Cognitive impairment and behavioral changes in amyotrophic lateral sclerosis (ALS) are now recognized as part of the disease. Whether it is solely related to the extent of TDP-43 pathology is currently unclear. We aim to evaluate the influence of age, genetics, neuropathological features, and concomitant pathologies on cognitive impairment in ALS patients. We analyzed a postmortem series of 104 ALS patients and retrospectively reviewed clinical and neuropathological data. We assessed the burden and extent of concomitant pathologies, the role of APOE ε4 and mutations, and correlated these findings with cognitive status. We performed a logistic regression model to identify which pathologies are related to cognitive impairment. Cognitive decline was recorded in 38.5% of the subjects. Neuropathological features of frontotemporal lobar degeneration (FTLD) were found in 32.7%, explaining most, but not all, cases with cognitive impairment. Extent of TDP-43 pathology and the presence of hippocampal sclerosis were associated with cognitive impairment. Mutation carriers presented a higher burden of TDP-43 pathology and FTLD more frequently than sporadic cases. Most cases (89.4%) presented some degree of concomitant pathologies. The presence of concomitant pathologies was associated with older age at death. FTLD, but also Alzheimer’s disease, were the predominant underlying pathologies explaining the cognitive impairment in ALS patients. In sum, FTLD explained the presence of cognitive decline in most but not all ALS cases, while other non-FTLD related findings can influence the cognitive status, particularly in older age groups.

中文翻译：

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肌萎缩侧索硬化症的认知能力下降：神经病理学基础和遗传决定因素

肌萎缩侧索硬化症（ALS）的认知障碍和行为改变现在被认为是该疾病的一部分。目前尚不清楚它是否仅与 TDP-43 病理范围相关。我们的目的是评估年龄、遗传学、神经病理学特征和伴随病理学对 ALS 患者认知障碍的影响。我们分析了 104 名 ALS 患者的尸检结果，并回顾性审查了临床和神经病理学数据。我们评估了伴随病理的负担和程度、 APOE ε4 和突变的作用，并将这些发现与认知状态相关联。我们进行了逻辑回归模型来确定哪些病理与认知障碍相关。38.5% 的受试者出现认知能力下降。32.7% 的人发现额颞叶变性 (FTLD) 的神经病理学特征，这解释了大多数（但不是全部）认知障碍病例。TDP-43 病理的程度和海马硬化的存在与认知障碍相关。突变携带者比散发病例更频繁地表现出更高的 TDP-43 病理负担和 FTLD。大多数病例（89.4%）存在某种程度的伴随病理。伴随病理的存在与死亡年龄较大有关。FTLD 以及阿尔茨海默病是解释 ALS 患者认知障碍的主要潜在病理。总之，FTLD 解释了大多数但不是所有 ALS 病例中认知能力下降的情况，而其他非 FTLD 相关的发现可能会影响认知状态，特别是在老年群体中。