Neuroinflammation Extends Brain Tissue at Risk to Vital Peri-Infarct Tissue: A Double Tracer [11C]PK11195- and [18F]FDG-PET Study

Focal cerebral ischemia elicits strong inflammatory responses involving activation of resident microglia and recruitment of monocytes/macrophages. These cells express peripheral benzodiazepine receptors (PBRs) and can be visualized by positron emission tomography (PET) using [11C]PK11195 that selectively binds to PBRs. Earlier research suggests that transient ischemia in rats induces increased [11C]PK11195 binding within the infarct core. In this study, we investigated the expression of PBRs during permanent ischemia in rats. Permanent cerebral ischemia was induced by injection of macrospheres into the middle cerebral artery. Multimodal imaging 7 days after ischemia comprised (1) magnetic resonance imaging that assessed the extent of infarcts; (2) [18F]-2-fluoro-2-deoxy-d-glucose ([18F]FDG)-PET characterizing cerebral glucose transport and metabolism; and (3) [11C]PK11195-PET detecting neuroinflammation. Immunohistochemistry verified ischemic damage and neuroinflammatory processes. Contrasting with earlier data for transient ischemia, no [11C]PK11195 binding was found in the infarct core. Rather, permanent ischemia caused increased [11C]PK11195 binding in the normoperfused peri-infarct zone (mean standard uptake value (SUV): 1.93 ± 0.49), colocalizing with a 60% increase in the [18F]FDG metabolic rate constant with accumulated activated microglia and macrophages. These results suggest that after permanent focal ischemia, neuroinflammation occurring in the normoperfused peri-infarct zone goes along with increased energy demand, therefore extending the tissue at risk to areas adjacent to the infarct.

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