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Brain Advance Access published online on August 4, 2008
Brain, doi:10.1093/brain/awn175
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© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Selective neuronal loss in rescued penumbra relates to initial hypoperfusion

J. V. Guadagno1, P. S. Jones1, F. I. Aigbirhio2, D. Wang2, T. D. Fryer2, D. J. Day1, N. Antoun3, I. Nimmo-Smith4, E. A. Warburton1,5 and J. C. Baron1

1Department of Clinical Neurosciences, Neurology Unit, 2Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, 3Department of Radiology, Addenbrooke's Hospital, 4MRC Cognition and Brain Sciences Unit and 5Stroke Unit, Addenbrooke's Hospital, Cambridge, UK

Correspondence to: Prof. J. C. Baron, Addenbrooke's Hospital Box 83, Cambridge, CB2 2QQ, UK E-mail: jcb54{at}cam.ac.uk

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 11C-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 ({Delta}NIHSS ≥6 at 24 h), good clinical outcome (NIHSS ≤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.

Key Words: stroke; cerebral ischaemia; 11C-flumazenil; benzodiazepine receptor; cerebral infarction; positron emission tomography; CT perfusion

Abbreviations: AIF, arterial input function; cBZR, central benzodiazepine receptor; CT, computerized tomography; CTp, CT perfusion; DWI, diffusion-weighted imaging; FLAIR, fluid-attenuation inversion-recovery; FMZ, 11C-flumazenil; MCA, middle cerebral artery; MTT, mean transit time; PET, positron emission tomography; ROI, regions of interest; SNL, selective neuronal loss; SPECT, single-photon emission tomography; SPGR, spoiled-gradient recalled; SRTM, simplified reference tissue model; TIA, transient ischaemic attack

Received January 10, 2008. Revised June 16, 2008. Accepted July 7, 2008.


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