Abstract
Glial activation in the setting of central nervous system inflammation is a key feature of the multiple sclerosis (MS) pathology. Monitoring glial activation in subjects with MS, therefore, has the potential to be informative with respect to disease activity. The translocator protein 18 kDa (TSPO) is a promising biomarker of glial activation that can be imaged by positron emission tomography (PET). To characterize the in vivo TSPO expression in MS, we analyzed brain PET scans in subjects with MS and healthy volunteers in an observational study using [11C]PBR28, a newly developed translocator protein-specific radioligand. The [11C]PBR28 PET showed altered compartmental distribution of TSPO in the MS brain compared to healthy volunteers (p = 0.019). Focal increases in [11C]PBR28 binding corresponded to areas of active inflammation as evidenced by significantly greater binding in regions of gadolinium contrast enhancement compared to contralateral normal-appearing white matter (p = 0.0039). Furthermore, increase in [11C]PBR28 binding preceded the appearance of contrast enhancement on magnetic resonance imaging in some lesions, suggesting a role for early glial activation in MS lesion formation. Global [11C]PBR28 binding showed correlation with disease duration (p = 0.041), but not with measures of clinical disability. These results further define TSPO as an informative marker of glial activation in MS.
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References
Bagasra O, Michaels FH, Zheng YM et al (1995) Activation of the inducible form of nitric oxide synthase in the brains of patients with multiple sclerosis. Proc Natl Acad Sci USA 92:12041–12045
Banati RB, Newcombe J, Gunn RN et al (2000) The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. Brain 123(Pt 11):2321–2337
Briard E, Zoghbi SS, Imaizumi M et al (2008) Synthesis and evaluation in monkey of two sensitive 11C-labeled aryloxyanilide ligands for imaging brain peripheral benzodiazepine receptors in vivo. J Med Chem 51:17–30
Cosenza-Nashat M, Zhao ML, Suh HS et al (2008) Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain. Neuropathol Appl Neurobiol 35(3):306–328
Debruyne JC, Versijpt J, Van Laere KJ et al (2003) PET visualization of microglia in multiple sclerosis patients using [11C]PK11195. Eur J Neurol 10:257–264
Fujita M, Imaizumi M, Zoghbi SS et al (2008) Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral benzodiazepine receptor, a potential biomarker for inflammation. Neuroimage 40:43–52
Henderson AP, Barnett MH, Parratt JD, Prineas JW (2009) Multiple sclerosis: distribution of inflammatory cells in newly forming lesions. Ann Neurol 66:739–753
Katz D, Taubenberger JK, Cannella B, McFarlin DE, Raine CS, McFarland HF (1993) Correlation between magnetic resonance imaging findings and lesion development in chronic, active multiple sclerosis. Ann Neurol 34:661–669
Kreisl WC, Fujita M, Fujimura Y et al (2010) Comparison of [(11)C]-(R)-PK 11195 and [(11)C]PBR28, two radioligands for translocator protein (18 kDa) in human and monkey: implications for positron emission tomographic imaging of this inflammation biomarker. Neuroimage 49:2924–2932
Logan J (2003) A review of graphical methods for tracer studies and strategies to reduce bias. Nucl Med Biol 30:833–844
Logan J, Fowler JS, Volkow ND et al (1990) Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(-)-cocaine PET studies in human subjects. J Cereb Blood Flow Metab 10:740–747
McDonald WI, Compston A, Edan G et al (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 50:121–127
McEnery MW, Snowman AM, Trifiletti RR, Snyder SH (1992) Isolation of the mitochondrial benzodiazepine receptor: association with the voltage-dependent anion channel and the adenine nucleotide carrier. Proc Natl Acad Sci USA 89:3170–3174
Owen DR, Howell OW, Tang SP et al (2010) Two binding sites for [(3)H]PBR28 in human brain: implications for TSPO PET imaging of neuroinflammation. J Cereb Blood Flow Metab 30:1608–1618
Versijpt J, Debruyne JC, Van Laere KJ et al (2005) Microglial imaging with positron emission tomography and atrophy measurements with magnetic resonance imaging in multiple sclerosis: a correlative study. Mult Scler 11:127–134
Werner P, Pitt D, Raine CS (2001) Multiple sclerosis: altered glutamate homeostasis in lesions correlates with oligodendrocyte and axonal damage. Ann Neurol 50:169–180
Zhang Y, Brady M, Smith S (2001) Segmentation of brain MR images through a hidden Markov random field model and the expectation-maximization algorithm. IEEE Trans Med Imaging 20:45–57
Acknowledgement
We thank Maria Ferraris Araneta (MIB/NIMH) and Kaylan Fenton (NIB/NINDS) for clinical support. This research was supported by the Intramural Research Program of the NIH (NINDS and NIMH).
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The authors have no financial conflicts of interest to disclose.
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Unsong Oh and Masahiro Fujita contributed equally to the manuscript.
An erratum to this article can be found at http://dx.doi.org/10.1007/s11481-011-9273-8
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Oh, U., Fujita, M., Ikonomidou, V.N. et al. Translocator Protein PET Imaging for Glial Activation in Multiple Sclerosis. J Neuroimmune Pharmacol 6, 354–361 (2011). https://doi.org/10.1007/s11481-010-9243-6
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DOI: https://doi.org/10.1007/s11481-010-9243-6