Department of Radiology and Imaging Sciences, Indiana University School of Medicine,, Indianapolis, IN 46202, USA; Indiana Alzheimer Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA.
Department of Radiology and Imaging Sciences, Indiana University School of Medicine,, Indianapolis, IN 46202, USA; Indiana Alzheimer Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA.
Neuroimage. 2021 Feb 1;226:117560. doi: 10.1016/j.neuroimage.2020.117560. Epub 2020 Nov 12.
Progressive accumulation of tau neurofibrillary tangles in the brain is a defining pathologic feature of Alzheimer's disease (AD). Tau pathology exhibits a predictable spatiotemporal spreading pattern, but the underlying mechanisms of this spread are poorly understood. Although AD is conventionally considered a disease of the gray matter, it is also associated with pronounced and progressive deterioration of the white matter (WM). A link between abnormal tau and WM degeneration is suggested by findings from both animal and postmortem studies, but few studies demonstrated their interplay in vivo. Recent advances in diffusion magnetic resonance imaging and the availability of tau positron emission tomography (PET) have made it possible to evaluate the association of tau and WM degeneration (tau-WM) in vivo. In this study, we explored the spatial pattern of tau-WM associations across the whole brain to evaluate the hypothesis that tau deposition is associated with WM microstructural alterations not only in isolated tracts, but in continuous structural connections in a stereotypic pattern. Sixty-two participants, including 22 cognitively normal subjects, 22 individuals with subjective cognitive decline, and 18 with mild cognitive impairment were included in the study. WM characteristics were inferred by classic diffusion tensor imaging (DTI) and a complementary diffusion compartment model - neurite orientation dispersion and density imaging (NODDI) that provides a proxy for axonal density. A data-driven iterative searching (DDIS) approach, coupled with whole-brain graph theory analyses, was developed to continuously track tau-WM association patterns. Without applying prior knowledge of the tau spread, we observed a distinct spatial pattern that resembled the typical propagation of tau pathology in AD. Such association pattern was not observed between diffusion and amyloid-β PET signal. Tau-related WM degeneration is characterized by an increase in the mean diffusivity (with a dominant change in the radial direction) and a decrease in the intra-axonal volume fraction. These findings suggest that cortical tau deposition (as measured in tau PET) is associated with a lower axonal packing density and greater diffusion freedom. In conclusion, our in vivo findings using a data-driven method on cross-sectional data underline the important role of WM alterations in the AD pathological cascade with an association pattern similar to the postmortem Braak staging of AD. Future studies will focus on longitudinal analyses to provide in vivo evidence of tau pathology spreads along neuroanatomically connected brain areas.
tau 神经原纤维缠结在大脑中的进行性积累是阿尔茨海默病 (AD) 的一个明确的病理特征。tau 病理学表现出可预测的时空扩散模式，但这种扩散的潜在机制知之甚少。尽管 AD 通常被认为是一种灰质疾病，但它也与白质 (WM) 的明显和进行性恶化有关。动物和尸检研究的结果表明，异常 tau 与 WM 退化之间存在联系，但很少有研究证明它们在体内的相互作用。扩散磁共振成像的最新进展和 tau 正电子发射断层扫描 (PET) 的可用性使得在体内评估 tau 和 WM 退化 (tau-WM) 的相关性成为可能。在这项研究中，我们探索了整个大脑中 tau-WM 相关性的空间模式，以评估 tau 沉积不仅与孤立束中的 WM 微观结构改变有关，而且与刻板模式中的连续结构连接有关的假设。该研究纳入了 62 名参与者，包括 22 名认知正常的受试者、22 名有主观认知减退的个体和 18 名有轻度认知障碍的个体。通过经典扩散张量成像 (DTI) 和补充扩散隔室模型 - 神经丝取向弥散和密度成像 (NODDI) 来推断 WM 特征，NODDI 提供了轴突密度的替代物。开发了一种数据驱动的迭代搜索 (DDIS) 方法，结合全脑图论分析，连续跟踪 tau-WM 关联模式。在没有应用 tau 扩散先验知识的情况下，我们观察到了一个与 AD 中 tau 病理学典型传播相似的独特空间模式。这种关联模式在扩散和淀粉样蛋白-β PET 信号之间没有观察到。tau 相关的 WM 退化的特征是平均弥散度增加（以径向方向为主）和轴内体积分数减少。这些发现表明，皮质 tau 沉积（如 tau PET 测量所示）与较低的轴突包装密度和更大的扩散自由度有关。总之，我们使用横断面数据的基于数据驱动的方法的体内发现强调了 WM 改变在 AD 病理级联中的重要作用，其关联模式与 AD 的死后 Braak 分期相似。未来的研究将集中于纵向分析，以提供 tau 病理学沿神经解剖连接的脑区扩散的体内证据。
