Purpose

Accumulating evidence suggests that aerobic fitness promotes cerebrovascular function and neuroplasticity^{1, 2,} protecting against age-related decline and potentially slowing neurological disease onset³. Still, there is limited understanding of both the biological mechanisms and the extent to which fitness exerts neuroprotective effects. Research efforts to date have been focused on older adults and patient populations; but, it is necessary to study the effects of fitness on cerebrovascular function in young, healthy adults to understand the lifelong effects of physical activity. This cross-sectional study in young adults used arterial spin labelling (ASL) fMRI to examine differences related to aerobic fitness in cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) to CO2, which are measures of overall cerebrovascular health.

Methods

20 participants (11 females, mean age = 25.4±4.6), eligible to undergo intensive exercise and respiratory gas modulations, completed a VO₂peak test to measure aerobic fitness and underwent 3T fMRI (GE HDx system). CBF data was acquired at baseline and during hypercapnia using multiple inversion time (MTI) pulsed ASL (TIs: 400, 500, 600, 700, 1100, 1400, 1700 and 2000ms, TE = 2.7ms; PICORE QUIPSS II⁴ cut-off at TI=700 ms, TI2 = 300ms, dual-echo gradient-echo readout⁵ and spiral k-space acquisition⁶). A variable TR was used for efficiency (min. 100ms for short TIs, min. 1600ms for long TIs), 15 slices, resolution = 3.1x3.1x8.4mm3, matrix size = 64x64mm, FOV = 19.8cm, flip angle = 20°. For the hypercapnia challenge (target +5 mmHg P_ETCO₂), gas mixtures of 5% CO₂ were delivered using the prospective control method, breathing circuit described previously⁷. Perfusion quantification was performed using a two-compartment model7 for grey matter (GM). CBF CVR was calculated as the unit change in CBF per unit change in P^_ETCO₂. Region of interest (ROI) analysis of GM was performed using BASIL within FSL⁸ and followed up with voxelwise analysis using FSL Randomise⁹.

Results

CBF or CVR were not predicted by gender, age or body mass index (F(3, 16) = 0.216, p > 0.05, R² = 0.039, R²Adjusted = -.141).Correlation analysis between VO₂peak, CBF and CVR (ROI GM) revealed a non-significant inverse correlation between VO₂peak and CBF at rest; r = -.4, p = 0.07, p’ = 0.17 and during hypercapnia; r = -.23, p = 0.33, p’ = 0.58. There was a significant positive correlation between VO₂peak and CVR; r = .62, p = 0.004, p’ = 0.009. The P_ETCO₂ response was not driven by VO₂peak; r = -.26, p = 0.27, nor was CVR by resting CBF; r = -.14, p = 0.55 (Figure 1). Follow-up voxelwise analysis of GM to further explore the ROI trends showed a significant inverse association between VO₂peak and CBF at rest in portions of the thalamus, brainstem, visual cortex, precuneous and cerebellum; this relationship was not present for CBF during hypercapnia (Figure 2) where a significant inverse association was found in the frontal pole. Voxelwise GM CVR was not strongly correlated with VO₂peak.

Conclusions

This novel demonstration of an inverse relationship between GM CBF and VO₂peak and positive association between GM CVR and VO₂peak in young, healthy adults suggests that aerobic fitness may benefit brain health early in life. While the CBF results may seem counterintuitive as higher fitness is known to increase CBF in older adults, it is possible that exercise counteracts the overall CBF decline seen in ageing but reflects a cerebrovascular efficiency mechanism in early adulthood. It is known that physical training increases the ability to extract oxygen from tissue peripherally, a similar central mechanism would result in lower CBF requirements. A second possibility is that high aerobic fitness may increase capillary density through angiogenesis which would translate to a smaller diffusion distance and lower CBF. CVR is higher with increased fitness but baseline CBF is lower; this may be driven by a greater vasodilatory or vascular reserve capacity resulting from fitness induced vascular plasticity. The P_ETCO₂ increase during hypercapnia was not strongly related to VO₂peak although the % hypercapnic CBF change was, this suggests subjects with higher fitness were more sensitive to any change in P_ETCO₂ which again supports the idea of fitness induced vascular plasticity. The VO₂peak correlations with CBF and CVR require replication in a larger sample to determine a true significant effect. Nevertheless, these results suggest maintenance of physical fitness may be important for optimal cerebrovascular function at all ages.

Acknowledgements

This work was supported by the Wellcome Trust and Cardiff University.

References

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