Brain, Vol. 123, No. 11, 2321-2337,
November 2000
© 2000 Oxford University Press
The peripheral benzodiazepine binding site in the brain in multiple sclerosis
Quantitative in vivo imaging of microglia as a measure of disease activity
1 MRC Cyclotron Unit and 2 Robert Steiner Magnetic Resonance Imaging Unit, Imperial College School of Medicine, Hammersmith Hospital, 3 Department of Neuroscience, Imperial College School of Medicine, Charing Cross Hospital, 4 Neuroinflammation Group and 5 NMR Research Unit, Institute of Neurology, University College London, 6 Eisai London Research Laboratories, University College London, London, 7 Department of Neuroscience Research, SmithKline-Beecham Pharmaceuticals, Harlow, 8 Department of Physiology, University of Cambridge, Cambridge, UK, 9 Paul Flechsig Institute, Leipzig, 10 Department of Neuromorphology,Max-Planck-Institute of Neurobiology, Munich, Germany and 11 Department of Neuropathology, University of Zurich, Switzerland
Correspondence to:
R. B. Banati, MRC Cyclotron Unit, Imperial College School of Medicine, Hammersmith Hospital, Ducane Road, London W12 0NN, UK
This study identifies by microautoradiography activated microglia/macrophages as the main cell type expressing the peripheral benzodiazepine binding site (PBBS) at sites of active CNS pathology. Quantitative measurements of PBBS expression in vivo obtained by PET and [11C](R)-PK11195 are shown to correspond to animal experimental and human post-mortem data on the distribution pattern of activated microglia in inflammatory brain disease. Film autoradiography with [3H](R)-PK11195, a specific ligand for the PBBS, showed minimal binding in normal control CNS, whereas maximal binding to mononuclear cells was found in multiple sclerosis plaques. However, there was also significantly increased [3H](R)-PK11195 binding on activated microglia outside the histopathologically defined borders of multiple sclerosis plaques and in areas, such as the cerebral central grey matter, that are not normally reported as sites of pathology in multiple sclerosis. A similar pattern of [3H](R)-PK11195 binding in areas containing activated microglia was seen in the CNS of animals with experimental allergic encephalomyelitis (EAE). In areas without identifiable focal pathology, immunocytochemical staining combined with high-resolution emulsion autoradiography demonstrated that the cellular source of [3H](R)-PK11195 binding is activated microglia, which frequently retains a ramified morphology. Furthermore, in vitro radioligand binding studies confirmed that microglial activation leads to a rise in the number of PBBS and not a change in binding affinity. Quantitative [11C](R)-PK11195 PET in multiple sclerosis patients demonstrated increased PBBS expression in areas of focal pathology identified by T1- and T2-weighted MRI and, importantly, also in normal-appearing anatomical structures, including cerebral central grey matter. The additional binding frequently delineated neuronal projection areas, such as the lateral geniculate bodies in patients with a history of optic neuritis. In summary, [11C](R)-PK11195 PET provides a cellular marker of disease activity in vivo in the human brain.
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