Review article: Biomedical intelligence
Vol. 143 No. 4748 (2013)
Brain atrophy: an in-vivomeasure of disease activity in multiple sclerosis
- Ernst Wilhelm Radü
- K. Bendfeldt
- Nicole Mueller-Lenke
- Stefano Magon
- T. Sprenger
Summary
Multiple sclerosis (MS) has traditionally been considered to be primarily an inflammatory demyelinating disorder. Nowadays it is recognised as both an inflammatory and a neurodegenerative condition. This recognition is reflected in the development of new disease-modifying therapies that may offer the potential to reduce axon damage, either by inhibiting neurodegeneration or by promoting endogenous repair mechanisms. Since there is only a limited correlation between the clinical features of MS and findings on conventional magnetic resonance imaging (MRI), for the evaluation of such therapies new outcome measures are warranted. Grey matter atrophy occurs in the earliest stages of MS, progresses faster than in healthy individuals, and shows significant correlations with MRI lesion load, cognitive function and measures of physical disability; indeed, brain atrophy is the best predictor of subsequent disability and can be readily measured using MRI. Furthermore, it is becoming clear that currently available therapies differ in their effects on brain atrophy, and this may have important implications for the management of MS. New MRI techniques and advances in software development offer an opportunity to extend brain atrophy measurements beyond research studies to the routine management of MS patients.
References
- Murray TJ. The history of multiple sclerosis: the changing frame of the disease over the centuries. J Neurol Sci. 2009;277(Suppl 1):S3–8.
- Trapp BD, Nave KA. Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci. 2008;31:247–69.
- Barkhof F, Calabresi PA, Miller DH, Reingold SC. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol. 2009;5(5):256–66.
- Compston A, Coles A. Multiple sclerosis. Lancet. 2002;359(9313):1221–31.
- Tourdias T, Dousset V. Neuroinflammatory Imaging Biomarkers: Relevance to Multiple Sclerosis and its Therapy. Neurotherapeutics: the journal of the American Society for Experimental NeuroTherapeutics. 2012.
- Inglese M, Petracca M. Imaging multiple sclerosis and other neurodegenerative diseases. Prion. 2012;7(1).
- Barkhof F. The clinico-radiological paradox in multiple sclerosis revisited. Curr Opin Neurol. 2002;15(3):239–45.
- Horakova D, Dwyer MG, Havrdova E, Cox JL, Dolezal O, Bergsland N, et al. Gray matter atrophy and disability progression in patients with early relapsing-remitting multiple sclerosis: a 5-year longitudinal study. Journal of the neurological sciences. 2009;282(1-2):112–9.
- Kolasinski J, Stagg CJ, Chance SA, Deluca GC, Esiri MM, Chang EH, et al. A combined post-mortem magnetic resonance imaging and quantitative histological study of multiple sclerosis pathology. Brain. 2012;135(Pt 10):2938–51.
- Zivadinov R, Bakshi R. Central nervous system atrophy and clinical status in multiple sclerosis. J Neuroimaging. 2004;14(3 Suppl):27S–35S.
- van den Elskamp I, Boden B, Dattola V, Knol D, Filippi M, Kappos L, et al. Cerebral atrophy as outcome measure in short-term phase 2 clinical trials in multiple sclerosis. Neuroradiology. 2010;52(10):875–81.
- Kappos L, Radue EW, O'Connor P, Polman C, Hohlfeld R, Calabresi P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387–401.
- Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402–15.
- Vrenken H, Jenkinson M, Horsfield MA, Battaglini M, Schijndel RA, Rostrup E, et al. Recommendations to improve imaging and analysis of brain lesion load and atrophy in longitudinal studies of multiple sclerosis. J Neurol. 2012:1–14.
- Bermel RA, Bakshi R. The measurement and clinical relevance of brain atrophy in multiple sclerosis. Lancet Neurol. 2006;5(2):158–70.
- Dorr J, Wernecke KD, Bock M, Gaede G, Wuerfel JT, Pfueller CF, et al. Association of retinal and macular damage with brain atrophy in multiple sclerosis. PLoS One. 2011;6(4):e18132.
- Rocca MA, Valsasina P, Damjanovic D, Horsfield MA, Mesaros S, Stosic-Opincal T, et al. Voxel-wise mapping of cervical cord damage in multiple sclerosis patients with different clinical phenotypes. J Neurol Neurosurg Psychiatry. 2013;84(1):35–41.
- Derakhshan M, Caramanos Z, Giacomini PS, Narayanan S, Maranzano J, Francis SJ, et al. Evaluation of automated techniques for the quantification of grey matter atrophy in patients with multiple sclerosis. NeuroImage. 2010;52(4):1261–7.
- Simon JH, Jacobs LD, Campion MK, Rudick RA, Cookfair DL, Herndon RM, et al. A longitudinal study of brain atrophy in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Neurology. 1999;53(1):139–48.
- Vrenken H, Vos EK, van der Flier WM, Sluimer IC, Cover KS, Knol DL, et al. Validation of the automated method VIENA: An accurate, precise, and robust measure of ventricular enlargement. Human Brain Mapping. 2013.
- Rudick RA, Fisher E, Lee JC, Simon J, Jacobs L. Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Neurology. 1999;53(8):1698–704.
- Smith SM, Zhang Y, Jenkinson M, Chen J, Matthews PM, Federico A, et al. Accurate, Robust, and Automated Longitudinal and Cross-Sectional Brain Change Analysis. NeuroImage. 2002;17(1):479–89.
- Simon JH. Brain atrophy in multiple sclerosis: what we know and would like to know. Multiple Sclerosis. 2006;12(6):679–87.
- Ziehn MO, Avedisian AA, Dervin SM, Umeda EA, O’Dell TJ, Voskuhl RR. Therapeutic testosterone administration preserves excitatory synaptic transmission in the hippocampus during autoimmune demyelinating disease. J Neurosci. 2012;32(36):12312–24.
- Zimmermann H, Freing A, Kaufhold F, Gaede G, Bohn E, Bock M, et al. Optic neuritis interferes with optical coherence tomography and magnetic resonance imaging correlations. Multiple Sclerosis. 2013;19(4):443–50.
- Sun SW, Thiel T, Liang HF. Impact of repeated topical-loaded manganese-enhanced MRI on the mouse visual system. Invest Ophthalmol Vis Sci. 2012;53(8):4699–709.
- Henry RG, Shieh M, Okuda DT, Evangelista A, Gorno-Tempini ML, Pelletier D. Regional grey matter atrophy in clinically isolated syndromes at presentation. Journal of Neurology, Neurosurgery & Psychiatry. 2008;79(11):1236–44.
- Chard DT, Griffin CM, Parker GJ, Kapoor R, Thompson AJ, Miller DH. Brain atrophy in clinically early relapsing-remitting multiple sclerosis. Brain: a journal of neurology. 2002;125(Pt 2):327–37.
- Raz E, Cercignani M, Sbardella E, Totaro P, Pozzilli C, Bozzali M, et al. Gray- and White-Matter Changes 1 Year after First Clinical Episode of Multiple Sclerosis: MR Imaging. Radiology. 2010;257(2):448–54.
- Audoin B, Davies G, Rashid W, Fisniku L, Thompson AJ, Miller DH. Voxel-based analysis of grey matter magnetization transfer ratio maps in early relapsing remitting multiple sclerosis. Multiple sclerosis. 2007;13(4):483–9.
- Chard D, Miller D. Grey matter pathology in clinically early multiple sclerosis: evidence from magnetic resonance imaging. J Neurol Sci. 2009;282(1-2):5–11.
- Dalton CM, Chard DT, Davies GR, Miszkiel KA, Altmann DR, Fernando K, et al. Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes. Brain. 2004;127(5):1101–7.
- Tedeschi G, Lavorgna L, Russo P, Prinster A, Dinacci D, Savettieri G, et al. Brain atrophy and lesion load in a large population of patients with multiple sclerosis. Neurology. 2005;65(2):280–5.
- De Stefano N, Giorgio A, Battaglini M, Rovaris M, Sormani MP, Barkhof F, et al. Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes. Neurology. 2010;74(23):1868–76.
- Ge Y, Grossman RI, Udupa JK, Wei L, Mannon LJ, Polansky M, et al. Brain atrophy in relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis: longitudinal quantitative analysis. Radiology. 2000;214(3):665–70.
- Furby J, Hayton T, Altmann D, Brenner R, Chataway J, Smith K, et al. A longitudinal study of MRI-detected atrophy in secondary progressive multiple sclerosis. J Neurol. 2010;257(9):1508–16.
- Calabrese M, Agosta F, Rinaldi F, Mattisi I, Grossi P, Favaretto A, et al. Cortical lesions and atrophy associated with cognitive impairment in relapsing-remitting multiple sclerosis. Arch Neurol. 2009;66(9):1144–50.
- Ceccarelli A, Rocca M, Valsasina P, Rodegher M, Pagani E, Falini A, et al. A multiparametric evaluation of regional brain damage in patients with primary progressive multiple sclerosis. Human Brain Mapp. 2009;30(9):3009–19.
- Sepulcre J, Sastre-Garriga J, Cercignani M, Ingle GT, Miller DH, Thompson AJ. Regional gray matter atrophy in early primary progressive multiple sclerosis: a voxel-based morphometry study. Archives of neurology. 2006;63(8):1175–80.
- Fisher E, Lee JC, Nakamura K, Rudick RA. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol. 2008;64(3):255–65.
- Fotenos AF, Mintun MA, Snyder AZ, Morris JC, Buckner RL. Brain volume decline in aging: evidence for a relation between socioeconomic status, preclinical Alzheimer disease, and reserve. Arch Neurol. 2008;65(1):113–20.
- Vigeveno RM, Wiebenga OT, Wattjes MP, Geurts JJ, Barkhof F. Shifting imaging targets in multiple sclerosis: from inflammation to neurodegeneration. J Magn Reson Imaging. 2012;36(1):1–19.
- Fernandez O, Alvarez-Cermeno JC, Arroyo-Gonzalez R, Brieva L, Calles-Hernandez MC, Casanova-Estruch B, et al. Review of the novelties presented at the 27th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (I). Revista de neurologia. 2012;54(11):677–91.
- Zivadinov R, Weinstock-Guttman B, Hashmi K, Abdelrahman N, Stosic M, Dwyer M, et al. Smoking is associated with increased lesion volumes and brain atrophy in multiple sclerosis. Neurology. 2009;73(7):504–10.
- Simon JH, Jacobs LD, Campion MK, Rudick RA, Cookfair DL, Herndon RM, et al. A longitudinal study of brain atrophy in relapsing multiple sclerosis. Neurology. 1999;53(1):139–48.
- McNeill A. PLA2G6 mutations and other rare causes of neurodegeneration with brain iron accumulation. Curr Drug Targets. 2012;13(9):1204–6.
- Simon JH. From enhancing lesions to brain atrophy in relapsing MS. J Neuroimmunol. 1999;98(1):7–15.
- Chard DT, Griffin CM, Parker GJM, Kapoor R, Thompson AJ, Miller DH. Brain atrophy in clinically early relapsing-remitting multiple sclerosis. Brain. 2002;125(2):327–37.
- Chard DT, Griffin CM, Rashid W, Davies GR, Altmann DR, Kapoor R, et al. Progressive grey matter atrophy in clinically early relapsing-remitting multiple sclerosis. Multiple Sclerosis. 2004;10(4):387–91.
- Calabrese M, Rinaldi F, Mattisi I, Bernardi V, Favaretto A, Perini P, et al. The predictive value of gray matter atrophy in clinically isolated syndromes. Neurology. 2011;77(3):257–63.
- Jenkins TM, Ciccarelli O, Atzori M, Wheeler-Kingshott CAM, Miller DH, Thompson AJ, et al. Early pericalcarine atrophy in acute optic neuritis is associated with conversion to multiple sclerosis. Journal of Neurology, Neurosurgery & Psychiatry. 2011;82(9):1017–21.
- Amato MP, Bartolozzi ML, Zipoli V, Portaccio E, Mortilla M, Guidi L, et al. Neocortical volume decrease in relapsing-remitting MS patients with mild cognitive impairment. Neurology. 2004;63(1):89–93.
- De Stefano N, Matthews PM, Filippi M, Agosta F, De Luca M, Bartolozzi ML, et al. Evidence of early cortical atrophy in MS: Relevance to white matter changes and disability. Neurology. 2003;60(7):1157–62.
- Ge Y, Grossman RI, Udupa JK, Babb JS, Nyul LG, Kolson DL. Brain Atrophy in Relapsing-Remitting Multiple Sclerosis: Fractional Volumetric Analysis of Gray Matter and White Matter. Radiology. 2001;220(3):606–10.
- Quarantelli M, Ciarmiello A, Morra VB, Orefice G, Larobina M, Lanzillo R, et al. Brain tissue volume changes in relapsing-remitting multiple sclerosis: correlation with lesion load. NeuroImage. 2003;18(2):360–6.
- Sailer M, Fischl B, Salat D, Tempelmann C, Schonfeld MA, Busa E, et al. Focal thinning of the cerebral cortex in multiple sclerosis. Brain. 2003;126(8):1734–44.
- Sanfilipo MP, Benedict RHB, Sharma J, Weinstock-Guttman B, Bakshi R. The relationship between whole brain volume and disability in multiple sclerosis: A comparison of normalized gray vs. white matter with misclassification correction. NeuroImage. 2005;26(4):1068–77.
- Sanfilipo MP, Benedict RHB, Weinstock-Guttman B, Bakshi R. Gray and white matter brain atrophy and neuropsychological impairment in multiple sclerosis. Neurology. 2006;66(5):685–92.
- Tiberio M, Chard DT, Altmann DR, Davies G, Griffin CM, Rashid W, et al. Gray and white matter volume changes in early RRMS: A 2-year longitudinal study. Neurology. 2005;64(6):1001–7.
- Audoin B, Davies GR, Finisku L, Chard DT, Thompson AJ, Miller DH. Localization of grey matter atrophy in early RRMS. J Neurol. 2006;253(11):1495–501.
- Horakova D, Dwyer MG, Havrdova E, Cox JL, Dolezal O, Bergsland N, et al. Gray matter atrophy and disability progression in patients with early relapsing-remitting multiple sclerosis: A 5-year longitudinal study. J Neurol Sci. 2009;282(1-2):112–9.
- Calabrese M, Atzori M, Bernardi V, Morra A, Romualdi C, Rinaldi L, et al. Cortical atrophy is relevant in multiple sclerosis at clinical onset. J Neurol. 2007;254(9):1212–20.
- Bodini B, Khaleeli Z, Cercignani M, H. Miller D, Thompson AJ, Ciccarelli O. Exploring the relationship between white matter and gray matter damage in early primary progressive multiple sclerosis: An in vivo study with TBSS and VBM. Human Brain Mapp. 2009;30(9):2852–61.
- Ceccarelli A, Rocca MA, Pagani E, Colombo B, Martinelli V, Comi G, et al. A voxel-based morphometry study of grey matter loss in MS patients with different clinical phenotypes. NeuroImage. 2008;42(1):315–22.
- Peterson JW, Bö L, Mörk S, Chang A, Trapp BD. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol. 2001;50(3):389–400.
- Brück W. Inflammatory demyelination is not central to the pathogenesis of multiple sclerosis. J Neurol. 2005;252(0):v10–v5.
- Oreja-Guevara C, Noval S, Alvarez-Linera J, Gabaldon L, Manzano B, Chamorro B, et al. Clinically isolated syndromes suggestive of multiple sclerosis: an optical coherence tomography study. PLoS One. 2012;7(3):e33907.
- Lucchinetti CF, Popescu BF, Bunyan RF, Moll NM, Roemer SF, Lassmann H, et al. Inflammatory cortical demyelination in early multiple sclerosis. N Engl J Med. 2011;365(23):2188–97.
- Charil A, Dagher A, Lerch JP, Zijdenbos AP, Worsley KJ, Evans AC. Focal cortical atrophy in multiple sclerosis: relation to lesion load and disability. NeuroImage. 2007;34(2):509–17.
- Salat DH, Buckner RL, Snyder AZ, Greve DN, Desikan RS, Busa E, et al. Thinning of the cerebral cortex in aging. Cerebral Cortex. 2004;14(7):721–30.
- Prinster A, Quarantelli M, Orefice G, Lanzillo R, Brunetti A, Mollica C, et al. Grey matter loss in relapsing-remitting multiple sclerosis: a voxel-based morphometry study. NeuroImage. 2006;29(3):859–67.
- Audoin B, Davies GR, Finisku L, Chard DT, Thompson AJ, Miller DH. Localization of grey matter atrophy in early RRMS : A longitudinal study. J Neurol. 2006;253(11):1495–501.
- Cifelli A, Arridge M, Jezzard P, Esiri MM, Palace J, Matthews PM. Thalamic neurodegeneration in multiple sclerosis. Ann Neurol. 2002;52(5):650–3.
- Wylezinska M, Cifelli A, Jezzard P, Palace J, Alecci M, Matthews PM. Thalamic neurodegeneration in relapsing-remitting multiple sclerosis. Neurology. 2003;60(12):1949–54.
- Henry RG, Shieh M, Amirbekian B, Chung S, Okuda DT, Pelletier D. Connecting white matter injury and thalamic atrophy in clinically isolated syndromes. J Neurol Sci. 2009;282(1-2):61–6.
- Simon JH, Kinkel RP, Jacobs L, Bub L, Simonian N. A Wallerian degeneration pattern in patients at risk for MS. Neurology. 2000;54(5):1155–60.
- Pagani E, Rocca MA, Gallo A, Rovaris M, Martinelli V, Comi G, et al. Regional brain atrophy evolves differently in patients with multiple sclerosis according to clinical phenotype. AJNR Am J Neuroradiol. 2005;26(2):341–6.
- Ceccarelli A, Rocca MA, Pagani E, Colombo B, Martinelli V, Comi G, et al. A voxel-based morphometry study of grey matter loss in MS patients with different clinical phenotypes. Neuroimage. 2008;42(1):315–22.
- Morgen K, Sammer G, Courtney SM, Wolters T, Melchior H, Blecker CR, et al. Evidence for a direct association between cortical atrophy and cognitive impairment in relapsing-remitting MS. NeuroImage. 2006;30(3):891–8.
- Prinster A, Quarantelli M, Orefice G, Lanzillo R, Brunetti A, Mollica C, et al. Grey matter loss in relapsing-remitting multiple sclerosis: A voxel-based morphometry study. NeuroImage. 2006;29(3):859–67.
- Charil A, Dagher A, Lerch JP, Zijdenbos AP, Worsley KJ, Evans AC. Focal cortical atrophy in multiple sclerosis: Relation to lesion load and disability. NeuroImage. 2007;34(2):509–17.
- Sepulcre J, Goni J, Masdeu JC, Bejarano B, Velez de Mendizabal N, Toledo JB, et al. Contribution of white matter lesions to gray matter atrophy in multiple sclerosis: evidence from voxel-based analysis of T1 lesions in the visual pathway. Arch Neurol. 2009;66(2):173–9.
- Bodini B, Khaleeli Z, Cercignani M, Miller DH, Thompson AJ, Ciccarelli O. Exploring the relationship between white matter and gray matter damage in early primary progressive multiple sclerosis: an in vivo study with TBSS and VBM. Human Brain Mapp. 2009;30(9):2852–61.
- Sepulcre J, Sastre-Garriga J, Cercignani M, Ingle GT, Miller DH, Thompson AJ. Regional Gray Matter Atrophy in Early Primary Progressive Multiple Sclerosis: A Voxel-Based Morphometry Study. Arch Neurol. 2006;63(8):1175–80.
- Pagani E, Rocca MA, Gallo A, Rovaris M, Martinelli V, Comi G, et al. Regional Brain Atrophy Evolves Differently in Patients with Multiple Sclerosis According to Clinical Phenotype. AJNR Am J Neuroradiol. 2005;26(2):341–6.
- Battaglini M, Giorgio A, Stromillo ML, Bartolozzi ML, Guidi L, Federico A, et al. Voxel-wise assessment of progression of regional brain atrophy in relapsing-remitting multiple sclerosis. J Neurol Sci. 2009;282(1-2):55–60.
- Bendfeldt K, Kuster P, Traud S, Egger H, Winklhofer S, Mueller-Lenke N, et al. Association of regional gray matter volume loss and progression of white matter lesions in multiple sclerosis – A longitudinal voxel-based morphometry study. NeuroImage. 2009;45(1):60–7.
- Bendfeldt K, Blumhagen JO, Egger H, Loetscher P, Denier N, Kuster P, et al. Spatiotemporal distribution pattern of white matter lesion volumes and their association with regional grey matter volume reductions in relapsing-remitting multiple sclerosis. Human brain mapping. 2010;31(10):1542–55.
- Evangelou N, Konz D, Esiri MM, Smith S, Palace J, Matthews PM. Regional axonal loss in the corpus callosum correlates with cerebral white matter lesion volume and distribution in multiple sclerosis. Brain. 2000;123(9):1845–9.
- Ramasamy DP, Benedict RH, Cox JL, Fritz D, Abdelrahman N, Hussein S, et al. Extent of cerebellum, subcortical and cortical atrophy in patients with MS: a case-control study. J Neurol Sci. 2009;282(1-2):47–54.
- Rudick RA, Lee J-C, Nakamura K, Fisher E. Gray matter atrophy correlates with MS disability progression measured with MSFC but not EDSS. J Neurol Sci. 2009;282(1-2):106–11.
- Yaldizli O, Atefy R, Gass A, Sturm D, Glassl S, Tettenborn B, et al. Corpus callosum index and long-term disability in multiple sclerosis patients. J Neurol. 2010;257(8):1256–64.
- Di Filippo M, Anderson VM, Altmann DR, Swanton JK, Plant GT, Thompson AJ, et al. Brain atrophy and lesion load measures over 1 year relate to clinical status after 6 years in patients with clinically isolated syndromes. J Neurol Neurosurg Psychiatry. 2010;81(2):204–8.
- Tedeschi G, Dinacci D, Lavorgna L, Prinster A, Savettieri G, Quattrone A, et al. Correlation between fatigue and brain atrophy and lesion load in multiple sclerosis patients independent of disability. J Neurol Sci. 2007;263(1-2):15–9.
- Penner I, Calabrese P. Managing fatigue: clinical correlates, assessment procedures and therapeutic strategies. Int MS J. 2010;17(1):28–34.
- Andreasen AK, Jakobsen J, Soerensen L, Andersen H, Petersen T, Bjarkam CR, et al. Regional brain atrophy in primary fatigued patients with multiple sclerosis. NeuroImage. 2010;50(2):608–15.
- Rao SM, Leo GJ, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology. 1991;41(5):685–91.
- Amato MP, Ponziani G, Siracusa G, Sorbi S. Cognitive dysfunction in early-onset multiple sclerosis: a reappraisal after 10 years. Arch Neurol. 2001;58(10):1602–6.
- Glanz BI, Holland CM, Gauthier SA, Amunwa EL, Liptak Z, Houtchens MK, et al. Cognitive dysfunction in patients with clinically isolated syndromes or newly diagnosed multiple sclerosis. Mult Scler. 2007;13(8):1004–10.
- Calabrese M, Rinaldi F, Mattisi I, Grossi P, Favaretto A, Atzori M, et al. Widespread cortical thinning characterizes patients with MS with mild cognitive impairment. Neurology. 2010;74(4):321–8.
- Houtchens MK, Benedict RH, Killiany R, Sharma J, Jaisani Z, Singh B, et al. Thalamic atrophy and cognition in multiple sclerosis. Neurology. 2007;69(12):1213–23.
- Riccitelli G, Rocca MA, Pagani E, Rodegher ME, Rossi P, Falini A, et al. Cognitive impairment in multiple sclerosis is associated to different patterns of gray matter atrophy according to clinical phenotype. Human Brain Mapping. 2011;32(10):1535–43.
- Sumowski JF, Chiaravalloti N, Wylie G, Deluca J. Cognitive reserve moderates the negative effect of brain atrophy on cognitive efficiency in multiple sclerosis. Journal of the International Neuropsychological Society: JINS. 2009;15(4):606–12.
- Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387–401.
- Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402–15.
- Comi G, Pulizzi A, Rovaris M, Abramsky O, Arbizu T, Boiko A, et al. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008;371(9630):2085–92.
- Comi G, Jeffery D, Kappos L, Montalban X, Boyko A, Rocca MA, et al. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med. 2012;366(11):1000–9.
- Leary SM, Miller DH, Stevenson VL, Brex PA, Chard DT, Thompson AJ. Neurology. 2003;60(1):44–51.
- Filippi M, Rovaris M, Inglese M, Barkhof F, De Stefano N, Smith S, et al. Interferon beta-1a for brain tissue loss in patients at presentation with syndromes suggestive of multiple sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet. 2004;364(9444):1489–96.
- Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, et al. Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol. 2009;8(11):987–97.
- Molyneux PD, Kappos L, Polman C, Pozzilli C, Barkhof F, Filippi M, et al. The effect of interferon beta-1b treatment on MRI measures of cerebral atrophy in secondary progressive multiple sclerosis. Brain. 2000;123(11):2256–63.
- Miller DH, Soon D, Fernando KT, MacManus DG, Barker GJ, Yousry TA, et al. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology. 2007;68(17):1390–401.
- Rovaris M, Comi G, Rocca MA, Wolinsky JS, Filippi M. Short-term brain volume change in relapsing-remitting multiple sclerosis: Effect of glatiramer acetate and implications. Brain. 2001;124(9):1803–12.
- Filippi M, Rovaris M, Iannucci G, Mennea S, Sormani MP, Comi G. Whole brain volume changes in patients with progressive MS treated with cladribine. Neurology. 2000;55(11):1714–8.
- Paolillo A, Coles AJ, Molyneux PD, Gawne-Cain M, MacManus D, Barker GJ, et al. Quantitative MRI in patients with secondary progressive MS treated with monoclonal antibody Campath 1H. Neurology. 1999;53(4):751–7.
- Barkhof F, Hulst HE, Drulovic J, Uitdehaag BM, Matsuda K, Landin R. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? Neurology. 2010;74(13):1033–40.
- Ashburner J, Friston KJ. Voxel-Based Morphometry – The Methods. NeuroImage. 2000;11(6):805–21.
- Good CD, Johnsrude IS, Ashburner J, Henson RNA, Friston KJ, Frackowiak RSJ. A Voxel-Based Morphometric Study of Ageing in 465 Normal Adult Human Brains. NeuroImage. 2001;14(1):21–36.
- Fischl B, Dale AM. Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci U S A. 2000;97(20):11050–5.
- Portaccio E, Stromillo ML, Goretti B, Hakiki B, Giorgio A, Rossi F, et al. Natalizumab may reduce cognitive changes and brain atrophy rate in relapsing-remitting multiple sclerosis: a prospective, non-randomized pilot study. Eur J Neuro. 2013;20(6):986–90.
- Jones CK, Riddehough A, Li DKB, Zhao G, Paty DW.MRI cerebral atrophy in relapsing-remitting MS: Results from the PRISMS Trial. Neurology 2001;56(suppl 3):A379.