MRI MARKERS TO UNDERSTAND PROGRESSION MECHANISMS

MRI MARKERS TO UNDERSTAND PROGRESSION MECHANISMS Maria A. Rocca Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.

Outline of presentation WM lesions: brain, spinal cord Atrophy WM damage: extent, topography GM damage: cortical lesions, diffuse and regional damage Spinal cord damage CNS reorganization (brain, spinal cord) Conclusions

Khaleeli et al., Mult Scler 2010 Tubridy et al., Neurology 1998 MRI & Progressive MS Brain WM lesions / Enhancement PPMS SPMS 45 PPMS with brain and spinal cord MRI for 5 years 15 (33%) had enhancing lesion at baseline 12 (26%) had enhancing lesion at 5 year 26 (58%) had 1 enhancing lesion during the study 19 (42%) had no enhancing lesion during the study 60 SPMS with monthly brain MRI for 4 months 32 (53%) had enhancing lesions at baseline 42 (70%) displayed one or more new enhancing lesions at follow-up 14 (23%) showed no enhancing lesions either at baseline or follow-up

Mesaros et al., J Neurol 2008 RRMS MRI & Progressive MS Brain WM lesions / Prognosis T2 lesions Similar slope of the relationship between baseline T2LV and EDSS in RRMS and SPMS Median yearly T2LV change: 0.27 ml in RRMS, and 0.30 ml in SPMS (p=0.59) 101 PPMS followed up for 10 yrs Khaleeli et al., Ann Neurol 2008 Sormani et al., Neurology 2009

Bodini et al., JNNP 2011 Ceccarelli et al., NeuroImage 2008 Di Perri et al., Arch Neurol 2008 MRI & Progressive MS Brain WM lesions / Distribution T2 lesion maps PPMS T1 lesion maps CIS RR SP PP PP vs RR: 29 vs 19% peak probability Higher T1 lesion occurrence in the CC, CST and other tracts adjacent to the lateral ventricles in SPMS vs RRMS Filli et al., MSJ 2012 T2 lesion location vs disability worsening

Spinal cord / T2 lesions Rovaris et al., Brain 2001 Controls 5.0 4.0 3.0 2.0 1.0 0.0 Number of cord lesions SPMS 6.0 5.0 4.0 3.0 2.0 1.0 0.0 PPMS Number of damaged cord segments 90.0 p = 0.03 Multiple hyperintense lesions in the spinal cord Rovaris et al., Brain 2001 60.0 30.0 0.0 Cord area [mm 2 ]

Ventricular volume change 21 CIS, 30 early relapse-onset, 41 RRMS, 23 SPMS MRI & Progressive MS Atrophy 1 y FU: 963 untreated MS patients p=0.001 p=0.001 n.s. p=0.003 p = 0.003 CIS MS RRMS SPMS (<1 year) Dalton et al., Neurology 2006 De Stefano et al., Neurology 2010

NWMV ** p<0.001 * p<0.01 MRI & Progressive MS Atrophy NGMV ** p<0.001 * p<0.01 GM atrophy rates: CIS RRMS and RRMS stable > HC (p=0.05) RRMS SPMS and SPMS > HC (p= 0.005) GM atrophy explains physical disability and cognitive impairment better than WM volume WM atrophy rates similar in all disease groups Fisher et al., Ann Neurol 2008 Roosendaal et al., MSJ 2011

FA MD MRI & Progressive MS NAWM damage RRMS BMS SPMS PPMS p=0.003 - p=0.004 p=0.01 Pulizzi et al., Arch Neurol 2007 CIS vs HC PPMS vs HC RRMS vs BMS SPMS vs RRMS SPMS vs PPMS 8 6 4 2 t value t value 5 4 3 2 1 t value t value Preziosa et al., Radiology 2011 Tortorella et al., Neurology 2000

GM damage / Cortical lesions Extensive subpial demyelination of the cerebellum in a PPMS case Focal demyelinated plaques in WM Cortical demyelination Demyelinated plaques in deep GM Kutzelnigg et al., Brain 2005

Calabrese et al., Neurology 2010 Geurts et al., Radiology 2005 Multi-slab 3D DIR MRI & PROGRESSIVE MS GM damage / Cortical lesions T2*-w / 7 T vs. SE = +538%; vs. FLAIR = +152% RRMS PPMS Cohen-Adad et al., NeuroImage 2011 DIR and disease evolution 48 PPMS patients followed up for 2 years Baseline CL volume: B: -0.525, p <0.001 Baseline T2-WM-LV: B: -0.448, p <0.001 Calabrese et al., Neurology 2009

GM damage / Cortical lesions Filippi et al., MSJ 2012 107 relapse-onset MS patients, 3-year FU Baseline CL volume: entire group: B=0.511; p<0.001 RRMS: B=0.512; p<0.001 SPMS: B=0.495; p<0.001 Calabrese et al., Ann Neurol 2010 334 relapse-onset MS patients, 5 years FU Age: OR 1.2, p =0.001 Baseline CL volume: OR 1.7, p <0.001 Baseline cerebellar cortical volume: OR 0.2, p <0.001 Calabrese et al., Ann Neurol 2013 Power to discriminate SPMS from BMS FA MD

Diffuse GM damage 241 relapse-onset MS patients followed up for 9 years Baseline GMF: OR 0.79 (CI 0.7 0.9) Baseline EDSS: OR 2.88 (CI 1.9 4.36) Lavorgna et al., MSJ 2013 73 relapse-onset MS patients followed up for 13 years Baseline GMF: OR 0.79, p=0.01 C index: 69% Cognitive deterioration at 13 year FU: Baseline average GM MTR (OR=0.87, p=0.03) Baseline disease duration (OR=1.50, p=0.08) C-index: 97% Filippi et al., Neurology 2013 Evolution to SPMS at 13 year FU: Baseline T2 LV (OR=1.13, p=0.005) Baseline GMF (OR=0.71, p=0.04) C-index: 84%

Regional GM damage Selective GM loss SPMS vs RRMS SPMS vs PPMS Ceccarelli et al., NeuroImage 2008

Rocca et al., Neurology 2011 CSAn MRI & Progressive MS Spinal cord / Atrophy C CSAn vs EDSS: r=-0.49, p<0.0001 EDSS Differential effect among disease clinical phenotypes (p<0.001): no association in CIS and BMS patients association in RRMS (r=-0.30), SPMS (r=-0.34) and PPMS patients (r=-0.27)

Rocca et al., JNNP 2013 PPMS vs HC MRI & Progressive MS Spinal cord damage BMS vs RRMS SPMS vs RRMS SPMS vs BMS SPMS vs PPMS P A L R P A L R P A L R P A L R P A L R CIS RRMS BMS PPMS SPMS T2 lesion probability

Spinal cord / Diffuse damage Normalized pixel count Average MD [x10-3 mm 2 s -1 ] (SD) Mean FA (SD) Controls 1.203 (0.09) 0.42 (0.04) PPMS 1.280 (0.10) 0.38 (0.05) p 0.024 0.007 70 60 50 40 30 20 10 0 Controls SPMS PPMS 0 10 20 30 40 50 60 70 80 MTR [%] Agosta et al., Neurology 2005 Composite MR model vs EDSS: Cord area + cord MTR peak height (r=0.21, p=0.04) Rovaris et al., Brain 2001

Spinal cord damage Crosssectional area RRMS SPMS PPMS Overall MD FA -10% -5% 0 +5% +10% +15% +20% UCCA, T1LV, diffuse abnormalities and number of involved segments were significant explanatory factors for clinical disability (R 2 = 0.564) Lukas et al., Radiology 2013 Baseline cross-sectional area and FA vs EDSS at follow-up: r = -0.40; p = 0.01 Agosta et al., Brain 2007

CNS reorganization / Brain CIS vs non-disabled RRMS SMC Mildly disabled RRMS vs SPMS SII SPMS vs mildly disabled RRMS Precuneus, IPL, MFG Non-disabled vs mildly disabled RRMS Precuneus, CMA, MFG SMC, SMA Thalamus MFG, IPL Rocca et al., Lancet Neurol 2005

CNS reorganization / Brain PPMS SPMS (reduced activations) STG L SMA BMS MFG L putamen Insula R cerebellum L SMC vs T2 lesion volume: r = 0.63, p < 0.001 Rocca et al., Neurology 2010 Filippi et al., NeuroImage 2002 Rocca et al., Neurology 2010

Rocca et al., Neurology 2010 MRI & Progressive MS CNS reorganization / Brain DMN fluctuations in progressive MS patients HC PPMS SPMS Correlations between DMN fluctuations and: PASAT (r=0.42, p<0.001) CC FA and JD (r ranging from 0.54 to 0.87, p<0.001) Cingulum FA (r=0.83, p<0.001)

CNS reorganization / Brain HC CP CI L SFG ACC ACC MCC Thal Precun MTG Put Cereb ITG (cr I) Cereb (cr II) Caud MCC Thal MTG OFC Cereb Sup TP ITG (cr I) Cereb (cr II) Sup TP MCC R ACC OFC Ling ACC ITG MTG Cereb (cr I) OFC Cereb (IV-V) Cereb (cr II) MCC MTG Cereb ITG (cr I) Cereb (cr II) MCC Thal ACC MTG Pall OFC ITG Cereb (cr I) Cereb (VIII) Put MCC ITG MTG Cereb (cr I) HCs RRMS BMS SPMS L SFG MCC Precun Put Thal ACC MTG Cer-crus-I ITG MCC Cer-crus-II MTG ACC Cer-crus-I SupTP ITG Cer-crus-II BMS MCC Thal MTG Cer-lobule-IV-V SupTP Cer-crus-I ITG Cer- Cer-lobule-VIII crus-ii Thal MTG SupTP Ling Cer-lobule-IV-V PHG ITG Cer-crus-I Cer-crus-II R ACC OFC ACC OFC MCC ITG MCC Put Pall MCC MTG Cer-crus-I Cer-crus-II MTG ITG Cer-crus-I ACC Thal MTG Ling Pall OFC Cer-crus-I ITG Cer-crus-II Cer-lobule-VIII ACC Put Thal MTG OFC Ling Pall ITG Cer- PHG crus-i Cerlobule-VI

Task-related average signal change [%] Cord average signal change (%) MRI & Progressive MS CNS reorganization / Spinal cord Controls SPMS PPMS Tactile stimulation of the palm of the R hand 5.0 4.5 4.0 3.5 2.7 % 0.7 % p=0.05 vs controls 3. 3 % 1.1 % p=0.02 vs controls 3.9 % 1.3 % Progressive MS vs controls: p=0.003 SPMS vs PPMS: p=0.05 Valsasina et al., Hum Brain Mapp 2011 3.0 2.5 Cord fmri vs fatigue 2.0 1.5 1.0 0.5 0.0 Controls RRMS SPMS Valsasina et al., JNNP 2010 Rocca et al., Mult Scler 2012

Outline of presentation T2 lesions: brain, spinal cord Atrophy WM damage: extent, topography GM damage: cortical lesions, diffuse and regional damage Spinal cord damage CNS reorganization (brain, spinal cord) Conclusions

Conclusions Modality Potential clinical value Feasibility Gd+ lesions Focal lesions Whole-brain atrophy NAWM damage GM damage Spinal cord damage Functional changes - + ++ ++ +++ +++ ++ +++ +++ +++ ++ ++ ++ +

Severity MRI in SPMS Theoretical background T2 lesions Functional changes Atrophy NAWM damage GM damage Cord damage Gd+ lesions RIS CIS RRMS SPMS/PPMS Time

DIVISION OF NEUROSCIENCE INSTITUTE OF EXPERIMENTAL NEUROLOGY Neuroimaging Research Unit & WM diseases group Director: M. Filippi Scientific coordinator: M.A. Rocca Department of Neurology G. Comi, B. Colombo, M. Comola, F. Esposito, V. Martinelli, F. Martinelli Boneschi, L. Moiola, G. Pavan, M. Rodegher Physicians: M. Absinta A. Bisecco G. Boffa S. Cirillo E. De Meo G. Longoni F. Mele R. Messina M.E. Morelli L. Parisi P. Preziosa G. Riccitelli Department of Neuroradiology A. Falini Gallarate Hospital, MS Centre A. Ghezzi Physicists: Technicians: MAGNIMS M. Copetti E. Pagani P. Valsasina L. Dall Occhio A. Meani P. Misci M. Petrolini S. Sala M. Sibilia R. Vuotto University of Belgrade V.S. Kostic, J. Drulovic, S. Mesaros