The biological underpinnings of Motoric Cognitive Risk syndrome: a multi-center study

运动认知风险综合征(MCR)是一种以主观存在为特征的痴呆前期综合征 认知障碍和步态缓慢。MCR几乎每10个老年人中就有1个受到影响，并且在老龄化中有很高的发病率。 MCR预测阿尔茨海默病(AD)和血管性痴呆的风险，即使在考虑到临床情况后 与轻度认知障碍综合征(MCI)重叠。复杂的认知测试或实验室分析不是 用于诊断MCR，增加了其临床实用价值。MCR对痴呆症的预测有效性增加 关于其个别认知(认知投诉)和运动(缓慢步态)部分。然而，生物学上的 MCR的基础尚未确立。为了解决这一知识鸿沟，我们建议建立一个 由8个队列组成的联盟，约有11,000名具有临床表型的社区老年人， 生物/遗传和神经成像数据；检查MCR生物学的一种既省时又省钱的方法。 目的1.明确MCR发病的生物学机制。事件MCR的可修改风险因素 包括抑郁症状、肥胖和低体力活动；这些都是相互关联的 在炎症、氧化应激和血管通路方面有共同的生物紊乱。我们还链接了 在横断面上，阿尔茨海默病和肥胖相关的多基因风险分数与流行的MCR之间的关系。建立在这些基础上 我们将研究生物标记物和发生MCR的多基因风险。我们将检验我们的假设 主要是在个人队列中，其次是在具有生物标志物数据的8300人的池样本中。 目的：建立MCR综合征的神经解剖学基础。我们发现了一种新的灰质萎缩 在我们的3个队列中，网络到MCR的横截面由主要相连的区域组成，但不是 独家提供给马达控制系统。在这里，我们将检查这个大脑网络在MCR早期是否脆弱，并预测 事件MCR。这一目标将首先在个人队列中进行测试，其次在以下几个子样本中进行测试 ~2120人接受3T核磁共振检查。此外，在1,100人的子集中，最多可进行3次序列核磁共振检查，我们将 在MCR和小血管疾病的背景下，检查这一独特的大脑网络的纵向变化。 目的3.对MCR和MCI综合征的生物学和脑基质进行比较和对比。我们将探索 新的生物学关联以及已知的AD危险因素与MCR和MCI的异同。 MCR和MCI之间只有部分临床重叠。虽然我们预计会有部分生物重叠，但我们的 研究表明，MCR的独特遗传易感性、脑病理和脑底物是 MCI。MCR综合征不是MCI的替代，而是互补的。

Motoric Cognitive Risk syndrome (MCR) is a pre-dementia syndrome characterized by the presence of subjective cognitive complaints and slow gait. MCR affects almost in 1 in 10 older adults, and has a high incidence in aging. MCR predicts risk of both Alzheimer’s disease (AD) and vascular dementia even after accounting for clinical overlap with Mild Cognitive Impairment syndrome (MCI). Complex cognitive tests or laboratory assays are not required for diagnosing MCR, increasing its clinical utility. MCR has incremental predictive validity for dementia over its individual cognitive (cognitive complaints) and motoric (slow gait) components. Yet, the biological underpinnings of MCR are not yet established. To address this knowledge gap, we propose to establish a consortium of eight cohorts with ~11,000 community-dwelling older adults with clinical phenotypes, biological/genetic, and neuroimaging data; a time and cost efficient approach to examine the biology of MCR. Aim 1. Identify biological mechanisms underlying MCR incidence. Modifiable risk factors for incident MCR include depressive symptoms, obesity, and low physical activity; which are correlated with each other as well as share common biological derangements in inflammatory, oxidative stress and vascular pathways. We also linked Alzheimer and obesity-related polygenic risk scores to prevalent MCR at cross-section. Building on these findings, we will examine biomarkers and polygenic risk of developing incident MCR. We will test our hypotheses primarily in individual cohorts and secondarily in a pooled sample of 8,300 individuals with biomarker data. Aim 2. Establish neuroanatomical substrates of MCR syndrome. We linked a novel gray matter atrophy network to MCR at cross-section in 3 of our cohorts, which was composed of areas linked primarily, but not exclusively, to motor control. Herein, we will examine if this brain network is vulnerable early in MCR, and predicts incident MCR. This aim will be tested primarily in individual cohorts, and secondarily in a pooled subsample of ~2,120 individuals with 3T MRIs. Furthermore, in a subset of 1,100 individuals with up to 3 serial MRIs, we will examine longitudinal changes in this unique brain network in the context of MCR and small vessel disease. Aim 3. Compare and contrast biology and brain substrates for MCR and MCI syndromes. We will explore similarities and differences in new biological associations as well as known AD risk factors with MCR and MCI. There is only partial clinical overlap between MCR and MCI. While we expect partial biological overlap, our studies show exclusive genetic predispositions, brain pathologies and brain substrates for MCR not seen with MCI. The MCR syndrome is not conceptualized as an alternate to MCI but complementary.