MRI measures show significant cerebellar gray matter volume loss in multiple sclerosis and are associated with cerebellar dysfunction

Abstract

Background

Regional atrophy measures may offer useful information about the causes of specific clinical deficits in multiple sclerosis (MS).

Objective

To determine the magnitude of cerebellar gray and white matter (GM and WM) atrophy in patients with clinically isolated syndromes (CIS) and MS, and their role in clinical manifestations of cerebellar damage.

Methods

T1-weighted volumetric magnetic resonance imaging (MRI) of 73 patients [29 CIS, 33 relapsing–remitting MS (RRMS), 11 secondary progressive MS (SPMS)] was compared with 25 controls. GM and WM regions were generated using SPM5 and cerebellar regions delineated. Linear regression was used to investigate differences in tissue-specific cerebellar volumes between groups and the association with clinical measures.

Results

Mean cerebellar GM volume (CGMV) was 100.1 cm³ in controls, 96.4 cm³ in CIS patients, 91.8 cm³ in RRMS patients, and 88.8 cm³ in SPMS patients. Mean cerebellar WM volumes (CWMV) were 21.3 cm³, 20.4 cm³, 19.9 cm³, and 18.8 cm³, respectively. CGMV was reduced by 4.8 cm³ (P = 0.054) in RRMS patients, and 8.5 cm³ (P = 0.012) in SPMS patients, relative to controls. Only patients with SPMS showed a borderline significant reduction in CWMV compared with controls (mean 2.1 cm³, P = 0.053). CGMV was significantly smaller in patients assessed as having cerebellar dysfunction compared with patients who had normal cerebellar function. Significant associations of CGMV and CWMV with performance on the nine-hole peg test were also observed.

Conclusion

Clinically relevant GM atrophy occurs in the cerebellum of MS patients and is more prominent than WM atrophy. As such, it may provide complementary data to other regional atrophy and intrinsic tissue measures.

Keywords

atrophy cerebellum gray matter multiple sclerosis region of interest

Get full access to this article

View all access options for this article.

References

1 Bo L Vedeler CA Nyland HI Trapp BD Mork SJ . Subpial demyelination in the cerebral cortex of multiple sclerosis patients. J Neuropathol Exp Neurol 2003; 62: 723–732.

2 Peterson JW Bo L Mork S Chang A Trapp BD . Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 2001; 50: 389–400.

3 Kutzelnigg A Lucchinetti CF Stadelmann C . Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005; 128: 2705–2712.

4 Geurts JJ Pouwels PJ Uitdehaag BM Polman CH Barkhof F Castelijns JA . Intracortical lesions in multiple sclerosis: improved detection with 3D double inversion-recovery MR imaging. Radiology 2005; 236: 254–260.

5 Bagnato F Butman JA Gupta S . In vivo detection of cortical plaques by MR imaging in patients with multiple sclerosis. AJNR Am J Neuroradiol 2006; 27: 2161–2167.

6 Nelson F Poonawalla AH Hou P Huang F Wolinsky JS Narayana PA . Improved identification of intracortical lesions in multiple sclerosis with phase-sensitive inversion recovery in combination with fast double inversion recovery MR imaging. AJNR Am J Neuroradiol 2007; 28: 1645–1649.

7 Calabrese M De Stefano N Atzori M . Detection of cortical inflammatory lesions by double inversion recovery magnetic resonance imaging in patients with multiple sclerosis. Arch Neurol 2007; 64: 1416–1422.

8 Sastre-Garriga J Ingle GT Chard DT . Grey and white matter volume changes in early primary progressive multiple sclerosis: a longitudinal study. Brain 2005; 128: 1454–1460.

9 Tiberio M Chard DT Altmann DR . Gray and white matter volume changes in early RRMS: a 2-year longitudinal study. Neurology 2005; 64: 1001–1007.

10.

10 Valsasina P Benedetti B Rovaris M Sormani MP Comi G Filippi M . Evidence for progressive gray matter loss in patients with relapsing-remitting MS. Neurology 2005; 65: 1126–1128.

11.

11 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 Scler 2007; 13: 490–501.

12.

12 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. Brain 2004; 127: 1101–1107.

13.

13 Fisniku LK Chard DT Jackson JS . Gray matter atrophy is related to long-term disability in multiple sclerosis. Ann Neurol 2008; 64: 247–254.

14.

14 Sanfilipo MP Benedict RH 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: 1068–1077.

15.

15 Mesaros S Rovaris M Pagani E . A magnetic resonance imaging voxel-based morphometry study of regional gray matter atrophy in patients with benign multiple sclerosis. Arch Neurol 2008; 65: 1223–1230.

16.

16 Prinster A Quarantelli M Orefice G . Grey matter loss in relapsing-remitting multiple sclerosis: a voxel-based morphometry study. Neuroimage 2006; 29: 859–867.

17.

17 Morgen K Sammer G Courtney SM . Evidence for a direct association between cortical atrophy and cognitive impairment in relapsing-remitting MS. Neuroimage 2006; 30: 891–898.

18.

18 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: 1495–1501.

19.

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. Arch Neurol 2006; 63: 1175–1180.

20.

20 Henry RG Shieh M Okuda DT Evangelista A Gorno-Tempini ML Pelletier D . Regional grey matter atrophy in clinically isolated syndromes at presentation. J Neurol Neurosurg Psychiatry 2008; 79: 1236–1244.

21.

21 Bermel RA Innus MD Tjoa CW Bakshi R . Selective caudate atrophy in multiple sclerosis: a 3D MRI parcellation study. Neuroreport 2003; 14: 335–339.

22.

22 Cifelli A Arridge M Jezzard P Esiri MM Palace J Matthews PM . Thalamic neurodegeneration in multiple sclerosis. Ann Neurol 2002; 52: 650–653.

23.

23 Wylezinska M Cifelli A Jezzard P Palace J Alecci M Matthews PM . Thalamic neurodegeneration in relapsing-remitting multiple sclerosis. Neurology 2003; 60: 1949–1954.

24.

24 Kutzelnigg A Faber-Rod JC Bauer J . Widespread demyelination in the cerebellar cortex in multiple sclerosis. Brain Pathol 2007; 17: 38–44.

25.

25 Ceccarelli A Rocca MA Pagani E . A voxel-based morphometry study of grey matter loss in MS patients with different clinical phenotypes. Neuroimage 2008; 42: 315–322.

26.

26 Amato MP Ponziani G . A prospective study on the prognosis of multiple sclerosis. Neurol Sci 2000; 21: S831–S838.

27.

27 Poser CM Paty DW Scheinberg L . New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13: 227–231.

28.

28 Lublin FD Reingold SC . Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 1996; 46: 907–911.

29.

29 Ashburner J Friston KJ . Unified segmentation. Neuroimage 2005; 26: 839–851.

30.

30 Plummer DL . DispImage: a display and analysis tool for medical images. Revista di Neuroradiologia 1992; 5: 489–495.

31.

31 Kurtzke JF . Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983; 33: 1444–1452.

32.

32 Cutter GR Baier ML Rudick RA . Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain 1999; 122: 871–882.

33.

33 Altman DG; . Practical statistics for medical research. 1991 Chapman & Hall.

34.

34 Edwards SG Gong QY Liu C . Infratentorial atrophy on magnetic resonance imaging and disability in multiple sclerosis. Brain 1999; 122: 291–301.

35.

35 Liu C Edwards S Gong Q Roberts N Blumhardt LD . Three dimensional MRI estimates of brain and spinal cord atrophy in multiple sclerosis. J Neurol Neurosurg Psychiatry 1999; 66: 323–330.

36.

36 Filippi M Mastronardo G Rocca MA Pereira C Comi G . Quantitative volumetric analysis of brain magnetic resonance imaging from patients with multiple sclerosis. J Neurol Sci 1998; 158: 148–153.

37.

37 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 MRI study. Acta Neurol Scand 2003; 108: 401–406.

38.

38 Li Y Chiaravalloti ND Hillary FG . Differential cerebellar activation on functional magnetic resonance imaging during working memory performance in persons with multiple sclerosis. Arch Phys Med Rehabil 2004; 85: 635–639.

39.

39 Rocca, MA, Valsasina, P, Ceccarelli, A, et al. Structural and functional MRI correlates of Stroop control in benign MS. Hum Brain Mapp 2009; 30: 276–290.

40.

40 Davie CA Barker GJ Webb S . Persistent functional deficit in multiple sclerosis and autosomal dominant cerebellar ataxia is associated with axon loss. Brain 1995; 118: 1583–1592.

41.

41 Brenneis C Boesch SM Egger KE . Cortical atrophy in the cerebellar variant of multiple system atrophy: a voxel-based morphometry study. Mov Disord 2006; 21: 159–165.

42.

42 Ginestroni A Della NR Tessa C . Brain structural damage in spinocerebellar ataxia type 1 : a VBM study. J Neurol 2008; 255: 1153–1158.

43.

43 Lukas C Schols L Bellenberg B . Dissociation of grey and white matter reduction in spinocerebellar ataxia type 3 and 6: a voxel-based morphometry study. Neurosci Lett 2006; 408: 230–235.

44.

44 Gilmore CP Donaldson I Bo L Owens T Lowe JS Evangelou N . Regional variations in the extent and pattern of grey matter demyelination in Multiple Sclerosis: a comparison between the cerebral cortex, cerebellar cortex, deep grey matter nuclei and the spinal cord. J Neurol Neurosurg Psychiatry 2009; 80: 182–187.

45.

45 Tjoa CW Benedict RH Weinstock-Guttman B Fabiano AJ Bakshi R . MRI T2 hypointensity of the dentate nucleus is related to ambulatory impairment in multiple sclerosis. J Neurol Sci 2005; 234: 17–24.

46.

46 Fisniku LK Brex PA Altmann DR . Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis. Brain 2008; 131: 808–817.