Neuropathological and in vivo studies have revealed a tight relationship between tau pathology and cognitive impairment across the Alzheimer's disease spectrum. However, tau pathology is also intimately associated with neurodegeneration and amyloid pathology. The aim of the present study was therefore to assess whether grey matter atrophy and amyloid pathology contribute to the relationship between tau pathology, as measured with 18F-AV-1451-PET imaging, and cognitive deficits in Alzheimer's disease. We included 40 amyloid-positive patients meeting criteria for mild cognitive impairment due to Alzheimer's disease (n = 5) or probable Alzheimer's disease dementia (n = 35). Twelve patients additionally fulfilled the diagnostic criteria for posterior cortical atrophy and eight for logopenic variant primary progressive aphasia. All participants underwent 3 T magnetic resonance imaging, amyloid (11C-PiB) positron emission tomography and tau (18F-AV-1451) positron emission tomography, and episodic and semantic memory, language, executive and visuospatial functions assessment. Raw cognitive scores were converted to age-adjusted Z-scores (W-scores) and averaged to compute composite scores for each cognitive domain. Independent regressions were performed between 18F-AV-1451 binding and each cognitive domain, and we used the Biological Parametric Mapping toolbox to further control for local grey matter volumes, 11C-PiB uptake, or both. Partial correlations and causal mediation analyses (mediation R package) were then performed in brain regions showing an association between cognition and both 18F-AV-1451 uptake and grey matter volume. Our results showed that decreased cognitive performance in each domain was related to increased 18F-AV-1451 binding in specific brain regions conforming to established brain-behaviour relationships (i.e. episodic memory: medial temporal lobe and angular gyrus; semantic memory: left anterior temporal regions; language: left posterior superior temporal lobe and supramarginal gyrus; executive functions: bilateral frontoparietal regions; visuospatial functions: right more than left occipitotemporal regions). This pattern of regional associations remained essentially unchanged-although less spatially extended-when grey matter volume or 11C-PiB uptake maps were added as covariates. Mediation analyses revealed both direct and grey matter-mediated effects of 18F-AV-1451 uptake on cognitive performance. Together, these results show that tau pathology is related in a region-specific manner to cognitive impairment in Alzheimer's disease. These regional relationships are weakly related to amyloid burden, but are in part mediated by grey matter volumes. This suggests that tau pathology may lead to cognitive deficits through a variety of mechanisms, including, but not restricted to, grey matter loss. These results might have implications for future therapeutic trials targeting tau pathology.

中文翻译：

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Tau 蛋白病理学和神经变性会导致阿尔茨海默病的认知障碍。


神经病理学和体内研究揭示了阿尔茨海默病谱系中 tau 蛋白病理学与认知障碍之间的密切关系。然而，tau 病理学也与神经变性和淀粉样蛋白病理学密切相关。因此，本研究的目的是评估灰质萎缩和淀粉样蛋白病理学是否与 18F-AV-1451-PET 成像测量的 tau 蛋白病理学与阿尔茨海默病认知缺陷之间的关系有关。我们纳入了 40 名淀粉样蛋白阳性患者，这些患者符合因阿尔茨海默病 (n = 5) 或可能的阿尔茨海默病痴呆 (n = 35) 导致的轻度认知障碍的标准。 12 名患者还满足后皮质萎缩的诊断标准，8 名患者满足语言减少变异型原发性进行性失语症的诊断标准。所有参与者均接受了 3 T 磁共振成像、淀粉样蛋白 (11C-PiB) 正电子发射断层扫描和 tau (18F-AV-1451) 正电子发射断层扫描，以及情景和语义记忆、语言、执行和视觉空间功能评估。原始认知分数被转换为年龄调整的 Z 分数（W 分数），并进行平均以计算每个认知领域的综合分数。在 18F-AV-1451 结合和每个认知域之间进行独立回归，我们使用生物参数映射工具箱进一步控制局部灰质体积、11C-PiB 摄取或两者。然后在大脑区域进行偏相关和因果中介分析（中介 R 包），显示认知与 18F-AV-1451 摄取和灰质体积之间存在关联。 我们的结果表明，每个领域的认知能力下降与符合已建立的大脑行为关系的特定大脑区域中 18F-AV-1451 结合的增加有关（即情景记忆：内侧颞叶和角回；语义记忆：左前颞区） ; 语言：左后上颞叶和上缘回；执行功能：双侧额顶叶区域；视觉空间功能：右侧多于左侧枕颞区域。当灰质体积或 11C-PiB 摄取图被添加为协变量时，这种区域关联模式基本上保持不变，尽管空间扩展较少。中介分析揭示了 18F-AV-1451 摄取对认知表现的直接影响和灰质介导影响。总之，这些结果表明 tau 病理学以区域特异性方式与阿尔茨海默病的认知障碍相关。这些区域关系与淀粉样蛋白负荷微弱相关，但部分由灰质体积介导。这表明 tau 蛋白病理学可能通过多种机制导致认知缺陷，包括但不限于灰质损失。这些结果可能对未来针对 tau 病理学的治疗试验产生影响。