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.

该项目的目的是表征认知能力下降，轻度认知的存在和相关性 糖尿病预防计划结果研究（DPPOS）队列中的障碍[MCI]和痴呆症。 许多流行病学研究表明，糖尿病前（PREP）和2型糖尿病（T2D）是相关的 具有更高的认知障碍风险。但是，知识的差距仍然有关PRED的认知障碍 和T2D：（a）除了对认知障碍和痴呆症的血管贡献以外的神经病理学是什么 （vcid）？ （b）存在神经元胰岛素失调，它与外周胰岛素抵抗有关 pred和t2d的特征？ （c）通过相关的社会数字学，包括性别， 种族/种族，教育成就和扫盲？ （d）是与行为相关的关联 （睡眠障碍和抑郁症状），在PRED和T2D中也很常见？我们将表征朝鲜 在所有参与者中，以及非脉络性认知下降，MCI和痴呆症（n = 1979）。我们将测量血浆 淀粉样蛋白（Aβ42/40比），tau（PTAU-181），神经变性（Neurodegeneration（Neurofilements Light [nfl]）的生物标志物和 所有参与者中的神经炎症（神经纤维纤维酸性蛋白[GFAP]）和淀粉样蛋白的脑成像标记物， 神经变性（皮质厚度），脑血管疾病（白质超强度[WMH]和 在650名参与者的子样本中，梗塞），白质微观结构和功能连通性。我们将 使用血浆PTAU-181和淀粉样蛋白正电子来表征AD连续体和非AD病理变化 发射断层扫描（PET），遵循国家老化研究所（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的特征。 我们将隔离所有循环细胞外蔬菜（EV）和神经元来源 - 富含EVS（NEVS） 参与者曾经检查系统性和神经元胰岛素信号传导。我们将通过 以下特定目的：（1）检查弱体和非遗物认知的患病率和发病率 下降，MCI和痴呆症，并检查其与淀粉样蛋白，Tau，神经变性的生物标志物的关联， 神经炎症，并带有VCID； （2）检查认知综合征与全身和 使用NEV测量神经元胰岛素信号传导。 （3）检查社会人口统计学因素的关联 包括性别，种族/种族，教育和扫盲，认知能力下降，MCI和痴呆以及 神经病理学生物标志物； （4）探索抑郁症状，睡眠质量和 阻塞性睡眠呼吸暂停，认知能力下降，MCI和痴呆症。我们还将探索他们与 神经病理学的生物标志物。我们还将探索（a）神经元胰岛素信号是否与周围有关 与项目2合作的代谢措施； （b）目标1和2中的发现是否因使用T2D而有所不同 与项目3合作的药物； （c）与认知综合症合作的物理相关性 项目4。