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: 10612349
• 负责人: JOE VERGHESE
• 金额: $ 149.2万
• 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/10612349
• 关键词: Acceleration; 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; Impaired cognition; Incidence; India; Individual; Inflammatory; Japan; Knowledge; Laboratories; Lacunar Infarctions; Link; Longitudinal Studies; Magnetic Resonance Imaging; Microvascular Dysfunction; Motor; Multicenter Studies; Nerve Degeneration; Neuroanatomy; 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; 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; risk prediction

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）是一种前痴呆症综合征，其特征是主观的存在 认知投诉和步态缓慢。 MCR几乎影响十分之一的老年人中有1个，并且在衰老中有很高的事件。 MCR预测阿尔茨海默氏病（AD）和血管性痴呆的风险，即使考虑到临床 与轻度认知障碍综合征（MCI）重叠。复杂的认知测试或实验室测定不是 诊断MCR所需的需要，增加了其临床实用性。 MCR具有痴呆的预测有效性 在其个人认知（认知抱怨）和摩托车（慢步态）组成部分上。但是，生物学 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 八个队列的财团，约有11,000名居住在社区的老年人患有临床表型， 生物/遗传和神经影像学数据；一种时间和成本效益的方法来检查MCR的生物学。 目标1。确定MCR事件的生物学机制。事件MCR的可修改风险因素 包括抑郁症状，肥胖和身体活动较低；彼此相关的 在炎症，氧化应激和血管途径中共享常见的生物发展。我们也链接了 阿尔茨海默氏症和与肥胖相关的多基因风险评分在横截面上流行的MCR。建立在这些基础上 调查结果，我们将检查生物标志物和出现事件MCR的多基因风险。我们将检验我们的假设 主要在单个同类群体中，并在8300名具有生物标志物数据的人的合并样本中。 AIM 2。建立MCR综合征的神经解剖底物。我们联系了一种新颖的灰质萎缩 在我们的3个同类中，在横截面的MCR网络，由主要的区域组成，但不是 仅限于电动机控制。在此，我们将检查该大脑网络是否在MCR早期很脆弱，并预测 事件MCR。该目标将主要在单个队列中测试 〜2,120个患有3T MRI的人。此外，在1,100个最多3个串行MRI的人中，我们将 在MCR和小血管疾病的背景下，检查了这个独特的大脑网络中的纵向变化。 AIM 3。比较MCR和MCI综合征的生物学和对比生物学以及脑底物。我们将探索 与MCR和MCI的新生物学关联以及已知的AD风险因素的相似性和差异。 MCR和MCI之间只有部分临床重叠。虽然我们期望部分生物学重叠，但我们 研究表明，独家遗传易感性，脑病理和脑底物的MCR未见 MCI。 MCR综合征不是被概念化为MCI的替代方案，而是完善的。