Biomarkers of Inflammation, Neurodegeneration and Age-Associated Cognitive Impairment

项目摘要 随着美国老龄化人口的迅速增加， 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， 存在筛选工具或治疗策略，并且许多患者对治疗是难治的。最近的研究 提示改变的神经炎症信号可能在正常老化中起重要的早期作用， 但促炎和抗炎途径的复杂相互作用的机制 在生命周期中的变化，或调节认知，尚不清楚。因此，使用动物模型的研究 这些科学家们迫切需要在更短的时间内， 总的假设是，神经炎症水平的上升发生在神经退行性变和衰老之前， 相关的认知障碍，并代表一个潜在的早期标志物。为了满足这一需求，中心目标 我的项目的一部分将是查询神经炎症标记物与大脑形态之间的关系 和微观结构，和认知，在自然发生的恒河猴模型的年龄相关的认知 损伤我将使用超灵敏的脑脊液（CSF）蛋白生物标志物检测， 激活的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，高分辨率 脑形态学和微结构的磁共振成像（MRI），以及 空间工作记忆这些研究的优势在于它们有可能表征新的生物标志物 与记忆障碍相关的神经炎症和神经退行性通路， 以确定新的潜在的生物标志物，可以作为筛选工具和未来的治疗目标。

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.