Refereed journal article or data article (A1)

In Vivo PET Imaging Demonstrates Diminished Microglial Activation After Fingolimod Treatment in an Animal Model of Multiple Sclerosis




List of Authors: Airas L, Dickens A, Elo P, Marjamäki, P, Johansson J, Eskola O, Jones P, Trigg W, Solin O, Haaparanta-Solin M, Anthony D, Rinne J

Publisher: Society of Nuclear Medicine and Molecular Imaging, Inc

Publication year: 2015

Journal: Journal of Nuclear Medicine

Journal acronym: J Nucl Med

Volume number: 56

Issue number: 2

Number of pages: 6

ISSN: 0161-5505

DOI: http://dx.doi.org/10.2967/jnumed.114.149955


Abstract

There is a great need for the monitoring of microglial activation surrounding multiple sclerosis lesions as this is thought to be driving the widespread neuronal damage. Recently, 'second generation' positron emission tomography (PET) radioligands have been developed which can reveal the extent of microglial activation by quantifying the increased expression of the 18 kDa translocator (TSPO) protein. 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 following treatment with fingolimod, an established MS therapy.



METHODS:

Chronic focal experimental autoimmune encephalitis (EAE)-like lesions were induced in Lewis rats (n = 24) via stereotaxic intrastriatal injection of heat-killed bacillus Calmette-Guérin (BCG) and subsequent activation using an intradermal injection of BCG in complete Freund's adjuvant. This results in a delayed type hypersensitivity (DTH)-like EAE-lesion. The extent of neuroinflammation surrounding the lesion was measured using 18F-GE180 as a PET radioligand. The imaging was performed before and after treatment with fingolimod (0.3 mg/kg/day po, 28 days) or vehicle as a control. In addition to this, 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 to contralateral hemisphere when PET imaging was performed with the TSPO-binding radioligand 18F-GE180. Treatment with fingolimod led to 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 18F-GE180 signal mapped closely to the area of activated microglial cells detected by immunohistochemistry.



CONCLUSION:

PET-imaging, unlike magnetic resonance imaging (MRI), can be used to visualise the microglial activation surrounding a chronic DTH-EAE lesion. Importantly, 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 introduction of new outcome measures applicable in treatment studies of progressive MS.


Last updated on 2021-24-06 at 11:51