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病理学和神经变性导致阿尔茨海默氏病的认知障碍。

神经病理学和体内研究表明，在整个阿尔茨海默氏病谱中，tau病理与认知障碍之间存在紧密的关系。但是，tau病理也与神经变性和淀粉样蛋白病理密切相关。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有助于tau病理学（如用18F-AV-1451-PET成像测量）与阿尔茨海默氏病认知缺陷之间的关系。我们纳入了40名符合因阿尔茨海默氏病（n = 5）或可能的阿尔茨海默氏病痴呆症（n = 35）而引起的轻度认知障碍标准的淀粉样蛋白阳性患者。另外十二名患者符合后皮质萎缩的诊断标准，八名针对低水平变异性原发进行性失语症的诊断标准。所有参与者均进行了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，以及情节和语义记忆，语言，执行力和视觉空间功能评估。将原始的认知分数转换为年龄调整后的Z分数（W分数），并取平均值以计算每个认知域的综合分数。在18F-AV-1451结合与每个认知域之间进行了独立的回归，我们使用生物参数映射工具箱进一步控制了局部灰质的体积，11C-PiB的吸收或两者。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的关联。我们的结果表明，每个域中认知能力的下降与特定脑区域中18F-AV-1451结合的增加有关，这些特定区域符合既定的脑-行为关系（即情节记忆：颞中叶和角回；语义记忆：左前颞区） ；语言：左后颞上叶和上颌上回；执行功能：双侧额前额叶区域；视觉空间功能：比左枕颞区更右。当将灰质体积或11C-PiB摄取图作为协变量添加时，这种区域关联的模式基本上保持不变-尽管空间扩展程度较小。中介分析显示18F-AV-1451摄取对认知能力的直接和灰质介导的作用。一起，这些结果表明，tau病理学以区域特定的方式与阿尔茨海默氏病的认知障碍相关。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病理可能通过多种机制导致认知缺陷，包括但不限于灰质损失。这些结果可能对将来针对tau病理学的治疗性试验产生影响。