Synopsis

Exercise is potentially therapeutic via vascular adaptations (angiogenesis, improved cerebral perfusion and metabolism) however the underlying dynamics are not fully understood. In Huntington´s disease (HD), where the therapeutic potential of exercise is being explored, cerebral vasculature alterations have been reported.

Here we used arterial spin labelling to examine the acute effect of aerobic exercise on the cerebrovasculature in HD patients. We show that genetic disease load is related to both baseline cerebral blood flow (CBF) and the exercise-induced change in CBF.

Purpose

It is increasingly being realised that exercise has beneficial effects on brain health, and its role as a therapeutic for various neurological conditions is under investigation. However, the dynamic mechanisms of adaptive plasticity are poorly understood, with emerging evidence of exercise-induced cerebrovascular adaptations (angiogenesis, improved cerebral perfusion and metabolism)¹. In mouse models and patient studies of Huntington´s disease (HD), cerebral vasculature alterations have been reported². and in patients, long-term exercise intervention trials are underway, with the aim to slow or halt disease progression. Here, using arterial spin labelling (ASL) we examined whether cerebral blood flow is altered in HD patients at baseline, and in response to a single session of exercise.

Methods.

18 gene-positive HD patients (11 males, 45.0 ± 8.5 years old) and 18 healthy age-matched controls underwent a baseline MRI scan (3T GE HDx system) with physiological monitoring (heart rate, blood pressure, blood gases). A multi-inversion time PICORE³ pulsed ASL sequence was used to measure cerebral blood flow (CBF, ml/100g/min). Images were acquired with a spiral gradient echo sequence with a variable TR (1100-2000ms) for efficiency (TE = 2.7 ms, 15 slices, slice delay = 52 ms, slice gap = 1 mm, QUIPSS II⁴ cutoff TI>700 ms, voxel size 3 × 3 × 8 mm3) and 8 inversion times (TIs: 400,500, 600,700,1100, 1400, 1700, 2000ms). A structural FSPGR (1mm3 resolution) was also acquired.

Participants then completed 20-minutes of moderate (60-70% intensity) aerobic exercise on a cycle ergometer. Immediately after, participants underwent a repeat MRI session with the ASL sequence occurring 15 minutes after exercise cessation. Baseline fitness was assessed on a separate day using cardiopulmonary testing.

Perfusion quantification was performed on a voxel-by-voxel basis using a two-compartment model⁵ with partial volume correction⁶. Median grey matter CBF values were compared pre- and post-exercise using a repeated-measure ANOVA. The relationship between CAG repeat length, a genetic marker of disease load in HD and CBF was examined.

Results.

There was no interaction between time (pre- vs. post exercise) and gene status (HD vs. controls) for grey matter CBF, and similarly, no main effect of gene status (Fig, 1a). Cardiorespiratory fitness, assessed on a separate day, was not found to be related to baseline grey matter CBF in HD and control participants alike. When examining the variance within the HD group, CBF was found to be significantly correlated with CAG repeat length (~genetic mutation load) in HD at baseline and post-exercise (Fig. 1b,d, n=13, p < 0.005).

In order to explore individual variability in exercise response, the absolute exercise-induced change in CBF (post-exercise CBF - baseline CBF) was calculated, and found to be negatively related to CAG repeat length in HD participants (Fig. 1f).

The partial volume fraction of grey matter was significantly lower in HD participants (Fig1c), however this fraction was not related to CAG repeat length (p>0.05).

Conclusions

We have demonstrated that grey matter CBF is not altered in HD, in contrast to previous evidence of cerebrovascular changes in HD postmortem tissue. For both healthy control participants and HD patients, a single session of aerobic exercise was not found to significantly affect grey matter CBF. However, both baseline CBF and the absolute change in CBF following exercise were found to be related to CAG repeat length, an index of genetic load in HD. This suggests that the variability in grey matter cerebral perfusion in the HD group is clinically meaningful, and the relationship with exercise-induced CBF change may suggest that disease load affects the responsiveness to exercise. Importantly, the relationship between genetic load and CBF does not appear to be driven by atrophy-derived partial volume effects.

Acknowledgements

References

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