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From the Departments of Neurology (Mellen Center) (Dr. Rudick), Biomedical Engineering (Dr. Fisher), and Biostatistics and Epidemiology (J.-C. Lee), Cleveland Clinic Foundation, Cleveland, OH; the Department of Radiology–MRI (Dr. Simon), University of Colorado Health Sciences Center, Denver, CO; and the Department of Neurology (Dr. Jacobs), Buffalo General Hospital, Buffalo, NY.
Address correspondence and reprint requests to Dr. Rudick, Area U100, Mellen Center, Cleveland Clinic Foundation, Cleveland, OH 44195.
BACKGROUND: Episodic inflammation in the CNS during the early stages of MS results in progressive disability years later, presumably due to myelin and axonal injury. MRI demonstrates ongoing disease activity during the early disease stage, even in some patients who are stable clinically. The optimal MRI measure for the destructive pathologic process is uncertain, however.
METHODS: In this post-hoc study, MRI scans were analyzed from patients with relapsing MS participating in a placebo-controlled trial of interferon ß-1a. The brain parenchymal fraction, defined as the ratio of brain parenchymal volume to the total volume within the brain surface contour, was used to measure whole brain atrophy. The relationship between disease features and brain atrophy and effect of interferon ß-1a were determined.
RESULTS: MS patients had significant brain atrophy that worsened during each of 2 years of observation. In many patients, brain atrophy worsened without clinical disease activity. Baseline clinical and MRI abnormalities were not strongly related to the rate of brain atrophy during the subsequent 2 years. Treatment with interferon ß-1a resulted in a reduction in brain atrophy progression during the second year of the clinical trial.
CONCLUSIONS: Patients with relapsing-remitting MS have measurable amounts of whole brain atrophy that worsens yearly, in most cases without clinical manifestations. The brain parenchymal fraction is a marker for destructive pathologic processes ongoing in relapsing MS patients, and appears useful in demonstrating treatment effects in controlled clinical trials.
Key words: MS—MRI—Brain atrophy—Interferon beta.
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R. Rudick Mechanisms of disability progression in primary progressive multiple sclerosis: are they different from secondary progressive multiple sclerosis? Multiple Sclerosis, April 1, 2003; 9(2): 210 - 212. [PDF]
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C. Confavreux, S. Vukusic, and P. Adeleine Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process Brain, April 1, 2003; 126(4): 770 - 782. [Abstract] [Full Text] [PDF]
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D. M Miller, R. A Rudick, M. Baier, G. Cutter, D. S Doughtery, B. Weinstock-Guttman, M. K Mass, E. Fisher, and N. Simonian Factors that predict Health-Related Q uality of Life in patients with relapsing -remitting multiple sclerosis Multiple Sclerosis, February 1, 2003; 9(1): 1 - 5. [Abstract] [PDF]
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B. Turner, X. Lin, G. Calmon, N. Roberts, and L. D Blumhardt C erebral atrophy and disability in relapsing-remitting and secondary progressive multiple sclerosis over four years Multiple Sclerosis, February 1, 2003; 9(1): 21 - 27. [Abstract] [PDF]
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M. Filippi, M. Bozzali, M. Rovaris, O. Gonen, C. Kesavadas, A. Ghezzi, V. Martinelli, R. I. Grossman, G. Scotti, G. Comi, et al. Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis Brain, February 1, 2003; 126(2): 433 - 437. [Abstract] [Full Text] [PDF]
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C. Caon, M. Zvartau-Hind, W. Ching, R.P. Lisak, A.C. Tselis, and O.A. Khan Intercaudate nucleus ratio as a linear measure of brain atrophy in multiple sclerosis Neurology, January 28, 2003; 60(2): 323 - 325. [Abstract] [Full Text] [PDF]
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 J. S. Burks, B. G. Arnason, P. K. Coyle, C. C. Ford, A. Noronha, and K. W. Rammohan Issues and Practices in Multiple Sclerosis Neurorehabil Neural Repair, December 1, 2002; 16(4): 307 - 320. [Abstract] [PDF]
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M. Clanet, E.W. Radue, L. Kappos, H.P. Hartung, R. Hohlfeld, M. Sandberg-Wollheim, M.F. Kooijmans-Coutinho, E.C. Tsao, and A.W. Sandrock A randomized, double-blind, dose-comparison study of weekly interferon {beta}-1a in relapsing MS Neurology, November 26, 2002; 59(10): 1507 - 1517. [Abstract] [Full Text] [PDF]
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E. Fisher, R. A. Rudick, J. H. Simon, G. Cutter, M. Baier, J. -C. Lee, D. Miller, B. Weinstock-Guttman, M. K. Mass, D. S. Dougherty, et al. Eight-year follow-up study of brain atrophy in patients with MS Neurology, November 12, 2002; 59(9): 1412 - 1420. [Abstract] [Full Text] [PDF]
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 S. L. Galetta, C. Markowitz, and A. G. Lee Immunomodulatory Agents for the Treatment of Relapsing Multiple Sclerosis: A Systematic Review Arch Intern Med, October 28, 2002; 162(19): 2161 - 2169. [Abstract] [Full Text] [PDF]
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E L. Hoogervorst, C H Polman, and F Barkhof Cerebral volume changes in multiple sclerosis patients treated with high-dose intravenous methylprednisolone Multiple Sclerosis, October 1, 2002; 8(5): 415 - 419. [Abstract] [PDF]
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R Leigh, J Ostuni, D Pham, A Goldszal, B K Lewis, T Howard, N Richert, H McFarland, and J A Frank Estimating cerebral atrophy in multiple sclerosis patients from various MR pulse sequences Multiple Sclerosis, October 1, 2002; 8(5): 420 - 429. [Abstract] [PDF]
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N. De Stefano, S. Narayanan, S. J. Francis, S. Smith, M. Mortilla, M. C. Tartaglia, M. L. Bartolozzi, L. Guidi, A. Federico, and D. L. Arnold Diffuse Axonal and Tissue Injury in Patients With Multiple Sclerosis With Low Cerebral Lesion Load and No Disability Arch Neurol, October 1, 2002; 59(10): 1565 - 1571. [Abstract] [Full Text] [PDF]
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N. F. Kalkers, N. Ameziane, J. C. J. Bot, A. Minneboo, C. H. Polman, and F. Barkhof Longitudinal Brain Volume Measurement in Multiple Sclerosis: Rate of Brain Atrophy Is Independent of the Disease Subtype Arch Neurol, October 1, 2002; 59(10): 1572 - 1576. [Abstract] [Full Text] [PDF]
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 O. Gonen, D. M. Moriarty, B. S. Y. Li, J. S. Babb, J. He, J. Listerud, D. Jacobs, C. E. Markowitz, and R. I. Grossman Relapsing-remitting Multiple Sclerosis and Whole-Brain N-Acetylaspartate Measurement: Evidence for Different Clinical Cohorts—Initial Observations Radiology, October 1, 2002; 225(1): 261 - 268. [Abstract] [Full Text] [PDF]
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A. B. Rao, N. Richert, T. Howard, B.K. Lewis, C.N. Bash, H.F. McFarland, and J. A. Frank Methylprednisolone effect on brain volume and enhancing lesions in MS before and during IFN{beta}-1b Neurology, September 10, 2002; 59(5): 688 - 694. [Abstract] [Full Text] [PDF]
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H. McFarland, F. Barkhof, J. Antel, and D. Miller The role of MRI as a surrogate outcome measure in multiple sclerosis Multiple Sclerosis, September 1, 2002; 8(1_suppl): 40 - 51. [Abstract] [PDF]
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R. J. Fox, E. Fisher, R. Rudick, B.O. Khatri, M.P. McQuillen, and D. S. Goodin Disease modifying therapies in multiple sclerosis Neurology, August 13, 2002; 59(3): 471 - 473. [Full Text] [PDF]
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C M Dalton, P A Brex, R Jenkins, N C Fox, K A Miszkiel, W R Crum, J I O'Riordan, G T Plant, A J Thompson, and D H Miller Progressive ventricular enlargement in patients with clinically isolated syndromes is associated with the early development of multiple sclerosis J. Neurol. Neurosurg. Psychiatry, August 1, 2002; 73(2): 141 - 147. [Abstract] [Full Text] [PDF]
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S J Hickman, C M. Brierley, P A Brex, D G MacManus, N J Scolding, D A. Compston, and D H Miller Continuing optic nerve atrophy following optic neuritis: a serial MRI study Multiple Sclerosis, August 1, 2002; 8(4): 339 - 342. [Abstract] [PDF]
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D. H. Miller, F. Barkhof, J. A. Frank, G. J. M. Parker, and A. J. Thompson Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance Brain, August 1, 2002; 125(8): 1676 - 1695. [Abstract] [Full Text] [PDF]
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M. Filippi and R. I. Grossman MRI techniques to monitor MS evolution: The present and the future Neurology, April 23, 2002; 58(8): 1147 - 1153. [Abstract] [Full Text] [PDF]
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P. A. Calabresi Considerations in the treatment of relapsing-remitting multiple sclerosis Neurology, April 23, 2002; 58(90084): S10 - 22. [Abstract] [Full Text]
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D. L. Arnold and P.M. Matthews MRI in the diagnosis and management of multiple sclerosis Neurology, April 23, 2002; 58(90084): S23 - 31. [Abstract] [Full Text]
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C Gasperini, A Paolillo, E Giugni, S Galgani, F Bagnato, C Mainero, E Onesti, S Bastianello, and C Pozzilli MRI brain volume changes in relapsing-remitting multiple sclerosis patients treated with interferon beta-1a Multiple Sclerosis, April 1, 2002; 8(2): 119 - 123. [Abstract] [PDF]
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F. Bonneville, D. M. Moriarty, B. S.Y. Li, J. S. Babb, R. I. Grossman, and O. Gonen Whole-Brain N-Acetylaspartate Concentration: Correlation with T2-Weighted Lesion Volume and Expanded Disability Status Scale Score in Cases of Relapsing-Remitting Multiple Sclerosis AJNR Am. J. Neuroradiol., March 1, 2002; 23(3): 371 - 375. [Abstract] [Full Text] [PDF]
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R. Giess, M. Maurer, R. Linker, R. Gold, M. Warmuth-Metz, K. V. Toyka, M. Sendtner, and P. Rieckmann Association of a Null Mutation in the CNTF Gene With Early Onset of Multiple Sclerosis Arch Neurol, March 1, 2002; 59(3): 407 - 409. [Abstract] [Full Text] [PDF]
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