Neurobiological drivers of mobility resilience: the dopaminergic system

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ABSTRACT In older age, walking becomes slower and less automated, requiring more attention and prefrontal resources. Common causes of age-related walking impairments are cerebral small vessel disease (cSVD) and changes in peripheral systems. We have recently discovered that ~20% of older adults maintain fast gait speed even in the presence of common locomotor risk factors, thus appearing resilient. Our work suggests that the nigrostriatal dopamine (DA) system may be a source of this resilience. We hypothesize that higher nigrostriatal DA neurotransmission drives resilience to locomotor risk factors via higher connectivity with sensorimotor networks, thus reducing prefrontal-mediated motor control and restoring automated control of walking. Resilience due to the nigrostriatal DA system is a novel and highly promising area of inquiry. Unlike vascular lesions and brain structural impairments, DA neurotransmission is potentially modifiable, thereby offering novel approaches to reduce age-related walking impairments. Although of substantial potential value to wellbeing in aging, there is a critical gap in knowledge of age-related mobility with simultaneous measures of nigrostriatal DA system, cSVD and peripheral system impairments. Our aims are: AIM 1: Quantify the DA-related contribution to mobility resilience, cross-sectionally and longitudinally. We hypothesize that nigrostriatal DA neurotransmission predicts walking performance, during usual and dual task conditions and reduces the negative effects of cSVD and peripheral system impairment on walking performance. AIM 2: Assess DA-related automated control of walking, cross-sectionally and longitudinally. We hypothesize nigrostriatal DA neurotransmission acts synergistically with connectivity of sensorimotor networks to predict higher walking performance and lower prefrontal activation while walking. As a first translational step in testing the effects of DA on resilience, we propose to collect pilot data for a mechanistic target-engagement study in slow-walking older adults with cSVD and pronounced age-associated striatal DA loss. Exploratory AIM 3: To assess the effects of 1 week of L-DOPA administration on connectivity and gait speed as a function of molecular markers of striatal DA release in non-resilient elderly with pronounced age-associated striatal DA losses. This research is innovative in that it goes beyond explaining impairments, to revealing resilience factors and their mechanisms as the basis for novel interventions. It has high impact because recent findings suggest that pharmacological and behavioral interventions can improve DA signaling. Our team has unique expertise in the use of novel technologies and represents decades as thought leaders in the study of aging, brain and mobility.