Cognitive impairment in the DPPOS cohort and its neuropathologic, neurophysiologic, sociodemographic, and behavioral correlates

该项目的目标是描述认知能力下降、轻度认知能力下降、 糖尿病预防项目结果研究（DPPOS）队列中的轻度认知功能障碍（MCI）和痴呆。 许多流行病学研究表明，糖尿病前期（PreD）和2型糖尿病（T2 D）相关 认知障碍的风险更高然而，在认知障碍方面仍然存在着知识上的差距。 和T2 D：（a）除了血管对认知障碍和痴呆的贡献外， （VCID）？(b)是否存在神经元胰岛素调节异常，是否与外周胰岛素抵抗有关 PreD和T2 D的特征？(c)这些关联是否因相关的社会人口统计学（包括性别）而不同， 种族/民族、教育程度和识字率？(d)这些关联是否与行为相关 （睡眠障碍和抑郁症状），也常见于preD和T2 D？我们会把失忆症 和非遗忘性认知下降，MCI和痴呆，在所有参与者（n =1979）。我们将测量血浆 淀粉样蛋白（Aβ42/40比值）、tau（ptau-181）、神经变性（神经丝光[NfL]）和 所有参与者的神经炎症（胶质细胞酸性蛋白[GFAP]），以及淀粉样蛋白的脑成像标志物， 神经变性（皮质厚度）、脑血管疾病（白色高信号[WMH]和 梗死）、白色物质微观结构和功能连接性。我们将 使用血浆ptau-181和淀粉样蛋白正电子能谱表征AD连续体和非AD病理变化 发射断层扫描（PET），根据国家老龄化研究所（NIA）/阿尔茨海默氏症协会（AA） 研究框架，并将探索tau，神经变性，神经炎症和VCID的表征。 我们将在所有受试者中分离总循环细胞外囊泡（EV）和神经元来源富集的EV（nEV）。 参与者一次检查全身和神经元胰岛素信号传导。我们将通过以下方式实现我们的目标： 以下具体目的：（1）检查遗忘和非遗忘认知的患病率和发生率 下降，MCI和痴呆，并检查它们与淀粉样蛋白，tau，神经变性， （2）研究认知综合征与全身性和神经性炎症的关系， 使用nEV测量神经元胰岛素信号传导。(3)研究社会人口学因素之间的关联 包括性别、种族/民族、教育和识字，伴认知功能减退、MCI和痴呆，以及 （4）探讨抑郁症状、睡眠质量和神经病理学标志物之间的关系。 阻塞性睡眠呼吸暂停伴认知功能下降、MCI和痴呆。我们还将探讨它们与 神经病理学的生物标志物。我们还将探讨（a）神经元胰岛素信号是否与外周血胰岛素水平有关。 与项目2合作的代谢测量;（B）目标1和2中的发现是否因T2 D的使用而异 与项目3合作的药物;（c）与项目3合作的认知综合征的物理相关性 项目4。

The goal of this project is to characterize the presence and correlates of cognitive decline, mild cognitive impairment [MCI] and dementia in the Diabetes Prevention Program Outcomes Study (DPPOS) cohort. Numerous epidemiologic studies have shown that pre-diabetes (PreD) and type 2 diabetes (T2D) are associated with higher risk of cognitive impairment. However, gaps in knowledge remain about cognitive impairment in preD and T2D: (a) What is the neuropathology other than vascular contributions to cognitive impairment and dementia (VCID)? (b) Is neuronal insulin dysregulation present, and is it related to peripheral insulin resistance characteristic of preD and T2D? (c) Do the associations differ by pertinent sociodemographics, including sex, race/ethnicity, educational attainment, and literacy? (d) Are the associations related to behavioral correlates (sleep disturbances and depressive symptoms), also common in preD and T2D? We will characterize amnestic and non-amnestic cognitive decline, MCI, and dementia, in all participants (n =1979). We will measure plasma biomarkers of amyloid (Aβ42/40 ratio), tau (ptau-181), neurodegeneration (neurofilament light [NfL]), and neuroinflammation (glial fibrillary acidic protein [GFAP]) in all participants, and brain imaging markers of amyloid, neurodegeneration (cortical thickness), cerebrovascular disease (white matter hyperintensities [WMH] and infarcts), white matter microstructure, and functional connectivity, in a subsample of 650 participants. We will characterize the AD continuum and non-AD pathologic change using plasma ptau-181 and Amyloid Positron Emission Tomography (PET), following the National Institute on Aging (NIA)/Alzheimer’s Association (AA) research framework, and will explore characterization by tau, neurodegeneration, neuroinflammation, and VCID. We will isolate total circulating extracellular vesicles (EVs) and neuronal origin-enriched EVs (nEVs) in all participants once to examine systemic and neuronal insulin signaling. We will achieve our goal through the following specific aims: (1) To examine the prevalence and incidence of amnestic and non-amnestic cognitive decline, MCI and dementia, and examine their association with biomarkers of amyloid, tau, neurodegeneration, neuroinflammation, and with VCID; (2) To examine the association of cognitive syndromes with systemic and neuronal insulin signaling measured using nEVs. (3) To examine the association of sociodemographic factors including sex, race/ethnicity, education, and literacy, with cognitive decline, MCI, and dementia, and neuropathology biomarkers; (4) To explore the association of depressive symptoms, sleep quality, and obstructive sleep apnea with cognitive decline, MCI, and dementia. We will also explore their association with biomarkers of neuropathology. We will also explore (a) whether neuronal insulin signaling is related to peripheral metabolic measures collaborating with Project 2; (b) whether findings in aims 1 and 2 vary by use of T2D medications collaborating with Project 3; (c) the physical correlates of cognitive syndromes collaborating with Project 4.