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.

运动性认知风险综合征的生物学基础：一项多中心研究 运动性认知风险综合征（MCR）是最近描述的痴呆前综合征，其特征在于： 存在主观认知主诉和步态缓慢。MCR几乎影响十分之一的老年人， 衰老的发病率。MCR预测阿尔茨海默病（AD）和血管性痴呆的风险， 在解释了与轻度认知障碍综合征（MCI）的临床重叠后。与MCI不同， 诊断MCR不需要认知测试或测定，增加了其临床实用性。MCR具有增量 对痴呆症在其个体认知（认知主诉）和运动（步态缓慢）方面的预测有效性 件. 虽然已经描述了MCR的流行病学，但MCR的生物学基础和神经基质 尚未建立。我们召集了一个多学科团队，全面开展第一项研究， 探讨MCR综合征的发病机制。MCR财团包括估计10，080名老年人 来自美国、加拿大、欧洲、亚洲和澳大利亚的8个队列。MCR联盟已经合作，分享， 协调数据，并发布MCR主题，确定可行性。 目标1。确定MCR发生率的生物学机制。外周炎症升高， 这些途径中的氧化应激生物标志物以及单核苷酸多态性预测了 我们的试点研究。我们将前瞻性地研究炎症和氧化应激生物标志物的作用， 探索MCR发病机制中这些和相关通路的遗传变异。我们将报告协会在 作为第二步，在我们的MCR联盟的9，370名个体的合并样本中， 生物标志物/基因检测可用或计划。 目标二。建立MCR综合征的脑病理学和基质。根据研究，大脑小 脑血管疾病与皮质变薄，我们假设脑小血管疾病（腔隙性梗死，脑梗死）， 微出血和白色高信号）可能加速或刺激灰质损失， 作为MCR。这一目标将使用先进的成像采集和分析方法进行前瞻性测试， 个体队列，其次是3，100名神经影像学个体的合并样本。 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 目标1和2中发现的新生物学关联以及已知AD风险的相似性和差异 因素（APOE、海马萎缩等）与MCR和MCI合作。MCR和MCR之间仅存在部分临床重叠 和MCI。虽然我们预计部分生物重叠，但我们的研究显示， 病理学和脑基质的MCR没有看到与MCI。MCR综合征并不被概念化为 与MCI交替但互补。发现MCR的独特生物学关联可能会导致新的 补充当前MCI预防的治疗。 我们的提案高度响应PAR-17-054：根据PAR指南，我们将使用和/或协调 现有数据，收集所有队列中不存在的新的生物学和成像数据，并添加新的受试者，以及 在8个队列中扩展随访，以通过MCR阐明AD和相关痴呆的风险和保护因素 通路我们的提案也符合国家阿尔茨海默病计划的几个行动重点， 努力识别AD的早期阶段，识别痴呆症的生物学机制，扩大遗传学， 流行病学研究，以确定风险因素，并扩大国际推广，以加强合作。