MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, W1W 7FF, UK.
Department of Infectious Disease Epidemiology, School of Public Health, Faculty of Medicine, Imperial College London, London, W2 1PG, UK.
Sci Rep. 2020 Sep 3;10(1):14579. doi: 10.1038/s41598-020-71305-2.
Alzheimer's disease patients typically present with multiple co-morbid neuropathologies at autopsy, but the impact of these pathologies on cognitive impairment during life is poorly understood. In this study, we developed cognitive trajectories for patients with common co-pathologies in the presence and absence of Alzheimer's disease neuropathology. Cognitive trajectories were modelled in a Bayesian hierarchical regression framework to estimate the effects of each neuropathology on cognitive decline as assessed by the mini-mental state examination and the clinical dementia rating scale sum of boxes scores. We show that both TDP-43 proteinopathy and cerebral amyloid angiopathy associate with cognitive impairment of similar magnitude to that associated with Alzheimer's disease neuropathology. Within our study population, 63% of individuals given the 'gold-standard' neuropathological diagnosis of Alzheimer's disease in fact possessed either TDP-43 proteinopathy or cerebral amyloid angiopathy of sufficient severity to independently explain the majority of their cognitive impairment. This suggests that many individuals diagnosed with Alzheimer's disease may actually suffer from a mixed dementia, and therapeutics targeting only Alzheimer's disease-related processes may have severely limited efficacy in these co-morbid populations.
阿尔茨海默病患者在尸检时通常表现出多种并存的神经病理学，但这些病理学对生前认知障碍的影响知之甚少。在这项研究中，我们针对存在和不存在阿尔茨海默病神经病理学的常见共病开发了认知轨迹。在贝叶斯分层回归框架中对认知轨迹进行建模，以估计每种神经病理学通过迷你精神状态检查和临床痴呆评定量表总分评估对认知下降的影响。我们表明，TDP-43 蛋白病和脑淀粉样血管病与认知障碍的关联程度与阿尔茨海默病神经病理学相关联的认知障碍程度相当。在我们的研究人群中，被给予阿尔茨海默病“金标准”神经病理学诊断的个体中，实际上有 63%存在 TDP-43 蛋白病或脑淀粉样血管病，严重程度足以独立解释其大部分认知障碍。这表明，许多被诊断为阿尔茨海默病的患者实际上可能患有混合性痴呆症，而仅针对与阿尔茨海默病相关过程的治疗方法在这些共病患者中可能疗效严重受限。
