190 Chapter 7 suggest that in this small patient sample no large metabolic or vascular changes occurred in the late-acute phase following SRS in patients with brain metastases. Tissue-specific differences were observed pre-radiotherapy across both metabolic and vascular parameters. The tissue-differences for CBF and CVR were similar to those reported in our previous study14 and in healthy subjects49, with both WM areas and edema characterized by lower CBF and CVR than GM. CMRO2 values were higher in GM compared to WM, consistent with the higher neuronal density in GM and previous studies.50 The OEF in GM was lower than in WM, while previous research has shown relatively homogeneous OEF in GM and WM using either QQCCTV42 or PET51. Lower OEF values in deep GM structures due to iron depositions52 cannot explain this phenomenon, as restricting the comparison to cortical GM yielded similar results. This may indicate the lower GM OEF is a compensatory auto regulatory response to the increased GM CBF, aiming to sustain stable GM CMRO2. However, due to the smaller number of voxels present in the GM and thereby its heightened susceptibility to extreme values and minor spatial misalignment, this could also potentially account for some of the observed differences. Large variability in the physiological parameters was seen within tissue containing untreated brain metastases, as was expected based on previous literature.12,14,53 The primary tumor (i.e. origin of metastatic cells), might cause some of this heterogeneity as it affects the brain metastases growth pattern, metabolism and vasculature.6,10,54,55 As the CMRO2 was not different from that of healthy-appearing tissue, this could be illustrative of the Warburg effect (i.e. less reliant on oxidative metabolism and more on aerobic glycolysis), especially since the OEF was lower than in healthy-appearing WM.56–58 Moreover, we observed low OEF, CBF, CMRO2 and CVR within edema regions. This is in line with previous research13,14 and may be reflective of the local pressure in these regions restricting the ability of vessels to dilate and thus maintain adequate perfusion. However, the extent of the edema did not correlate to either the metabolic or vascular reserve in the healthy-appearing brain tissue. This indicates that the edema volume, which is indicative of the pressure exerted on the whole-brain, does not appear to impact the overall vascular and metabolic capacities of the brain. Instead, its effects seem to be primarily localized. As the effect-sizes of these non-significant relationships were moderate to high, future research should further validate these findings in larger samples. As patients with signs of increased intracranial pressure were excluded from participation, the generalizability of these findings to the wider brain metastases population may be limited.
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