Neural and Energetic Drivers of Performance and Perceived Fatigability in Older Adults

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ABSTRACT Higher fatigability, the degree to which someone is physically or mentally limited due to fatigue, is common and disabling in community-dwelling older adults. While fatigue associated with a disease can be ameliorated by targeting the underlying condition, the causes and definitions of fatigability in older age are not well understood and treatments are not available. Studies in older adults show associations with lower muscle mitochondrial function and cardiopulmonary fitness; fitness and strength training can improve fatigability, but benefits are often limited by poor motivation, reduced effort, and impaired locomotor factors (weight bearing pain, arthritis). Fatigability appears influenced by neuro-energetic processes, and specifically striatal dopamine (DA) signaling and cerebral metabolic rate of oxygen. Emerging pharmacologic and behavioral interventions promoting these neuro-energetic processes also appear to reduce fatigability in young healthy adults. However, these findings cannot be translated to older adults because the neuro-energetic contributions to fatigability have not been studied. We propose to address this gap in knowledge and examine the multi-systemic contribution (brain, muscle, cardiopulmonary) to physical performance fatigability (PPF), defined as performance decline during a standardized physical task. Our overarching hypothesis is that higher striatal DA, related networks’ activity, and brain energy metabolism predict lower PPF in older adults; we also propose that these neural markers, individually and in combination explain PPF beyond what is predicted by muscle energetic and cardiopulmonary function. Our recently optimized neuro-energetic imaging protocol uses a state-of-the-art MRI-PET scanner to simultaneously measure striatal DA (PET), cerebral metabolic rate of O2 non-invasively (total brain MRI-based O2 extraction fraction, blood flow), resting state activity of striatal networks; and task-related activation (functional near- infrared spectroscopy of prefrontal cortex during dual tasks). We are currently collecting this protocol at baseline in 150 participants of SOMMA (Study of Muscle, Mobility and Aging),a 3 year longitudinal ongoing study. We propose to relate these neuroimaging measures with objective PPF (slowing down during the fast paced 400m walk), cross- sectionally and longitudinally over 3 years. We leverage the measures that SOMMA is already obtaining: a) perceived fatigability (rating of perceived exertion at end of 5-min treadmill walk; Pittsburgh Fatigability Scale); b) muscle mitochondrial function (biopsy, P31magnetic resonance spectroscopy) and mass; c) cardiopulmonary function (VO2 peak, cardio-pulmonary exercise test); d) locomotor factors (sleep, pain, arthritis, BMI, comorbidities). This innovative research has high potential impact, because it will quantify energetic and metabolic processes in brain, muscle, and cardiopulmonary systems, separately and in combination, in relation to fatigability. This study offers an unprecedented opportunity for a cost-effective, longitudinal, multi-system assessment of determinants of physical performance fatigability.