Alzheimers Disease Project: Primate Models of Neurocognitive Aging

该项目的研究建立在对记忆、执行功能和其他认知能力的神经系统组织的长期调查基础上。在这个神经心理学框架的指导下，我们最近汇总了来自多个年龄组的年轻和老年恒河猴的研究结果，这些恒河猴接受了一系列认知任务的标准化测试，这些认知任务已知不同地依赖于前额叶皮层和海马以及包括内侧颞叶记忆系统的相关大脑区域。研究结果为迄今为止公布的最大样本建立了群体标准，包括100多名年轻成年人（n=34，4-14岁）和20岁至30岁以上的动物（n=71）。神经心理学测试包括3个为猴子设计的表征良好的评估;时空工作记忆的延迟反应（DR）测试，延迟非匹配样本视觉（DNMS）物体识别任务，以及一系列物体辨别（OD）和保持测试。在关键发现中，尽管老年受试者在所有3项任务上的得分都低于年轻人，但反映前额叶皮质功能的表现指标与依赖于内侧颞叶的记忆能力之间没有关系。这意味着衰老独立地影响这些认知能力，而不是作为一个全球性的衰老过程，将不同功能领域的结果联系起来。此外，性别和实际年龄通常是老年受试者认知结果个体差异的不可靠预测因素。这些结果共同建立了衰老的规范特征，这对于探索老年灵长类动物大脑中介导认知障碍和恢复力下降的区域和回路特异性改变的努力很重要。 磁共振成像提供了一种非侵入性和预防性的手段来评估与年龄相关的灵长类动物大脑结构和功能连接的差异，这些差异与衰老认知结果的个体差异有关。在最近的一项分析中，我们利用上述非人类灵长类动物模型对年轻和老年动物的区域体积进行了无偏见的全脑调查，确定了与物体识别记忆表现的显著区域相关性。对于年轻人来说，任务获取和遗忘率的体积相关性突出地精确涉及已知对记忆至关重要的内侧颞叶区域，即，海马体和侧面相邻的鼻皮质区。出乎意料的是，小脑也是任务表现的重要相关因素。相比之下，老年人的记忆与前额叶皮层和纹状体结构有关。我们的研究结果表明，区域体积的区域分布加上记忆的可能性是重组的寿命，与灵长类动物大脑结构重组的能力持续到老年的观点一致。 最近发表的一项研究证实了我们的发现，并利用巴尔的摩老龄化纵向研究的数据，在猴子身上测试了我们观察结果的转化有效性。在该分析中，线性混合模型和偏相关被用来测试小脑体积变化与衰老过程中记忆力之间的关联。总之，研究结果表明，小脑体积和记忆力下降之间的关系是年龄依赖性和区域选择性的。未来的一个重要方向是探索小脑介导临床研究中报告的身体功能下降和认知衰老之间的显著联系的可能性。

Research in this project is founded on a long history of investigation on the neural systems organization of memory, executive function and other cognitive capacities. Informed by this neuropsychological framework, we recently aggregated findings from multiple cohorts of young and aged rhesus monkeys tested on a standardized battery of cognitive tasks known to differentially depend on the prefrontal cortex and the hippocampus and related brain regions comprising the medial temporal lobe memory system. The results establish population norms for the largest sample published to date, comprising over 100 young adults (n=34, 4-14 years) and animals aged 20 to over 30 years (n=71). Neuropsychological testing included 3 well-characterized assessments designed for monkeys; a delayed response (DR) test of spatiotemporal working memory, the delayed nonmatching-to-sample visual (DNMS) object recognition task, and a series of object discrimination (OD) and retention tests. Among the key findings, whereas aged subjects scored poorly relative to young on all 3 tasks, there was no relationship between performance measures that reflect prefrontal cortex function, and memory capacities that depend on the medial temporal lobe. The implication is that aging impacts these cognitive capacities independently, rather than as a global aging process that links outcomes across distinct functional domains. In addition, sex and chronological age were generally unreliable predictors of individual differences in cognitive outcome among the aged subjects. Together the results establish normative features of aging important for efforts to probe region and circuit specific alterations in the aged primate brain that mediate cognitive impairment and resilience to decline. Magnetic resonance imaging provides a non-invasive and translation-amenable means of evaluating age-related differences in primate brain structure and functional connectivity associated with individual differences in the cognitive outcome of aging. In one recent analysis, we took advantage of the nonhuman primate model described above in an unbiased, brain-wide survey of regional volumes in young and aged animals, identifying significant regional correlations with object recognition memory performance. For young adults, volumetric correlates of task acquisition and forgetting rates prominently involved precisely the medial temporal lobe regions known to be critical for memory, i.e., the hippocampus and laterally adjacent rhinal cortical areas. Less expected, the cerebellum was also a significant correlate of task performance. Memory in aged subjects, by comparison, was coupled with prefrontal cortex and striatal structure. Our results suggest the possibility that the regional distribution of regional volumes coupled with memory is reorganized over the lifespan, consistent with the perspective that the capacity for structural reorganization in the primate brain persists into old age. Prompted by our findings, a recently published study tested the translational validity of our observations in monkeys using data from the Baltimore Longitudinal Study of Aging. In that analysis linear mixed models and partial correlations were used to test for associations between changes in cerebellum volume and memory during aging. Together the findings suggest that the relationship between cerebellum volume and memory decline is age-dependent and regionally selective. An important future direction is to explore the possibility that the cerebellum mediates the prominent link between decline in physical function and cognitive aging reported in clinical research.