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 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.

中文翻译：

---

沿空间选择性途径的 Tau 相关白质变化

大脑中 tau 神经原纤维缠结的逐渐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传播模式，但人们对这种传播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) 的显着和进行性恶化有关。动物和死后研究的结果表明异常 tau 和 WM 变性之间存在联系，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的可用性使得在体内评估 tau 和 WM 变性 (tau-WM) 的关联成为可能。在这项研究中，我们探索了整个大脑中 tau-WM 关联的空间模式，以评估 tau 沉积与 WM 微观结构改变相关的假设，不仅在孤立的区域中，而且在刻板模式中的连续结构连接中。62 名参与者，包括 22 名认知正常的受试者、22 名主观认知下降的个体和 18 名轻度认知障碍的个体被纳入研究。WM 特征通过经典扩散张量成像 (DTI) 和互补扩散室模型 - 神经突定向分散和密度成像 (NODDI) 推断，该模型提供轴突密度的代理。开发了一种数据驱动的迭代搜索 (DDIS) 方法，再加上全脑图论分析，以持续跟踪 tau-WM 关联模式。在没有应用 tau 传播的先验知识的情况下，我们观察到了一种独特的空间模式，类似于 AD 中 tau 病理学的典型传播。在扩散和淀粉样蛋白-β PET 信号之间没有观察到这种关联模式。Tau 相关的 WM 变性的特征是平均扩散率增加（径向方向的主要变化）和轴突内体积分数的减少。这些发现表明，皮质 tau 沉积（在 tau PET 中测量）与较低的轴突堆积密度和较大的扩散自由度有关。总之，我们在横截面数据上使用数据驱动方法的体内研究结果强调了 WM 改变在 AD 病理级联中的重要作用，其关联模式类似于 AD 的死后 Braak 分期。