Neural substrates of diffusion imaging in cognitively aging rhesus monkeys

7.摘要。 识别和跟踪大脑成熟和老化过程中发生的神经生物学变化的能力是 不仅对我们对认知的理解至关重要，而且对关注以下问题的临床研究也至关重要 神经发育或神经退行性疾病，包括临床试验。而尸检研究 提供在局部组织学变化方面具有良好特征的数据，这些数据可能是有限的 由于它们的横截面性质和小样本量。相比之下，非侵入性的活体成像允许 在更大的人口中收集纵向数据，是研究生命的更强大的工具 跨越大脑成熟和老化的轨迹。 神经成像的最新发展已经为成像变化之间的关系提供了证据 猴子和人类的认知老化。不幸的是，认知年龄的细胞基础是 争论的主题以及可用成像措施的生物学特异性还没有得到很好的确立。 更令人担忧的是，虽然旧的成像方法仍然缺乏彻底的验证，但新的“更具体”的方法 不断被引入临床研究的药物离验证还有很长的路要走。在过去的时间里 在资助期间，我们使用了大量的组织学、认知和成像遗留数据 认知老化的恒河猴，测试神经炎症和髓鞘退行性变起作用的假设 神经成像生物标记物可以反映这些生物过程。 我们建议在这个方向上进一步开展我们的工作，提出包括1)在内的翻译实验。 获取新的、高分辨率的“人类连接组计划”兼容的成像数据，2)。扩展我们的 通过添加神经炎症和髓鞘特异性的PET放射配基进行神经成像，3)。发展神经成像 轻度认知障碍的白质特异性生物标记物--阿尔茨海默病的风险因素，以及4)。 研究衰老过程中性别差异的生物学基础。这通过三个PI的协作来实现， 在核磁共振成像、形态测量、神经解剖学方面拥有独特的互补专业知识， 免疫组织化学和认知老化，并将通过获取和分析行为， 影像、血液和尸检数据来自24只恒河猴，不同性别，8只年轻成年人(4只 男性和4名女性)和16名老年人(8名男性和8名女性，一半被诊断为轻度认知障碍 (MCI))。 这项拟议研究的结果将极大地影响我们对衰老过程及其 机制，并提供组织验证的成像措施的理解，可应用于研究 人类正常衰老以及许多神经发育和神经退行性疾病的中枢 神经系统。

7. Abstract. The ability to identify and follow-up neurobiological changes that occur during brain maturation and aging is not only fundamental to our understanding of cognition, but is also crucial for clinical studies that focus on either neurodevelopmental or neurodegenerative disorders, including clinical trials. While post-mortem studies provide data that are well characterized in terms of localized histological changes, these data can be limited due to their cross sectional nature and small samples sizes. In contrast, non-invasive in vivo imaging allows for the collection of longitudinal data in much larger populations, and is a more powerful tool to investigate life span trajectories of brain maturation and aging. Recent developments in neuroimaging have provided evidence for the relationship between imaging changes and cognitive aging in monkeys, and humans. Unfortunately, the cellular underpinnings of cognitive age are a subject of debate and hence the biological specificity of available imaging measures is not well established. More alarming, while older imaging measures still lack thorough validation, newer “more specific” measures that are being constantly introduced into clinical research are even further from validation. Over the past funding period, we have worked with a large repository of histological, cognitive and imaging legacy data from cognitively aging rhesus monkeys, testing the hypothesis that neuroinflammation and myelin degeneration play crucial roles in cognitive aging, and that neuroimaging biomarkers can reflect those biological processes. We propose to further our work in this direction, by proposing translational experiments that will include 1). acquiring new, high resolution “Human Connectome Project (HCP)” compatible imaging data, 2). Expand our neuroimaging by adding neuroinflammation- and myelin-specific PET radioligands, 3). Develop neuroimaging white matter-specific biomarkers of mild cognitive impairment- a risk factor for Alzheimer’s disease, and 4). Investigate biological underpinnings of sex differences in aging. This is enabled by a collaboration of three PIs, with unique and complementary expertise in MRI imaging, morphometry, neuroanatomy, immunohistochemistry and cognitive aging, and will be further facilitated by acquiring and analyzing behavioral, imaging, blood and post mortem data from a cohort of 24 rhesus monkeys of both sexes, 8 young adults (4 males and 4 females) and 16 old adults (8 males and 8 females, half diagnosed with mild cognitive impairment (MCI)). The results of this proposed study will greatly impact our understanding of aging processes and their mechanisms and provide tissue validated understanding of imaging measures that can be applied to studies of normal human aging as well as many neurodevelopmental and neurodegenerative diseases of the central nervous system.