Correlation Between Brain Volume Loss and Clinical and MRI Outcomes in Multiple Sclerosis

Overview

Journal Neurology

Specialty Neurology

Date 2015 Jan 30

PMID 25632085

Citations 77

Authors

Ernst-Wilhelm Radue

Frederik Barkhof

Ludwig Kappos

Till Sprenger

Dieter A Haring

Ana de Vera

Philipp von Rosenstiel

Jeremy R Bright

Gordon Francis

Jeffrey A Cohen

Affiliations

Soon will be listed here.

Abstract

Objective: We investigated the determinants and clinical correlations of MRI-detected brain volume loss (BVL) among patients with relapsing-remitting multiple sclerosis from the phase 3 trials of fingolimod: FREEDOMS, FREEDOMS II, and TRANSFORMS.

Methods: Post hoc analyses were conducted in the intent-to-treat populations from each trial and in a combined dataset of 3,635 patients from the trials and their extensions. The relationship between brain volume changes and demographic, clinical, and MRI parameters was studied in pairwise correlations (Pearson) and in multiple regression models. The relative frequency of confirmed disability progression was evaluated in the combined dataset by strata of concurrent BVL at up to 4 years.

Results: Increasing age, disease duration, T2 lesion volume, T1-hypointense lesion volume, and disability were associated with reduced brain volume (p < 0.001, all). The strongest individual baseline predictors of on-study BVL were T2 lesion volume, gadolinium-enhancing lesion count, and T1-hypointense lesion volume (p < 0.01, all). During each study, BVL correlated most strongly with cumulative gadolinium-enhancing lesion count, new/enlarged T2 lesion count (p < 0.001, both), and number of confirmed on-study relapses (p < 0.01). Over 4 years in the combined dataset (mean exposure to study drug, 2.4 years), confirmed disability progression was most frequent in patients with greatest BVL.

Conclusions: Rate of BVL in patients during the fingolimod trials correlated with disease severity at baseline and new disease activity on study, and was associated with worsening disability.

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References

De Stefano N, Matthews P, Filippi M, Agosta F, De Luca M, Bartolozzi M . Evidence of early cortical atrophy in MS: relevance to white matter changes and disability. Neurology. 2003; 60(7):1157-62. DOI: 10.1212/01.wnl.0000055926.69643.03. View

Rudick R, Fisher E, Lee J, Simon J, Jacobs L . Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Multiple Sclerosis Collaborative Research Group. Neurology. 1999; 53(8):1698-704. DOI: 10.1212/wnl.53.8.1698. View

Roosendaal S, Bendfeldt K, Vrenken H, Polman C, Borgwardt S, Radue E . Grey matter volume in a large cohort of MS patients: relation to MRI parameters and disability. Mult Scler. 2011; 17(9):1098-106. DOI: 10.1177/1352458511404916. View

Miller D, Barkhof F, Frank J, Parker G, Thompson A . Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain. 2002; 125(Pt 8):1676-95. DOI: 10.1093/brain/awf177. View

Calabresi P, Radue E, Goodin D, Jeffery D, Rammohan K, Reder A . Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014; 13(6):545-56. DOI: 10.1016/S1474-4422(14)70049-3. View

Jacobsen C, Hagemeier J, Myhr K, Nyland H, Lode K, Bergsland N . Brain atrophy and disability progression in multiple sclerosis patients: a 10-year follow-up study. J Neurol Neurosurg Psychiatry. 2014; 85(10):1109-15. DOI: 10.1136/jnnp-2013-306906. View

Rudick R, Lee J, Nakamura K, Fisher E . Gray matter atrophy correlates with MS disability progression measured with MSFC but not EDSS. J Neurol Sci. 2008; 282(1-2):106-11. PMC: 2726444. DOI: 10.1016/j.jns.2008.11.018. View

Chard D, Griffin C, Parker G, Kapoor R, Thompson A, Miller D . Brain atrophy in clinically early relapsing-remitting multiple sclerosis. Brain. 2002; 125(Pt 2):327-37. DOI: 10.1093/brain/awf025. View

Rudick R, Fisher E . Preventing brain atrophy should be the gold standard of effective therapy in MS (after the first year of treatment): Yes. Mult Scler. 2013; 19(8):1003-4. DOI: 10.1177/1352458513482385. View

10.

Fotenos A, Mintun M, Snyder A, Morris J, Buckner R . Brain volume decline in aging: evidence for a relation between socioeconomic status, preclinical Alzheimer disease, and reserve. Arch Neurol. 2008; 65(1):113-20. DOI: 10.1001/archneurol.2007.27. View

11.

Kappos L, Radue E, OConnor P, Polman C, Hohlfeld R, Calabresi P . A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010; 362(5):387-401. DOI: 10.1056/NEJMoa0909494. View

12.

Zivadinov R, Bergsland N, Dolezal O, Hussein S, Seidl Z, Dwyer M . Evolution of cortical and thalamus atrophy and disability progression in early relapsing-remitting MS during 5 years. AJNR Am J Neuroradiol. 2013; 34(10):1931-9. PMC: 7965442. DOI: 10.3174/ajnr.A3503. View

13.

Tremlett H, Paty D, Devonshire V . Disability progression in multiple sclerosis is slower than previously reported. Neurology. 2006; 66(2):172-7. DOI: 10.1212/01.wnl.0000194259.90286.fe. View

14.

Sanfilipo M, Benedict R, 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. DOI: 10.1016/j.neuroimage.2005.03.008. View

15.

Paolillo A, Piattella M, Pantano P, Di Legge S, Caramia F, Russo P . The relationship between inflammation and atrophy in clinically isolated syndromes suggestive of multiple sclerosis: a monthly MRI study after triple-dose gadolinium-DTPA. J Neurol. 2004; 251(4):432-9. DOI: 10.1007/s00415-004-0349-8. View

16.

Cohen J, Barkhof F, Comi G, Hartung H, Khatri B, Montalban X . Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010; 362(5):402-15. DOI: 10.1056/NEJMoa0907839. View

17.

Kitzler H, Su J, Zeineh M, Harper-Little C, Leung A, Kremenchutzky M . Deficient MWF mapping in multiple sclerosis using 3D whole-brain multi-component relaxation MRI. Neuroimage. 2011; 59(3):2670-7. PMC: 3673309. DOI: 10.1016/j.neuroimage.2011.08.052. View

18.

De Stefano N, Giorgio A, Battaglini M, Rovaris M, Sormani M, Barkhof F . Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes. Neurology. 2010; 74(23):1868-76. DOI: 10.1212/WNL.0b013e3181e24136. View

19.

Filippi M, Rocca M, Barkhof F, Bruck W, Chen J, Comi G . Association between pathological and MRI findings in multiple sclerosis. Lancet Neurol. 2012; 11(4):349-60. DOI: 10.1016/S1474-4422(12)70003-0. View

20.

Fisher E, Rudick R, Simon J, Cutter G, Baier M, Lee J . Eight-year follow-up study of brain atrophy in patients with MS. Neurology. 2002; 59(9):1412-20. DOI: 10.1212/01.wnl.0000036271.49066.06. View