Positron Emission Tomography Imaging of Neuroinflammation

Abstract

In the diseased brain, upon activation microglia express binding sites for synthetic ligands designed to recognize the 18-kDa translocator protein TP-18, which is part of the so-called peripheral benzodiazepine receptor complex. PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide], the prototype synthetic ligand, has been widely used for the functional characterization of TP-18. Its cellular source in activated microglia has been established using high-resolution, single-cell autoradiography with the R-enantiomer [3H](R)-PK11195. Radiolabeled [11C](R)-PK11195 has been used to image active brain disease with positron emission tomography. Consistent with experimental and postmortem observations of a characteristically distributed pattern of microglia activation in areas of focal pathology, as well as in anterograde and retrograde projection areas, the in vivo regional [11C](R)-PK11195 signal is found in active focal lesions and over time also along the affected neural tracts and their respective cortical and subcortical projection areas. Thus, a profile of active disease emerges that matches some of the typical distribution patterns known from structural neuroimaging techniques, but additionally shows involvement of brain regions linked through neural pathways. In the context of cell-based in vivo neuropathology, the image data are thus best interpreted in the context of the emerging cellular understanding of brain disease or damage, rather than the definitions of clinical diagnosis. One important observation, borne out by experiment, is the long latency with which activated microglia or increased PK11195 retention appear to gradually emerge and remain in distal areas secondarily affected by disease, supporting speculations that the presence of activated microglia is an important corollary of brain plasticity

Imaging microglial activation and glucose consumption in a mouse model of Alzheimer's disease

“…Therefore, the expression of TSPO is a marker of choice to study the extent and role of neuroinflammation in several neurological disorders with the use of radiolabeled TSPO-targeted compounds (Cagnin et al, 2007;Venneti et al, 2009b;Winkeler et al, 2010).…”

N-3 PUFAs and neuroinflammatory processes in cognitive disorders

“…While it is biologically plausible that peripheral inflammatory modulation may reflect brain health, further human studies are required to elucidate whether dietary n-3 PUFAs target microglia. The use of imaging techniques like positron emission tomography (PET) imaging to measure in vivo changes in microglia activation (Cagnin et al, 2007) would be of high benefit to decipher this important question.…”

Neuroinflammation in bipolar disorders

“…The demonstration of peripheral benzodiazepine receptor alterations in bipolar I disorder patients may constitute a definitive demonstration, [43] but it should also be considered that such alterations in the brain of people with bipolar disorder, which are consistent with microglial activation, may not be specifically related to the pathogenesis of bipolar disorder or any diagnosis, but rather to disease activity. [47] Causality effects, that is, whether it is bipolar disorder that once established, triggers neuroinflammation, either through the adoption of a reckless lifestyle that is likely to promote a metabolic syndrome that facilitates the onset of neuroinflammation, or rather it is neuroinflammation that has always existed in a given individual that eventually ensued in bipolar behavior and disorder, cannot be probed. In fact, to demonstrate causality we need longitudinal study designs, and in the case of neuroinflammation and bipolar disorder all relevant articles were based on cross-sectional articles.…”