BACKGROUND: Gray matter (GM) and white matter (WM) pathology has an important role in disease progression of multiple sclerosis (MS). OBJECTIVES: To investigate the association between the development of GM and WM pathology and clinical disease progression in patients with clinically isolated syndrome (CIS). METHODS: This prospective, observational, 48-month follow-up study examined 210 CIS patients treated with 30 µg of intramuscular interferon beta-1a once a week. MRI and clinical assessments were performed at baseline, 6, 12, 24, 36 and 48 months. Associations between clinical worsening [24-weeks sustained disability progression (SDP) and occurrence of a second clinical attack] and longitudinal changes in lesion accumulation and brain atrophy progression were investigated by a mixed-effect model analysis after correction for multiple comparisons. RESULTS: SDP was observed in 32 (15.2%) CIS patients, while 146 (69.5%) were stable and 32 (15.2%) showed sustained disability improvement. 112 CIS patients (53.3%) developed clinically definite MS (CDMS). CIS patients who developed SDP showed increased lateral ventricle volume (p < .001), and decreased GM (p = .011) and cortical (p = .001) volumes compared to patients who remained stable or improved in disability. Converters to CDMS showed an increased rate of accumulation of number of new/enlarging T2 lesions (p < .001), decreased whole brain (p = .007) and increased lateral ventricle (p = .025) volumes. CONCLUSIONS: Development of GM pathology and LVV enlargement are associated with SDP. Conversion to CDMS in patients with CIS over 48 months is dependent on the accumulation of new lesions, LVV enlargement and whole brain atrophy progression.

Buffalo Neuroimaging Analysis Center Department of Neurology School of Medicine and Biomedical Sciences University at Buffalo State University of New York Buffalo NY USA

Buffalo Neuroimaging Analysis Center Department of Neurology School of Medicine and Biomedical Sciences University at Buffalo State University of New York Buffalo NY USA ; IRCCS S Maria Nascente Don Gnocchi Foundation Milan Italy

Buffalo Neuroimaging Analysis Center Department of Neurology School of Medicine and Biomedical Sciences University at Buffalo State University of New York Buffalo NY USA ; MR Imaging Clinical Translational Research Center School of Medicine and Biomedical Sciences University at Buffalo State University of New York Buffalo NY USA

Department of Neurology and Center of Clinical Neuroscience Charles University Prague 1st Faculty of Medicine and General University Hospital Prague Czech Republic

Department of Neurology and Center of Clinical Neuroscience Charles University Prague 1st Faculty of Medicine and General University Hospital Prague Czech Republic ; Buffalo Neuroimaging Analysis Center Department of Neurology School of Medicine and Biomedical Sciences University at Buffalo State University of New York Buffalo NY USA

Department of Radiology 1st Faculty of Medicine and General University Hospital Charles University Prague Czech Republic

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Audoin B., Zaaraoui W., Reuter F., Rico A., Malikova I., Confort-Gouny S., Cozzone P.J., Pelletier J., Ranjeva J.P. Atrophy mainly affects the limbic system and the deep grey matter at the first stage of multiple sclerosis. Journal of Neurology, Neurosurgery, and Psychiatry. 2010;81:690–695. 20392976 PubMed

Bergsland N., Horakova D., Dwyer M.G., Dolezal O., Seidl Z.K., Vaneckova M., Krasensky J., Havrdova E., Zivadinov R. Subcortical and cortical gray matter atrophy in a large sample of patients with clinically isolated syndrome and early relapsing–remitting multiple sclerosis. AJNR. American Journal of Neuroradiology. 2012;33:1573–1578. 22499842 PubMed PMC

Calabrese M., Atzori M., Bernardi V., Morra A., Romualdi C., Rinaldi L., McAuliffe M.J., Barachino L., Perini P., Fischl B., Battistin L., Gallo P. Cortical atrophy is relevant in multiple sclerosis at clinical onset. Journal of Neurology. 2007;254:1212–1220. 17361339 PubMed

Calabrese M., Favaretto A., Poretto V., Romualdi C., Rinaldi F., Mattisi I., Morra A., Perini P., Gallo P. Low degree of cortical pathology is associated with benign course of multiple sclerosis. Multiple Sclerosis (Houndmills, Basingstoke, England) 2013;19:904–911. 23069877 PubMed

Calabrese M., Filippi M., Rovaris M., Bernardi V., Atzori M., Mattisi I., Favaretto A., Grossi P., Barachino L., Rinaldi L., Romualdi C., Perini P., Gallo P. Evidence for relative cortical sparing in benign multiple sclerosis: a longitudinal magnetic resonance imaging study. Multiple Sclerosis (Houndmills, Basingstoke, England) 2009;15:36–41. 18755823 PubMed

Calabrese M., Poretto V., Favaretto A., Alessio S., Bernardi V., Romualdi C., Rinaldi F., Perini P., Gallo P. Cortical lesion load associates with progression of disability in multiple sclerosis. Brain: A Journal of Neurology. 2012;135:2952–2961. 23065788 PubMed

Calabrese M., Rinaldi F., Mattisi I., Bernardi V., Favaretto A., Perini P., Gallo P. The predictive value of gray matter atrophy in clinically isolated syndromes. Neurology. 2011;77:257–263. 21613600 PubMed

Ceccarelli A., Rocca M.A., Pagani E., Colombo B., Martinelli V., Comi G., Filippi M. A voxel-based morphometry study of grey matter loss in MS patients with different clinical phenotypes. Neuroimage. 2008;42:315–322. 18501636 PubMed

Crespy L., Zaaraoui W., Lemaire M., Rico A., Faivre A., Reuter F., Malikova I., Confort-Gouny S., Cozzone P.J., Pelletier J., Ranjeva J.P., Audoin B. Prevalence of grey matter pathology in early multiple sclerosis assessed by magnetization transfer ratio imaging. PloS One. 2011;6:e24969. 21949813 PubMed PMC

Dalton C.M., Chard D.T., Davies G.R., Miszkiel K.A., Altmann D.R., Fernando K., Plant G.T., Thompson A.J., Miller D.H. Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes. Brain: A Journal of Neurology. 2004;127:1101–1107. 14998914 PubMed

De Stefano N., Stromillo M.L., Rossi F., Battaglini M., Giorgio A., Portaccio E., Hakiki B., Malentacchi G., Gasperini C., Santangelo M., Bartolozzi M.L., Sormani M.P., Federico A., Amato M.P. Improving the characterization of radiologically isolated syndrome suggestive of multiple sclerosis. PloS One. 2011;6:e19452. 21559385 PubMed PMC

Dwyer M.G., Bergsland N., Zivadinov R. Improved longitudinal gray and white matter atrophy assessment via application of a 4-dimensional hidden Markov random field model. Neuroimage. 2014;90:207–217. 24333394 PubMed

Dwyer M.G., Zivadinov R., Tao Y., Zhang X., Kennedy C., Bergsland N., Ramasamy D.P., Durfee J., Hojnacki D., Weinstock-Guttman B., Hayward B., Dangond F., Markovic-Plese S., Relapsing–remitting multiple sclerosis treated with interferon beta-1A: immunological and short-term brain volume changes (2014b) Poster DX02. In: CMSC ACTRIMS Cooperative Meeting, May 28–31, 2014 Dallas, TX

Fischer M.T., Wimmer I., Höftberger R., Gerlach S., Haider L., Zrzavy T., Hametner S., Mahad D., Binder C.J., Krumbholz M., Bauer J., Bradl M., Lassmann H. Disease-specific molecular events in cortical multiple sclerosis lesions. Brain: A Journal of Neurology. 2013;136:1799–1815. 23687122 PubMed PMC

Fisher E., Lee J.C., Nakamura K., Rudick R.A. Gray matter atrophy in multiple sclerosis: a longitudinal study. Annals of Neurology. 2008;64:255–265. 18661561 PubMed

Fox R.J., Fisher E., Tkach J., Lee J.C., Cohen J.A., Rudick R.A. Brain atrophy and magnetization transfer ratio following methylprednisolone in multiple sclerosis: short-term changes and long-term implications. Multiple Sclerosis (Houndmills, Basingstoke, England) 2005;11:140–145. 15794385 PubMed

Geurts J.J., Stys P.K., Minagar A., Amor S., Zivadinov R. Gray matter pathology in (chronic) MS: modern views on an early observation. Journal of the Neurological Sciences. 2009;282:12–20. 19249061 PubMed

Giorgio A., Stromillo M.L., Rossi F., Battaglini M., Hakiki B., Portaccio E., Federico A., Amato M.P., De Stefano N. Cortical lesions in radiologically isolated syndrome. Neurology. 2011;77:1896–1899. 22076541 PubMed

Hardmeier M., Wagenpfeil S., Freitag P., Fisher E., Rudick R.A., Kooijmans M., Clanet M., Radue E.W., Kappos L. Rate of brain atrophy in relapsing MS decreases during treatment with IFNbeta-1a. Neurology. 2005;64:236–240. 15668419 PubMed

Havrdova E., Galetta S., Stefoski D., Comi G. Freedom from disease activity in multiple sclerosis. Neurology. 2010;74(Suppl. 3):S3–S7. PubMed

Healy B.C., Engler D., Glanz B., Musallam A., Chitnis T. Assessment of definitions of sustained disease progression in relapsing–remitting multiple sclerosis. Multiple Sclerosis International. 2013;2013:189624. 23555057 PubMed PMC

Henry R.G., Shieh M., Okuda D.T., Evangelista A., Gorno-Tempini M.L., Pelletier D. Regional grey matter atrophy in clinically isolated syndromes at presentation. Journal of Neurology, Neurosurgery, and Psychiatry. 2008;79:1236–1244. 18469033 PubMed PMC

Horakova D., Cox J.L., Havrdova E., Hussein S., Dolezal O., Cookfair D., Dwyer M.G., Seidl Z., Bergsland N., Vaneckova M., Zivadinov R. Evolution of different MRI measures in patients with active relapsing–remitting multiple sclerosis over 2 and 5 years: a case–control study. Journal of Neurology, Neurosurgery, and Psychiatry. 2008;79:407–414. 17550987 PubMed

Horakova D., Kalincik T., Dusankova J.B., Dolezal O. Clinical correlates of grey matter pathology in multiple sclerosis. BMC Neurology. 2012;12:10. 22397707 PubMed PMC

Horakova D., Zivadinov R., Weinstock-Guttman B., Havrdova E., Qu J., Tamaño-Blanco M., Badgett D., Tyblova M., Bergsland N., Hussein S., Willis L., Krasensky J., Vaneckova M., Seidl Z., Lelkova P., Dwyer M.G., Zhang M., Yu H., Duan X., Kalincik T., Ramanathan M. Environmental factors associated with disease progression after the first demyelinating event: results from the multi-center SET study. PloS One. 2013;8:e53996. 23320113 PubMed PMC

Jacobs L.D., Beck R.W., Simon J.H., Kinkel R.P., Brownscheidle C.M., Murray T.J., Simonian N.A., Slasor P.J., Sandrock A.W. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. Champs Study Group. New England Journal of Medicine. 2000;343:898–904. 11006365 PubMed

Jacobsen C., Hagemeier J., Myhr K.M., Nyland H., Lode K., Bergsland N., Ramasamy D.P., Dalaker T.O., Larsen J.P., Farbu E., Zivadinov R. Brain atrophy and disability progression in multiple sclerosis patients: a 10-year follow-up study. Journal of Neurology, Neurosurgery, and Psychiatry. 2014;85:1109–1115. 24554101 PubMed

Jure L., Zaaraoui W., Rousseau C., Reuter F., Rico A., Malikova I., Confort-Gouny S., Cozzone P.J., Pelletier J., Ranjeva J.P., Audoin B. Individual voxel-based analysis of brain magnetization transfer maps shows great variability of gray matter injury in the first stage of multiple sclerosis. Journal of Magnetic Resonance Imaging: JMRI. 2010;32:424–428. 20677272 PubMed

Kalincik T., Guttmann C.R., Krasensky J., Vaneckova M., Lelkova P., Tyblova M., Seidl Z., De Jager P.L., Havrdova E., Horakova D. Multiple sclerosis susceptibility loci do not alter clinical and MRI outcomes in clinically isolated syndrome. Genes and Immunity. 2013;14:244–248. 23575354 PubMed

Kalincik T., Vaneckova M., Tyblova M., Krasensky J., Seidl Z., Havrdova E., Horakova D. Volumetric MRI markers and predictors of disease activity in early multiple sclerosis: a longitudinal cohort study. PloS One. 2012;7:e50101. 23166826 PubMed PMC

Magnano C., Schirda C., Weinstock-Guttman B., Wack D.S., Lindzen E., Hojnacki D., Bergsland N., Kennedy C., Belov P., Dwyer M.G., Poloni G.U., Beggs C.B., Zivadinov R. Cine cerebrospinal fluid imaging in multiple sclerosis. Journal of Magnetic Resonance Imaging: JMRI. 2012;36:825–834. 22733409 PubMed

Minagar A., Barnett M.H., Benedict R.H., Pelletier D., Pirko I., Sahraian M.A., Frohman E., Zivadinov R. The thalamus and multiple sclerosis: modern views on pathologic, imaging, and clinical aspects. Neurology. 2013;80:210–219. 23296131 PubMed PMC

Patenaude B., Smith S.M., Kennedy D.N., Jenkinson M. A Bayesian model of shape and appearance for subcortical brain segmentation. Neuroimage. 2011;56:907–922. 21352927 PubMed PMC

Pérez-Miralles F., Sastre-Garriga J., Tintoré M., Arrambide G., Nos C., Perkal H., Río J., Edo M.C., Horga A., Castilló J., Auger C., Huerga E., Rovira A., Montalban X. Clinical impact of early brain atrophy in clinically isolated syndromes. Multiple Sclerosis (Houndmills, Basingstoke, England) 2013;19:1878–1886. 23652215 PubMed

Polman C.H., Reingold S.C., Banwell B., Clanet M., Cohen J.A., Filippi M., Fujihara K., Havrdova E., Hutchinson M., Kappos L., Lublin F.D., Montalban X., O'Connor P., Sandberg-Wollheim M., Thompson A.J., Waubant E., Weinshenker B., Wolinsky J.S. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Annals of Neurology. 2011;69:292–302. 21387374 PubMed PMC

Polman C.H., Reingold S.C., Edan G., Filippi M., Hartung H.P., Kappos L., Lublin F.D., Metz L.M., McFarland H.F., O'Connor P.W., Sandberg-Wollheim M., Thompson A.J., Weinshenker B.G., Wolinsky J.S. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Annals of Neurology. 2005;58:840–846. 16283615 PubMed

Popescu B.F., Lucchinetti C.F. Meningeal and cortical grey matter pathology in multiple sclerosis. BMC Neurology. 2012;12:11. 22397318 PubMed PMC

Raz E., Cercignani M., Sbardella E., Totaro P., Pozzilli C., Bozzali M., Pantano P. Gray- and white-matter changes 1 year after first clinical episode of multiple sclerosis: MR imaging. Radiology. 2010;257:448–454. 20858849 PubMed

Rocca M.A., Agosta F., Sormani M.P., Fernando K., Tintorè M., Korteweg T., Tortorella P., Miller D.H., Thompson A., Rovira A., Montalban X., Polman C., Barkhof F., Filippi M. A three-year, multi-parametric MRI study in patients at presentation with CIS. Journal of Neurology. 2008;255:683–691. 18274802 PubMed

Roosendaal S.D., Bendfeldt K., Vrenken H., Polman C.H., Borgwardt S., Radue E.W., Kappos L., Pelletier D., Hauser S.L., Matthews P.M., Barkhof F., Geurts J.J. Grey matter volume in a large cohort of MS patients: relation to MRI parameters and disability. Multiple Sclerosis (Houndmills, Basingstoke, England) 2011;17:1098–1106. 21586487 PubMed

Smith S.M., De Stefano N., Jenkinson M., Matthews P.M. Normalized accurate measurement of longitudinal brain change. Journal of Computer Assisted Tomography. 2001;25:466–475. 11351200 PubMed

Vidal-Jordana A., Sastre-Garriga J., Pérez-Miralles F., Tur C., Tintoré M., Horga A., Auger C., Río J., Nos C., Edo M.C., Arévalo M.J., Castilló J., Rovira A., Montalban X. Early brain pseudoatrophy while on natalizumab therapy is due to white matter volume changes. Multiple Sclerosis (Houndmills, Basingstoke, England) 2013;19:1175–1181. 23319072 PubMed

Weinstock-Guttman B., Horakova D., Zivadinov R., Tamaño-Blanco M., Badgett D., Tyblova M., Vaneckova M., Seidl Z., Krasensky J., Bergsland N., Ramasamy D.P., Hagemeier J., Havrdova E., Ramanathan M. Interactions of serum cholesterol with anti-herpesvirus responses affect disease progression in clinically isolated syndromes. Journal of Neuroimmunology. 2013;263:121–127. 23916695 PubMed

Weinstock-Guttman B., Zivadinov R., Horakova D., Havrdova E., Qu J., Shyh G., Lakota E., O'Connor K., Badgett D., Tamaño-Blanco M., Tyblova M., Hussein S., Bergsland N., Willis L., Krasensky J., Vaneckova M., Seidl Z., Ramanathan M. Lipid profiles are associated with lesion formation over 24 months in interferon-beta treated patients following the first demyelinating event. Journal of Neurology, Neurosurgery, and Psychiatry. 2013;84:1186–1191. 23595944 PubMed

Zivadinov R., Bergsland N., Dolezal O., Hussein S., Seidl Z., Dwyer M.G., Vaneckova M., Krasensky J., Potts J.A., Kalincik T., Havrdova E., Horakova D. Evolution of cortical and thalamus atrophy and disability progression in early relapsing–remitting MS during 5 years. AMJR: American Journal of Neuroradiology. 2013;34:1931–1939. PubMed PMC

Zivadinov R., Havrdová E., Bergsland N., Tyblova M., Hagemeier J., Seidl Z., Dwyer M.G., Vaneckova M., Krasensky J., Carl E., Kalincik T., Horáková D. Thalamic atrophy is associated with development of clinically definite multiple sclerosis. Radiology. 2013;268:831–841. 23613615 PubMed

Zivadinov R., Pirko I. Advances in understanding gray matter pathology in multiple sclerosis: are we ready to redefine disease pathogenesis? BMC Neurology. 2012;12:9. 22394621 PubMed PMC

Zivadinov R., Reder A.T., Filippi M., Minagar A., Stüve O., Lassmann H., Racke M.K., Dwyer M.G., Frohman E.M., Khan O. Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis. Neurology. 2008;71:136–144. 18606968 PubMed

Peripheral blood lymphocytes immunophenotyping predicts disease activity in clinically isolated syndrome patients

Serum lipid profile changes predict neurodegeneration in interferon-β1a-treated multiple sclerosis patients

Longitudinal Mixed-Effect Model Analysis of the Association between Global and Tissue-Specific Brain Atrophy and Lesion Accumulation in Patients with Clinically Isolated Syndrome