Effects of chronic inflammation on brain structure and function

 描述(申请人提供)：慢性炎症是典型衰老过程的主要特征。然而，认为中枢神经系统具有免疫特权的观点受到了挑战，因为有证据表明，低水平的慢性炎症与神经损伤、神经退化和认知功能障碍有关。炎症造成的风险程度和损伤的潜在机制仍不清楚。这项提案的首要目标是更好地定义慢性炎症对大脑结构和功能的影响。我们建议研究慢性炎症对大脑的四种潜在下游影响：1)阿尔茨海默氏症相关变化；2)脑白质损伤；3)网络连接；4)认知。我们将从加州大学旧金山分校正在进行的、特征良好的队列中挑选出150名年龄在65岁以上的正常社区居民进行纵向研究。我们将使用血清、血浆和脑脊液中几个公认的标记物来量化慢性炎症。创新的MRI和PET分子神经成像方法将测量白质束、功能连接网络和阿尔茨海默病相关的脑淀粉样蛋白沉积的微观结构完整性。从部分病例中获得的脑脊液(CSF)将进一步加深我们对周围和大脑中特定炎症特征的了解。与慢性炎症相关的认知表型(S)将使用认知神经科学的方法来定义，我们将探索慢性炎症与脑结构和功能相互作用的潜在机制。该项目的结果可能会指导临床试验，并确定具有不良神经和认知老化的可治疗和可逆风险的老年受试者。

 DESCRIPTION (provided by applicant): Chronic inflammation is a major characteristic of the typical aging process. The view that the central nervous system is immunologically privileged, however, is challenged by evidence linking low level, chronic inflammation to neurologic injury, neurodegeneration, and cognitive dysfunction. The degree of risk posed by inflammation and the underlying mechanisms of injury remain unclear. The overarching goal of this proposal is to better define the impact of chronic inflammation on brain structure and function. We propose to study four potential downstream effects of chronic inflammation on the brain: 1) Alzheimer's-related changes; 2) white matter injury; 3) network connectivity; and 4) cognition. We will longitudinally study 150 functionally normal community-dwelling subjects over the age of 65 selected from on-going, well-characterized cohorts at UCSF. We will quantify chronic inflammation using several well established markers in serum, plasma, and cerebrospinal fluid. Innovative MRI and PET molecular neuroimaging methods will measure microstructural integrity of white matter tracts, functional connectivity networks, and Alzheimer's-related deposition of brain amyloid. Cerebrospinal fluid (CSF) obtained on a subset of cases will further our understanding of specific inflammatory profiles in the periphery and brain. The cognitive phenotype(s) associated with chronic inflammation will be defined using methods from cognitive neuroscience, and we will explore potential mechanisms by which chronic inflammation interacts with brain structure and function. Results from this project will potentially guide clinial trials and identify elderly subjects with treatable and reversible risks for adverse neurological and cognitive aging.