Contributions
Abstract: P1105
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - MRI and PET
Background: Multiple sclerosis (MS) is a chronic inflammatory disease that often begins with a relapsing-remitting phenotype (RRMS) and with time progresses into secondary progressive type (SPMS) in most patients. Little is known about the neuropathological changes that lead to progression in MS. Adenosine 2a receptors (A2AR) are ubiquitous receptors involved in resolution of inflammation. Their significance in MS progression is largely unknown. We aimed to investigate A2AR distribution in the MS brain using [11C]TMSX PET imaging and immunohistochemical evaluation on post mortem MS tissue.
Methods: 17 MS patients (8 RRMS and 9 SPMS) and 9 healthy controls were PET imaged using the A2AR-specific radioligand [11C]TMSX. To investigate cellular expression of A2AR in MS tissue, histological sections were fluorescent-labeled for A2AR and cellular markers for astrocytes and microglia. A total of 16 lesions from 8 MS patients were examined.
Results: Specific binding of [11C]TMSX to A2AR (distribution volume ratio, DVR) was significantly increased in the normal-appearing white matter (NAWM) of SPMS patients compared to RRMS patients (p=0.024) and age-matched healthy controls (p=0.024). No difference in [11C]TMSX binding was found between RRMS patients and healthy controls. In addition, periplaque binding (pooled 3-6mm area surrounding each MS plaque) was significantly greater in SPMS patients compared to RRMS patients (p=0.018). In histological sections, A2AR was highly expressed in reactive, GFAP-positive astrocytes at the rim and adjacent NAWM of chronic active white matter lesions but not in chronic silent lesions. Moreover, A2AR was only minimally expressed in activated CD68-positive microglia and macrophages.
Conclusion: [11C]TMSX binding to A2AR was significantly greater in SPMS compared to RRMS patients in the NAWM and periplaque areas. Immunohistochemistry demonstrated that the increased binding in MS brain is likely due to increased A2AR expression on reactive astrocytes. A2AR signaling in astrocytes at the perimeter of chronic active lesions in progressive MS may play a role modulating innate immune responses and present a possible target for therapeutic intervention in progressive MS.
Disclosure: Anna Vuorimaa: nothing to disclose, Gerald Ponath: nothing to disclose, Eero Rissanen has received speaker honoraria from Teva, Biogen, and Roche, a consultational fee for Merck and personal research grants from Turku University Hospital and the Finnish MS Foundation, Jouni Tuisku: nothing to disclose, Markus Matilainen: nothing to disclose, David Pitt: nothing to disclose, Laura Airas has received honoraria from Biogen, F. Hoffmann-La Roche Ltd, Genzyme, Merck Serono and Teva, and institutional research grant support from Biogen, Genzyme, Merck Serono and Novartis.
Abstract: P1105
Type: Poster Sessions
Abstract Category: Pathology and pathogenesis of MS - MRI and PET
Background: Multiple sclerosis (MS) is a chronic inflammatory disease that often begins with a relapsing-remitting phenotype (RRMS) and with time progresses into secondary progressive type (SPMS) in most patients. Little is known about the neuropathological changes that lead to progression in MS. Adenosine 2a receptors (A2AR) are ubiquitous receptors involved in resolution of inflammation. Their significance in MS progression is largely unknown. We aimed to investigate A2AR distribution in the MS brain using [11C]TMSX PET imaging and immunohistochemical evaluation on post mortem MS tissue.
Methods: 17 MS patients (8 RRMS and 9 SPMS) and 9 healthy controls were PET imaged using the A2AR-specific radioligand [11C]TMSX. To investigate cellular expression of A2AR in MS tissue, histological sections were fluorescent-labeled for A2AR and cellular markers for astrocytes and microglia. A total of 16 lesions from 8 MS patients were examined.
Results: Specific binding of [11C]TMSX to A2AR (distribution volume ratio, DVR) was significantly increased in the normal-appearing white matter (NAWM) of SPMS patients compared to RRMS patients (p=0.024) and age-matched healthy controls (p=0.024). No difference in [11C]TMSX binding was found between RRMS patients and healthy controls. In addition, periplaque binding (pooled 3-6mm area surrounding each MS plaque) was significantly greater in SPMS patients compared to RRMS patients (p=0.018). In histological sections, A2AR was highly expressed in reactive, GFAP-positive astrocytes at the rim and adjacent NAWM of chronic active white matter lesions but not in chronic silent lesions. Moreover, A2AR was only minimally expressed in activated CD68-positive microglia and macrophages.
Conclusion: [11C]TMSX binding to A2AR was significantly greater in SPMS compared to RRMS patients in the NAWM and periplaque areas. Immunohistochemistry demonstrated that the increased binding in MS brain is likely due to increased A2AR expression on reactive astrocytes. A2AR signaling in astrocytes at the perimeter of chronic active lesions in progressive MS may play a role modulating innate immune responses and present a possible target for therapeutic intervention in progressive MS.
Disclosure: Anna Vuorimaa: nothing to disclose, Gerald Ponath: nothing to disclose, Eero Rissanen has received speaker honoraria from Teva, Biogen, and Roche, a consultational fee for Merck and personal research grants from Turku University Hospital and the Finnish MS Foundation, Jouni Tuisku: nothing to disclose, Markus Matilainen: nothing to disclose, David Pitt: nothing to disclose, Laura Airas has received honoraria from Biogen, F. Hoffmann-La Roche Ltd, Genzyme, Merck Serono and Teva, and institutional research grant support from Biogen, Genzyme, Merck Serono and Novartis.