Chapter 2 - Imaging Brain Microglial Activation Using Positron Emission Tomography and Translocator Protein-Specific Radioligands

https://doi.org/10.1016/B978-0-12-387718-5.00002-XGet rights and content

Abstract

Microglia are rapidly activated by a wide range of neuropathological insults. Quantifying microglial density in vivo would allow a new, potentially important range of clinic-pathological correlations. Microglia express the 18 kDa translocator protein (TSPO) which can be quantified by the positron emission tomography (PET) ligand [11C]PK11195, although signal quantification is limited by nonspecific binding. New generation TSPO radioligands with an improved signal-to-noise ratio are now available, but variation in their binding affinity for the TSPO between subjects complicates their use. This review describes the principles of PET imaging, the rationale and challenges in targeting the TSPO as means of quantifying microglial activation in vivo, and disease applications that have been studied with TSPO-PET hitherto.

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.

References (105)

  • H. Akiyama et al.

    Inflammation and Alzheimer's disease

    Neurobiol. Aging

    (2000)
  • R.R. Anholt et al.

    Peripheral-type benzodiazepine receptors: autoradiographic localization in whole-body sections of neonatal rats

    J. Pharmacol. Exp. Ther.

    (1985)
  • S.E. Arnold et al.

    Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia

    Arch. Gen. Psychiatry

    (1998)
  • R.B. Banati et al.

    Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson's disease

    Mov. Disord.

    (1998)
  • R.B. Banati et al.

    [11C](R)-PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen's encephalitis

    Neurology

    (1999)
  • R.B. Banati et al.

    The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity

    Brain

    (2000)
  • S.W. Barger et al.

    Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E

    Nature

    (1997)
  • F. Barkhof

    The clinico-radiological paradox in multiple sclerosis revisited

    Curr. Opin. Neurol.

    (2002)
  • A.L. Bartels et al.

    [11C]-PK11195 PET: quantification of neuroinflammation and a monitor of anti-inflammatory treatment in Parkinson's disease?

    Parkinsonism Relat. Disord.

    (2010)
  • A. Cagnin et al.

    In-vivo measurement of activated microglia in dementia

    Lancet

    (2001)
  • A. Cagnin et al.

    Positron emission tomography imaging of neuroinflammation

    Neurotherapeutics

    (2007)
  • B. Cameron et al.

    Inflammation, microglia, and Alzheimer's disease

    Neurobiol. Dis.

    (2010)
  • X. Canat et al.

    Distribution profile and properties of peripheral-type benzodiazepine receptors on human hemopoietic cells

    Life Sci.

    (1993)
  • P. Charbonneau et al.

    Peripheral-type benzodiazepine receptors in the living heart characterized by positron emission tomography

    Circulation

    (1986)
  • F. Chauveau et al.

    Nuclear imaging of neuroinflammation: a comprehensive review of [11C]PK11195 challengers

    Eur. J. Nucl. Med. Mol. Imaging

    (2008)
  • A. Cifelli et al.

    Thalamic neurodegeneration in multiple sclerosis

    Ann. Neurol.

    (2002)
  • E.L. Conway et al.

    Temporal changes in glial fibrillary acidic protein messenger RNA and [3H]PK11195 binding in relation to imidazoline-I2-receptor and alpha 2-adrenoceptor binding in the hippocampus following transient global forebrain ischaemia in the rat

    Neuroscience

    (1998)
  • M. Cosenza-Nashat et al.

    Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain

    Neuropathol. Appl. Neurobiol.

    (2009)
  • J.C. Debruyne et al.

    PET visualization of microglia in multiple sclerosis patients using [11C]PK11195

    Eur. J. Neurol.

    (2003)
  • D. Diorio et al.

    Peripheral benzodiazepine binding sites in Alzheimer's disease frontal and temporal cortex

    Neurobiol. Aging

    (1991)
  • A. Doble et al.

    Labelling of peripheral-type benzodiazepine binding sites in human brain with [3H]PK 11195: anatomical and subcellular distribution

    Brain Res. Bull.

    (1987)
  • J. Doorduin et al.

    Neuroinflammation in schizophrenia-related psychosis: a PET study

    J. Nucl. Med.

    (2009)
  • A. Dubois et al.

    Imaging of primary and remote ischaemic and excitotoxic brain lesions: An autoradiographic study of peripheral type benzodiazepine binding sites in the rat and cat

    Brain Res.

    (1988)
  • P. Edison et al.

    Microglia, amyloid, and cognition in Alzheimer's disease: an [11C](R)PK11195-PET and [11C]PIB-PET study

    Neurobiol. Dis.

    (2008)
  • C.J. Endres et al.

    Initial evaluation of 11C-DPA-713, a novel TSPO PET ligand, in humans

    J. Nucl. Med.

    (2009)
  • C.J. Fookes et al.

    Synthesis and biological evaluation of substituted [18F]imidazo[1,2-a]pyridines and [18F]pyrazolo[1,5-a]pyrimidines for the study of the peripheral benzodiazepine receptor using positron emission tomography

    J. Med. Chem.

    (2008)
  • Y. Fujimura et al.

    Quantification of translocator protein (18 kDa) in the human brain with PET and a novel radioligand, (18)F-PBR06

    J. Nucl. Med.

    (2009)
  • M. Gavish et al.

    Enigma of the peripheral benzodiazepine receptor

    Pharmacol. Rev.

    (1999)
  • J. Gehrmann et al.

    Microglia: intrinsic immuneffector cell of the brain

    Brain Res. Brain Res. Rev.

    (1995)
  • A. Gerhard et al.

    [11C](R)-PK11195 PET imaging of microglial activation in multiple system atrophy

    Neurology

    (2003)
  • A. Gerhard et al.

    In vivo imaging of microglial activation with [11C](R)-PK11195 PET in corticobasal degeneration

    Mov. Disord.

    (2004)
  • A. Gerhard et al.

    Evolution of microglial activation in patients after ischemic stroke: a [11C](R)-PK11195 PET study

    Neuroimage

    (2005)
  • A. Gerhard et al.

    In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson's disease

    Neurobiol. Dis.

    (2006)
  • A. Gerhard et al.

    In vivo imaging of microglial activation with [11C](R)-PK11195 PET in progressive supranuclear palsy

    Mov. Disord.

    (2006)
  • D. Giulian et al.

    Reactive mononuclear phagocytes release neurotoxins after ischemic and traumatic injury to the central nervous system

    J. Neurosci. Res.

    (1993)
  • B. Gulyas et al.

    A comparative autoradiography study in post mortem whole hemisphere human brain slices taken from Alzheimer patients and age-matched controls using two radiolabelled DAA1106 analogues with high affinity to the peripheral benzodiazepine receptor (PBR) system

    Neurochem. Int.

    (2009)
  • Q. Guo et al.

    A biomathematical modeling approach to central nervous system radioligand discovery and development

    J. Nucl. Med.

    (2009)
  • K. Henkel et al.

    Imaging of activated microglia with PET and [11C]PK 11195 in corticobasal degeneration

    Mov. Disord.

    (2004)
  • H.E. Hulshoff Pol et al.

    Focal gray matter density changes in schizophrenia

    Arch. Gen. Psychiatry

    (2001)
  • Y. Ikoma et al.

    Quantitative analysis for estimating binding potential of the peripheral benzodiazepine receptor with [(11)C]DAA1106

    J. Cereb. Blood Flow Metab.

    (2007)
  • M. Imaizumi et al.

    Brain and whole-body imaging in nonhuman primates of [11C]PBR28, a promising PET radioligand for peripheral benzodiazepine receptors

    Neuroimage

    (2008)
  • Y. Itzhak et al.

    Characterization of the peripheral-type benzodiazepine receptors in cultured astrocytes: evidence for multiplicity

    Glia

    (1993)
  • B. Ji et al.

    Imaging of peripheral benzodiazepine receptor expression as biomarkers of detrimental versus beneficial glial responses in mouse models of Alzheimer's and other CNS pathologies

    J. Neurosci.

    (2008)
  • S.N. Joshi et al.

    Rat microglia exhibit increased density on Alzheimer's plaques in vitro

    Exp. Neurol.

    (1998)
  • G.W. Kreutzberg

    Microglia: a sensor for pathological events in the CNS

    Trends Neurosci.

    (1996)
  • M.A. Kropholler et al.

    Evaluation of reference tissue models for the analysis of [11C](R)-PK11195 studies

    J. Cereb. Blood Flow Metab.

    (2006)
  • J. Krupinski et al.

    Immunocytochemical studies of cellular reaction in human ischemic brain stroke. MAB anti-CD68 stains macrophages, astrocytes and microglial cells in infarcted area

    Folia Neuropathol.

    (1996)
  • A. Kurumaji et al.

    Decreases in peripheral-type benzodiazepine receptors in postmortem brains of chronic schizophrenics

    J. Neural Transm.

    (1997)
  • A. Kutzelnigg et al.

    Cortical demyelination and diffuse white matter injury in multiple sclerosis

    Brain

    (2005)
  • S. Lehnardt et al.

    Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway

    Proc. Natl. Acad. Sci. USA

    (2003)
  • Cited by (0)

    View full text