We have shown that: (1) CBF is the optimal CTP parameter for estimating DWI-defined infarct core, exceeding CT-CBV in accuracy, and that (2) significant variation exists between the optimal parameter threshold values for different post-processing platforms. Strengths of our study include the use of advanced “second generation” CTP acquisition protocols that are sufficiently long to permit the complete transit of IV contrast through the brain (thus resulting in more physiologically correct perfusion maps), a co-registered CTP-DWI voxel based ROC analysis, comparison of multiple vendor software and post-processing platforms, and inclusion of heterogeneous patients with hemodynamic irregularities from both large vessel occlusion and atrial fibrillation. These methodological considerations may explain much of the difference between our results and those of earlier reports, and highlight the significant variability in optimal parameter thresholds between different platforms. Despite the variability in our reported thresholds, they remain within the range of prior meta-analyses,5, 10, 11, 14-16
and our conclusion that CBF is nominally more accurate than CBV in delineating core appears to be generalizable across platforms.
Our use of DWI as a reference standard, rather than follow-up infarct size in patients with early complete recanalization, may also have contributed to quantitative differences between our results and prior studies, including one that found higher CBF/CBV thresholds using the “A-std” software12
. Technical differences in post-processing (such as our use of the “vessel exclusion off” clinical default mode) were likely also important. Although DWI lacks perfect specificity for infarct core, it is both highly accurate and widely accepted in research and clinical care.3, 17
With regard to our use of a more lengthy 66 second CTP acquisition time, rather than a “first generation” time of 45 seconds,10-12, 18
there is recent consensus that acquisition should be sufficiently long to permit the full wash-in and wash-out of contrast, so that complete, non-truncated time-density tissue curves can be obtained (crucial if concurrent permeability imaging is also performed).17
Short imaging times can lead to truncation of the tissue time-density curves (TDC) in regions with severe hemodynamic derangement due to severe vascular stenosis/occlusion and/or atrial fibrillation, which can distort the – typically vendor dependent - CTP parameter value calculations.9, 19
Indeed, our conclusion regarding the accuracy of CBF versus CBV in determining core is supported by the fact that calculation of CBV is typically more sensitive to TDC truncation than is CBF, and by previous work suggesting that CBV lesion size can be overestimated in the setting of marked hemodynamic derangement.13
That CBV has greater variability than CBF in delineating core is also consistent with the established hemodynamic alterations accompanying ischemia. Most relevant of these is luxury perfusion – CBV hyperemia
of penumbra, or recanalized core – that occurs not infrequently in maximally vasodilated, critically ischemic tissue.20, 21
Our study highlights several technical limitations to the interpretation of CTP data. First, it is clear that the parameter thresholds obtained using one CTP post-processing platform may not be generalizable to other CTP methodologies. Currently, there is no standardization of CTP post-processing software across different vendors, different reconstruction algorithms, or even different versions of the same software package for a given vendor.9, 17, 19
Further variability in absolute quantification of flow values can be introduced by volume averaging effects in selecting the venous outflow ROI for normalization during CTP map construction.6
Indeed, variability in quantitation of perfusion parameter values has recently been identified in a simulated dataset comparing delay sensitive to delay insensitive deconvolution techniques.9
Unlike most prior investigations of CTP thresholds for infarct core, we minimized bias by using a more objective, voxel - rather than regional - based image analysis method. We determined the optimal core threshold values for each CTP parameter by transposing the segmented DWI core lesion directly onto the co-registered CTP maps, and performing ROC curve analyses to determine the optimal operating points for distinguishing infarcted from non-infarcted voxels. Hence, subjective differences in image display such as gray scale, window/level settings, and pixel conspicuity, which might introduce subjectivity in manual segmentation, were eliminated. A limitation inherent in all perfusion studies of acute ischemia is that they represent a “snapshot” in time, and that – specifically for very early times post ictus (<3 hours) – thresholds for irreversible ischemic damage may vary. Unfortunately, our study lacked sufficient patients to stratify our data by time-post-ictus. Moreover, although we could not control for the potential confounding effects of reperfusion just prior to scanning on our threshold analysis, there were no imaging findings (such as partially recanalized vessels on CTA) to suggest this.