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: 9562162
• 负责人: JOE VERGHESE
• 金额: $ 92.67万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9562162
• 关键词: Accounting; Address; Adult; Adverse effects; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Asia; Australia; Biological; Biological Assay; Biological Markers; Biology; Blood Vessels; Brain; Brain Pathology; Canada; Cerebral small vessel disease; Clinical; Cognition; Cognitive; Collaborations; Communities; Complement; Complex; Country; Data; Dementia; Development; Diagnosis; Elderly; Epidemiology; Europe; Gait; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Variation; Geriatrics; Gerontology; Guidelines; Image; Impairment; Incidence; Individual; Inflammation; Inflammatory; International; Intervention; Knowledge; Lacunar Infarctions; Lead; Link; Longitudinal Studies; Mediating; Medical; Mental Depression; Microvascular Dysfunction; Motor; Multicenter Studies; Nerve Degeneration; Obesity; Oxidative Stress; Oxidative Stress Pathway; Participant; Pathogenesis; Pathology; Pathway interactions; Peripheral; Persons; Physical activity; Pilot Projects; Prevalence; Prevention; Preventive; Publishing; Quebec; Reporting; Risk; Risk Factors; Role; Sampling; Secondary Prevention; Single Nucleotide Polymorphism; Stroke; Structure; Syndrome; Thick; Thinness; Time; Vascular Dementia; White Matter Hyperintensity; analytical method; base; cerebral microbleeds; clinical phenotype; cognitive testing; cohort; cost efficient; disorder prevention; epidemiology study; follow-up; frontal lobe; genetic epidemiology; genetic variant; gray matter; high risk; hippocampal atrophy; insight; mild cognitive impairment; modifiable risk; multidisciplinary; neuroimaging; nutrition; outreach; prevent; prospective; prospective test; relating to nervous system; sedentary

The biological underpinnings of Motoric Cognitive Risk syndrome: a multi-center study Motoric Cognitive Risk syndrome (MCR) is a recently described 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 developing both Alzheimer’s disease (AD) and vascular dementia even after accounting for clinical overlap with Mild Cognitive Impairment syndrome (MCI). Unlike MCI, complex cognitive tests or 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. While the epidemiology of MCR has been described, the biological underpinnings and neural substrates of MCR are not yet established. We draw together a multidisciplinary team to comprehensively conduct the first study to examine the pathogenesis of MCR syndrome. The MCR consortium includes an estimated 10,080 older individuals from 8 cohorts in USA, Canada, Europe, Asia and Australia. The MCR consortium has collaborated, shared and harmonized data, and published on MCR topics, establishing feasibility. Aim 1. Identify biological mechanisms underlying MCR incidence. Elevated peripheral inflammatory and oxidative stress biomarkers as well as single nucleotide polymorphisms in these pathways predicted incident MCR in our pilot studies. We will prospectively examine the role of inflammatory and oxidative stress biomarkers and explore genetic variants in these and related pathways in the pathogenesis of MCR. We will report associations in individual cohorts and as a second step in the pooled sample of 9,370 individuals in our MCR consortium with biomarker/genetic assays available or planned. Aim 2. Establish brain pathologies and substrates of MCR syndrome. Based on studies linking cerebral small vessel disease to cortical thinning, we hypothesize that cerebral small vessel disease (lacunar infarctions, cerebral microbleeds and white matter hyperintensities) may accelerate or incite gray matter loss that will clinically manifest as MCR. This aim will be prospectively tested using advanced imaging acquisition and analytical methods in individual cohorts and secondarily in the pooled sample of 3,100 individuals with neuroimaging. Aim 3. Compare and contrast biology and brain substrates for MCR and MCI syndromes. We will explore similarities and differences in new biological associations discovered in Aims 1 & 2 as well as known AD risk factors (APOE, hippocampal atrophy, etc.) 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. Discovering unique biological associations of MCR may lead to new treatments that complement current MCI preventions. Our proposal is highly responsive to PAR-17-054: As per the PAR guidelines, we will use and/or harmonize existing data, collect new biological and imaging data not present in all cohorts, and add new participants as well as extend follow-up in 8 cohorts to clarify risk and protective factors for AD and related dementias via the MCR pathway. Our proposal also meets several action priorities of the National Alzheimer Plan such as accelerating efforts to identify early stages of AD, identifying biological mechanisms underlying dementia, expanding genetic epidemiology research to identify risk factors, and expanding international outreach to enhance collaboration.

运动认知风险综合征的生物基础：一项多中心研究 Motoric认知风险综合征（MCR）是最近描述的痴呆症综合征，其特征是 主观认知抱怨和步态缓慢的存在。 MCR几乎影响十分之一的老年人，并且有高度 衰老的发病率。 MCR预测患阿尔茨海默氏病（AD）和血管性痴呆的风险甚至 在考虑了轻度认知障碍综合征（MCI）的临床重叠之后。与MCI不同，复杂 诊断MCR不需要认知测试或测定，从而增加了其临床实用性。 MCR具有增量 痴呆症对其个体认知（认知抱怨）的预测有效性（慢速步态） 成分。 尽管已经描述了MCR的流行病学，但MCR的生物基础和神经底物是 尚未确定。我们将一个多学科团队汇总在一起，全面进行首次研究 检查MCR综合征的发病机理。 MCR财团包括大约10,080个年龄较大的人 来自美国，加拿大，欧洲，亚洲和澳大利亚的8个队列。 MCR联盟已合作，共享和 协调数据，并在MCR主题上发表，以建立可行性。 目标1。确定MCR发生率的生物学机制。外围炎症和 这些途径中的氧化应激生物标志物以及单个核苷酸多态性预测了MCR的MCR 我们的试点研究。我们可能会检查炎症性和氧化应激生物标志物的作用以及 探索MCR发病机理中这些和相关途径中的遗传变异。我们将报告协会 个人队列，作为我们MCR联盟中9,370个人的合并样本的第二步 可用或计划的生物标志物/遗传测定。 目标2。建立MCR综合征的脑病理和底物。基于与脑小的研究 血管疾病至皮质变薄，我们假设脑小血管疾病（lacunar梗死，脑梗死 微粒和白质超强度）可能会加速或促进灰质损失，从而在临床上表现出来 作为MCR。该目标将通过高级成像采集和分析方法进行预期测试 在3,100名神经影像学患者的汇总样本中，各个队列和次要。 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 在目标1和2中发现的新生物学协会的相似性和差异以及已知的AD风险 使用MCR和MCI的因素（APOE，海马萎缩等）。 MCR之间只有部分临床重叠 和MCI。尽管我们期望部分生物学重叠，但我们的研究表明遗传易感性，大脑 MCI未见MCR的病理和脑底物。 MCR综合征没有被概念化为 替代MCI，但完善。发现MCR的独特生物学协会可能会导致新的 补充当前MCI预防的治疗方法。 我们的建议对PAR-17-054的反应很高：根据PAR指南，我们将使用和/或协调一致 现有数据，收集所有队列中不存在的新生物学和成像数据，并添加新的参与者以及 扩展8个队列中的随访，以阐明通过MCR的AD和相关痴呆症的风险和保护因素 路径。我们的建议还符合国家阿尔茨海默氏症计划的几个行动优先事项，例如加速 识别AD早期阶段的努力，确定痴呆症的生物学机制，扩大遗传 流行病学研究以识别危险因素，并扩大国际外展以增强协作。