Contributions
Abstract: 115
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - Imaging
Background: Neuropathological studies of multiple sclerosis (MS) suggest that microglia activation plays a key role in cortical lesions (CL) pathogenesis, and that the innate immune system-mediated inflammatory events underlying the development of MS pathology are dissociated in cortex and white matter (WM).
Goals: To investigate, using 7T MRI and magnetic resonance-positron emission tomography (MR-PET) imaging with 11C-PBR28, the in vivo pathological and clinical relevance of microglia activation in lesioned and non-lesioned tissue in cortex and WM in secondary-progressive and relapsing-remitting MS (SPMS, RRMS).
Methods: Thirteen SPMS and 9 RRMS patients, and 14 age- and translocator protein (TSPO) affinity matched healthy controls (HC) underwent 11C-PBR28 MR-PET imaging. Anatomical MR scans were acquired for FreeSurfer reconstruction. 11C-PBR28 binding was measured in all cases using normalized 60-90 minutes standardized uptake values (SUVR), in 14 MS and 11 HC also with volume of distribution ratios (VTR). MS WM and cortical lesions (CL, in 12 MS) were segmented on 7T T2* scans. 11C-PBR28 SUVR and VTR were extracted in lesions, whole cortex, normal-appearing WM (NAWM). MS cognitive function was assessed using a modified version of the Minimal Assessment of Cognitive Function in MS and by averaging z-scores from individual tests. Linear regression was used to compare 11C-PBR28 uptake between groups, and assess the relation with clinical metrics. Age, gender, TSPO affinity were included as regressors.
Results: Relative to HC, all MS exhibited abnormally increased 11C-PBR28 SUVR in CL (SUVR: 27%, p=0.001), whole cortex (SUVR: 22%, p=0.002; VTR: 31%, p=0.0001), and NAWM (22%, p=0.008; VTR: 29%, p=0.008). 11C-PBR28 uptake in MS WM lesions was modestly increased vs HC (SUVR: 10%; VTR: 17%, p=0.06). Twenty-seven CL were identified in RRMS, 223 in SPMS with a ~21% (p=0.01) and a ~32% (p=0.007) increase in SUVR, respectively, relative to HC cortex. Microglia activation, relative to HC, was greater in SPMS than in RRMS in NAWM (p=0.004). Reduced cognitive function correlated with increased SUVR in NAWM (p=0.02) and CL (p=0.05). Worsening of EDSS was related to increased NAWM PBR uptake (p=0.04).
Conclusions: Distinct microglia-mediated events may underlie cortical and WM pathology. Quantification of microglia activation is a sensitive tool for evaluating in vivo the inflammatory component of cortical pathology at all disease stages.
Disclosure: This study was supported partly by the Clafin Award; partly by a grant from the National MS Society (NMSS) RG 4729A2/1, and partly by the Department of Defense (DoD) US Army W81XWH-13-1-0112 Award.
EH, GM, ML, CAT, STG, NW, JAS, RO, CC, JMH,TG: no disclosure
Dr Mainero has received research support from EMD Merck Serono and speaker fees from Biogen
Dr Giannì has received a fellowship from FISM 2012/B/4
Dr Louapre received a fellowship from ARSEP foundation
Dr Klawiter has received consulting fees from Biogen Idec and Mallinckrodt Pharmaceuticals and
research funding from Roche and Atlas5d
Dr. Kinkel reports personal fees from Genzyme ; A Sanofi Corp, personal fees from Biogen Idec,
grants from Acclerated Cure Project, personal fees from Novartis, outside the submitted work
Abstract: 115
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - Imaging
Background: Neuropathological studies of multiple sclerosis (MS) suggest that microglia activation plays a key role in cortical lesions (CL) pathogenesis, and that the innate immune system-mediated inflammatory events underlying the development of MS pathology are dissociated in cortex and white matter (WM).
Goals: To investigate, using 7T MRI and magnetic resonance-positron emission tomography (MR-PET) imaging with 11C-PBR28, the in vivo pathological and clinical relevance of microglia activation in lesioned and non-lesioned tissue in cortex and WM in secondary-progressive and relapsing-remitting MS (SPMS, RRMS).
Methods: Thirteen SPMS and 9 RRMS patients, and 14 age- and translocator protein (TSPO) affinity matched healthy controls (HC) underwent 11C-PBR28 MR-PET imaging. Anatomical MR scans were acquired for FreeSurfer reconstruction. 11C-PBR28 binding was measured in all cases using normalized 60-90 minutes standardized uptake values (SUVR), in 14 MS and 11 HC also with volume of distribution ratios (VTR). MS WM and cortical lesions (CL, in 12 MS) were segmented on 7T T2* scans. 11C-PBR28 SUVR and VTR were extracted in lesions, whole cortex, normal-appearing WM (NAWM). MS cognitive function was assessed using a modified version of the Minimal Assessment of Cognitive Function in MS and by averaging z-scores from individual tests. Linear regression was used to compare 11C-PBR28 uptake between groups, and assess the relation with clinical metrics. Age, gender, TSPO affinity were included as regressors.
Results: Relative to HC, all MS exhibited abnormally increased 11C-PBR28 SUVR in CL (SUVR: 27%, p=0.001), whole cortex (SUVR: 22%, p=0.002; VTR: 31%, p=0.0001), and NAWM (22%, p=0.008; VTR: 29%, p=0.008). 11C-PBR28 uptake in MS WM lesions was modestly increased vs HC (SUVR: 10%; VTR: 17%, p=0.06). Twenty-seven CL were identified in RRMS, 223 in SPMS with a ~21% (p=0.01) and a ~32% (p=0.007) increase in SUVR, respectively, relative to HC cortex. Microglia activation, relative to HC, was greater in SPMS than in RRMS in NAWM (p=0.004). Reduced cognitive function correlated with increased SUVR in NAWM (p=0.02) and CL (p=0.05). Worsening of EDSS was related to increased NAWM PBR uptake (p=0.04).
Conclusions: Distinct microglia-mediated events may underlie cortical and WM pathology. Quantification of microglia activation is a sensitive tool for evaluating in vivo the inflammatory component of cortical pathology at all disease stages.
Disclosure: This study was supported partly by the Clafin Award; partly by a grant from the National MS Society (NMSS) RG 4729A2/1, and partly by the Department of Defense (DoD) US Army W81XWH-13-1-0112 Award.
EH, GM, ML, CAT, STG, NW, JAS, RO, CC, JMH,TG: no disclosure
Dr Mainero has received research support from EMD Merck Serono and speaker fees from Biogen
Dr Giannì has received a fellowship from FISM 2012/B/4
Dr Louapre received a fellowship from ARSEP foundation
Dr Klawiter has received consulting fees from Biogen Idec and Mallinckrodt Pharmaceuticals and
research funding from Roche and Atlas5d
Dr. Kinkel reports personal fees from Genzyme ; A Sanofi Corp, personal fees from Biogen Idec,
grants from Acclerated Cure Project, personal fees from Novartis, outside the submitted work