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

This study identifies by microautoradiography activated microglia/macrophag es as the main cell type expressing the peripheral benzodiazepine binding s ite (PBBS) at sites of active CNS pathology. Quantitative measurements of P BBS expression in vivo obtained by PET and [C-11] are shown to correspond t o animal experimental and human post-mortem data on the distribution patter n of activated microglia in inflammatory brain disease. Film autoradiograph y with [H-3](R)-PK11195, a specific ligand for the PBBS, showed minimal bin ding in normal control CNS, whereas maximal binding to mononuclear cells wa s found in multiple sclerosis plaques. However, there was also significantl y increased [H-3](R)-PK11195 binding on activated microglia outside the his topathologically 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 [H-3](R)- PK11195 binding in areas containing activated microglia was seen in the CNS of animals with experimental allergic encephalomyelitis (EAE), In areas wi thout identifiable focal pathology, immunocytochemical staining combined wi th high-resolution emulsion autoradiography demonstrated that the cellular source of [H-3](R)-PK11195 binding is activated microglia, which frequently retains a ramified morphology, Furthermore, in vitro radioligand binding s tudies confirmed that microglial activation leads to a rise in the number o f PBBS and not a change in binding affinity. Quantitative [C-11](R)-PK11195 PET in multiple sclerosis patients demonstrated increased PBBS expression in areas of focal pathology identified by T-1- and T-2-weighted MRI and, im portantly, also in normal-appearing anatomical structures, including cerebr al central grey matter, The additional binding frequently delineated neuron al projection areas, such as the lateral geniculate bodies in patients with a history of optic neuritis, In summary, [C-11](R)-PK11195 PET provides a cellular marker of disease activity in vivo in the human brain.