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

翻译后摘要：进行日常功能活动的困难是一个关键的诊断特征， 痴呆综合征然而，对功能衰退的神经信号知之甚少， 在痴呆症的早期阶段。在观察到明显的损害之前进行早期干预是最好的 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的合理性， 需要更早和更准确地发现那些有风险的人。 据报道，复杂的日常功能（CdF）下降，如管理药物， 日常生活的基本活动受损（例如，吃饭，穿衣）。我们的目标是建立神经信号 在临床前痴呆期间CdF的下降。步态是许多CdF和基于社区的 因此，为了阐明CdF的神经特征，我们验证了一种新的脑电图， (EEG)当参与者执行复杂步态时，测量步态相关大脑激活的方法 功能性任务。我们的假设是，痴呆相关的病理学在临床前阶段激活了一个 独特的步态相关EEG模式，预测随后的CdF下降。我们提供初步调查结果 表明老年人认可CdF限制可以通过独特的步态相关神经系统来表征， 特征：较弱的感觉运动和较强的运动控制激活。这个子样本也有较小的大脑 体积和WMH在受痴呆症影响的早期地区，从事较少的体育锻炼。 我们提出了一项前瞻性的观察性队列研究，在认知功能未受损的老年人中， 亚临床阿尔茨海默病（血浆淀粉样蛋白-β [Aβ]）和血管（白色高信号[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签名， 在临床前痴呆期间CdF下降的预测因子; 2）确定 痴呆相关的病理和CdF神经信号的发生率; 3）建立 痴呆风险因素、缺乏身体活动和CdF的神经特征。 通过建立CdF下降的神经信号的临床相关性和生物学基础，我们的目标是 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，因为步态相关的EEG协议相对 廉价和便携，预测CdF下降可能有真实的世界利益。 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