Translating the cellular neuropathology of microglia into neuroimaging results

R.B. Banati*, F.E. Turkheimer, L. Moran, D. Duke and M.B. Graeber

*Imperial College, Hammersmith Hospital, London, UK


Brain disease often result in significant changes in the functional state of glial cells, one of which is the activation of microglia, the brain’s resident tissue macrophages. The response is increasingly thought to be an important  step in the pathophysiology of traumatic, inflammatory, neoplastic and degenerative brain disease. Part of the structural and functional plasticity of microglia is the de novo expression of the “peripheral benzodiazepine binding site" (PBBS). PBBS is linked to functions, such as immune modulation, steroid synthesis and mitochondrial activity. We have studied PBBS by integrating several data layers, including gene expression arrays and immunocytochemistry, in order to identify the functional significance of the PBBS and microglial activation more generally. The PBBS is bound by the isoquinoline PK11195, which labeled with carbon-11 can be used for positron emission tomography (PET). This opens a unique window to study glial action in the living human brain. Using 11C-(R)-PK11195 PET in inflammatory and neurodegenerative brain disease as well as receptor autoradiography, we have shown that distributed regional PBBS up-regulation correlates with clinical deficit and mirrors the histologically described activation of microglia in the penumbra of focal lesions, but importantly also in the distant, anterograde and retrograde projection areas of the lesioned neural pathway as well as in structurally normal trans-synaptic areas.

References:

Graeber MB (2003) “Microglia,” Encyclopedia of Neuroscience, 3rd Edition, New York: Elsevier Science.

Turkheimer FE, Aston JAD, Banati RB, Riddell C, Cunningham VJ (2003) "A linear wavelet filter for parametric imaging with dynamic PET," IEEE Transactions on Medical Imaging (Special Issue on Wavelets in Medical Imaging), 22(3):1-18.

Gerhard A, Banati RB, Goerres GB, Cagnin A, Myers R, Gunn RN, Turkheimer F, Good CD, Mathias CJ, Quinn N, Schwarz J, Brooks DJ (2003)”[11C]R-PK11195 PET imaging of microglial activation in multiple system atrophy,” Neurology, In Press.

Cagnin A, Brooks DJ, Kennedy AM, Gunn RN, Myers R, Turkheimer FE, Jones T, Banati RB (2001) "In vivo measurement of neuroinflammation in mild/moderate dementia", The Lancet 358:461-467

Banati RB, Newcombe J, Gunn RN, Cagnin A, Turkheimer FE et al., (2000) "The Peripheral Benzodiazepine Binding Site in the Brain  in Multiple Sclerosis", Brain 123, 2321-2337