Microglial activation and traumatic brain injury

It has long been recognized that that traumatic brain injury (TBI) induces a neuroinflammatory response that involves both infiltration of white blood cells into the central nervous system (CNS) and the activation of resident microglia. Animal and human studies have shown that post-traumatic neuroinflammation may persist for months to years after injury. Moreover, both experimental and clinical reports have demonstrated that TBI induces chronic as well as acute neurodegeneration. As with classical chronic neurodegenerative disorders, it has been proposed that microglial activation may contribute to delayed cell death and tissue loss. In this issue of the Annals of Neurology, Ramlackhansingh and colleagues utilize the positron emission tomography (PET) ligand [C] (R)PK11195 (PK) to assess chronic microglial activation in 10 patients studied >11 months after moderate to severe TBI. They report significantly increased binding bilaterally at sites distant from areas of focal injury, such as thalamus, and correlate the thalamic changes with several measures of cognitive dysfunction. From these observations, the authors suggest that TBI, at least at the moderate or severe levels, does not reflect a static disorder but rather induces chronic microglial activation that may affect long-term outcome, and therefore that there may be a potentially longer therapeutic window for this disorder than traditionally accepted. The authors raise appropriate caveats for their observations, including the small sample size, the diversity of microglial actions, and the interpretation of the cognitive correlation. However, there are also important methodological issues relating to the interpretation of data using this PET ligand that should be addressed, some reference citations that require clarification, and several reported findings that are difficult to reconcile with prior literature. The PK ligand targets what has in the past been termed the peripheral benzodiazepine receptor (PBR) to distinguish it from a distinct central benzodiazepine receptor that is located on the plasma membrane of gamma-aminobutyric acidergic neurons. More recently renamed Translocator protein (18 kDa), the PBR has highly diverse functions that may include cholesterol transport and cell death regulation, as well as effects on mitochondrial respiration, ion transport, and cell proliferation/differentiation, among others. Therefore, the interpretation of expression changes after injury and relation to outcome is not straightforward. PBRs are prominently expressed in microglia, and associated with microglial activation. Rodent models, in which microglia are activated using classical chemical activating agents, show increased PBR binding. But the PBR is also expressed in other CNS cell types, notably activated astroglia. Given the marked and sustained increase of glial fibrillary acidic protein (GFAP) after TBI, the conclusion that increased PK binding reflects exclusively or even predominantly microglial activation under all conditions may not be supportable without additional corroborative data. Mechanism studies to delineate correlations between changes in PBR ligand binding and specific cellular changes in vivo for specific disorders are nontrivial and few in number. The experimental paper cited by the authors to provide support that increased PK binding reflects microglial activation also showed significant correlations with activated astroglia, albeit with lower correlation coefficients and fold changes than for microglia. Perhaps more problematic is that the increased PK binding observed after TBI was correlated neither with time after injury nor injury severity as reflected by white matter damage. In addition, significantly increased binding was not found in the areas of focal damage or surrounding penumbra long after injury, in contrast to what has been observed in certain animal TBI models, including primates. In part, issues relating both to specificity for microglia and the lack of increased observed PK binding at the site of injury may reflect the choice of PET ligand. Thus, Venneti and colleagues reported that the PBR ligand [C]DAA1106 binds with higher affinity to microglia as compared to [C]PK11195, and shows greater retention at the site of contusion. There are also concerns about high nonspecific binding with PK. Finally, it should be recognized that PBR-specific ligands, including PK, themselves can cause microglial activation through a proposed nicotinamide adenine dinucleotide phosphate-oxidase mechanism, further complicating interpretation of findings with these ligands. Prolonged microglial activation after TBI has been reported across experimental models and in humans. That this occurs most predominantly in the thalamus, as