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

运动性认知风险综合征的生物学基础：一项多中心研究 运动认知风险综合征(MCR)是最近被描述的一种痴呆前期综合征，其特征是 存在主观认知方面的抱怨和步态缓慢。MCR影响几乎每10个老年人中就有一个，并且有很高的 老龄化的发病率。MCR预测阿尔茨海默病(AD)和血管性痴呆的风险，甚至 在考虑了与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不需要认知测试或分析，从而增加了其临床实用价值。MCR具有增量 痴呆症个体认知(认知主诉)和运动(步态缓慢)的预测效度 组件。 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础是 还没有确立。我们召集了一个多学科的团队，全面进行了第一次研究，以 探讨MCR综合征的发病机制。据估计，MCR联盟包括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财团合作、共享和 统一数据，并就MCR专题发表，确立可行性。 目的1.明确MCR发病的生物学机制。外周炎症和 氧化应激生物标记物和这些途径中的单核苷酸多态性预测MCR的发生 我们的初步研究。我们将前瞻性地研究炎症和氧化应激生物标记物和 探索这些途径中的遗传变异以及在MCR发病机制中的相关途径。我们将在以下位置报告关联 作为我们MCR联盟中9,370名个人的第二步 生物标记物/遗传分析已完成或计划完成。 目的2.建立MCR综合征的脑病理基础。基于将大脑小脑 血管病变到皮质变薄，我们假设大脑小血管病变(腔隙性脑梗塞、脑 微出血和白质高信号)可能加速或刺激临床表现的灰质丢失 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 在个人队列中，其次是在3100名接受神经成像的人的池样本中。 目的3.对MCR和MCI综合征的生物学和脑基质进行比较和对比。我们将探索 在AIMS 1和2中发现的新生物关联以及已知AD风险的异同 影响因素(APOE、海马区萎缩等)使用MCR和MCI。MCR之间只有部分临床重叠 和MCI。虽然我们预计会有部分生物重叠，但我们的研究表明，大脑具有独特的遗传倾向 MCR的病理和脑基质在MCI中看不到。MCR综合征没有被概念化为 替代MCI，但互为补充。发现MCR独特的生物关联可能导致新的 补充目前MCI预防措施的治疗。 我们的建议高度响应PAR-17-054：根据PAR指南，我们将使用和/或协调 收集未在所有队列中出现的新的生物和成像数据，并添加新的参与者以及 延长对8个队列的随访，通过MCR澄清AD和相关痴呆的风险和保护因素 路径。我们的建议还符合国家阿尔茨海默病计划的几个行动优先事项，例如加速 努力确定阿尔茨海默病的早期阶段，确定痴呆症的生物学机制，扩大基因 进行流行病学研究以确定危险因素，并扩大国际推广范围以加强合作。

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.