Evidence of association between higher cardiorespiratory fitness and higher cerebral myelination in aging

Abstract

Emerging evidence suggests that altered myelination is an important pathophysiologic correlate of several neurodegenerative diseases, including Alzheimer and Parkinson's diseases. Thus, improving myelin integrity may be an effective intervention to prevent and treat age-associated neurodegenerative pathologies. It has been suggested that cardiorespiratory fitness (CRF) may preserve and enhance cerebral myelination throughout the adult lifespan, but this hypothesis has not been fully tested. Among cognitively normal participants from two well-characterized studies spanning a wide age range, we assessed CRF operationalized as the maximum rate of oxygen consumption (VO₂max) and myelin content defined by myelin water fraction (MWF) estimated through our advanced multicomponent relaxometry MRI method. We found significant positive correlations between VO₂max and MWF across several white matter regions. Interestingly, the effect size of this association was higher in brain regions susceptible to early degeneration, including the frontal lobes and major white matter fiber tracts. Further, the interaction between age and VO₂max exhibited i) a steeper positive slope in the older age group, suggesting that the association of VO₂max with MWF is stronger at middle and older ages and ii) a steeper negative slope in the lower VO₂max group, indicating that lower VO₂max levels are associated with lower myelination with increasing age. Finally, the nonlinear pattern of myelin maturation and decline is VO₂max-dependent with the higher VO₂max group reaching the MWF peak at later ages. This study provides evidence of an interconnection between CRF and cerebral myelination and suggests therapeutic strategies for promoting brain health and attenuating white matter degeneration.

Keywords: MRI; aging; cardiorespiratory fitness; myelin.

Fig. 1.

Examples of axial and sagittal MWF parameter maps averaged across participants with either lower, moderate, or higher VO₂max levels. Participants were drawn from the full age range as well as from restricted age ranges to mitigate the effect of age. Results are shown for representative slices. Visual inspection indicates that, overall, participants with higher VO₂max levels exhibit greater regional MWF values, especially at middle and older ages.

Fig. 2.

Association of MWF with maximum rate of oxygen consumption (VO₂max) within the WB ROI derived using (I) model #1 or (V) model #2. The line of best fit (blue solid line), confidence bounds (shaded red region), regression coefficient (SE), and P value were derived from the linear regression models adjusted for covariates. The adjusted response function describes the relationship between the fitted response and MWF, with the remaining z-scored predictors set to 0. III and IV illustrate age-stratified and VO₂max-stratified associations between MWF and either standardized VO₂max or age, respectively, derived using model #1, while VII and VIII illustrate age-stratified and VO₂max-stratified associations between MWF and either standardized VO₂max or age, respectively, derived using model #2. The colored lines correspond to the 30th (red), 50th (green), and 70th (blue) quantiles of age or VO₂max. Finally, the association between age and MWF derived using model #1 or model #2 are shown in II and VI, respectively.