From the Rush Alzheimer's Disease Center (S.O., L.Y., S.A., S.N., D.A.B., A.S.B., J.A.S.), Department of Neurological Sciences (S.O., L.Y., D.A.B., A.S.B., J.A.S.), and Department of Pathology (S.A., S.N., J.A.S.), Rush University Medical Center, Chicago, IL.
Neurology. 2023 Oct 10;101(15):e1542-e1553. doi: 10.1212/WNL.0000000000207726. Epub 2023 Aug 21.
Limbic-predominant age-related transactive response DNA-binding protein 43 (TDP-43) encephalopathy neuropathologic change (LATE-NC) is common and is a major contributor to cognitive decline and Alzheimer dementia in older adults. The objective of the current study was to examine whether LATE-NC was also associated with declining motor function in older adults.
Participants were from 2 longitudinal clinical pathologic studies of aging who did not have dementia at the time of enrollment. Postmortem pathologic examination included immunohistochemical staining for TDP-43 in 8 brain regions, which was summarized as a dichotomous variable indicating advanced LATE-NC stages at which TDP-43 pathology had accumulated in the hippocampus, entorhinal, or neocortical regions. Annual motor testing included maximal inspiratory and expiratory pressures (summarized as respiratory muscle strength), grip and pinch strength (summarized as hand strength), finger tapping speed and the Purdue Pegboard Test (summarized as hand dexterity), and walking 8 feet and turning 360° (summarized as gait function). The severity of parkinsonism was also assessed and summarized as a global parkinsonism score. Global cognition was a summary of standardized scores of 19 neuropsychological tests. We used linear mixed-effect models to examine the associations of LATE-NC with longitudinal changes of motor decline and used multivariate random coefficient models to simultaneously examine the associations of LATE-NC with cognitive and motor decline.
Among 1,483 participants (mean age at death 90.1 [SD = 6.4] years, 70% women, mean follow-up 7.4 [SD = 3.8] years), LATE-NC was present in 34.0% (n = 504). In separate linear mixed-effect models controlling for demographics and other brain pathologies, LATE-NC was associated with faster decline in respiratory muscle strength (estimate = -0.857, SE = 0.322, = 0.008) and hand strength (estimate = -0.005, SE = 0.002, = 0.005) but was not related to hand dexterity, gait function, or parkinsonism. In multivariate random coefficient models including respiratory muscle strength, hand strength, and global cognition as the outcomes, LATE-NC remained associated with a faster respiratory muscle strength decline rate (estimate = -0.021, SE = 0.009, = 0.023), but the association with hand strength was no longer significant (estimate = -0.002, SE = 0.003, = 0.390).
Motor impairment, specifically respiratory muscle weakness, may be an unrecognized comorbidity of LATE-NC that highlights the potential association of TDP-43 proteinopathy with noncognitive phenotypes in aging adults.
边缘为主的与年龄相关的转译反应 DNA 结合蛋白 43（TDP-43）脑病变（LATE-NC）在老年人中很常见，是认知能力下降和阿尔茨海默病的主要原因。本研究的目的是探讨 LATE-NC 是否也与老年人运动功能下降有关。
参与者来自于 2 项老龄化纵向临床病理研究，在入组时没有痴呆。死后病理检查包括 8 个大脑区域的 TDP-43 免疫组织化学染色，将其总结为一个二分变量，表明 TDP-43 病理学在海马体、内嗅皮层或新皮层区域积累的高级 LATE-NC 阶段。每年的运动测试包括最大吸气和呼气压力（总结为呼吸肌力量）、握力和捏力（总结为手部力量）、手指敲击速度和 Purdue 钉板测试（总结为手部灵巧度）以及 8 英尺行走和 360°转身（总结为步态功能）。帕金森病的严重程度也进行了评估，并总结为一个整体帕金森病评分。总体认知是 19 项神经心理学测试标准化得分的总结。我们使用线性混合效应模型来检验 LATE-NC 与运动下降的纵向变化之间的关系，并使用多变量随机系数模型同时检验 LATE-NC 与认知和运动下降的关系。
在 1483 名参与者中（死亡时的平均年龄为 90.1[标准差=6.4]岁，70%为女性，平均随访 7.4[标准差=3.8]年），有 34.0%（n=504）存在 LATE-NC。在单独的线性混合效应模型中，控制了人口统计学和其他脑部病变，LATE-NC 与呼吸肌力量（估计值=-0.857，SE=0.322，p=0.008）和手部力量（估计值=-0.005，SE=0.002，p=0.005）的下降速度更快有关，但与手部灵巧度、步态功能或帕金森病无关。在包括呼吸肌力量、手部力量和总体认知作为结果的多变量随机系数模型中，LATE-NC 仍然与呼吸肌力量下降速度更快有关（估计值=-0.021，SE=0.009，p=0.023），但与手部力量的关联不再显著（估计值=-0.002，SE=0.003，p=0.390）。
运动障碍，特别是呼吸肌无力，可能是 LATE-NC 的一种未被认识到的合并症，这突出了 TDP-43 蛋白病与老年人非认知表型之间的潜在关联。
