Published Online
on June 8, 2006

A more recent version of this article appeared on July 1, 2006

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Submitted on November 24, 2005
Revised on January 21, 2006
Accepted on March 8, 2006

Intrinsic Activated Microglia Map to the Peri-infarct Zone in the Subacute Phase of Ischemic Stroke

Christopher J.S. Price MRCP^*; Dechao Wang PhD; David K. Menon PhD; Joe V. Guadagno MRCP; Marcel Cleij PhD; Tim Fryer PhD; Franklin Aigbirhio PhD; Jean-Claude Baron MD; and Elizabeth A. Warburton DM

From the Department of Medicine, University of Cambridge, Addenbrookes Hospital, Cambridge, UK (C.J.S.P.); Wolfson Brain Imaging Centre, University of Cambridge, Addenbrookes Hospital, Cambridge, UK (C.J.S.P., D.W., D.K.M., J.V.G., M.C., T.F., F.A., J.C.B.); Anesthesia Section, Department of Medicine, University of Cambridge, Addenbrookes Hospital, Cambridge, UK (D.K.M.); Department of Neurology, University of Cambridge, Addenbrookes Hospital, Cambridge, UK (C.J.S.P., J.V.G., J.C.B.); and Department of Clinical Neurosciences, Cambridge University Teaching Hospitals Trust, Cambridge, UK (E.A.W.).

^* To whom correspondence should be addressed. E-mail: cp252{at}medschl.cam.ac.uk.

Background and Purpose--Microglial activation is an important component of the neuroinflammatory response to ischemic stroke. Experimental studies have outlined such patterns temporally and spatially. In vivo studies in stroke patients have relied on positron emission tomography and (R)-PK11195, a ligand that binds peripheral benzodiazepine binding sites. In this study we sought to establish temporal and spatial patterns of microglial activation in ischemic stroke with particular emphasis on a defined peri-infarct zone.

Methods--Using this technique, we studied carotid territory ischemic stroke patients in 3 time windows up to 30 days after ictus. Controls were studied in a single session. [¹¹C](R)-PK11195 injection was followed by 3-dimensional acquisition over 60 minutes. Cerebral blood volume (CBV) was measured afterward with the use of standard C¹⁵O paradigms. Analysis employed the reference tissue model in which ipsilateral cerebellum was used to generate parametric binding potential maps corrected for CBV. Data were coregistered to T1-based MRI. Using control data to identify 99% confidence limits, a region of interest analysis was applied to identify significant binding in core infarction, contralateral hemisphere, and within a defined peri-infarct zone.

Results--Four patients (mean age, 66 years) were imaged across 9 sessions. Four age-matched controls were studied. Within this model, ipsilateral cerebellum was validated as a reference tissue. With the use of control-derived confidence limits and correction for CBV, significant binding potential rises were identified beyond 72 hours and extending to 30 days in core infarction, contralateral hemisphere, and peri-infarct zone.

Conclusions--In ischemic stroke patients, minimal activation of microglia is seen before 72 hours. Beyond this, binding potential rises in core infarction, peri-infarct zone, and contralateral hemisphere to 30 days. This may represent a therapeutic opportunity that extends beyond time windows traditionally reserved for neuroprotection.

Key words: inflammation • microglia • positron emission tomography • tomograpy, emission computed

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