Laura Airas1, Alex M Dickens2, Petri Elo2, Päivi Marjamäki2, Jarkko Johansson3, Olli Eskola4, Paul A Jones5, William Trigg5, Olof Solin4, Merja Haaparanta-Solin2, Daniel C Anthony6, Juha Rinne3. 1. Division of Clinical Neurosciences, Turku University Hospital, Turku, Finland laura.airas@utu.fi. 2. Medicity/Preclinical Imaging, Turku PET Centre, University of Turku, Turku, Finland. 3. Clinical Neurology, Turku PET Centre, University of Turku, Turku, Finland. 4. Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, University of Turku, Turku, Finland. 5. GE Healthcare Ltd., The Grove Centre, Amersham, United Kingdom; and. 6. Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
Abstract
UNLABELLED: There is a great need for the monitoring of microglial activation surrounding multiple sclerosis lesions because the activation of microglia is thought to drive widespread neuronal damage. Recently, second-generation PET radioligands that can reveal the extent of microglial activation by quantifying the increased expression of the 18-kDa translocator protein have been developed. Here, we investigate whether PET imaging can be used to demonstrate the reduction in microglial activation surrounding a chronic focal multiple sclerosis (MS)-like lesion after treatment with fingolimod, an established MS therapy. METHODS: Chronic focal experimental autoimmune encephalitis (EAE)-like lesions were induced in Lewis rats (n = 24) via stereotactic intrastriatal injection of heat-killed bacillus Calmette-Guérin (BCG) and subsequent activation using an intradermal injection of BCG in complete Freund adjuvant. This process resulted in a delayed-type hypersensitivity (DTH)-like EAE lesion. The extent of neuroinflammation surrounding the lesion was measured using (18)F-GE180 as a PET radioligand. The imaging was performed before and after treatment with fingolimod (0.3 mg/kg/d by mouth, 28 d) or vehicle as a control. In addition to imaging, autoradiography and immunohistochemistry experiments were performed to verify the in vivo results. RESULTS: The chronic DTH EAE lesion led to increased ligand binding in the ipsilateral, compared with contralateral, hemisphere when PET imaging was performed with the translocator protein-binding radioligand (18)F-GE180. Treatment with fingolimod led to a highly significant reduction in the binding potential, which could be demonstrated using both in vivo and ex vivo imaging (fingolimod vs. vehicle treatment, P < 0.0001). The area of increased (18)F-GE180 signal mapped closely to the area of activated microglial cells detected by immunohistochemistry. CONCLUSION: PET imaging, unlike MR imaging, can be used to visualize the microglial activation surrounding a chronic DTH EAE lesion. Importantly, the treatment effect of fingolimod can be monitored in vivo by measuring the degree of microglial activation surrounding the chronic DTH EAE lesion. This work gives promise for the introduction of new outcome measures applicable in treatment studies of progressive MS.
UNLABELLED: There is a great need for the monitoring of microglial activation surrounding multiple sclerosis lesions because the activation of microglia is thought to drive widespread neuronal damage. Recently, second-generation PET radioligands that can reveal the extent of microglial activation by quantifying the increased expression of the 18-kDa translocator protein have been developed. Here, we investigate whether PET imaging can be used to demonstrate the reduction in microglial activation surrounding a chronic focal multiple sclerosis (MS)-like lesion after treatment with fingolimod, an established MS therapy. METHODS: Chronic focal experimental autoimmune encephalitis (EAE)-like lesions were induced in Lewis rats (n = 24) via stereotactic intrastriatal injection of heat-killed bacillus Calmette-Guérin (BCG) and subsequent activation using an intradermal injection of BCG in complete Freund adjuvant. This process resulted in a delayed-type hypersensitivity (DTH)-like EAE lesion. The extent of neuroinflammation surrounding the lesion was measured using (18)F-GE180 as a PET radioligand. The imaging was performed before and after treatment with fingolimod (0.3 mg/kg/d by mouth, 28 d) or vehicle as a control. In addition to imaging, autoradiography and immunohistochemistry experiments were performed to verify the in vivo results. RESULTS: The chronic DTH EAE lesion led to increased ligand binding in the ipsilateral, compared with contralateral, hemisphere when PET imaging was performed with the translocator protein-binding radioligand (18)F-GE180. Treatment with fingolimod led to a highly significant reduction in the binding potential, which could be demonstrated using both in vivo and ex vivo imaging (fingolimod vs. vehicle treatment, P < 0.0001). The area of increased (18)F-GE180 signal mapped closely to the area of activated microglial cells detected by immunohistochemistry. CONCLUSION: PET imaging, unlike MR imaging, can be used to visualize the microglial activation surrounding a chronic DTH EAE lesion. Importantly, the treatment effect of fingolimod can be monitored in vivo by measuring the degree of microglial activation surrounding the chronic DTH EAE lesion. This work gives promise for the introduction of new outcome measures applicable in treatment studies of progressive MS.
Authors: Bao Ying Chen; Chiara Ghezzi; Brendon Villegas; Andrew Quon; Caius G Radu; Owen N Witte; Peter M Clark Journal: J Nucl Med Date: 2019-10-25 Impact factor: 10.057
Authors: Valerie L Jewells; Hong Yuan; Joseph R Merrill; Jonathan E Frank; Akhil Patel; Stephanie M Cohen; Ben Giglio; Nana Nikolaishvili Feinberg; Glenn K Matsushima; Zibo Li Journal: Diagnostics (Basel) Date: 2021-04-27
Authors: Bin Liu; Kevin X Le; Mi-Ae Park; Shuyan Wang; Anthony P Belanger; Shipra Dubey; Jeffrey L Frost; Peter Holton; Vladimir Reiser; Paul A Jones; William Trigg; Marcelo F Di Carli; Cynthia A Lemere Journal: J Neurosci Date: 2015-11-25 Impact factor: 6.167