Cognitive Correlates of Mitochondrial Function in Older Adults

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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.