Biomarkers of Inflammation, Neurodegeneration and Age-Associated Cognitive Impairment

炎症、神经退行性变和年龄相关认知障碍的生物标志物

• 批准号: 10669285
• 负责人: Alison Ruth Weiss
• 金额: $ 19.43万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669285
• 关键词: Address; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; American; Animal Model; Animals; Anti-Inflammatory Agents; Area; Astrocytes; Atrophic; Behavior; Biological Assay; Biological Markers; Biometry; Brain; Cells; Cerebrospinal Fluid; Cognition; Complex; Corpus striatum structure; Data; Dementia; Diffusion; Disease model; Early Diagnosis; Early identification; Exhibits; Foundations; Future; Gliosis; Goals; Human; Image; Impaired cognition; Independent Living; Inflammation; Inflammatory; Infrastructure; Longevity; Macaca; Macaca mulatta; Magnetic Resonance Imaging; Measures; Mediating; Memory impairment; Microglia; Modeling; Monkeys; Morbidity - disease rate; Morphology; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neuroimmune; Neurosciences; Pathway interactions; Patients; Pattern; Play; Population; Positron-Emission Tomography; Pre-Clinical Model; Process; Productivity; Proliferating; Proteomics; Public Health; Refractory; Research; Research Technics; Resolution; Resources; Role; Sampling; Screening procedure; Sensitivity and Specificity; Short-Term Memory; Signal Transduction; Structure; Symptoms; Technology; Testing; Thalamic structure; Therapeutic; Tissue Banks; Work; age related; age related neurodegeneration; aged; biomarker identification; brain morphology; cerebral atrophy; clinically relevant; cognitive testing; density; gray matter; healthy aging; histological studies; innovation; long-term sequelae; microPET; middle age; minimally invasive; morphometry; multimodal neuroimaging; multimodality; neuroinflammation; novel; novel marker; pathological aging; potential biomarker; prevent; programs; protein biomarkers; therapeutic target; therapeutically effective; white matter; young adult

Project Summary With a rapidly increasing population of aging Americans, cognitive impairment associated with normative aging, or neurodegenerative diseases including Alzheimer's Disease and other related dementias (ADOD), will place increasing burden on our public health infrastructure. Unfortunately, few effective screening tools or therapeutic strategies exist, and many patients are refractory to treatment. Recent studies suggest that altered neuroinflammatory signaling may play an important early role in normative aging, and in ADOD, but the mechanisms by which the complex interaction of pro- and anti-inflammatory pathways change over the lifespan, or modulate cognition, are unclear. For this reason, studies using animal models that closely recapitulate normative human aging, but on a shorter timescale, are desperately needed to test the overall hypothesis that rising levels neuroinflammation occurs prior to neurodegeneration and age- related cognitive impairment, and represent a potential early marker. To address this need, the central goal of my project will be to query the relationship between markers of neuroinflammation with brain morphology and microstructure, and cognition, in naturally-occurring rhesus macaque model of age-related cognitive impairment. I will use a combination of ultra-sensitive cerebral spinal fluid (CSF) protein biomarker assays, Positron Emission Tomography (PET) imaging of activated astrocytes and microglia, high-resolution Magnetic Resonance Imaging (MRI) of brain morphology and microstructure, and cognitive assessment for spatial working memory. The strength of these studies lies in their potential to characterize novel biomarkers of neuroinflammatory and neurodegenerative pathways that are associated with memory impairment, and to identify new potential biomarkers that can serve as screening tools and future therapeutic targets.

项目摘要 随着美国老龄化人口的迅速增长，认知障碍与 正常衰老，或神经退行性疾病，包括阿尔茨海默病和其他相关痴呆 (ADOD)，将给我们的公共卫生基础设施带来越来越大的负担。不幸的是，几乎没有什么有效的 存在筛查工具或治疗策略，许多患者对治疗难以治疗。最新研究 提示神经炎性信号的改变可能在正常衰老的早期发挥重要作用 在ADOD中，但促炎和抗炎途径的复杂相互作用的机制 对寿命的改变，或对认知的调节，目前尚不清楚。为此，使用动物模型进行的研究 我们迫切需要用更短的时间来测试这些数据 总体假设是，神经炎症水平上升发生在神经退行性变和年龄之前- 相关的认知损害，并代表了一个潜在的早期标志。为了满足这一需求，中心目标是 我的项目的重点是质疑神经炎标志物与脑形态之间的关系 自然发生的恒河猴年龄相关认知模型中的微观结构和认知 减损。我将结合使用超灵敏的脑脊液(CSF)蛋白质生物标志物分析， 高分辨率激活星形胶质细胞和小胶质细胞的正电子发射断层扫描(PET)成像 脑部形态和微结构的磁共振成像(MRI)和认知评估 空间工作记忆。这些研究的优势在于它们表征新的生物标志物的潜力 与记忆障碍相关的神经炎性和神经退行性变化的通路，以及 寻找新的潜在生物标志物，作为筛查工具和未来的治疗靶点。