI 可能有助于直接检测紧邻灰质 tau 病理学的白质微观结构变化。为了验证这一假设，我们从退伍军人事务部-波士顿大学-脑震荡遗产基金会脑库获得了来自 10 名 CTE 确诊患者的额上皮质福尔马林固定的尸检组织块。在华盛顿大学使用 11.74 T MRI 扫描仪以 250×250×500 µm 空间分辨率采集高级扩散 MRI 数据。在盲法下进行扩散张量成像、扩散峰度成像和广义 q 采样成像分析。在 MRI 采集后，对灰质脑沟深度中的磷酸化 tau 免疫反应性进行组织切片检测。使用二维傅里叶变换分析髓鞘黑金染色评估下方白质中的轴突中断。应用稳健的图像配准方法准确量化扩散 MRI 参数与组织病理学之间的关系。我们发现，tau 病理学水平高的脑沟下的白质的髓鞘黑金傅里叶变换功率相干性显著受损，表明轴突微观结构中断（r=-0.55，p=0.0015）。使用扩散张量 MRI，我们发现分数各向异性（FA）适度（r=0.53）但显著（p=0.0012）与轴突中断相关，其中较低的 FA 与紧邻过度磷酸化 tau 阳性脑沟的白质中更大的轴突中断相关。总之，我们的研究结果表明，轴突中断和 tau 病理学密切相关，高空间分辨率的离体扩散 MRI 具有检测 CTE 组织中观察到的微观结构改变的潜力。需要进一步的研究来确定这种方法是否可以应用于活体。
