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L. Václavu° et al.
the lack of knowledge of expected values precluded a comprehensive sample size calculation so we were possi- bly underpowered to detect the hypothesized negative correlation between CVR and lesion volume. Another lim- itation is the cross-sectional design of our study. If CVR is an early indication of hemodynamic compromise in a cer- tain brain region, then ischemic injury may not occur until oxygen delivery is repeatedly interrupted, which may explain the fact that no association between CVR and SCI was found. Or their treatment has improved their CVR and precluded detection of the association between CVR and SCIs that had formed prior to effective therapy. Interestingly, in a previous study in non-SCD patients severely affected with white matter lesions, a link between low CVR and progression of cerebral lesions was found one year later.13 Additionally, our study may have lacked sensitivity in white matter CVR values. The reason for this is that with ASL, CBF signal in the deep white matter is often below the noise level, which makes small changes in CBF after a CVR challenge even more difficult to detect. Hence, CVR values become less reliable further away from gray matter. Improving CBF signal in white matter can be achieved by acquiring ASL for a longer dura- tion. Improvements in ASL technology and scan accelera- tion will hopefully make this available for clinical research soon.
In conclusion, using ASL MRI in combination with hemodynamic provocation by acetazolamide, we demon-
strated that CVR is globally reduced in adult sickle cell patients without a history of stroke. Even in steady state and at rest, patients with SCD utilize half of the cerebral vasodilatory reserve in comparison to control participants to compensate for anemia. Complete depletion of CVR can occur in the presence of additional strain on the vas- culature such as in moyamoya syndrome, leading to extreme vulnerability to hypoxia and ischemic events. It remains to be seen whether increasing hemoglobin levels by transfusion, hydroxyurea or new disease-modifying drugs can relieve some of the restrictions imposed on the brain by anemia and whether they also reduce cerebral infarction.
Acknowledgments
The authors would like to thank all the participants involved in this study, Magdalena J Sokolska and David L Thomas for their expertise and contribution to the simulations on labelling efficiency for the pCASL sequence implementation, Moss Y Zhao and Michael Chappell for their contribution to the arterial transit time calculations, Sandra van den Berg and Raschel van Luijk for their excellent clinical and MR support, Erfan Nur and Charlotte van Tuijn for their help with recruitment and clinical expertise and Jan Petr for assistance with the ASL data analysis.
Funding
We wish to thank the Dutch fund “Fonds Nuts Ohra” for funding this research (grant no. 1303-055).
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