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

运动认知风险综合征的生物学基础：一项多中心研究

• 批准号: 10359867
• 负责人: JOE VERGHESE
• 金额: $ 22.47万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10359867
• 关键词: Accounting; Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Area; Atrophic; Biological; Biological Assay; Biological Markers; Biology; Blood Vessels; Brain; Brain Pathology; Clinical; Cognitive; Communities; Complex; Data; Dementia; Diagnosis; Elderly; Epidemiology; Gait; Genetic; Genetic Predisposition to Disease; Incidence; Individual; Inflammatory; Knowledge; Laboratories; Link; Microvascular Dysfunction; Motor; Multicenter Studies; Obesity; Oxidative Stress; Pathogenesis; Pathway interactions; Physical activity; Risk; Risk Factors; Sampling; Syndrome; Testing; Time; Vascular Dementia; clinical phenotype; cognitive testing; cohort; cost efficient; depressive symptoms; gray matter; high risk; mild cognitive impairment; modifiable risk; motor control; neuroimaging; novel; polygenic risk score

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.

运动性认知风险综合征（MCR）是一种痴呆前综合征，其特征在于存在主观的 认知障碍和步态迟缓。MCR几乎影响十分之一的老年人，并且在衰老中发病率很高。 MCR预测阿尔茨海默病（AD）和血管性痴呆的风险，即使在考虑临床 轻度认知障碍综合征（MCI）复杂的认知测试或实验室检测不是 这是诊断MCR所必需的，增加了其临床实用性。MCR对痴呆的预测有效性增加 在其个人认知（认知投诉）和运动（缓慢步态）组件。然而，生物学 MCR的基础尚未建立。为弥补这方面的知识差距，我们建议设立一个 8个队列的联盟，约11，000名社区居住的老年人，具有临床表型， 生物学/遗传学和神经影像学数据;检查MCR生物学的时间和成本有效的方法。 目标1。确定MCR发生率的生物学机制。事件MCR的可修改风险因素 包括抑郁症状、肥胖和体力活动不足;这些症状彼此相关， 在炎症、氧化应激和血管通路中具有共同的生物学紊乱。我们还联系了 阿尔茨海默病和肥胖相关的多基因风险评分与横截面流行MCR根据这些 研究结果，我们将检查生物标志物和多基因风险的发展事件MCR。我们将测试我们的假设 主要是在单个队列中，其次是在具有生物标志物数据的8，300个个体的合并样本中。 目标二。建立MCR综合征的神经解剖学基础。我们将一种新的灰质萎缩 在我们的3个队列中，网络与MCR的横截面相关，主要由相关区域组成，但不 专门用于电机控制。在此，我们将检查这个大脑网络是否在MCR早期就脆弱，并预测 事故MCR。这一目标将主要在单个队列中进行测试，其次是在一个合并的子样本中进行测试。 ~ 2，120例患者接受了3 T MRI检查。此外，在一个1,100人的子集中，最多进行3次连续MRI，我们将 在MCR和小血管疾病的背景下检查这个独特的大脑网络的纵向变化。 目标3.比较和对比MCR和MCI综合征的生物学和脑基质。我们将探讨 新的生物学关联以及已知的AD风险因素与MCR和MCI的相似性和差异。 MCR和MCI之间仅存在部分临床重叠。虽然我们预计部分生物重叠， 研究表明，MCR的独特遗传倾向、脑病理和脑基质在 MCI。MCR综合征的概念不是MCI的替代，而是补充。