Establishing Equivalent Aerobic Exercise Parameters Between Early-Stage Parkinson's Disease and Pink1 Knockout Rats.

BACKGROUND: Rodent Parkinson's disease (PD) models are valuable to interrogate neurobiological mechanisms of exercise that mitigate motor impairment. Translating these mechanisms to human PD must account for physical capabilities of the patient. OBJECTIVE: To establish cardiovascular parameters as a common metric for cross-species translation of aerobic exercise impact. METHOD: We evaluated aerobic exercise impact on heart rate (HR) in 21 early-stage PD subjects (Hoehn Yahr ≤1.5) exercising in non-contact boxing training for ≥3 months, ≥3x/week. In 4-month-old Pink1 knockout (KO) rats exercising in a progressively-increased treadmill speed regimen, we determined a specific treadmill speed that increased HR to an extent similar in human subjects. RESULTS: After completing aerobic exercise for ∼30 min, PD subjects had increased HR∼35% above baseline (∼63% maximum HR). Motor and cognitive test results indicated the exercising subjects completed the timed up and go (TUG) and trail-making test (TMT-A) in significantly less time versus exercise-naïve PD subjects. In KO and age-matched wild-type (WT) rats, treadmill speeds of 8-10 m/min increased HR up to 25% above baseline (∼67% maximum HR), with no further increases up to 16 m/min. Exercised KO, but not WT, rats showed increased locomotor activity compared to an age-matched exercise-naïve cohort at 5 months old. CONCLUSION: These proof-of-concept results indicate HR is a cross-species translation parameter to evaluate aerobic exercise impact on specific motor or cognitive functions in human subjects and rat PD models. Moreover, a moderate intensity exercise regimen is within the physical abilities of early-stage PD patients and is therefore applicable for interrogating neurobiological mechanisms in rat PD models.

Premature cognitive decline in specific domains found in young veterans with mTBI coincide with elder normative scores and advanced-age subjects with early-stage Parkinson's disease.

IMPORTANCE: Epidemiologists report a 56% increased risk of veterans with (+) mild traumatic brain injury (mTBI) developing Parkinson's disease (PD) within 12-years post-injury. The most relevant contributors to this high risk of PD in veterans (+) mTBI is unknown. As cognitive problems often precede PD diagnosis, identifying specific domains most involved with mTBI-related PD onset is critical. OBJECTIVES: To discern which cognitive domains underlie the mTBI-PD risk relationship proposed in epidemiology studies. DESIGN AND SETTING: This exploratory match-controlled, cross-sectional study was conducted in a medical school laboratory from 2017-2020. PARTICIPANTS: Age- and IQ-matched veterans with (+) and without mTBI, non-veteran healthy controls, and IQ-matched non-demented early-stage PD were compared. Chronic neurological, unremitted/debilitating diseases, disorders, dementia, and substance use among others were excluded. EXPOSURE: Veterans were or were not exposed to non-penetrating combat-related mTBI occurring within the past 7-years. No other groups had recent military service or mTBI. MAIN OUTCOMES / MEASURES: Cognitive flexibility, attention, memory, visuospatial ability, and verbal fluency were examined with well-known standardized neuropsychological assessments. RESULTS: Out of 200 volunteers, 114 provided evaluable data. Groups significantly differed on cognitive tests [F (21,299) = 3.09, p<0.0001]. Post hoc tests showed veterans (+) mTBI performed significantly worse than matched-control groups on four out of eight cognitive tests (range: p = .009 to .049), and more often than not performed comparably to early-stage PD (range: p = .749 to .140). CONCLUSIONS AND RELEVANCE: We found subtle, premature cognitive decline occurring in very specific cognitive domains in veterans (+) mTBI that would typically be overlooked in a clinic setting, This result potentially puts them at-risk for continual cognitive decline that may portend to the eventual onset of PD or some other neurodegenerative disease.