Chapter 2 - Imaging Brain Microglial Activation Using Positron Emission Tomography and Translocator Protein-Specific Radioligands
Introduction
Microglia are brain resident macrophages which continuously sample their local environment by sending out and retracting extensions (Gehrmann et al., 1995, Kreutzberg, 1996). Microglia are believed to be central effectors of neuroinflammation, neurodegeneration, and brain repair, and they are rapidly activated by a wide range of insults (including trauma, ischemia, inflammation, neurodegeneration, and infection). When activated, microglia adopt an amoeboid shape and express cytokines regulating an inflammatory response (Gehrmann et al., 1995, Kreutzberg, 1996, Venneti et al., 2006). There is therefore considerable interest in developing imaging techniques to quantify microglial activation in vivo, because such a technique would allow new and potentially important ranges of clinic-pathological correlations.
Microglia express the 18 kDa translocator protein (TSPO), which is found in many cell types throughout the body but with relatively low background expression in the healthy brain (Doble et al., 1987) which can be quantified by positron emission tomography (PET) imaging (Cagnin et al., 2007). However, signal quantification is limited by the poor specific signal-to-background noise ratio (SBR) of the TSPO targeting radioligand, [11C]PK11195. New generation TSPO ligands with an improved SBR relative to [11C]PK11195 are now available (Chauveau et al., 2008), but variation in their binding affinity for the TSPO between subjects may complicate their use (Owen et al., 2011). This review describes the principles of PET imaging analysis, along with the rationale and challenges in targeting the TSPO as a means of quantifying microglial activation in vivo. In addition, we describe several applications for the study of neuropsychiatric and neurodegenerative diseases which have been studied with TSPO-PET imaging.
Section snippets
Principles of PET Imaging
PET imaging studies require the design of a ligand which binds with high specificity to a desired target, but with minimal nonspecific binding to other structures. The ligand is labeled with a positron emitting radioisotope with a short half-life (t1\2), commonly 11C (t1\2 ∼ 20 min) or 18F (t1\2 ∼ 110 min). Following intravenous administration of the radiolabeled ligand (radioligand), the emitted positrons will collide with nearby electrons resulting in the production of pairs of photons that
TSPO for Assessment of Microglial Expression
Microglia express TSPO. Quantifying TSPO expression therefore provides a means of estimating microglial density, particularly since baseline expression of TSPO in most other cells in the healthy human brain is low (Doble et al., 1987). Indeed, a number of in vitro studies using postmortem human brain tissue have shown increased TSPO density (measured as [3H]PK11195 binding) in diseases characterized by microglial proliferation. These include studies of multiple sclerosis (MS; Banati et al.,
Challenges Facing PET Imaging of the TSPO
PK11195 is a TSPO antagonist with nanomolar affinity (Shah et al., 1994), which was first labeled with 11C for use as a PET radioligand in humans in 1986 (Charbonneau et al., 1986). Since then [11C]PK11195 has been used in PET studies to investigate various brain diseases (Matthews and Comley, 2009), as well as in studies of systemic innate immune responses, owing to its expression in peripheral macrophages as well as microglia.
However, it is well recognized that in vivo PET applications of the
Neuroinflammatory Diseases
Numerous [3H]PK11195 in vitro radioligand binding studies in human postmortem tissues have documented an increase in TSPO expression associated with lesions in MS patients. Tissue samples containing white matter lesions express TSPO at levels three to four times greater than the levels in normal white matter (Banati et al., 2000, Venneti et al., 2008), with the majority of binding seen at the periphery of the plaque (Owen et al., 2010, Vowinckel et al., 1997; Fig. 2). However, even in
Conclusion
Because microglial proliferation is a stereotyped response following a wide variety of pathological insults, there has been great interest in quantifying microglial density in vivo both as a research tool and as an aid to clinical decision making. TSPO imaging with PET analysis is potentially helping us to take the first steps toward this goal. However, in vivo studies to date have been hindered by the lack of an appropriate radioligand for robust quantification of specific binding. With the
Acknowledgments
DRJO has been funded by the Wellcome Trust-GSK Translational Medicine Training Programme in Imperial College London. P. M. M. is a full time employee of GlaxoSmithKline.
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