Mixed Neuropathologies, Neural Motor Resilience and Target Discovery for Therapies of Late-Life Motor Impairment

Abstract

By age 85, most adults manifest some degree of motor impairment. However, in most individuals a specific etiology for motor decline and treatment to modify its inexorable progression cannot be identified. Recent clinical-pathologic studies provide evidence that mixed-brain pathologies are commonly associated with late-life motor impairment. Yet, while nearly all older adults show some degree of accumulation of Alzheimer’s disease and related dementias (ADRD) pathologies, the extent to which these pathologies contribute to motor decline varies widely from person to person. Slower or faster than expected motor decline in the presence of brain injury and/or pathology has been conceptualized as more or less “resilience” relative to the average person This suggests that other factors, such as lifestyles or other neurobiologic indices may offset or exacerbate the negative effects of pathologies via other molecular pathways. The mechanisms underlying neural motor resilience are just beginning to be illuminated. Unlike its cousin, cognitive resilience which is restricted to neural mechanisms above the neck, the motor system extends the total length of the CNS and beyond the CNS to reach muscle and musculoskeletal structures, all of which are crucial for motor function. Building on prior work, we propose that by isolating motor decline unrelated to neuropathologies and degeneration, investigators can identify genes and proteins that may provide neural motor resilience. Elucidating these molecular mechanisms will advance our understanding of the heterogeneity of late-life motor impairment. This approach will also provide high value therapeutic targets for drug discovery of therapies that may offset the negative motor consequences of CNS pathologies that are currently untreatable.