We have shown that ischemic vulnerability varies across brain regions, and that the caudate, putamen, insula, precentral gyrus, inferior frontal, and middle frontal gyri are among the top 20% of locations most highly sensitive to reductions in CBF. We have quantified that – for our particular CTP acquisition protocol and post-processing software – an approximately 60% reduction in rCBF in these highly vulnerable locations distinguishes infarct core, whereas an approximately 85% reduction in rCBF distinguishes infarct core in the remainder of the brain.
The literature supports our findings. Previous studies in rats have shown higher frequency of DWI changes in the hippocampus, cortex, and caudate/putamen,5
and greater degree of selective neuronal loss in the caudate/putamen following unilateral hypoxia-ischemia.6
Cheng and colleagues have also reported higher probabilities of infarct growth in the striatocapsular region of stroke patients with MCA stem occlusion.4
Interestingly, the spatial pattern of sensitivity to hypoperfusion in our patients ( and ) resembles the topographic distribution of early DWI hyperintensities reported in patients with hypoxic ischemic encephalopathy.7, 8
This suggests the possibility that similar pathophysiological mechanisms of regionally-selective neuronal loss may underlie cerebral injury in patients with embolic-occlusive and hypoxic ischemic stroke. There are also well-documented differences in the neurochemical response to ischemia of WM versus GM, likely due to greater metabolic demands of GM.9
Within GM, certain cortical regions in our study appeared more vulnerable than others, including the insular, precentral, and inferior frontal gyri. The specific cortical areas with the highest ischemic sensitivity to hypoperfusion displayed on our mean “vulnerability map” () and regional regression results () could, in part, be attributed to the high volume of convoluted GM at these locations. Our results may also reflect selective neurophysiologic vulnerability of these regions. In support of this latter hypothesis, Woo et al found selective cerebral GM loss in the frontal and insular cortices of patients with long-term heart failure, presumably due to ischemia accompanying perfusion deficits.10
The vulnerability map of the brain reveals subtle topographic asymmetry (e.g., of the frontal paracentral lobules) ( and ) that may be artifactual, however, there may be other explanations for these findings. The inhomogenous distribution of infarction in our patients () and/or the presence of outliers could contribute to this asymmetry, or it might reflect true asymmetric vulnerability of these regions.
In agreement with previous studies, our rCBF threshold for infarct core was much higher (<0.42) in vulnerable cerebral areas versus the rest of the brain (<0.16). Arakawa et al reported CBF thresholds of 34.6 mL/100g/min for GM and 20.8 mL/100g/min for WM in an MR perfusion study.11
Bristow et al found CBF thresholds of 20.0 mL/100g/min and 12.3 mL/100g/min for infarction in GM and WM, respectively.12
Optimal CTP parameter thresholds for infarct core can vary significantly between vendors and even between different software from the same vendor.13
The optimal rCBF threshold (0.16) that we found in this study for less vulnerable brain voxels is in agreement with thresholds previously reported for an independent cohort who underwent a >65 second acquisition with post-processing by the same software, using the same default parameters (CT Perfusion 3).13
Given the variability in absolute quantification with different softwares, we chose to report “relative” – rather than “absolute” – values.14
Although rCBV as a surrogate for infarct core
is well established, in our study we sought to study ischemic vulnerability based on the degree of hypoperfusion
. The intrinsic physiological variability of CBV changes with ischemia which include such phenomenon as luxury perfusion and elevated CBV due to autoregulatory mechanisms – make CBV a less desirable parameter given the aims of our study.15
Previous work has also suggested that CBV measurements are likely more sensitive to subtle differences in acquisition and post-processing protocols than are CBF measurements.
Our findings may have clinical implications. Although we did not include time-post-ictus in our models, it is reasonable to hypothesize that less vulnerable areas may have a longer therapeutic time window for reperfusion treatment. This may also suggest that for those patients with ischemia at the most highly vulnerable brain locations, even early robust recanalization might be more effective if accompanied by neuroprotective therapies. There are a number of limitations to our study. Our results are limited by the spatial distribution of stroke lesions in our cohort (). We could not evaluate voxels which had few or no infarctions, most notably in the posterior circulation. The variable time between stroke onset, admission CTP, and admission DWI for different patients may also have distorted our results. Moreover, because CTP quantification is not yet standardized between different acquisition and post-processing protocols from different vendors, the rCBF thresholds we report could vary slightly between different imaging platforms.13
Although the choice of a 20% cutoff in was arbitrary, this allowed us to visually threshold the “most” highly vulnerable regions for demonstration purposes in the figures.
Finally, the difference between our reported CBF thresholds and those of the literature is likely attributable to both differences in CTP acquisition length (45 seconds versus > 65 seconds in current generation protocols) and that we did not apply vessel exclusion post-processing algorithms, so as to be consistent with our current clinical defaults and in order to maximize contrast-to-noise ratio. This suggests that the specific thresholds which we report may have limited generalizability to other acquisition and post-processing platforms.
In conclusion, we have shown regional differences in ischemic susceptibility of the brain to hypoperfusion. Of the territories with infarction in our cohort, we found that the caudate and putamen were highly vulnerable, as were specific cortical areas including the insula, precentral gyrus, and middle and inferior frontal gyri. Our findings support the hypothesis that location-specific thresholds may be more accurate than whole-brain thresholds for estimating the likelihood of infarction with CTP, and hence have the potential to be of value in clinical management.