Physical activity, physical function, and frailty in relation to cognitive impairment and AD/ADRD biomarkers in DPPOS

DPPOS 中与认知障碍和 AD/ADRD 生物标志物相关的体力活动、身体功能和虚弱

• 批准号: 10507637
• 负责人: Priya Palta
• 金额: $ 14.03万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10507637
• 关键词: Adult; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid; Amyloid beta-42; Biological Markers; Blood Vessels; Body mass index; Brain; Brain imaging; Brain-Derived Neurotrophic Factor; Cerebrovascular Disorders; Cognition; Cognitive; Complex; Data; Dementia; Development; Diabetes prevention; Educational Background; Elderly; Enrollment; Ethnic Origin; Exercise; Glial Fibrillary Acidic Protein; Goals; Impaired cognition; Individual; Inflammation; Insulin-Like Growth Factor I; Joints; Life Style; Light; Lower Extremity; Measures; Mediating; Mediator of activation protein; Metabolic; Microvascular Dysfunction; Modeling; Muscle; Nerve Degeneration; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Outcome Study; Participant; Peripheral; Persons; Phenotype; Physical Function; Physical activity; Plasma; Population; Prediabetes syndrome; Race; Randomized; Research; Risk; Thick; Vascular Diseases; apolipoprotein E-4; cognitive function; cognitive reserve; comorbidity; diabetes prevention program; frailty; imaging biomarker; lifestyle intervention; macrovascular disease; metabolic phenotype; middle age; mild cognitive impairment; neurofilament; neuroinflammation; neuropathology; preservation; prevent; sex; tau Proteins; tau-1; β-amyloid burden

The goal of Project 4 is to study the interrelationships of physical activity (PA), lower extremity physical function (PF), and frailty, with cognitive impairment and its underlying neuropathology in older adults in the continuum of pre-diabetes (PreD) and type 2 diabetes (T2D) in the Diabetes Prevention Program (DPP) Outcomes Study (DPPOS). PA is a common lifestyle target in T2D prevention and treatment and was a key component of the lifestyle intervention in the DPP. Higher sustained PA levels are hypothesized to be associated with a lower risk of cognitive impairment. PF decline and frailty, increased in older adults with PreD/T2D, are closely related to PA, and are also associated with cognitive impairment. Thus, this project seeks to better understand the individual and joint associations of PA, PF, and frailty with cognitive outcomes and underlying neuropathology among persons with PreD/T2D. Our preliminary data show that lower PA and PF levels and higher frailty at midlife are concurrently associated with poorer global and domain-specific cognitive function. We now propose to examine the association among PA, PF, and frailty trajectories, across the mid- to late-life transition period, with cognitive decline, mild cognitive impairment (MCI) and dementia, and with plasma and imaging biomarkers of neuropathology. Further, we will evaluate (1) exercise-induced myokines as mediators, and (2) T2D-related metabolic factors and complications as moderators and mediators. We will leverage >25 years of PA data, >15 years of PF and frailty data, and extensive metabolic phenotyping in the longitudinal framework of DPPOS among participants (N = 1,979) expected to enroll in DPPOS-AD/ADRD. We will achieve our goal through the following specific aims: (1) To relate PA, PF, and frailty trajectories, separately and jointly, to amnestic and non-amnestic cognitive decline and risk of MCI and dementia (AD continuum vs. non-AD pathology as exploratory) in PreD/T2D; 2) To relate PA, PF, and frailty trajectories, separately and jointly, to changes in plasma biomarkers of amyloid (Aβ42/40 ratio), tau (phosphorylated tau 181 [ptau-181]), neurodegeneration (neurofilament light [NfL]), and neuroinflammation (glial fibrillary acidic protein [GFAP]). Among participants with brain imaging (N = 650), we will relate PA, PF, and frailty trajectories to amyloid burden, cortical thickness, and cerebrovascular disease; (3) To examine the association of PA, PF, and frailty with exercise-induced myokines (e.g., brain- derived neurotrophic factor [BDNF], insulin-like growth factor 1 [IGF-1]) and the relationship of myokines with cognitive outcomes examined in Aim 1 and biomarkers in Aim 2. (4) To explore whether glycemic burden, vascular burden, microvascular/macrovascular complications, and peripheral inflammation moderate and/or mediate the associations examined across aims 1-3; (5) Exploratory Aim: Aims 1-4 will also explore interactions by APOE-ε4, sex, body mass index (BMI), original randomized treatment assignment, race/ethnicity, and measures of cognitive reserve (e.g., education level).

项目4的目标是研究身体活动（PA）、下肢身体功能的相互关系 (PF) 和虚弱，以及老年人的认知障碍及其潜在的神经病理学 糖尿病预防计划 (DPP) 结果研究中的糖尿病前期 (PreD) 和 2 型糖尿病 (T2D) （DPPOS）。 PA 是 T2D 预防和治疗中常见的生活方式目标，也是 T2D 预防和治疗的关键组成部分 民进党的生活方式干预。假设较高的持续 PA 水平与较低的风险相关 的认知障碍。患有 PreD/T2D 的老年人中 PF 下降和虚弱程度增加，与以下因素密切相关： PA 也与认知障碍有关。因此，该项目旨在更好地了解 PA、PF 和虚弱与认知结果和潜在神经病理学的个体和联合关联 PreD/T2D 患者。我们的初步数据显示，PA 和 PF 水平较低，虚弱程度较高 中年同时与较差的整体和特定领域认知功能相关。我们现在提议 研究中年到晚年过渡时期 PA、PF 和衰弱轨迹之间的关联， 认知能力下降、轻度认知障碍 (MCI) 和痴呆，以及血浆和影像生物标志物 神经病理学。此外，我们将评估 (1) 运动诱发的肌因子作为调节剂，以及 (2) T2D 相关的 代谢因素和并发症作为调节剂和调节剂。我们将利用 >25 年的 PA 数据，>15 多年的 PF 和虚弱数据，以及 DPPOS 纵向框架中广泛的代谢表型分析 预计参加 DPPOS-AD/ADRD 的参与者 (N = 1,979)。我们将通过以下方式实现我们的目标 具体目标：(1) 将 PA、PF 和虚弱轨迹分别和联合地与记忆删除和非记忆删除联系起来 认知能力下降以及 MCI 和痴呆的风险（AD 连续体与非 AD 病理学作为探索性） PreD/T2D； 2) 将 PA、PF 和衰弱轨迹分别和联合与血浆生物标志物的变化联系起来 淀粉样蛋白（Aβ42/40 比率）、tau（磷酸化 tau 181 [ptau-181]）、神经变性（神经丝光 [NfL]）和神经炎症（胶质纤维酸性蛋白[GFAP]）。在进行脑成像的参与者中（N = 650），我们将 PA、PF 和衰弱轨迹与淀粉样蛋白负荷、皮质厚度和脑血管联系起来 疾病; (3) 检查 PA、PF 和虚弱与运动诱发的肌因子（例如脑- 衍生神经营养因子 [BDNF]、胰岛素样生长因子 1 [IGF-1]）以及肌因子与 目标 1 中检查的认知结果和目标 2 中检查的生物标志物。 (4) 探讨血糖负荷是否 血管负担、微血管/大血管并发症和外周炎症中度和/或 调解目标 1-3 所检查的关联； (5)探索性目标：目标1-4还将探索交互作用 按 APOE-ε4、性别、体重指数 (BMI)、原始随机治疗分配、种族/民族和 认知储备的衡量标准（例如教育水平）。