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

项目4的目标是研究身体活动（PA）、下肢身体功能 (PF)，和虚弱，认知障碍及其潜在的神经病理学在老年人的连续性， 糖尿病预防项目（DPP）结局研究中的糖尿病前期（PreD）和2型糖尿病（T2 D） （政治事务司）。PA是T2 D预防和治疗中常见的生活方式目标，也是T2 D治疗的关键组成部分。 在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 认知障碍PF下降和虚弱，在PreD/T2 D老年人中增加，与以下因素密切相关： 与之相关的还有认知障碍。因此，本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/T2 D患者中。我们的初步数据表明，PA和PF水平较低， 中年人同时与较差的整体和特定领域的认知功能有关。我们现建议 检查PA、PF和虚弱轨迹之间的关联，跨越中年到晚年的过渡期， 认知功能减退、轻度认知障碍（MCI）和痴呆，以及血浆和影像学生物标志物 神经病理学此外，我们将评估（1）运动诱导的肌因子作为介质，和（2）T2 D相关的 代谢因素和并发症作为调节剂和介质。我们将利用超过25年的PA数据， 多年的PF和虚弱数据，以及DPPOS纵向框架中的广泛代谢表型， 预计入组DPPOS-AD/ADRD的受试者（N = 1，979）。我们将通过以下方式实现目标 具体目标：（1）将PA、PF和虚弱轨迹分别或联合与遗忘和非遗忘相关联 认知下降和MCI和痴呆的风险（AD连续性与非AD病理学作为探索性）， PreD/T2 D; 2）将PA、PF和虚弱轨迹分别和联合与血浆生物标志物的变化相关 淀粉样蛋白（Aβ42/40比值）、tau（磷酸化tau 181 [ptau-181]）、神经变性（神经丝轻 [NfL]）和神经炎症（胶质细胞酸性蛋白[GFAP]）。在接受脑成像的参与者中（N = 650），我们将PA，PF和虚弱轨迹与淀粉样蛋白负荷，皮质厚度和脑血管 疾病;（3）检查PA、PF和虚弱与运动诱导的肌因子（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中的生物标志物。(4)为了探索血糖负荷， 血管负荷、微血管/大血管并发症和外周炎症中度和/或 调解目标1-3之间的关联;（5）探索性目标：目标1-4也将探索相互作用 按APOE-ε4、性别、体重指数（BMI）、初始随机化治疗分配、人种/种族和 认知储备的测量（例如，教育水平）。

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).