Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies (4RT), including cortico-basal degeneration and progressive supranuclear palsy (PSP). Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4RTs, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assessed whether connectivity drives 4R-tau spreading patterns by combining resting-state fMRI connectomics with both 2^nd generation ¹⁸F- PI-2620 tau-PET in 46 patients with clinically diagnosed 4RTs and post-mortem cell-type- specific regional tau assessments from two independent PSP samples (n=97/96). We found that inter-regional connectivity was associated with higher inter-regional correlation of both tau- PET and post-mortem tau levels in 4RTs. In regional cell-type specific post-mortem tau assessments, this association was stronger for neuronal than for astroglial or oligodendroglial tau, suggesting that connectivity is primarily associated with trans-neuronal tau spread. Using tau-PET we found that patient-level tau patterns can be predicted by the connectivity of subcortical tau epicenters. Together, the current study provides combined in vivo tau-PET and histopathological evidence for brain connectivity as a key mediator of trans-neuronal tau spreading in 4RTs.

中文翻译：

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Tau 扩散是由原发性 tauopathies 中的神经元连接驱动的——来自 tau-PET 和组织病理学的证据

Tau 病理是 4 重复 tauopathies (4RT) 中神经元功能障碍的主要驱动因素，包括皮质基底节变性和进行性核上性麻痹 (PSP)。假设 Tau 在连接的神经元中传播类似朊病毒，但在 4RT 中，tau 传播的机制在很大程度上难以捉摸，其特征不仅在于神经元，还在于星形胶质细胞和少突胶质细胞 tau 积累。在这里，我们通过将静息态 fMRI 连接组学与^第二代¹⁸F-PI-2620 tau-PET 在 46 名临床诊断为 4RT 的患者中进行，并从两个独立的 PSP 样本 (n=97/96) 进行死后细胞类型特异性区域 tau 评估。我们发现区域间连通性与 4RT 中 tau-PET 和死后 tau 水平的更高区域间相关性相关。在区域细胞类型特定的死后 tau 评估中，这种关联对于神经元比星形胶质细胞或少突胶质细胞 tau 更强，这表明连接性主要与跨神经元 tau 扩散有关。使用 tau-PET，我们发现可以通过皮层下 tau 震中的连通性来预测患者水平的 tau 模式。总之，目前的研究提供了体内 tau-PET 和组织病理学证据的结合，证明大脑连通性是 4RT 中跨神经元 tau 扩散的关键介质。