Selective neuronal loss in rescued penumbra relates to initial hypoperfusion

Abstract

Selective neuronal loss (SNL) in the rescued penumbra could account for suboptimal clinical recovery despite effective early reperfusion. Previous studies of SNL used single-photon emission tomography (SPECT), did not account for potential volume loss secondary to collapse of the infarct cavity, and failed to show a relationship with initial hypoperfusion. Here, we obtained acute-stage computerized tomography (CT) perfusion and follow-up quantitative (11)C-flumazenil (FMZ)-PET to map SNL in the non-infarcted tissue and assess its relationship with acute-stage hypoperfusion. We prospectively recruited seven patients with evidence of (i) acute (<6 h) extensive middle cerebral artery territory ischaemia based on clinical deficit (National Institutes of Health stroke scale, NIHSS score range: 8-23) and CT Perfusion (CTp) findings and (ii) early recanalization (spontaneous or following thrombolysis) based on spectacular clinical recovery (DeltaNIHSS > or =6 at 24 h), good clinical outcome (NIHSS < or =5) and small final infarct (6/7 subcortical) on late-stage MRI. Ten age-matched controls were also studied. FMZ image analysis took into account potential post-stroke volume loss. Across patients, clusters of significantly reduced FMZ binding were more prevalent and extensive in the non-infarcted middle cerebral artery cortical areas than in the non-affected hemisphere (P = 0.028, Wilcoxon sign rank test). Voxel-based between-group comparisons revealed several large clusters of significantly reduced FMZ binding in the affected peri-insular, superior temporal and prefrontal cortices (FDR P < 0.05), as compared with no cluster on the unaffected side. Finally, comparing CTp and PET data revealed a significant negative correlation between FMZ binding and initial hypoperfusion. Applying correction for volume loss did not substantially alter the significance of these results. Although based on a small patient sample sometimes studied late after the index stroke, and as such preliminary, our results establish the presence and distribution of FMZ binding loss in ultimately non-infarcted brain areas after stroke. In addition, the data suggest that this binding loss is proportional to initial hypoperfusion, in keeping with the hypothesis that the rescued penumbra is affected by SNL. Although its clinical counterparts remain uncertain, it is tempting to speculate that peri-infarct SNL could represent a new therapeutic target.

Meta-analysis of preclinical studies of mesenchymal stromal cells for ischemic stroke

“…29 Infarct volume reduction might therefore reflect many different processes including tissue salvage, but also cellular proliferation 30 and reduction in delayed neuronal death. 31,32 Regarding restorative stroke therapies, MSCs introduced $24 hours poststroke had a very large and favorable effect on behavioral outcomes (table 3). Restorative therapies, as with acute stroke therapies, have discrete time windows for maximum therapeutic effectiveness.…”

Occurrence and Predictors of Futile Recanalization following Endovascular Treatment among Patients with Acute Ischemic Stroke: A Multicenter Study

“…Selective neuronal loss in rescued penumbra has been reported and linked to initial hypoperfusion. 56 Microvascular compromise (also termed the "no reflow phenomenon") is another important factor that can prevent effective tissue perfusion at the capillary level despite macrovascular patency. This is secondary to plugging of microvessels by leukocytes and platelets due to activation of endothelial receptors.…”

Radionuclide Imaging in Ischemic Stroke

“…3), the pathophysiologic changes early after ischemic stroke could be accurately specified: 55% of the volume of the final infarct had 11 C-flumazenil uptake indicative of infarction in the first hours after stroke; 21% of the final infarct had flow below 14 mL/100 g/min but 11 C-flumazenil uptake above the critical value, thereby indicating penumbral tissue (44). Selective neuronal loss can also occur in tissue outside the documented penumbra or in reperfused penumbral areas, which can be documented by decreased cortical 11 C-flumazenil binding (52). With a comparable SPECT tracer, 123 I-iomazenil, irreversible tissue damage can be visualized in subacute or chronic stages of ischemic stroke (53).…”