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: 10377509
• 负责人: JOE VERGHESE
• 金额: $ 153.4万
• 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/10377509
• 关键词: Accounting; Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Area; Atrophic; Australia; Biological; Biological Assay; Biological Markers; Biology; Blood Vessels; Brain; Brain Pathology; Canada; Clinical; Cognition; Cognitive; Communities; Complex; Country; Data; Dementia; Diagnosis; Digit structure; Elderly; Epidemiology; France; Gait; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Geriatrics; Gerontology; IL10 gene; Incidence; India; Individual; Inflammatory; Japan; Knowledge; Laboratories; Lacunar Infarctions; Lead; Link; Longitudinal Studies; Magnetic Resonance Imaging; Microvascular Dysfunction; Motor; Multicenter Studies; Nerve Degeneration; Obesity; Oxidative Stress; Participant; Pathogenesis; Pathway interactions; Pattern; Persons; Phenotype; Physical activity; Polygenic Traits; Prevalence; Process; Publishing; Quebec; Reporting; Risk; Risk Factors; Sampling; Syndrome; Testing; Thinness; Time; Vascular Dementia; White Matter Hyperintensity; base; cerebral microbleeds; clinical phenotype; clinical risk; cognitive testing; cohort; cost efficient; data harmonization; depressive symptoms; executive function; gray matter; high risk; hippocampal atrophy; middle age; mild cognitive impairment; modifiable risk; motor control; multi-ethnic; neuroimaging; novel; nutrition; 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.

运动认知风险综合征（MCR）是一种痴呆前期综合征，其特征是存在主观认知障碍 认知障碍和缓慢的步态。 MCR 影响几乎十分之一的老年人，并且在老龄化中发病率很高。 即使在考虑了临床因素后，MCR 仍可预测阿尔茨海默病 (AD) 和血管性痴呆的风险 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 诊断 MCR 所需，增加其临床实用性。 MCR 对痴呆症具有增量预测有效性 其个人认知（认知抱怨）和运动（缓慢步态）成分。然而，生物 MCR 的基础尚未建立。为了解决这一知识差距，我们建议建立一个 由八个队列组成的联盟，约有 11,000 名具有临床表型的社区居住老年人， 生物/遗传和神经影像数据；一种检查 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；它们彼此相关并且 在炎症、氧化应激和血管通路方面具有共同的生物紊乱。我们还链接了 阿尔茨海默病和肥胖相关的多基因风险评分与横断面流行的 MCR 的关系。在此基础上 研究结果表明，我们将检查生物标志物和发生 MCR 事件的多基因风险。我们将检验我们的假设 主要是在个体队列中，其次是在 8,300 名具有生物标志物数据的个体的汇总样本中。 目标 2. 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联系起来 我们的 3 个队列的横截面中与 MCR 的网络，由主要相关但不相关的区域组成 专门用于电机控制。在这里，我们将检查该大脑网络在 MCR 早期是否脆弱，并预测 事件 MCR。该目标将主要在个体队列中进行测试，其次在集合子样本中进行测试 约 2,120 人接受过 3T MRI 检查。此外，在 1,100 名个体的子集中，最多进行 3 次连续 MRI 扫描，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 之间仅存在部分临床重叠。虽然我们预计部分生物学重叠，但我们的 研究表明，MCR 的独特遗传倾向、脑部病理学和脑底物未见于 MCI。 MCR 综合征并不是 MCI 的替代品，而是补充品。