Neuroaxonal loss is a pathological substrate of disability in progressive multiple sclerosis (MS) and can be estimated in vivo by measuring tissue atrophy on magnetic resonance imaging (MRI). While there is some evidence that brain atrophy correlates better with disability than T2 lesion load in secondary progressive MS, the clinical relevance of atrophy within specific regions of the central nervous system requires further evaluation.
Methods
Clinical and MRI examinations were performed in 117 subjects with secondary progressive MS. MRI analysis included measures of normalized brain volume (NBV), normalized grey matter (NGMV) and white matter volume (NWMV), central cerebral volume (CCV), spinal cord cross-sectional area (SCCA), and brain T2 and T1 lesion volume. Clinical assessments included the expanded disability status scale (EDSS) and MS functional composite (MSFC).
Results
All MRI measures correlated significantly with the MSFC score, with the strongest correlation being for the NBV (r = 0.47; P < 0.001). NBV and SCCA were the only significant independent predictors of the MSFC score in a stepwise regression model containing all the MRI measures, and SCCA was the only MRI measure to show a significant association with the EDSS. While NGMV had stronger correlations with the clinical variables than NWMV, NBV was more correlated with clinical impairment than either measure.
Conclusions
This data suggests that measures of atrophy, particularly of the whole brain and spinal cord, are relevant and useful disease markers in secondary progressive MS.
1 Smith KJ McDonald I Miller D Lassmann H . The pathophysiology of multiple sclerosis. In: A Compston C Confavreux H Lassmann . (eds). McAlpine's Multiple Sclerosis. London: Churchill Livingstone; 2006. p. 601–659.
2.
2 Losseff NA Wang L Lau HM . Progressive cerebral atrophy in multiple sclerosis. A serial MRI study. Brain1996; 119: 2009–2019.
3.
3 De Stefano N Matthews PM Fu L . Axonal damage correlates with disability in patients with relapsing remitting multiple sclerosis. Results of a longitudinal magnetic resonance spectroscopy study. Brain1998; 121: 1469–1477.
4.
4 Bjartmar C Kidd G Mork S Rudick R Trapp BD . Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann Neurol2000; 48: 893–901.
5.
5 IFNB Multiple Scelerosis Study Group. Interferon beta 1b is effective in relapsing remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double blind placebo-controlled trial. Neurology1993; 43: 655–661.
6.
6 Edan G Miller D Clanet M . Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria. J Neurol Neurosurg Psychiatry1997; 62: 112–118.
7.
7 Polman CH O'Connor PW Havrdova E . A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med2006; 354: 899–910.
8.
8 Kappos L Moeri D Radue EW . Predictive value of gadolinium enhanced magnetic resonance imaging for relapse rate and changes in disability or impairment in multiple sclerosis: a meta-analysis. Lancet1999; 353: 964–969.
9.
9 Kalkers NF Bergers L Castelijns JA . Optimizing the association between disability and biological markers of MS. Neurology2001; 57: 1253–1258.
10.
10 Li DK Held U Petkau J . MRI T2 lesion burden in multiple sclerosis: a plateauing relationship with clinical disability. Neurology2006; 66: 1384–1389.
11.
11 Fisher E Rudick RA Simon JH . Eight-year follow-up study of brain atrophy in patients with MS. Neurology2002; 59: 1412–1420.
12.
12 Miller DH . Biomarkers and Surrogate Outcomes in Neurodegenerative Disease: Lessons from multiple sclerosis. NeuroRx2004; 1: 284–294.
13.
13 Truyen L van Waesberghe JH van Walderveen MA . Accumulation of hypointense (black holes) on T1 spin-echo MRI correlates with disease progression in multiple sclerosis. Neurology1996; 47: 1469–1476.
14.
14 Filippi M Rovaris M Inglese M . Interferon beta-1a for brain tissue loss in patients at presentation with syndromes suggestive of multiple sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet2004; 364: 1489–1496.
15.
15 Anderson VM Fox NC Miller DH . Magnetic resonance imaging measures of brain atrophy in multiple sclerosis. J Magn Reson Imaging2006; 23: 605–618.
16.
16 Dalton CM Chard DT Davies GR . Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes. Brain2004; 127: 1101–1107.
17.
17 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. Neuroimage2005; 26: 1068–1077.
18.
18 Tiberio M Chard DT Altmann DR . Gray and white matter volume changes in early RRMS: a 2-year longitudinal study. Neurology2005; 64: 1001–1007.
19.
19 De Stefano N Matthews PM Filippi M . Evidence of early cortical atrophy in MS: relevance to white matter changes and disability. Neurology2003; 60: 1157–1162.
20.
20 Zivadinov R Locatelli L Cookfair D . Interferon beta-1a slows progression of brain atrophy in relapsing–remitting multiple sclerosis predominantly by reducing gray matter atrophy. Mult Scler2007; 13: 490–501.
21.
21 Molyneux PD Kappos L Polman C . The effect of interferon beta-1b treatment on MRI measures of cerebral atrophy in secondary progressive multiple sclerosis. European Study Group on Interferon beta-1b in secondary progressive multiple sclerosis. Brain2000; 123: 2256–2263.
22.
22 Stevenson VL Smith SM Matthews PM Miller DH Thompson AJ . Monitoring disease progression and activity in primary progressive multiple sclerosis using MRI: sub-voxel registration to identify lesion changes and to detect cerebral atrophy. J Neurol2002; 249: 171–177.
23.
23 Losseff NA Webb SL O'Riordan JI . Spinal cord atrophy and disability in multiple sclerosis. A new reproducible and sensitive MRI method with potential to monitor disease progression. Brain1996; 119: 701–708.
24.
24 Lin X Blumhardt LD Constantinescu CS . The relationship of brain and cervical cord volume to disability in clinical subtypes of multiple sclerosis: a three dimensional study. Acta Neurol Scand2003; 108: 401–406.
25.
25 Sastre-Garriga J Ingel GT Rovaris M . Long term clinical outcome of primary progressive MS: predictive value of clinical and MRI data. Neurology2005; 65: 633–635.
26.
26 Furby J Hayton T Smith KJ . [abstract] A randomised controlled trial of neuroprotection with lamotrigine in secondary progressive multiple sclerosis. Mult Scler2006; 12: S228.
27.
27 Smith SM Zhang Y Jenkinson M . Accurate, robust and automated longitudinal and cross-sectional brain change analysis. Neuroimage2002; 17: 479–489.
28.
28 Freeborough PA Fox NC Kitney RI . Interactive algorithms for the segmentation and quantitation of 3-D MRI brain scans. Comput Methods Programs Biomed1997; 53: 15–25.
29.
29 Cutter GR Baier ML Rudick RA . Development of the multiple sclerosis functional composite as a clinical trial outcome measure. Brain1999; 122: 871–882.
30.
30 Bermel RA Sharma J Tjoa CW Puli SR Bakshi R . A semi-automated measure of whole brain atrophy in multiple scelrosis. J Neurol Sci2003; 208: 57–65.
31.
31 Evangelou N Esiri M Smith S Palace J Matthews PM . Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis. Ann Neurol2000; 47: 391–395.
32.
32 Kutzelnigg A Lucchinetti CF Stadelmann C . Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain2005; 128: 2705–2712.
33.
33 Peterson JW Bo L Mork S Chang A Trapp BD . Transected neurites, apoptotic neurons and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol2001; 50: 389–400.
34.
34 Chard DT Griffin CM Rashid W . Progressive grey matter atrophy in clinically early relapsing–remitting multiple sclerosis. Mult Scler2004; 10: 387–391.
35.
35 Tedeschi G Lavorgna L Russo P . Brain atrophy and lesion load in a large population of patients with multiple sclerosis. Neurology2005; 65: 280–285.
36.
36 Sastre-Garriga J Ingle GT Chard DT Ramio-Torrenta L Miller DH Thompson AJ . Grey and white matter atrophy in early clinical stages of primary progressive multiple sclerosis. Neuroimage2004; 22: 353–359.
37.
37 Houtchens MK Benedict RH Killiany R . Thalamic atrophy and cognition in multiple sclerosis. Neurology2007; 69: 1213–1223.
38.
38 Ashburner J Friston K . Multimodal image coregistration and partitioning–a unified framework. Neuroimage1997; 6: 209–217.
39.
39 Comi G Fillippi M Martinelli V . Brain MRI correlates of cognitive impairment in primary and secondary progressive multiple sclerosis. J Neurol Sci1995; 132: 222–227.
40.
40 Amato MP Zipoli V Portaccio E . Multiple sclerosis-related cognitive changes: A review of cross-sectional and longitudinal studies. J Neurol Sci2006; 245: 41–46.
41.
41 Morgen K Sammer G Courtney SM . Evidence for a direct association between cortical atrophy and cognitive impairment in relapsing–remitting MS. Neuroimage2006; 30: 891–898.
42.
42 Sanfilpo MP Benedict RH Weinstock-Guttman B Bakshi R . Gray and white matter brain atrophy and neuropsychological impairment in multiple sclerosis. Neurology2006; 66: 685–692.
43.
43 Hobart J Kalkers N Barkhof F Uitdehaag B Polman C Thompson A . Outcome measures for multiple sclerosis clinical trials: relative measurement precision of the Expanded Disability Status Scale and Multiple Sclerosis Functional Composite. Mult Scler2004; 10: 41–46.
