Cardiorespiratory fitness does not predict longitudinal changes in manual dexterity, cognition or corticospinal excitability in multiple sclerosis

Introduction Neurodegeneration in multiple sclerosis leads to progressive cognitive and motor impairments. Cardiorespiratory fitness (CRF) is thought to protect against such decline, but its longitudinal effects remain unclear. This study examined whether CRF predicts changes in behavioral (i.e., hand dexterity and cognition) and neurophysiological (i.e., corticospinal excitability, an indicator of corticospinal tract function) outcomes in multiple sclerosis over 2 years, with a focus on participants who experienced no relapses between visits and were, therefore, classified as progression independent of relapse activity (PIRA). We hypothesized that higher baseline CRF would be associated with better follow-up outcomes. Methods Participants underwent assessments at two time points (∼2 years apart). CRF was measured using a graded maximal exercise test ( V . O 2 max). Behavioral outcomes included the Nine-Hole Peg Test and Montreal Cognitive Assessment. Corticospinal excitability was assessed via transcranial magnetic stimulation of the first dorsal interosseous muscle. Hierarchical regression analyses examined whether baseline CRF predicted change in follow-up scores, controlling for age, sex, and baseline performance. Results Among 38 participants (71% female), CRF at baseline did not significantly predict changes in behavioral or physiological outcomes ( p = 0.178–0.655). Instead, baseline performance was the strongest predictor of follow-up scores. Exploratory analyses revealed inter-individual variability, with some participants improving, declining, or remaining stable over the 2 years. Significant improvements were observed in the Montreal Cognitive Assessment ( p = 0.002) and non-dominant hand Nine-Hole Peg Test ( p = 0.036). Discussion CRF did not predict longitudinal changes in manual dexterity, cognition or corticospinal excitability in individuals living with multiple sclerosis. Instead, initial performance was the primary determinant of follow-up outcomes, suggesting that achieving better function at baseline (earlier in the disease) is an important rehabilitation target. Variability in longitudinal change underscores the heterogeneous nature of disease progression/improvement and the need for specific, targeted interventions and personalized strategies to disease management.