Alzheimer's disease and progressive supranuclear palsy (PSP) represent neurodegenerative tauopathies with predominantly cortical versus subcortical disease burden. In Alzheimer's disease, neuropathology and atrophy preferentially affect 'hub' brain regions that are densely connected. It was unclear whether hubs are differentially affected by neurodegeneration because they are more likely to receive pathological proteins that propagate trans-neuronally, in a prion-like manner, or whether they are selectively vulnerable due to a lack of local trophic factors, higher metabolic demands, or differential gene expression. We assessed the relationship between tau burden and brain functional connectivity, by combining in vivo PET imaging using the ligand AV-1451, and graph theoretic measures of resting state functional MRI in 17 patients with Alzheimer's disease, 17 patients with PSP, and 12 controls. Strongly connected nodes displayed more tau pathology in Alzheimer's disease, independently of intrinsic connectivity network, validating the predictions of theories of trans-neuronal spread but not supporting a role for metabolic demands or deficient trophic support in tau accumulation. This was not a compensatory phenomenon, as the functional consequence of increasing tau burden in Alzheimer's disease was a progressive weakening of the connectivity of these same nodes, reducing weighted degree and local efficiency and resulting in weaker 'small-world' properties. Conversely, in PSP, unlike in Alzheimer's disease, those nodes that accrued pathological tau were those that displayed graph metric properties associated with increased metabolic demand and a lack of trophic support rather than strong functional connectivity. Together, these findings go some way towards explaining why Alzheimer's disease affects large scale connectivity networks throughout cortex while neuropathology in PSP is concentrated in a small number of subcortical structures. Further, we demonstrate that in PSP increasing tau burden in midbrain and deep nuclei was associated with strengthened cortico-cortical functional connectivity. Disrupted cortico-subcortical and cortico-brainstem interactions meant that information transfer took less direct paths, passing through a larger number of cortical nodes, reducing closeness centrality and eigenvector centrality in PSP, while increasing weighted degree, clustering, betweenness centrality and local efficiency. Our results have wide-ranging implications, from the validation of models of tau trafficking in humans to understanding the relationship between regional tau burden and brain functional reorganization.

中文翻译：

---

阿尔茨海默病和进行性核上性麻痹中的 Tau 蛋白负荷和功能连接组。


阿尔茨海默病和进行性核上性麻痹 (PSP) 代表神经退行性 tau蛋白病，主要是皮质疾病负担，而不是皮质下疾病负担。在阿尔茨海默病中，神经病理学和萎缩优先影响紧密相连的“中枢”大脑区域。目前还不清楚中枢是否受到神经变性的不同影响，因为它们更有可能接收以类似朊病毒的方式跨神经元传播的病理蛋白，或者它们是否由于缺乏局部营养因子、更高的代谢需求而选择性地脆弱，或差异基因表达。我们通过结合使用配体 AV-1451 的体内 PET 成像和 17 名阿尔茨海默病患者、17 名 PSP 患者和 12 名对照者的静息态功能 MRI 图论测量，评估了 tau 负荷和大脑功能连接之间的关系。强连接的节点在阿尔茨海默氏病中表现出更多的 tau 病理学，独立于内在连接网络，验证了跨神经元传播理论的预测，但不支持代谢需求或缺乏营养支持在 tau 积累中的作用。这不是一种补偿现象，因为阿尔茨海默病中 tau 蛋白负担增加的功能后果是这些相同节点的连接性逐渐减弱，降低了加权程度和局部效率，并导致“小世界”特性减弱。相反，在 PSP 中，与阿尔茨海默氏病不同，那些产生病理性 tau 的节点是那些显示与代谢需求增加和缺乏营养支持相关的图形度量属性的节点，而不是与强大的功能连接相关的节点。 总之，这些发现在一定程度上解释了为什么阿尔茨海默病会影响整个皮质的大规模连接网络，而 PSP 的神经病理学则集中在少数皮质下结构中。此外，我们证明，在 PSP 中，中脑和深部核团中 tau 蛋白负担的增加与皮质-皮质功能连接的增强有关。皮质-皮质下和皮质-脑干相互作用的破坏意味着信息传递采用较少的直接路径，通过更多数量的皮质节点，降低了 PSP 中的紧密中心性和特征向量中心性，同时增加了加权度、聚类、介数中心性和局部效率。我们的结果具有广泛的影响，从验证人类 tau 蛋白贩运模型到理解区域 tau 蛋白负担与大脑功能重组之间的关系。