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)、肢体身体功能的相互关系 (PF)，和脆弱，与认知障碍及其潜在的神经病理在老年人中的连续 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，是T2D预防和治疗的关键组成部分 民进党的生活方式干预。假设持续较高的PA水平与较低的风险相关 认知障碍的症状。在患有PRED/T2D的老年人中，PF下降和虚弱增加与 PA，也与认知障碍有关。因此，这个项目试图更好地理解 PA、PF和脆弱性与认知结果和潜在神经病理学的个体和联合关联 在PRED/T2D携带者中。我们的初步数据显示，较低的PA和PF水平以及较高的 中年同时伴随着较差的整体和特定领域的认知功能。我们现在提议 为了检查PA、PF和脆弱轨迹之间的关联，跨越中老年过渡期， 有认知衰退、轻度认知障碍(MCI)和痴呆症，以及血浆和成像生物标志物 神经病理学的研究。此外，我们将评估(1)运动诱导的肌动蛋白作为介体，以及(2)与T2D相关的 代谢因素和并发症作为调节和调节因素。我们将利用&gt；25年的PA数据，&gt；15 多年的PF和脆弱数据，以及DPPOS纵向框架中广泛的代谢表型 预计参加DPPOS-AD/ADRD的参与者(N=1,979人)。我们将通过以下方式实现我们的目标 具体目标：(1)将PA、PF和脆弱轨迹分别和联合地与遗忘和非遗忘联系起来 认知功能减退与MCI和痴呆的风险(AD连续体与非AD病理对照为探索性) PRED/T2D；2)分别和联合将PA、PF和脆性轨迹与血浆生物标记物的变化联系起来 淀粉样蛋白(Aβ42/40比率)、tau(磷酸化tau181[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])。在接受脑部成像的参与者中(N= 650)，我们将把PA、PF和脆性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和脆弱与运动诱导的肌肉运动因子(例如，脑- 衍生神经营养因子[BDNF]、胰岛素样生长因子1[IGF-1])及其与肌细胞因子的关系 在目标1中检查认知结果，在目标2中检查生物标记物。(4)探讨血糖负荷、 血管负担、微血管/大血管并发症以及中度和/或外周炎症 调解目标1-3检查的关联；(5)探索性目标：目标1-4也将探索相互作用 按载脂蛋白E-ε4、性别、体重指数、最初的随机治疗分配、种族/民族以及 认知储备的衡量标准(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).