Midcareer Award for Research in Dementia Risk Factors and Prevention

痴呆症风险因素和预防研究职业中期奖

• 批准号: 10645176
• 负责人: Jose Alejandro Luchsinger
• 金额: $ 12.13万
• 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: 2022-06-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645176
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Applications Grants; Atrophic; Award; Biological Markers; Brain; Brain imaging; Brain region; Calendar; Cerebrovascular Disorders; Clinical Investigator; Cognition; Cognitive deficits; Collaborations; Complement; Data; Diabetes Mellitus; Funding; Future Generations; Glial Fibrillary Acidic Protein; Gliosis; Goals; Grant; Hispanic; Hispanic Populations; Human; Hyperglycemia; Image; Impaired cognition; Inflammation; Knowledge; Ligands; Light; Link; Magnetic Resonance Imaging; Measurement; Mediating; Memory; Memory impairment; Mentors; Methods; Microglia; Mid-Career Clinical Scientist Award (K24); Midcareer Investigator Award in Patient-Oriented Research; Mus; Nerve Degeneration; Neurodegenerative Disorders; New York City; Parents; Participant; Performance; Peripheral; Persons; Pilot Projects; Plasma; Positron-Emission Tomography; Prevention; Process; Proteins; Research; Research Personnel; Resources; Role; Standardization; Testing; Thick; Time; Training; Training Activity; aged; brain magnetic resonance imaging; cardiometabolic risk; career; cognitive testing; cohort; dementia risk; diabetic; glucose tolerance; metabolomics; middle age; neurofilament; neuroinflammation; patient oriented research; tau Proteins; uptake

This is a competitive renewal application for grant K24AG045334 (Midcareer Award for Research in Dementia Risk Factors and Prevention). Consistent with PA-20-186 (Midcareer Investigator Award in Patient Oriented Research [POR]), I propose to continue protecting 25% of my time to augment my capabilities in POR, and provide mentoring to junior clinical investigators in the conduct of POR. The current K24 supported scientific project and its related mentoring and training activities has leveraged grant R01AG050440 (Diabetes Status and Brain Amyloid in Middle Aged Hispanics; PI: Luchsinger). The current K24 award proposed the examination of plasma biomarkers of Alzheimer’s disease (AD), metabolomics, and a pilot study of tau Positron Emission Tomography (PET), which were successfully achieved while providing mentoring and resources to several early investigators, who have successfully obtained K and R funding. R01AG050440 will be renewed for another 5 years on 08/01/21 for another 5 years of funding, and will be leveraged again for the scientific, training, and mentoring goals of this proposal. The new funding period will extend the ascertainment of amyloid, tau, and neurodegeneration with brain imaging (18F-Florbetaben PET, 18F-MK6240 PET, 3T magnetic resonance imaging [MRI]) and plasma biomarkers (Aß42/40 ratio, neurofilament light, ptau-181) for two more waves, in addition to comprehensive cognitive testing and ascertainment of cerebrovascular disease (CVD). Preliminary data shows that microgliosis (neuroinflammation) accompanies neurodegeneration and cognitive impairment in diabetic (db/db) mice. Thus, I propose to train in neuroinflammation and its measurement in humans, including plasma Glial Fibrillary Acidic Protein (GFAP) and, brain imaging (11C-ER176 PET), and apply them to the parent study during the proposed period. The overarching hypothesis of this application is that diabetes causes neuroinflammation that leads to neurodegeneration and associated cognitive deficits, independent of amyloid, tau, and CVD. My primary scientific aim is to examine the association of neuroinflammation, ascertained with plasma GFAP, with neurodegeneration, ascertained as cortical thickness on brain MRI, and memory impairment, ascertained as total recall in the Buschke Selective Reminding Test. My first training aim 1: to train in the role of neuroinflammation in neurodegenerative diseases and in diabetes, its measurement in plasma, and its interpretation. My first mentoring aim is to train mentees in the primary (amyloid, tau, neurodegeneration) and secondary constructs (cognition, CVD) of the NIA/AA research framework, and their potential relation to diabetes and other cardiometabolic risk factors for AD/ADRD. My secondary scientific aim is to conduct a pilot study of brain imaging with the 18kDA translocator protein (TSPO) ligand 11C-ER-176 in 20 participants in the parent study. My second training aim is to train in the application of imaging of microglial activity and its interpretation. My second mentoring aim is to train mentees in the importance of neuroinflammation in neurodegenerative diseases with the assistance of the neuroinflammation experts collaborating in this proposal.

这是一个有竞争力的更新申请补助金K24 AG 045334（中期职业生涯奖研究痴呆症 危险因素及预防）。与PA-20-186（以患者为导向的职业生涯中期研究者奖）一致 研究[POR]），我建议继续保护我25%的时间，以增强我在POR方面的能力， 指导初级临床研究者进行POR。目前的K24支持科学 项目及其相关的指导和培训活动利用了R 01 AG 050440（糖尿病状态和 中年西班牙裔人的脑淀粉样蛋白; PI：Luchsinger）。目前的K24裁决建议审查 阿尔茨海默病（AD）的血浆生物标志物、代谢组学和tau正电子发射的初步研究 断层扫描（PET），这是成功实现的，同时提供指导和资源，以几个早期 成功获得K和R资金的调查人员。R 01 AG 050440将再更新5 2021年8月1日，再提供5年的资金，并将再次用于科学、培训和 本提案的指导目标。新的资助期将延长淀粉样蛋白、tau蛋白和 脑成像（18F-Florbetaben PET，18F-MK 6240 PET，3 T磁共振）检查神经变性 成像[MRI]）和血浆生物标志物（A β 42/40比值，神经丝光，ptau-181）， 除了全面的认知测试和脑血管疾病（CVD）的确定。初步 数据显示，小胶质细胞增生（神经炎症）伴随着神经变性和认知障碍， 糖尿病（db/db）小鼠。因此，我建议在人类神经炎症及其测量方面进行培训，包括 血浆胶质纤维酸性蛋白（GFAP）和脑成像（11 C-ER 176 PET），并将其应用于母体 在拟议期间进行研究。本申请的首要假设是糖尿病导致 导致神经变性和相关认知缺陷的神经炎症，独立于淀粉样蛋白， tau和CVD。我的主要科学目的是检查神经炎症的关联， 血浆GFAP，伴有神经变性，在脑MRI上确定为皮质厚度，和记忆障碍， 在Buschke选择性回忆测试中被确定为总回忆。我的第一个培训目标1：培养 神经退行性疾病和糖尿病中的神经炎症、其在血浆中的测量及其 解释。我的第一个指导目标是在初级（淀粉样蛋白，tau，神经变性）和 NIA/AA研究框架的二级结构（认知，CVD）及其与糖尿病的潜在关系 和其他心脏代谢危险因素。我的第二个科学目标是进行一项试点研究， 用18 kDA转运蛋白（TSPO）配体11 C-ER-176对20名参与者的父母进行脑成像 study.我的第二个培训目标是培训小胶质细胞活动成像及其解释的应用。 我的第二个指导目标是培训学员了解神经炎症在神经退行性疾病中的重要性。 在神经炎症专家的协助下，合作提出这一建议。