Characterizing the evolution of the ischemic penumbra using pH weighted imaging

Introduction

The decision to use thrombolytic agents for ischemic stroke treatment hinges on characterization of the ischemic penumbra, the still viable tissue under risk of progression to infarction. The diffusion-perfusion mismatch approach in MRI^{1, 2} identifies tissue that has not experienced cell depolarization but is at risk of infarction. However, areas of hypoperfusion may sometimes only reflect benign oligemia. Recently, the possibility to perform pH-weighted (pHw) imaging with MRI was developed. ³ Because reduced tissue pH directly reflects impairment of oxidative metabolism, we hypothesized that diffusion-pH mismatch may better define the fraction of the ischemic flow penumbra at risk of infarction. Here, pHw imaging was combined with diffusion, perfusion and relaxation imaging to characterize evolution of acute ischemia in a rat model of permanent middle cerebral artery occlusion (MCAO).

Methods

Adult male Wister rats (280–320 grams, n=15). Anesthesia: isoflurane(2.5%). Permanent MCAO preparation (suture). All images (4.7 T) acquired using single-shot EPI, facilitating co-registration. In-plane resolution: 0.5×0.5 mm², slice-thickness 2 mm. Evolution was followed until 3.5 hrs post-occlusion with 24 hr follow up to assess T2-hyperintensity, known to agree with infarction as assessed by histology.

Results/Discussion

In all animals, the maximal MCA area was hypoperfused, but no T1 and T2 changes were found during the first 3.5 hrs of imaging. Rats showed heterogeneous temporal evolution of the pHw and diffusion deficits. Based on data, we could assign three groups: 1) perfusion-deficit = pH-deficit = diffusion-deficit (n=5); 2) perfusion-deficit = pH-deficit > diffusion-deficit (n=6); 3) perfusion deficit > pH-deficit diffusion deficit (n=4). In groups 1 and 2, all animals evolved to full infarction over the initial area of perfusion-deficit. In group 3, in some animals the area of pH-deficit evolved to almost the area of perfusion-deficit (e.g. see first row in figure 1). Even though the pH-deficit area was larger than the diffusion area at 3.5 hrs, the animal evolved to full infarction over the remaining period to follow-up, in agreement with our hypothesis. In the second animal in the figure, the pH-diffusion mismatch remained small during the first 3.5 hrs. The 24 hr follow-up showed an infarcted region in reasonable agreement with the pH deficit at 3.5 hrs and much smaller than the perfusion deficit, again in line with our hypothesis.

Figure 1

Evolution of pHw-deficit (orange) and Diffusion deficit (black) with respect to perfusion deficit (purple) as a function of time post-MCAO occlusion. Hyperintensity in the T2 image at 24 hrs shows final infarction area.

Conclusions

These initial data show that pHw imaging may have the potential to be a useful addition to the acute stroke exam by providing an opportunity to subdivide the area of perfusion deficit into regions of benign oligemia and impaired oxygen metabolism, with the latter having more predictive power for ultimate progression to infarction. Follow-up studies with models of reversible ischemia are needed to further confirm the hypothesis that a pHw-diffusion mismatch may be a better predictor of treatment risk assessment.