Development and Application of a Novel Accelerometry-based Performance Fatigability Index in Older Adults - Public Health/Epidemiology, 

Committee
Nancy Glynn, Department of Epidemiology (advisor)
Marquis Hawkins, Department of Epidemiology
Pamela Toto, Department of Occupational Therapy, Pitt School of Health and Rehabilitation Sciences
Jaroslaw Harezlak, Department of Epidemiology and Biostatistics, School of Public Health-Bloomington, Indiana University
Adam Santanasto, Department of Epidemiology

Abstract

Performance fatigability, defined as performance deterioration during a standardized physical task, is disabling and multifactorial. It has been identified as an early indicator of aging and a prevalent energy disorder among older adults. More severe performance fatigability has been associated with functional limitations/mobility decline and frailty. Yet, given the major methodological constrains with existing measures (e.g. assuming participants’ gait speed decline linearly), there is a lack of performance fatigability measure with high sensitivity and accuracy. Fortunately, wearable devices and advanced statistics enable us to better monitor performance continuously, making it feasible to detect performance decline at a granular level. Developing an objective, sensitive, and valid accelerometry-based performance fatigability measure helps us better quantifying the prevalence in the general population and understanding the underlying biological mechanisms of performance fatigability.

Thus, this dissertation aimed to fill the gaps related to performance fatigability. Specifically, the overall objectives of this research were to 1) develop a novel accelerometry-based performance fatigability index and characterize the severity and sex differences of fatigability; 2) validate our novel and objective performance fatigability index in an external large cohort; 3) evaluate the associations between skeletal muscle energetics and accelerometry-based performance fatigability index. In Aim 1, I developed a novel measure – the Pittsburgh Performance Fatigability Index (PPFI) – to quantify walking-based performance fatigability using wrist-worn accelerometry in the Developmental Epidemiological Cohort Study (DECOS, N=63, mean age=78.3±5.7 years, 55.6% women). Conceptually, PPFI quantifies the percentage of performance decrement during the walking task by comparing area under the observed cadence-versus-time trajectory to a hypothetical area that would be observed in the absence of fatigue (i.e., if participant sustained maximal cadence throughout the entire walking task). PPFI scores from a fast-paced 400m walk were higher and more variable than from a usual-paced 400m walk and revealed sex differences. Higher PPFI scores from the fast-paced walk were strongly negatively correlated with all physical function measures and leg peak power, while PPFI scores from the usual-paced walk were moderately negatively correlated with these measures. In Aim 2, I correlated PPFI against physical function, leg peak power, cardiorespiratory fitness and perceived fatigability in the Study of Muscle, Mobility and Aging (SOMMA, N=805, mean age =76.4 ± 5.0 years, 58% women), which revealed good construct validity of PPFI. Furthermore, I used decision tree method to identify sex- and sample-specific PPFI cut-points that optimally discriminated gait speed to define PPFI severity strata, which showed strong discriminant power against physical function, leg peak power, cardiorespiratory fitness, and perceived fatigability. This validation work has established the utility of PPFI as a valid measure to quantify performance fatigability in future epidemiological and/or clinical settings. In Aim 3, I examined the associations between skeletal muscle energetics and PPFI to decipher underlying biological mechanisms associated with more severe performance fatigability in SOMMA. I included both mitochondrial respirations, in particular maximal oxidative phosphorylation (max OXPHOS) and complex I and II-supported electron transfer system capacity (max ETS), as quantified in vitro using high-resolution respirometry and maximal adenosine triphosphate production (ATPmax) as quantified in vivo using ³¹P magnetic resonance spectroscopy. I found lower max OXPHOS and APTmax were significantly associated with higher PPFI scores and higher odds of being in a more severe PPFI severity strata in the overall sample and stratified by sex, whereas lower max ETS was only significantly associated with higher PPFI scores among men.

The successful completion of these aims provided us an objective, sensitive, and valid accelerometer-based performance fatigability index to better capture performance fatigability during walking tasks. Our understanding of muscle energetics and performance fatigability also opens new horizons for future lifestyle interventions and pharmaceutical trials aimed at reducing fatigability, improving functional performance, and preventing mobility disability.