Primary age-related tauopathy (PART) is a form of Alzheimer-type neurofibrillary degeneration occurring in the absence of amyloid-beta (Aβ) plaques. While PART shares some features with Alzheimer disease (AD), such as progressive accumulation of neurofibrillary tangle pathology in the medial temporal lobe and other brain regions, it does not progress extensively to neocortical regions. Given this restricted pathoanatomical pattern and variable symptomatology, there is a need to reexamine and improve upon how PART is neuropathologically assessed and staged. We performed a retrospective autopsy study in a collection (n = 174) of post-mortem PART brains and used logistic regression to determine the extent to which a set of clinical and neuropathological features predict cognitive impairment. We compared Braak staging, which focuses on hierarchical neuroanatomical progression of AD tau and Aβ pathology, with quantitative assessments of neurofibrillary burden using computer-derived positive pixel counts on digitized whole slide images of sections stained immunohistochemically with antibodies targeting abnormal hyperphosphorylated tau (p-tau) in the entorhinal region and hippocampus. We also assessed other factors affecting cognition, including aging-related tau astrogliopathy (ARTAG) and atrophy. We found no association between Braak stage and cognitive impairment when controlling for age (p = 0.76). In contrast, p-tau burden was significantly correlated with cognitive impairment even when adjusting for age (p = 0.03). The strongest correlate of cognitive impairment was cerebrovascular disease, a well-known risk factor (p < 0.0001), but other features including ARTAG (p = 0.03) and hippocampal atrophy (p = 0.04) were also associated. In contrast, sex, APOE, psychiatric illness, education, argyrophilic grains, and incidental Lewy bodies were not. These findings support the hypothesis that comorbid pathologies contribute to cognitive impairment in subjects with PART. Quantitative approaches beyond Braak staging are critical for advancing our understanding of the extent to which age-related tauopathy changes impact cognitive function.

中文翻译：

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原发性年龄相关 tau 蛋白病认知障碍的预测因素：尸检研究


原发性年龄相关性 tau 蛋白病 (PART) 是一种阿尔茨海默型神经原纤维变性，发生在不存在β淀粉样蛋白 (Aβ) 斑块的情况下。虽然 PART 与阿尔茨海默病 (AD) 具有一些共同特征，例如内侧颞叶和其他大脑区域神经原纤维缠结病理的逐渐积累，但它不会广泛进展到新皮质区域。鉴于这种受限的病理解剖模式和可变的症状，有必要重新检查和改进 PART 的神经病理学评估和分期方式。我们对死后 PART 大脑集合（n = 174）进行了回顾性尸检研究，并使用逻辑回归来确定一组临床和神经病理学特征预测认知障碍的程度。我们将 Braak 分期（重点关注 AD tau 和 Aβ 病理学的分层神经解剖学进展）与使用针对异常过度磷酸化 tau (p-tau) 的抗体进行免疫组织化学染色的切片数字化全玻片图像上的计算机衍生正像素计数来定量评估神经原纤维负荷进行了比较。 ）在内嗅区和海马体。我们还评估了影响认知的其他因素，包括与衰老相关的 tau 星形胶质细胞病 (ARTAG) 和萎缩。当控制年龄时，我们发现 Braak 阶段和认知障碍之间没有关联 (p = 0.76)。相比之下，即使调整了年龄，p-tau 负荷也与认知障碍显着相关（p = 0.03）。与认知障碍最相关的是脑血管疾病，这是一种众所周知的危险因素 (p < 0.0001)，但其他特征包括 ARTAG (p = 0.03) 和海马萎缩 (p = 0.04) 也与之相关。 相比之下，性、APOE、精神疾病、教育、嗜银颗粒和偶然的路易体则不然。这些发现支持这样的假设：共病病理会导致 PART 受试者的认知障碍。 Braak 分期之外的定量方法对于加深我们对年龄相关 tau 蛋白病变化影响认知功能程度的理解至关重要。