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

DPPOS 队列中的认知障碍及其神经病理学、神经生理学、社会人口统计学和行为相关性

• 批准号: 10507634
• 负责人: James McCallum Noble
• 金额: $ 41.37万
• 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/10507634
• 关键词: Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid; Amyloid beta-42; Attenuated; Behavioral; Biological Markers; Brain imaging; Categories; Cerebrovascular Disorders; Characteristics; Classification; Cognition; Cognition Disorders; Cohort Studies; Dementia; Education; Ethnic Origin; Ethnic group; Female; Glial Fibrillary Acidic Protein; Goals; IRS1 gene; Impaired cognition; Incidence; Infarction; Insulin; Insulin Receptor; Insulin Resistance; Knowledge; Light; Measures; Metabolic; National Institute on Aging; Nerve Degeneration; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Not Hispanic or Latino; Obstructive Sleep Apnea; Outcome Study; Participant; Pathologic; Pathology; Peripheral; Persons; Pharmaceutical Preparations; Plasma; Population; Positron-Emission Tomography; Prediabetes syndrome; Prevalence; Prevention; Proto-Oncogene Proteins c-akt; Race; Research; Rest; Risk; Sampling; Sleep disturbances; Thick; Tyrosine; United States; Vascular Dementia; White Matter Hyperintensity; adjudication; aged; cognitive testing; depressive symptoms; diabetes prevention program; epidemiology study; extracellular vesicles; high risk; high risk population; imaging biomarker; insulin signaling; literacy; mild cognitive impairment; neurofilament; neuroimaging; neuroinflammation; neuropathology; neurophysiology; poor sleep; sex; sleep quality; sociodemographic factors; sociodemographics; tau Proteins; vascular cognitive impairment and dementia; white matter

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.

该项目的目标是描述认知衰退、轻度认知障碍的存在及其相关性 糖尿病预防计划结果研究 (DPPOS) 队列中的损伤 [MCI] 和痴呆。 大量流行病学研究表明，糖尿病前期 (PreD) 和 2 型糖尿病 (T2D) 之间存在相关性 然而，关于 preD 认知障碍的知识仍然存在差距。 和 T2D：(a) 除了血管因素之外，还有哪些神经病理学因素导致认知障碍和痴呆 (VCID)？(b) 是否存在神经元胰岛素失调，是否与外周胰岛素抵抗有关 preD 和 T2D 的特征是否存在差异？ (d) 这些关联是否与行为相关？ （睡眠障碍和抑郁症状），在 D 前期和 T2D 中也很常见，我们将描述遗忘症的特征？ 所有参与者 (n = 1979) 中的非遗忘性认知能力下降、轻度认知障碍 (MCI) 和痴呆症。 淀粉样蛋白（Aβ42/40 比率）、tau (ptau-181)、神经变性（神经丝光 [NfL]）和 所有参与者的神经炎症（胶质纤维酸性蛋白 [GFAP]），以及淀粉样蛋白的脑成像标记物， 神经退行性变（皮质厚度）、脑血管疾病（白质高信号 [WMH] 和 梗塞）、白质微观结构和功能连接，在 650 名参与者的子样本中进行。 使用血浆 ptau-181 和淀粉样正电子描述 AD 连续体和非 AD 病理变化 发射断层扫描 (PET)，遵循国家老龄化研究所 (NIA)/阿尔茨海默病协会 (AA) 研究框架，并将探索 tau、神经变性、神经炎症和 VCID 的表征。 我们将在所有细胞中分离总循环细胞外囊泡 (EV) 和富含神经起源的 EV (nEV) 参与者一旦检查系统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。 遵循以下具体目标：（1）检查遗忘和非遗忘认知的患病率和发生率 衰退、MCI 和痴呆，并检查它们与淀粉样蛋白、tau、神经退行性变等生物标志物的关系， (2) 检验认知综合征与全身和系统疾病的关系 (3) 考察社会人口因素的关联性 包括性别、种族/民族、教育和识字率，以及认知能力下降、MCI 和痴呆症，以及 神经病理学生物标志物；（4）探讨抑郁症状、睡眠质量和 我们还将探讨阻塞性睡眠呼吸暂停与认知能力下降、MCI 和痴呆的关系。 我们还将探讨（a）神经元胰岛素信号传导是否与外周相关。 与项目 2 合作的代谢测量结果；(b) 目标 1 和 2 的结果是否因 T2D 的使用而变化 与项目 3 合作的药物；(c) 与项目 3 合作的认知综合症的身体相关性 项目4。