To investigate in a large cohort of patients with multiple sclerosis (MS), lesion load and atrophy evolution, and the relationship between clinical and magnetic resonance imaging (MRI) correlates of disease progression.
Methods
Two hundred and sixty-seven patients with MS were studied at baseline and two years later using the same MRI protocol. Abnormal white matter fraction, normal appearing white matter fraction, global white matter fraction, gray matter fraction and whole brain fraction, T2-hyperintense, and T1-hypointense lesions were measured at both time points.
Results
The majority of patients were clinically stable, whereas MRI-derived brain tissue fractions were significantly different after 2 years. The correlation between MRI data at baseline and their variation during the follow-up showed that lower basal gray matter atrophy was significantly related with higher progression of gray matter atrophy during follow-up. The correlation between MRI parameters and disease duration showed that gray matter atrophy rate decreased with increasing disease duration, whereas the rate of white matter atrophy had a constant pattern. Lower basal gray matter atrophy was associated with increased probability of developing gray matter atrophy at follow-up, whereas gray matter atrophy progression over 2 years and new T2 lesion load were risk factors for whole brain atrophy progression.
Conclusions
In MS, brain atrophy occurs even after a relatively short period of time and in patients with limited progression of disability. Short-term brain atrophy progression rates differ across tissue compartments, as gray matter atrophy results more pronounced than white matter atrophy and appears to be a early phenomenon in the MS-related disease progression.
1 Trapp BD Peterson JW Ransohoff RM Rudick R Mork S Bo L . Axonal transection in the lesions of multiple sclerosis. N Engl J Med1998; 338: 278–285.
2.
2 Trapp BD . Pathogenesis of multiple sclerosis: the eyes only see what the mind is prepared to comprehend. Ann Neurol2004; 55: 455–457 [Review].
3.
3 Peterson JW Bo L Mork S Chang A Trapp BD . Transected neuritis, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol2001; 50: 389–400.
4.
4 Cifelli A Arridge M Jezzard P Esiri MM Palace J Matthews PM . Thalamic neurodegeneration in multiple sclerosis. Ann Neurol2002; 52: 650–653.
5.
5 Kidd D Barkof F McConnell R Algra PR Allen IV Revesz T . Cortical lesions in multiple sclerosis. Brain1999; 122: 17–26.
6.
6 Frohman EM Racke MK Raine CS . Multiple sclerosis–the plaque and its pathogenesis. N Engl J Med2006; 354: 942–955.
7.
7 Kutzelnigg A Lucchinetti CF Stadelmann C . Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain2005; 128: 2705–2712.
8.
8 Bjartmar C Kinkel RP Kidd G Rudick RA Trapp BD . Axonal loss in normal-appearing white matter in a patient with acute MS. Neurology2001; 57: 1248–1252.
9.
9 Dutta R McDonough J Yin X . Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann Neurol2006; 59: 478–489.
10.
10 Pirko I Lucchinetti CF Sriram S Bakshi R . Gray matter involvement in multiple sclerosis. Neurology2007; 68: 634–642 [Review].
11.
11 Lucchinetti CF Bruck W Lassmann H . Evidence for pathogenic heterogeneity in multiple sclerosis. Ann Neurol2004; 56: 308.
12.
12 Lucchinetti C Bruck W Parisi J Scheithauer B Rodriguez M Lassmann H . Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol2000; 47: 707–717.
13.
13 Tedeschi G Lavorgna L Russo P . Brain atrophy and lesion load in a large population of patients with multiple sclerosis. Neurology2005; 65: 280–285.
14.
14 De Stefano N Iannucci G Sormani MP . MR correlates of cerebral atrophy in patients with multiple sclerosis. J Neurol2002; 249: 1072–1077.
15.
15 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.
16.
16 Pittock SJ Lucchinetti CF . The pathology of MS: new insights and potential clinical applications. Neurologist2007; 13: 45–56 [Review].
17.
17 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. Radiology2001; 220: 606–610.
18.
18 Bermel RA Bakshi R . The measurement and clinical relevance of brain atrophy in multiple sclerosis. Lancet Neurol2006; 5: 158–170 [Review].
19.
19 Ge Y Grossman RI Udupa JK . Brain atrophy in relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis: longitudinal quantitative analysis. Radiology2000; 214: 665–670.
20.
20 Chard DT Brex PA Ciccarelli O . The longitudinal relation between brain lesion load and atrophy in multiple sclerosis: a 14 year follow up study. J Neurol Neurosurg Psychiatry2003; 74: 1551–1554.
21.
21 Fisher E Rudick RA Simon JH . Eight-year follow-up study of brain atrophy in patients with MS. Neurology2002; 59: 1412–1420.
22.
22 Kalkers NF Ameziane N Bot JC Minneboo A Polman CH Barkhof F . Longitudinal brain volume measurement in multiple sclerosis: rate of brain atrophy is independent of the disease subtype. Arch Neurol2002; 59: 1572–1576.
23.
23 Agosta F Rovaris M Pagani E Sormani MP Comi G Filippi M . Magnetization transfer MRI metrics predict the accumulation of disability 8 years later in patients with multiple sclerosis. Brain2006; 129: 2620–2627.
24.
24 Rudick RA Lee JC Simon J Fisher E . Significance of T2 lesions in multiple sclerosis: a 13-year longitudinal study. Ann Neurol2006; 60: 236–242.
25.
25 Horakova D Cox JL Havrdova E . Evolution of different MRI measures in patients with active relapsing-remitting multiple sclerosis over 2 and 5 years. A case control study. J Neurol Neurosurg Psychiatry2008; 79: 407–414.
26.
26 Tiberio M Chard DT Altmann DR . Gray and white matter volume changes in early RRMS: a 2-year longitudinal study. Neurology2005; 64: 1001–1007.
27.
27 Chard DT Griffin CM Rashid W . Progressive grey matter atrophy in clinically early relapsing-remitting multiple sclerosis. Mult Scler2004; 10: 387–391.
28.
28 Hardmeier M Wagenpfeil S Freitag P . European rIFN beta-1a in Relapsing MS Dose Comparison Trial Study Group. Atrophy is detectable within a 3-month period in untreated patients with active relapsing remitting multiple sclerosis. Arch Neurol2003; 60: 1736–1739.
29.
29 Valsasina P Benedetti B Rovaris M Sormani MP Comi G Filippi M . Evidence for progressive gray matter loss in patients with relapsing-remitting MS. Neurology2005; 65: 1126–1128.
30.
30 Richert ND Howard T Frank JA . Relationship between inflammatory lesions and cerebral atrophy in multiple sclerosis. Neurology2006; 66: 551–556.
31.
31 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.
32.
32 Fisniku LK Chard DT Jackson JS . Gray matter atrophy is related to long-term disability in multiple sclerosis.Ann Neurol2008; 64: 247–254.
33.
33 Zivadinov R Bagnato F Nasuelli D . Short-term brain atrophy changes in relapsing-remitting multiple sclerosis. J Neurol Sci2004; 223: 185–189.
34.
34 Alfano B Brunetti A Covelli EM . Unsupervised, automated segmentation of the normal brain using a multispectral relaxometric magnetic resonance approach. Magn Reson Med1997; 37: 84–93.
35.
35 Alfano B Brunetti A Larobina M . Automated segmentation and measurement of global white matter lesion volume in patients with multiple sclerosis. J Magn Reson Imaging2000; 12: 799–807.
36.
36 McDonald WI Compston A Edan G . Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol2001; 50: 121–127.
37.
37 Kurtzke JF . Rating neurological impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology1983; 33: 1444–1452.
38.
38 Collignon A Maes F Delaere D Vandermeulen D Suetens P Marchal G . Automated multi-modality image registration based on information theory. In Information Processing in Medical Imaging, YJC Bizais . Ed., 1995; p. 263–274.
39.
39 Studholme C Hill DLG Hawkes DJ . A normalized entropy measure for multi-modality image alignment. In Proceedings of SPIE, Medical Imaging: Image Processing, vol. 3338. San Diego, CA; 1998. p. 132–143
40.
40 Ge Y Grossman RI Babb JS Rabin ML Mannon LJ Kolson DL . Age-related total gray matter and white matter changes in normal adult brain. Part I: volumetric MR imaging analysis. AJNR Am J Neuroradiol2002; 23: 1327–1333.
41.
41 Calabrese M Atzori M Bernardi V . Cortical atrophy is relevant in multiple sclerosis at clinical onset. J Neurol2007; 254: 1212–1220.
42.
42 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. Multiple Sclerosis Collaborative Research Group. Neurology1999; 53: 1698–1704.
43.
43 Chard DT Griffin CM Parker GJ Kapoor R Thompson AJ Miller DH . Brain atrophy in clinically early relapsing-remitting multiple sclerosis. Brain2002; 125: 327–337.
44.
44 Dutta R Trapp BD . Pathogenesis of axonal and neuronal damage in multiple sclerosis. Neurology2007; 68(22 Suppl. 3): S22–S31 discussion S43–S54.
45.
45 Cutter GR Baier ML Rudick RA . Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain1999; 122: 871–882.
46.
46 Pittock SJ Mayr WT McClelland RL . Change in MS-related disability in a population-based cohort: a 10-year follow-up study. Neurol2004; 62: 51–59.
47.
47 Rudick R Antel J Confavreux C . Clinical outcomes assessment in multiple sclerosis. Ann Neurol1996; 40: 469–479.
48.
48 Sharrack B Hughes RA . Clinical scales for multiple sclerosis. J Neurol Sci1996; 135: 1–9.
49.
49 Rocca MA Filippi M . Functional MRI in multiple sclerosis. J Neuroimaging2007; 17(Suppl. 1): 36S–41S.
50.
50 Rocca MA Pagani E Ghezzi A . Functional cortical changes in patients with multiple sclerosis and non-specific findings on conventional magnetic resonance imaging scans of the brain. Neuroimage2003; 19: 826–836.
51.
51 Pantano P Mainero C Caramia F . Functional brain reorganization in multiple sclerosis: evidence from fMRI studies. J Neuroimaging2006; 16: 104–114.
52.
52 Mezzapesa DM Rocca MA Rodegher M Comi G Filippi M . Functional cortical changes of the sensorimotor network are associated with clinical recovery in multiple sclerosis. Hum Brain Mapp2008; 29: 562–567.
