. 2024 Jan 9;102(1):e207768.

doi: 10.1212/WNL.0000000000207768. Epub 2023 Dec 13.

Association of Spinal Cord Atrophy and Brain Paramagnetic Rim Lesions With Progression Independent of Relapse Activity in People With MS

Alessandro Cagol¹, Pascal Benkert¹, Lester Melie-Garcia¹, Sabine A Schaedelin¹, Selina Leber¹, Charidimos Tsagkas¹, Muhamed Barakovic¹, Riccardo Galbusera¹, Po-Jui Lu¹, Matthias Weigel¹, Esther Ruberte¹, Ernst-Wilhelm Radue¹, Özgür Yaldizli¹, Johanna Oechtering¹, Johannes Lorscheider¹, Marcus D'Souza¹, Bettina Fischer-Barnicol¹, Stefanie Müller¹, Lutz Achtnichts¹, Jochen Vehoff¹, Giulio Disanto¹, Oliver Findling¹, Andrew Chan¹, Anke Salmen¹, Caroline Pot¹, Claire Bridel¹, Chiara Zecca¹, Tobias Derfuss¹, Johanna M Lieb¹, Luca Remonda¹, Franca Wagner¹, Maria Isabel Vargas¹, Renaud A Du Pasquier¹, Patrice H Lalive¹, Emanuele Pravatà¹, Johannes Weber¹, Philippe C Cattin¹, Martina Absinta¹, Claudio Gobbi¹, David Leppert¹, Ludwig Kappos¹, Jens Kuhle¹, Cristina Granziera¹

Affiliations

Affiliation

¹ From Translational Imaging in Neurology (ThINk) Basel, Department of Biomedical Engineering, Faculty of Medicine (A. Cagol, L.M.-G., S.L., C.T., M.B., R.G., P.-J.L., M.W., E.R., E.-W.R., Ö.Y., L.K., C. Granziera), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB) (A. Cagol, L.M.-G., C.T., M.B., R.G., P.-J.L., M.W., E.R.,O.Y., J.O., J.L., M.D.S., B.F.-B., T.D., D.L., L.K., J.K., C. Granziera), Department of Clinical Research (P.B., S.A.S.), Division of Radiological Physics, Department of Radiology (M.W.), and Division of Diagnostic and Interventional Neuroradiology, Clinic for Radiology and Nuclear Medicine (J.M.L.), University Hospital Basel, University of Basel, Switzerland; Translational Neuroradiology Section (C.T), National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD; Medical Image Analysis Center (MIAC) and Quantitative Biomedical Imaging Group (qbig), Department of Biomedical Engineering (E.R., P.C.C.), University Basel; Departments of Neurology (S.M., J.V.) and Radiology (J.W.), Cantonal Hospital St. Gallen; Departments of Neurology (L.A., O.F.) and Radiology (L.R.), Cantonal Hospital Aarau; Departments of Neurology (G.D., C.Z., C.G.) and Neuroradiology (E.P.), Neurocenter of Southern Switzerland, Lugano; Departments of Neurology, Inselspital (A. Chan, A.S.), and Diagnostic and Interventional Neuroradiology, Inselspital (F.W.) Bern University Hospital and University of Bern; Departments of Clinical Neurosciences, Division of Neurology (C.P., R.A.D.P.), and Radiology (R.A.D.P.) Lausanne University Hospital and University of Lausanne; Department of Clinical Neurosciences, Division of Neurology (C.B., P.H.L.), and Radiology (M.I.V.) Geneva University Hospitals and Faculty of Medicine; Faculty of Biomedical Sciences (C.Z.), Università della Svizzera Italiana, Lugano, Switzerland; Institute of Experimental Neurology, Division of Neuroscience (M.A.); Vita-Salute San Raffaele University and Hospital, Milan, Italy.

PMID: 38165377
PMCID: PMC10834139
DOI: 10.1212/WNL.0000000000207768

Association of Spinal Cord Atrophy and Brain Paramagnetic Rim Lesions With Progression Independent of Relapse Activity in People With MS

Alessandro Cagol et al. Neurology. 2024.

. 2024 Jan 9;102(1):e207768.

doi: 10.1212/WNL.0000000000207768. Epub 2023 Dec 13.

Authors

Affiliation

¹ From Translational Imaging in Neurology (ThINk) Basel, Department of Biomedical Engineering, Faculty of Medicine (A. Cagol, L.M.-G., S.L., C.T., M.B., R.G., P.-J.L., M.W., E.R., E.-W.R., Ö.Y., L.K., C. Granziera), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB) (A. Cagol, L.M.-G., C.T., M.B., R.G., P.-J.L., M.W., E.R.,O.Y., J.O., J.L., M.D.S., B.F.-B., T.D., D.L., L.K., J.K., C. Granziera), Department of Clinical Research (P.B., S.A.S.), Division of Radiological Physics, Department of Radiology (M.W.), and Division of Diagnostic and Interventional Neuroradiology, Clinic for Radiology and Nuclear Medicine (J.M.L.), University Hospital Basel, University of Basel, Switzerland; Translational Neuroradiology Section (C.T), National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD; Medical Image Analysis Center (MIAC) and Quantitative Biomedical Imaging Group (qbig), Department of Biomedical Engineering (E.R., P.C.C.), University Basel; Departments of Neurology (S.M., J.V.) and Radiology (J.W.), Cantonal Hospital St. Gallen; Departments of Neurology (L.A., O.F.) and Radiology (L.R.), Cantonal Hospital Aarau; Departments of Neurology (G.D., C.Z., C.G.) and Neuroradiology (E.P.), Neurocenter of Southern Switzerland, Lugano; Departments of Neurology, Inselspital (A. Chan, A.S.), and Diagnostic and Interventional Neuroradiology, Inselspital (F.W.) Bern University Hospital and University of Bern; Departments of Clinical Neurosciences, Division of Neurology (C.P., R.A.D.P.), and Radiology (R.A.D.P.) Lausanne University Hospital and University of Lausanne; Department of Clinical Neurosciences, Division of Neurology (C.B., P.H.L.), and Radiology (M.I.V.) Geneva University Hospitals and Faculty of Medicine; Faculty of Biomedical Sciences (C.Z.), Università della Svizzera Italiana, Lugano, Switzerland; Institute of Experimental Neurology, Division of Neuroscience (M.A.); Vita-Salute San Raffaele University and Hospital, Milan, Italy.

PMID: 38165377
PMCID: PMC10834139
DOI: 10.1212/WNL.0000000000207768

Erratum in

Corrections to Received Date Information.
[No authors listed] [No authors listed] Neurology. 2024 Jul 9;103(1):e209596. doi: 10.1212/WNL.0000000000209596. Epub 2024 Jun 3. Neurology. 2024. PMID: 38830175 Free PMC article. No abstract available.

Abstract

Background and objectives: Progression independent of relapse activity (PIRA) is a crucial determinant of overall disability accumulation in multiple sclerosis (MS). Accelerated brain atrophy has been shown in patients experiencing PIRA. In this study, we assessed the relation between PIRA and neurodegenerative processes reflected by (1) longitudinal spinal cord atrophy and (2) brain paramagnetic rim lesions (PRLs). Besides, the same relationship was investigated in progressive MS (PMS). Last, we explored the value of cross-sectional brain and spinal cord volumetric measurements in predicting PIRA.

Methods: From an ongoing multicentric cohort study, we selected patients with MS with (1) availability of a susceptibility-based MRI scan and (2) regular clinical and conventional MRI follow-up in the 4 years before the susceptibility-based MRI. Comparisons in spinal cord atrophy rates (explored with linear mixed-effect models) and PRL count (explored with negative binomial regression models) were performed between: (1) relapsing-remitting (RRMS) and PMS phenotypes and (2) patients experiencing PIRA and patients without confirmed disability accumulation (CDA) during follow-up (both considering the entire cohort and the subgroup of patients with RRMS). Associations between baseline MRI volumetric measurements and time to PIRA were explored with multivariable Cox regression analyses.

Results: In total, 445 patients with MS (64.9% female; mean [SD] age at baseline 45.0 [11.4] years; 11.2% with PMS) were enrolled. Compared with patients with RRMS, those with PMS had accelerated cervical cord atrophy (mean difference in annual percentage volume change [MD-APC] -1.41; p = 0.004) and higher PRL load (incidence rate ratio [IRR] 1.93; p = 0.005). Increased spinal cord atrophy (MD-APC -1.39; p = 0.0008) and PRL burden (IRR 1.95; p = 0.0008) were measured in patients with PIRA compared with patients without CDA; such differences were also confirmed when restricting the analysis to patients with RRMS. Baseline volumetric measurements of the cervical cord, whole brain, and cerebral cortex significantly predicted time to PIRA (all p ≤ 0.002).

Discussion: Our results show that PIRA is associated with both increased spinal cord atrophy and PRL burden, and this association is evident also in patients with RRMS. These findings further point to the need to develop targeted treatment strategies for PIRA to prevent irreversible neuroaxonal loss and optimize long-term outcomes of patients with MS.

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Conflict of interest statement

A. Cagol, P. Benkert, L. Melie-Garcia, S.A. Schaedelin, S. Leber, C. Tsagkas, M. Barakovic, R. Galbusera, and P.-J. Lu have nothing to disclose. M. Weigel is partially funded by Biogen for the development of spinal cord MRI for patients with spinal muscular atrophy. E. Ruberte and E.-W. Radue have nothing to disclose. Ö. Yaldizli received grants from ECTRIMS/MAGNIMS, University of Basel, Pro Patient Stiftung University Hospital Basel, Free Academy Basel, Swiss Multiple Sclerosis Society and advisory board/lecture and consultancy fees from Roche, Sanofi Genzyme, Allmirall, Biogen and Novartis. J. Oechtering received research support by the Swiss MS Society and served on advisory boards for Roche and Merck. J. Lorscheider has received research support from Innosuisse-Swiss Innovation Agency, Biogen and Novartis, and speaking honoraria and/or fees for serving on advisory boards from Novartis, Roche and Teva. M. D'Souza has nothing to disclose in relationship to this work. B. Fisher-Barnicol has nothing to disclose. S. Müller received honoraria for travel, honoraria for lectures/consulting, and/or grants for studies from Almirall, Biogen, Celgene, Novartis, Teva, Merck Serono, Genzyme, Roche, and Bayer Schweiz. L. Achtnichts has nothing to disclose. J. Vehoff received honoraria for travel, honoraria for lectures/consulting and/or grants for studies from Allmiral, Biogen, Novartis, Teva, Merck-Serono, Genzyme, Roche and Bayer Schweiz AG, none related to this work. G. Disanto and O. Findling have nothing to disclose. A. Chan has served on advisory boards for, and received funding for travel or speaker honoraria from, Actelion-Janssen, Almirall, Bayer, Biogen, Celgene, Sanofi-Genzyme, Merck, Novartis, Roche, and Teva, all for hospital research funds; and research support from Biogen, Genzyme and UCB. A. Chan is associate editor of the European Journal of Neurology and serves on the editorial board for Clinical and Translational Neuroscience and as topic editor for the Journal of International Medical Research. A. Salmen received speaker honoraria for activities with Bristol Myers Squibb, CSL Behring, Novartis, and Roche, and research support by the Baasch Medicus Foundation, the Medical Faculty of the University of Bern and the Swiss MS Society. All not related to this work. C. Pot and C. Bridel have nothing to disclose. C. Zecca institution the Department of Neurology, Regional Hospital Lugano (EOC), Lugano, Switzerland receives financial support from Teva, Merck Serono, Biogen, Genzyme, Roche, Celgene, Bayer and Novartis. T. Derfuss received speaker fees, research support, travel support, and/or served on Advisory Boards or Steering Committees of Actelion, Alexion, Biogen, Celgene, GeNeuro, MedDay, Merck, Mitsubishi Pharma, Novartis, Roche and Sanofi-Genzyme; he received research support from Alexion, Biogen, Novartis, Roche, Swiss National Research Foundation, University of Basel, and Swiss MS Society. J.M. Lieb, L. Remonda, F. Wagner, M.I. Vargas, and R. Du Pasquier have nothing to disclose in relationship to this work. P.H. Lalive received honoraria for speaking and or travel expense from Biogen, Merck, Novartis, Roche; consulting fees from Biogen, GeNeuro, Merck, Novartis, Roche; research support from Biogen, Merck, Novartis. None were related to this work. E. Pravatà, J. Weber, and P.C. Cattin have nothing to disclose. M. Absinta is supported by the Conrad N. Hilton Foundation (17313), the Cariplo Foundation (2019-1677), the FRRB Early Career Award (1750327) and the International Progressive MS Alliance (PA-2107-38081); she received consultancy fees from GSK and Abata Therapeutics unrelated to this work. C. Gobbi institution the Department of Neurology, Regional Hospital Lugano (EOC), Lugano, Switzerland received financial support from Teva, Merck Serono, Biogen, Genzyme, Roche, Celgene, Bayer and Novartis. PHL received honoraria for speaking from Biogen-Idec, CSL Bering, Merck Serono, Novartis, Sanofi-Aventis, Teva; consulting fees from Biogen-Idec, Geneuro, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, Teva; research grants from Biogen-Idec, Merck Serono, Novartis. D. Leppert is Chief Medical Officer of GeNeuro. L. Kappos institution (University Hospital Basel) has received the following exclusively for research support: Steering committee, advisory board, and consultancy fees (Actelion, Bayer HealthCare, Biogen, BMS, Genzyme, Janssen, Merck, Novartis, Roche, Sanofi, Santhera, TG Therapeutics); speaker fees (Bayer HealthCare, Biogen, Merck, Novartis, Roche, and Sanofi); support of educational activities (Allergan, Bayer HealthCare, Biogen, CSL Behring, Desitin, Genzyme, Merck, Novartis, Roche, Pfizer, Sanofi, Shire, and Teva); license fees for Neurostatus products; and grants (Bayer HealthCare, Biogen, European Union, InnoSwiss, Merck, Novartis, Roche, Swiss MS Society, and Swiss National Research Foundation). J. Kuhle received speaker fees, research support, travel support, and/or served on advisory boards by Swiss MS Society, Swiss National Research Foundation (320030_189140/1), University of Basel, Progressive MS Alliance, Bayer, Biogen, Celgene, Merck, Novartis, Octave Bioscience, Roche, Sanofi. C. Granziera: The University Hospital Basel (USB), as the employer of C.G., has received the following fees which were used exclusively for research support: (1) advisory board and consultancy fees from Actelion, Genzyme-Sanofi, Novartis, GeNeuro and Roche; (2) speaker fees from Genzyme-Sanofi, Novartis, GeNeuro and Roche; (3) research support from Siemens, GeNeuro, Roche. Go to Neurology.org/N for full disclosures.

Figures

**Figure 1. Study Design**
Baseline scans were considered the MRI scans acquired ≤6 months from the beginning of clinical follow-up. 3D-EPI = 3-dimensional echo planar imaging; BPF = brain parenchymal fraction; CSA = cross-sectional area; PIRA = progression independent of relapse activity; PMS = progressive multiple sclerosis; RRMS = relapsing-remitting multiple sclerosis.

**Figure 2. Examples of PRLs in 2 Patients of the Cohort**
(A and C) Unwrapped-phase images and (B and D) quantitative susceptibility mapping images. PRLs are indicated by the arrows. PRL = paramagnetic rim lesion.

**Figure 3. Group Comparisons of Spinal Cord Atrophy Rates**
(A) Patients with PMS vs patients with RRMS, (B) patients experiencing PIRA during follow-up vs stable patients, and (C) patients experiencing PIRA during follow-up vs stable patients, considering exclusively patients with RRMS at baseline. The figures display predicted marginal effects from the multivariable mixed models. CSA = cross-sectional area; MD-APC = mean difference in annual C2-C3 cross-sectional area percentage change; PMS = progressive multiple sclerosis; PIRA = progression independent of relapse activity; RRMS = relapsing-remitting multiple sclerosis.

Figure 4. Survival Curves for Time to PIRA for Baseline Spinal Cord C2-C3 Cross sectional Area (A), Baseline Brain Parenchymal Fraction (B), Baseline Thalamic Fraction (C), and Baseline Cortical Fraction (D)
The curves display the longitudinal evolution in patients having baseline MRI measurements either higher (“upper half”) or lower (“lower half”) than the population average. Reported hazard ratio refers to the multivariable Cox regression models using baseline MRI measurements as continuous variables. BPF = brain parenchymal fraction; CSA = cross-sectional area; HR = hazard ratio; PIRA = progression independent of relapse activity.

**Figure 5. Group Comparisons of PRL Count**
(A) Patients with PMS vs patients with RRMS, (B) patients experiencing PIRA during follow-up vs stable patients, and (C) patients experiencing PIRA during follow-up vs stable patients, considering exclusively patients with RRMS at baseline. The reported p values were obtained with univariable negative binomial regression models. PIRA = progression independent of relapse activity; PMS = progressive multiple sclerosis; PRL = paramagnetic rim lesion; RRMS = relapsing-remitting multiple sclerosis.

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Association of Spinal Cord Atrophy and Brain Paramagnetic Rim Lesions With Progression Independent of Relapse Activity in People With MS

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Association of Spinal Cord Atrophy and Brain Paramagnetic Rim Lesions With Progression Independent of Relapse Activity in People With MS

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