Revisiting Brain Atrophy and Its Relationship to Disability in Multiple Sclerosis

Background Brain atrophy is a well-accepted imaging biomarker of multiple sclerosis (MS) that partially correlates with both physical disability and cognitive impairment. Methodology/Principal Findings Based on MRI scans of 60 MS cases and 37 healthy volunteers, we measured the volumes of white matter (WM) lesions, cortical gray matter (GM), cerebral WM, caudate nucleus, putamen, thalamus, ventricles, and brainstem using a validated and completely automated segmentation method. We correlated these volumes with the Expanded Disability Status Scale (EDSS), MS Severity Scale (MSSS), MS Functional Composite (MSFC), and quantitative measures of ankle strength and toe sensation. Normalized volumes of both cortical and subcortical GM structures were abnormally low in the MS group, whereas no abnormality was found in the volume of the cerebral WM. High physical disability was associated with low cerebral WM, thalamus, and brainstem volumes (partial correlation coefficients ∼0.3–0.4) but not with low cortical GM volume. Thalamus volumes were inversely correlated with lesion load (r = −0.36, p<0.005). Conclusion The GM is atrophic in MS. Although lower WM volume is associated with greater disability, as might be expected, WM volume was on average in the normal range. This paradoxical result might be explained by the presence of coexisting pathological processes, such as tissue damage and repair, that cause both atrophy and hypertrophy and that underlie the observed disability.

[1]  Rohit Bakshi,et al.  The relationship between whole brain volume and disability in multiple sclerosis: A comparison of normalized gray vs. white matter with misclassification correction , 2005, NeuroImage.

[2]  R. Rudick,et al.  Gray matter atrophy in multiple sclerosis: A longitudinal study , 2008, Annals of neurology.

[3]  Rohit Bakshi,et al.  Gray and white matter brain atrophy and neuropsychological impairment in multiple sclerosis , 2006, Neurology.

[4]  G. Bartzokis,et al.  Age-related changes in frontal and temporal lobe volumes in men: a magnetic resonance imaging study. , 2001, Archives of general psychiatry.

[5]  H. Lassmann Mechanisms of inflammation induced tissue injury in multiple sclerosis , 2008, Journal of the Neurological Sciences.

[6]  R. Rudick,et al.  Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS , 1999, Neurology.

[7]  L D Blumhardt,et al.  Infratentorial atrophy on magnetic resonance imaging and disability in multiple sclerosis. , 1999, Brain : a journal of neurology.

[8]  P. Matthews,et al.  Thalamic neurodegeneration in multiple sclerosis , 2002, Annals of neurology.

[9]  A. Thompson,et al.  Sample sizes for brain atrophy outcomes in trials for secondary progressive multiple sclerosis , 2009, Neurology.

[10]  Francis Eustache,et al.  Quantification and clinical relevance of brain atrophy in multiple sclerosis: a review , 2009, Journal of Neurology.

[11]  Peter A. Calabresi,et al.  A topology-preserving approach to the segmentation of brain images with multiple sclerosis lesions , 2010, NeuroImage.

[12]  R. Bakshi,et al.  Whole-brain atrophy in multiple sclerosis measured by automated versus semiautomated MR imaging segmentation. , 2004, AJNR. American journal of neuroradiology.

[13]  M. Sdika,et al.  Nonrigid registration of multiple sclerosis brain images using lesion inpainting for morphometry or lesion mapping , 2009, Human brain mapping.

[14]  M. Battaglini,et al.  Evaluating and reducing the impact of white matter lesions on brain volume measurements , 2012, Human brain mapping.

[15]  R. Rudick,et al.  Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS , 2011, Neurology.

[16]  Aaron Carass,et al.  Simple paradigm for extra-cerebral tissue removal: Algorithm and analysis , 2011, NeuroImage.

[17]  J K Udupa,et al.  Brain atrophy in relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis: longitudinal quantitative analysis. , 2000, Radiology.

[18]  Alan C. Evans,et al.  Focal cortical atrophy in multiple sclerosis: Relation to lesion load and disability , 2007, NeuroImage.

[19]  Stephen M. Smith,et al.  Segmentation of brain MR images through a hidden Markov random field model and the expectation-maximization algorithm , 2001, IEEE Transactions on Medical Imaging.

[20]  G Tedeschi,et al.  Brain atrophy and lesion load in a large population of patients with multiple sclerosis , 2005, Neurology.

[21]  C. Mainero,et al.  Correlates of MS disability assessed in vivo using aggregates of MR quantities , 2001, Neurology.

[22]  Marc A Sommer,et al.  The role of the thalamus in motor control , 2003, Current Opinion in Neurobiology.

[23]  A J Thompson,et al.  Gray and white matter volume changes in early RRMS , 2005, Neurology.

[24]  Robert Zivadinov,et al.  Basal ganglia, thalamus and neocortical atrophy predicting slowed cognitive processing in multiple sclerosis , 2011, Journal of Neurology.

[25]  Stephen M. Smith,et al.  Accurate, Robust, and Automated Longitudinal and Cross-Sectional Brain Change Analysis , 2002, NeuroImage.

[26]  R W Bohannon,et al.  Reference values for extremity muscle strength obtained by hand-held dynamometry from adults aged 20 to 79 years. , 1997, Archives of physical medicine and rehabilitation.

[27]  Bruno Alfano,et al.  Brain tissue volume changes in relapsing-remitting multiple sclerosis: correlation with lesion load , 2003, NeuroImage.

[28]  Ludwig Kappos,et al.  Atrophy is detectable within a 3-month period in untreated patients with active relapsing remitting multiple sclerosis. , 2003, Archives of neurology.

[29]  C R G Guttmann,et al.  Thalamic atrophy and cognition in multiple sclerosis , 2007, Neurology.

[30]  Stephen M. Smith,et al.  Regional brain atrophy development is related to specific aspects of clinical dysfunction in multiple sclerosis , 2007, NeuroImage.

[31]  Robert Zivadinov,et al.  Neocortical atrophy, third ventricular width, and cognitive dysfunction in multiple sclerosis. , 2006, Archives of neurology.

[32]  G. Salemi,et al.  Multiple Sclerosis Severity Score: Using disability and disease duration to rate disease severity , 2005, Neurology.

[33]  P. M. Matthews,et al.  Evidence of early cortical atrophy in MS , 2003, Neurology.

[34]  M Rovaris,et al.  Evidence for progressive gray matter loss in patients with relapsing-remitting MS , 2005, Neurology.

[35]  A. Dale,et al.  Focal thinning of the cerebral cortex in multiple sclerosis. , 2003, Brain : a journal of neurology.

[36]  Nick C Fox,et al.  Detection of ventricular enlargement in patients at the earliest clinical stage of MS , 2000, Neurology.

[37]  Jeffrey A. Cohen,et al.  Multiple Sclerosis Therapeutics , 1999 .

[38]  Measurement of central nervous system atrophy in multiple sclerosis , 2007 .

[39]  Eliza M. Gordon-Lipkin,et al.  Sensorimotor dysfunction in multiple sclerosis and column-specific magnetization transfer-imaging abnormalities in the spinal cord. , 2009, Brain : a journal of neurology.

[40]  Rohit Bakshi,et al.  A semiautomated measure of whole-brain atrophy in multiple sclerosis , 2003, Journal of the Neurological Sciences.

[41]  Rohit Bakshi,et al.  Selective caudate atrophy in multiple sclerosis: a 3D MRI parcellation study , 2003, Neuroreport.

[42]  Alan J. Thompson,et al.  Grey and white matter atrophy in early clinical stages of primary progressive multiple sclerosis , 2004, NeuroImage.

[43]  D. Ramasamy,et al.  Extent of cerebellum, subcortical and cortical atrophy in patients with MS A case-control study , 2009, Journal of the Neurological Sciences.

[44]  A J Thompson,et al.  Brain atrophy in clinically early relapsing-remitting multiple sclerosis. , 2002, Brain : a journal of neurology.

[45]  J H Simon,et al.  Eight-year follow-up study of brain atrophy in patients with MS , 2002, Neurology.

[46]  A. Charil,et al.  Medulla Oblongata Volume: A Biomarker of Spinal Cord Damage and Disability in Multiple Sclerosis , 2008, American Journal of Neuroradiology.

[47]  Stephen M. Rao,et al.  Development of a multiple sclerosis functional composite as a clinical trial outcome measure. , 1999, Brain : a journal of neurology.

[48]  P. Matthews,et al.  Grey matter volume in a large cohort of MS patients: relation to MRI parameters and disability , 2011, Multiple sclerosis.