Cognitive Correlates of Mitochondrial Function in Older Adults

项目摘要/摘要 随着成年人年龄超过65岁，最紧迫的公共健康问题之一是认知 衰退、向痴呆症的转变以及卫生保健资源的利用。因此，当务之急是确定和 描述特定神经机制对非规范性认知下降的贡献，目标是 寻找循证干预措施。有证据表明，线粒体效率和能量产生 随着年龄的增长而下降。大脑依靠线粒体来执行一系列重要的细胞功能，包括 能量代谢、呼吸和细胞凋亡，以维持神经元的完整性。临床相关、功能障碍或 线粒体受损被认为是神经退行性疾病发病机制的核心。 像阿尔茨海默氏症这样的过程。磷磁共振波谱(31-P-MRS)是一种独特的， 非侵入性的、强有力的体内线粒体功能检测方法。到目前为止，只有少数几项研究 使用这种方法来评估线粒体功能的标志物和认知之间的关系， 调查结果好坏参半。目前这项研究的目标是更好地理解 线粒体对老年人认知功能的影响。鉴于执行功能和记忆力的下降 对衰老特别敏感，中心假说是线粒体功能的区域性标记，即 三磷酸腺苷(ATP)将与额叶的领域特异性认知有区别地联系 和时间区域。这项研究的目的是(1)同时检测额叶的ATP功能标志物 使用一种非侵入性的、最先进的神经成像技术，31-P MRS，和(2) 确定基于区域~(31-P)MRS的ATP功能标志物与区域特异性的关系 认知(即执行力、记忆力)。这项研究的工作假设是(1)颞叶ATP的标记物 在高能量的情况下，与额叶ATP功能的标志物相比，功能将更集中 在颞区(如海马体)内的消耗以及与年龄相关的结构和功能的快速下降 额叶内功能，(2)额叶ATP功能的标志物与执行力的相关性更强 功能任务相对于记忆任务；(3)暂时性ATP功能的标记物将更强 与执行功能任务相比，与记忆任务相关。建议的创新特色 研究包括(1)假说指导下的额区和颞区线粒体功能，(2) 对依赖于这些区域内完整结构-功能的认知域的评估，以及(3)使用 体内ATP功能的新的、强大的和非侵入性的标记。这项研究的发现将增加目前的 了解31-P-MRS作为线粒体功能潜在生物标志物的适用性。大体上说，这些 这些发现有可能为正常和异常衰老过程之间更细微的区别提供信息。

PROJECT SUMMARY/ABSTRACT As the population of adults ages beyond 65 years, one of the most pressing public health concerns is cognitive decline, transition to dementia, and utilization of health care resources. Thus, it is imperative to identify and characterize the contribution of specific neural mechanisms to non-normative cognitive decline with the goal of finding evidence-based interventions. Evidence suggests that mitochondrial efficiency and energy production decline with older age. The brain is reliant on mitochondria to carry out a host of vital cellular functions including energy metabolism, respiration, and apoptosis to maintain neuronal integrity. Clinically relevant, dysfunctional or damaged mitochondria have been implicated as central to the pathogenesis of neurodegenerative disease processes like Alzheimer’s disease. Phosphorous magnetic resonance spectroscopy (31-P MRS) is a unique, non-invasive, and powerful method for examining in vivo mitochondrial function. To date, only a handful of studies have used this approach to assess the relationship between markers of mitochondrial function and cognition, and findings have been mixed. The goal of the current study is to better understand the differential influence of mitochondrial function on cognition in older adults. Given that declines in executive function and memory are particularly sensitive to aging, the central hypothesis is that regional markers of mitochondrial function, namely adenosine triphosphate (ATP), will be differentially associated with domain-specific cognition across frontal and temporal regions. The proposed study aims to (1) concurrently examine markers of ATP function over frontal and temporal regions using a non-invasive, state-of-the-science neuroimaging technique, 31-P MRS, and (2) determine the relationship between regional 31-P MRS-based markers of ATP function and domain-specific cognition (i.e., executive, memory). Working hypotheses for the proposed study are (1) markers of temporal ATP function will be greater in concentration as compared to markers of frontal ATP function given the high energy consumption within temporal regions (e.g., hippocampus) and more rapid age-related declines in structure and function within frontal regions, (2) markers of frontal ATP function will be more strongly associated with executive function tasks relative to memory tasks, and (3) markers of temporal ATP function will be more strongly associated with memory tasks as compared to executive function tasks. Innovative features of the proposed study include (1) hypothesis guided focus on mitochondrial function in frontal and temporal regions, (2) the assessment of cognitive domains that rely upon intact structure-function within these regions, and (3) the use of novel, powerful, and non-invasive markers of in vivo ATP function. Findings from this study will increase current understanding of the applicability of 31-P MRS as a potential biomarker of mitochondrial function. Broadly, these findings have the potential to inform more nuanced distinctions between normal and abnormal aging processes.