Linking dementia pathology and alteration in brain activation to complex daily functional decline during the preclinical dementia stage

摘要：进行性日常功能活动困难是该病的一个重要诊断特征 痴呆症。然而，人们对功能性衰退的神经特征了解不多，尤其是 在痴呆症的早期阶段。在观察到明显损害之前及早进行干预是最好的 希望减轻阿尔茨海默病和其他痴呆症的负担。但为了证明早期干预是合理的， 那些面临风险的人需要更早、更准确地被发现。 据报道，复杂的日常功能(CDF)的下降，如药物管理，出现在 日常生活基本活动障碍(如吃饭、穿衣)。我们的目标是建立神经信号 临床前痴呆期CDF下降的可能性。步态是许多CDF和基于社区的核心 2，3因此，为了阐明CDF的神经特征，我们验证了一种新的脑电 (EEG)方法测量参与者执行复杂步态时与步态相关的脑活动 功能性任务。我们的假设是，在临床前期，痴呆症相关的病理激活了一种 独特的步态相关脑电模式，可预测CDF随后的下降。我们提供初步调查结果 显示支持CDF限制的老年人可以通过一种独特的步态相关神经来表征 特点：感觉运动较弱，运动控制激活较强。这组样本也有较小的大脑 早期受痴呆症影响并从事较少体育锻炼的区域的体积和WMH。 我们提出了一项前瞻性观察队列研究，研究对象为认知正常的老年人和无认知障碍的老年人。 亚临床阿尔茨海默病(血浆淀粉样蛋白-β[Aβ])和血管(白质高信号[WMH]) 病理学。我们的目标是1)建立独特的步态相关脑电激活作为神经特征和 临床前痴呆期CDF下降的预测因子；2)确定 与痴呆相关的病理和CDF的神经标志的发生率；3)建立了 痴呆症危险因素、缺乏运动和CDF的神经特征。 通过建立CDF下降的神经特征的临床相关性和生物学基础，我们的目的是 改善阿尔茨海默病和其他痴呆症临床前阶段的预测。我们的方法 具有重要的研究和翻译意义，因为与步态相关的脑电协议相对 价格低廉，便于携带，预测CDF下降可能会带来现实的好处。 1

Abstract: Progressive difficulty in performing everyday functional activities is a key diagnostic feature of dementia syndromes. However, not much is known about the neural signature of functional decline, particularly during the very early stages of dementia. Early intervention before overt impairment is observed offers the best hope of reducing the burdens of Alzheimer’s disease and other dementias. But to justify early intervention, those at risk need to be detected earlier and more accurately. Decline in complex daily function (CdF) such as managing medications has been reported to precede impairment in basic activities of daily living (e.g., eating, dressing). Our goal is to establish the neural signature of decline in CdF during the preclinical dementia period. Gait is central to many CdF and community-based activities.2,3 Hence, to elucidate the neural signature of CdF, we validated a novel electroencephalographic (EEG) approach to measure gait-related brain activation while participants perform complex gait based functional tasks. Our hypothesis is that dementia-related pathology during the preclinical period activates a unique gait-related EEG pattern that predicts subsequent decline in CdF. We provide preliminary findings showing that older adults endorsing CdF limitations can be characterized by a unique gait-related neural signature: weaker sensorimotor and stronger motor control activation. This subsample also had smaller brain volume and WMH in regions affected early by dementia and engaged in less physical exercise. We propose a prospective observational cohort study in cognitively unimpaired older adults with and without subclinical Alzheimer’s disease (plasma amyloid-β [Aβ]) and vascular (white matter hyperintensities [WMH]) pathologies. Our aims are to 1) establish the unique gait-related EEG activation as the neural signature and predictor of decline in CdF during the preclinical dementia period; 2) determine associations between dementia-related pathologies and incidence of neural signature of CdF; 3) establish associations between a dementia risk factor, physical inactivity, and the neural signature of CdF. By establishing the clinical relevance and biological basis of the neural signature of CdF decline, we aim to improve prediction during the preclinical stages of Alzheimer’s diseases and other dementias. Our approach has important research and translational implications because gait-related EEG protocols are relatively inexpensive and portable, and predicting CdF decline may have real world benefits. 1