Clinical relevance of brain atrophy assessment in multiple sclerosis. Implications for its use in a clinical routine

ABSTRACT Introduction: Brain atrophy measurement in multiple sclerosis (MS) has become an important outcome for determining patients at risk for developing physical and cognitive disability. Areas covered: In this article, we discuss the methodological issues related to using this MRI metric routinely, in a clinical setting. Understanding trajectories of annualized whole brain, gray and white matter, thalamic volume loss, and enlargement of ventricular space in specific MS phenotypes is becoming increasingly important. Evidence is mounting that disease-modifying treatments exert a positive effect on slowing brain atrophy progression in MS. Expert Commentary: While there is a need to translate measurement of brain atrophy to clinical routine at the individual patient level, there are still a number of challenges to be met before this can actually happen, including how to account for biological confounding factors and pseudoatrophy, standardize acquisition and analyses parameters, which can influence the accuracy of the assessments.

[1]  R. Benedict,et al.  Localized atrophy of the thalamus and slowed cognitive processing speed in MS patients , 2016, Multiple sclerosis.

[2]  M. Ramanathan,et al.  Autoimmune Comorbidities Are Associated with Brain Injury in Multiple Sclerosis , 2016, American Journal of Neuroradiology.

[3]  D. Ramasamy,et al.  Neurological Software Tool for REliable Atrophy Measurement (NeuroSTREAM) in Multiple Sclerosis (S45.005) , 2016 .

[4]  M. Filippi,et al.  Regional hippocampal involvement and cognitive impairment in pediatric multiple sclerosis , 2016, Multiple sclerosis.

[5]  M. Sormani,et al.  The Effect of Disease-Modifying Drugs on Brain Atrophy in Relapsing-Remitting Multiple Sclerosis: A Meta-Analysis , 2016, PloS one.

[6]  D. Reich,et al.  Revised Recommendations of the Consortium of MS Centers Task Force for a Standardized MRI Protocol and Clinical Guidelines for the Diagnosis and Follow-Up of Multiple Sclerosis , 2016, American Journal of Neuroradiology.

[7]  D. Ramasamy,et al.  A serial 10-year follow-up study of brain atrophy and disability progression in RRMS patients , 2016, Multiple sclerosis.

[8]  M. Ramanathan,et al.  Humoral response to EBV is associated with cortical atrophy and lesion burden in patients with MS , 2016, Neurology: Neuroimmunology & Neuroinflammation.

[9]  D. Louis Collins,et al.  Non-Local Means Inpainting of MS Lesions in Longitudinal Image Processing , 2015, Front. Neurosci..

[10]  M. Sormani,et al.  Inclusion of brain volume loss in a revised measure of ‘no evidence of disease activity’ (NEDA-4) in relapsing–remitting multiple sclerosis , 2015, Multiple sclerosis.

[11]  D. Ramasamy,et al.  Immunological and short-term brain volume changes in relapsing forms of multiple sclerosis treated with interferon beta-1a subcutaneously three times weekly: an open-label two-arm trial , 2015, BMC Neurology.

[12]  A. Dibernardo,et al.  The natural history of brain volume loss among patients with multiple sclerosis: A systematic literature review and meta-analysis , 2015, Journal of the Neurological Sciences.

[13]  F. Barkhof,et al.  Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis—establishing disease prognosis and monitoring patients , 2015, Nature Reviews Neurology.

[14]  J. Geurts,et al.  Gray matter damage in multiple sclerosis: Impact on clinical symptoms , 2015, Neuroscience.

[15]  D. Louis Collins,et al.  Diurnal fluctuations in brain volume: Statistical analyses of MRI from large populations , 2015, NeuroImage.

[16]  G. Tsivgoulis,et al.  The effect of disease-modifying therapies on brain atrophy in patients with clinically isolated syndrome: a systematic review and meta-analysis , 2015, Therapeutic advances in neurological disorders.

[17]  R. Reynolds,et al.  Regional Distribution and Evolution of Gray Matter Damage in Different Populations of Multiple Sclerosis Patients , 2015, PloS one.

[18]  F. Barkhof,et al.  Evidence-based guidelines: MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis—clinical implementation in the diagnostic process , 2015, Nature Reviews Neurology.

[19]  Rohit Bakshi,et al.  Handling changes in MRI acquisition parameters in modeling whole brain lesion volume and atrophy data in multiple sclerosis subjects: Comparison of linear mixed-effect models , 2015, NeuroImage: Clinical.

[20]  D. Ramasamy,et al.  Early magnetic resonance imaging predictors of clinical progression after 48 months in clinically isolated syndrome patients treated with intramuscular interferon β‐1a , 2015, European journal of neurology.

[21]  Saurabh Jain,et al.  Automatic segmentation and volumetry of multiple sclerosis brain lesions from MR images , 2015, NeuroImage: Clinical.

[22]  M. Battaglini,et al.  Establishing pathological cut-offs of brain atrophy rates in multiple sclerosis , 2015, Journal of Neurology, Neurosurgery & Psychiatry.

[23]  Darin T. Okuda,et al.  Early CNS neurodegeneration in radiologically isolated syndrome , 2015, Neurology: Neuroimmunology & Neuroinflammation.

[24]  K. Gaston,et al.  Brain atrophy in Multiple Sclerosis , 2015 .

[25]  Francesca Baglio,et al.  Corticospinal tract integrity is related to primary motor cortex thinning in relapsing–remitting multiple sclerosis , 2015, Multiple sclerosis.

[26]  G. Tsivgoulis,et al.  The Effect of Disease Modifying Therapies on Brain Atrophy in Patients with Relapsing-Remitting Multiple Sclerosis: A Systematic Review and Meta-Analysis , 2015, PloS one.

[27]  M. Ramanathan,et al.  Cardiovascular risk factors are associated with increased lesion burden and brain atrophy in multiple sclerosis , 2015, Journal of Neurology, Neurosurgery & Psychiatry.

[28]  Rohit Bakshi,et al.  Quantification of Global Cerebral Atrophy in Multiple Sclerosis from 3T MRI Using SPM: The Role of Misclassification Errors , 2014, Journal of neuroimaging : official journal of the American Society of Neuroimaging.

[29]  D. Ramasamy,et al.  Relationship between gray matter volume and cognitive learning in CIS patients on disease-modifying treatment , 2014, Journal of the Neurological Sciences.

[30]  Vladimir S Fonov,et al.  Onset of multiple sclerosis before adulthood leads to failure of age-expected brain growth , 2014, Neurology.

[31]  Kesshi M Jordan,et al.  Spinal cord gray matter atrophy correlates with multiple sclerosis disability , 2014, Annals of neurology.

[32]  Robert Zivadinov,et al.  MRI correlates of disability progression in patients with CIS over 48 months , 2014, NeuroImage: Clinical.

[33]  C. Guttmann,et al.  An expanded composite scale of MRI-defined disease severity in multiple sclerosis: MRDSS2 , 2014, Neuroreport.

[34]  D. Arnold,et al.  Correlation between brain volume change and T2 relaxation time induced by dehydration and rehydration: Implications for monitoring atrophy in clinical studies , 2014, NeuroImage: Clinical.

[35]  Richard Nicholas,et al.  Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial , 2014, The Lancet.

[36]  D. Ramasamy,et al.  Longitudinal MRI and neuropsychological assessment of patients with clinically isolated syndrome , 2014, Journal of Neurology.

[37]  Massimo Filippi,et al.  Brain reserve and cognitive reserve protect against cognitive decline over 4.5 years in MS , 2014, Neurology.

[38]  Amandine Jullienne,et al.  Aquaporin and brain diseases. , 2014, Biochimica et biophysica acta.

[39]  Robert Zivadinov,et al.  Improved longitudinal gray and white matter atrophy assessment via application of a 4-dimensional hidden Markov random field model , 2014, NeuroImage.

[40]  F. Barkhof,et al.  Validation of the automated method VIENA: An accurate, precise, and robust measure of ventricular enlargement , 2014, Human brain mapping.

[41]  Turi O. Dalaker,et al.  Brain atrophy and disability progression in multiple sclerosis patients: a 10-year follow-up study , 2014, Journal of Neurology, Neurosurgery & Psychiatry.

[42]  M. Ramanathan,et al.  Apolipoproteins are associated with new MRI lesions and deep grey matter atrophy in clinically isolated syndromes , 2014, Journal of Neurology, Neurosurgery & Psychiatry.

[43]  H. Wiendl,et al.  Clinical Relevance of Brain Volume Measures in Multiple Sclerosis , 2014, CNS Drugs.

[44]  Christos Davatzikos,et al.  Cross‐sectional and longitudinal association of body mass index and brain volume , 2014, Human brain mapping.

[45]  D. Arnold,et al.  Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis , 2014, Annals of neurology.

[46]  M. Horsfield,et al.  Gray matter damage predicts the accumulation of disability 13 years later in MS , 2013, Neurology.

[47]  Vladimir S Fonov,et al.  Jacobian integration method increases the statistical power to measure gray matter atrophy in multiple sclerosis , 2013, NeuroImage: Clinical.

[48]  S. Hussein,et al.  Evolution of Cortical and Thalamus Atrophy and Disability Progression in Early Relapsing-Remitting MS during 5 Years , 2013, American Journal of Neuroradiology.

[49]  M. Dwyer,et al.  Thalamic atrophy is associated with development of clinically definite multiple sclerosis. , 2013, Radiology.

[50]  L. Wilkins Brain reserve and cognitive reserve in multiple sclerosis: What you’ve got and how you use it , 2013, Neurology.

[51]  M. Ramanathan,et al.  Lipid profiles are associated with lesion formation over 24 months in interferon-β treated patients following the first demyelinating event , 2013, Journal of Neurology, Neurosurgery & Psychiatry.

[52]  F. Lublin,et al.  Editors' welcome and a working definition for a multiple sclerosis cure. , 2013, Multiple sclerosis and related disorders.

[53]  M. Dwyer,et al.  Iron content of the pulvinar nucleus of the thalamus is increased in adolescent multiple sclerosis , 2013, Multiple sclerosis.

[54]  O. Almkvist,et al.  Callosal atrophy in multiple sclerosis is related to cognitive speed , 2013, Acta neurologica Scandinavica.

[55]  O. Ciccarelli,et al.  Brain atrophy and lesion load predict long term disability in multiple sclerosis , 2013, Journal of Neurology, Neurosurgery & Psychiatry.

[56]  M. Ramanathan,et al.  Interdependence and contributions of sun exposure and vitamin D to MRI measures in multiple sclerosis , 2013, Journal of Neurology, Neurosurgery & Psychiatry.

[57]  M. Ramanathan,et al.  Environmental Factors Associated with Disease Progression after the First Demyelinating Event: Results from the Multi-Center SET Study , 2013, PloS one.

[58]  H. D. de Vries,et al.  Grey matter damage in multiple sclerosis , 2013, Prion.

[59]  Massimiliano Calabrese,et al.  Measurement and clinical effect of grey matter pathology in multiple sclerosis , 2012, The Lancet Neurology.

[60]  Dana Horakova,et al.  Volumetric MRI Markers and Predictors of Disease Activity in Early Multiple Sclerosis: A Longitudinal Cohort Study , 2012, PloS one.

[61]  Massimo Filippi,et al.  Voxel-wise mapping of cervical cord damage in multiple sclerosis patients with different clinical phenotypes , 2012, Journal of Neurology, Neurosurgery & Psychiatry.

[62]  C. Besada,et al.  Brain atrophy at onset and physical disability in multiple sclerosis. , 2012, Arquivos de neuro-psiquiatria.

[63]  R. Kahn,et al.  Human brain changes across the life span: A review of 56 longitudinal magnetic resonance imaging studies , 2012, Human brain mapping.

[64]  Bruce Fischl,et al.  Within-subject template estimation for unbiased longitudinal image analysis , 2012, NeuroImage.

[65]  E. Havrdová,et al.  Corpus Callosum Atrophy – A Simple Predictor of Multiple Sclerosis Progression: A Longitudinal 9-Year Study , 2012, European Neurology.

[66]  Ondrej Dolezal,et al.  Clinical correlates of grey matter pathology in multiple sclerosis , 2012, BMC Neurology.

[67]  A. Giorgio,et al.  Association of MRI metrics and cognitive impairment in radiologically isolated syndromes , 2012, Neurology.

[68]  Vladimir S Fonov,et al.  Reduced head and brain size for age and disproportionately smaller thalami in child-onset MS , 2012, Neurology.

[69]  B. Scheithauer,et al.  Inflammatory cortical demyelination in early multiple sclerosis. , 2011, The New England journal of medicine.

[70]  M. Calabrese,et al.  The predictive value of gray matter atrophy in clinically isolated syndromes , 2011, Neurology.

[71]  Stephen M. Smith,et al.  A Bayesian model of shape and appearance for subcortical brain segmentation , 2011, NeuroImage.

[72]  D. Collins,et al.  MRI correlates of cognitive impairment in childhood-onset multiple sclerosis. , 2011, Neuropsychology.

[73]  Otto W. Witte,et al.  Changes in Brain Size during the Menstrual Cycle , 2011, PloS one.

[74]  P. Wolf,et al.  Association of matrix metalloproteinases with MRI indices of brain ischemia and aging , 2010, Neurobiology of Aging.

[75]  M. Ramanathan,et al.  Vitamin D metabolites are associated with clinical and MRI outcomes in multiple sclerosis patients , 2010, Journal of Neurology, Neurosurgery & Psychiatry.

[76]  Maria Assunta Rocca,et al.  Thalamic damage and long-term progression of disability in multiple sclerosis. , 2010, Radiology.

[77]  F. Barkhof,et al.  Early central atrophy rate predicts 5 year clinical outcome in multiple sclerosis , 2010, Journal of Neurology, Neurosurgery & Psychiatry.

[78]  M. Amato,et al.  Relevance of cognitive deterioration in early relapsing-remitting MS: a 3-year follow-up study , 2010, Multiple sclerosis.

[79]  M. Battaglini,et al.  Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes , 2010, Neurology.

[80]  Frauke Zipp,et al.  Multiple sclerosis – candidate mechanisms underlying CNS atrophy , 2010, Trends in Neurosciences.

[81]  M. Ramanathan,et al.  Increased tissue damage and lesion volumes in African Americans with multiple sclerosis , 2010, Neurology.

[82]  Yi Zhang,et al.  A longitudinal observational study of brain atrophy rate reflecting four decades of multiple sclerosis: a comparison of serial 1D, 2D, and volumetric measurements from MRI images , 2010, Neuroradiology.

[83]  D. Louis Collins,et al.  Gradient distortions in MRI: Characterizing and correcting for their effects on SIENA-generated measures of brain volume change , 2010, NeuroImage.

[84]  Chiara Romualdi,et al.  Magnetic resonance evidence of cerebellar cortical pathology in multiple sclerosis , 2009, Journal of Neurology, Neurosurgery & Psychiatry.

[85]  M Ramanathan,et al.  Magnetic resonance imaging characteristics of children and adults with paediatric-onset multiple sclerosis. , 2009, Brain : a journal of neurology.

[86]  J. Pankow,et al.  Genetic Ancestry Is Associated With Subclinical Cardiovascular Disease in African-Americans and Hispanics From the Multi-Ethnic Study of Atherosclerosis , 2009, Circulation. Cardiovascular genetics.

[87]  F. Moore INCIDENTAL MRI ANOMALIES SUGGESTIVE OF MULTIPLE SCLEROSIS: THE RADIOLOGICALLY ISOLATED SYNDROME , 2009, Neurology.

[88]  M. Ramanathan,et al.  Smoking is associated with increased lesion volumes and brain atrophy in multiple sclerosis , 2009, Neurology.

[89]  Aristide Merola,et al.  Demyelination, Inflammation, and Neurodegeneration in Multiple Sclerosis Deep Gray Matter , 2009, Journal of neuropathology and experimental neurology.

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

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

[92]  J. Brewer,et al.  Fully-Automated Quantification of Regional Brain Volumes for Improved Detection of Focal Atrophy in Alzheimer Disease , 2009, American Journal of Neuroradiology.

[93]  M. Filippi,et al.  Sample size requirements for treatment effects using gray matter, white matter and whole brain volume in relapsing–remitting multiple sclerosis , 2009, Journal of Neurology, Neurosurgery & Psychiatry.

[94]  J. Lowe,et al.  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 , 2008, Journal of Neurology, Neurosurgery, and Psychiatry.

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

[96]  David H. Miller,et al.  Gray matter atrophy is related to long‐term disability in multiple sclerosis , 2008, Annals of neurology.

[97]  M. Filippi,et al.  Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis , 2008, Neurology.

[98]  G. Comi,et al.  Clinical and conventional MRI predictors of disability and brain atrophy accumulation in RRMS , 2008, Journal of Neurology.

[99]  R. Henry,et al.  Regional grey matter atrophy in clinically isolated syndromes at presentation , 2008, Journal of Neurology, Neurosurgery, and Psychiatry.

[100]  Stephen M. Smith,et al.  Enhanced brain extraction improves the accuracy of brain atrophy estimation , 2008, NeuroImage.

[101]  M. Absinta,et al.  Evidence of thalamic gray matter loss in pediatric multiple sclerosis , 2008, Neurology.

[102]  M. Ron,et al.  Cognitive impairment in relapsing—remitting multiple sclerosis can be predicted by imaging performed several years earlier , 2008, Multiple sclerosis.

[103]  H. Butzkueven,et al.  Validation of linear cerebral atrophy markers in multiple sclerosis , 2008, Journal of Clinical Neuroscience.

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

[105]  J. L. Cox,et al.  Evolution of different MRI measures in patients with active relapsing-remitting multiple sclerosis over 2 and 5 years: a case–control study , 2007, Journal of Neurology, Neurosurgery, and Psychiatry.

[106]  R. Elashoff,et al.  Testosterone treatment in multiple sclerosis: a pilot study. , 2007, Archives of neurology.

[107]  Rohit Bakshi,et al.  Gray matter involvement in multiple sclerosis , 2007, Neurology.

[108]  P. Matthews,et al.  Neocortical neuronal, synaptic, and glial loss in multiple sclerosis , 2006, Neurology.

[109]  D. Arnold,et al.  Brain atrophy after immunoablation and stem cell transplantation in multiple sclerosis , 2006, Neurology.

[110]  Nick C Fox,et al.  Magnetic resonance imaging measures of brain atrophy in multiple sclerosis , 2006, Journal of magnetic resonance imaging : JMRI.

[111]  E. Frohman,et al.  Multiple sclerosis--the plaque and its pathogenesis. , 2006, The New England journal of medicine.

[112]  Rohit Bakshi,et al.  The measurement and clinical relevance of brain atrophy in multiple sclerosis , 2006, The Lancet Neurology.

[113]  J A Frank,et al.  Standardized MR imaging protocol for multiple sclerosis: Consortium of MS Centers consensus guidelines. , 2006, AJNR. American journal of neuroradiology.

[114]  Hans Lassmann,et al.  Cortical demyelination and diffuse white matter injury in multiple sclerosis. , 2005, Brain : a journal of neurology.

[115]  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.

[116]  Frederik Barkhof,et al.  Intracortical lesions in multiple sclerosis: improved detection with 3D double inversion-recovery MR imaging. , 2005, Radiology.

[117]  R. Zivadinov Steroids and brain atrophy in multiple sclerosis , 2005, Journal of the Neurological Sciences.

[118]  Mara Cercignani,et al.  Grey and white matter volume changes in early primary progressive multiple sclerosis: a longitudinal study. , 2005, Brain : a journal of neurology.

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

[120]  W. Heindel,et al.  Dehydration confounds the assessment of brain atrophy , 2005, Neurology.

[121]  M. Rovaris,et al.  Regional brain atrophy evolves differently in patients with multiple sclerosis according to clinical phenotype. , 2005, AJNR. American journal of neuroradiology.

[122]  David H. Miller,et al.  Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes. , 2004, Brain : a journal of neurology.

[123]  P. Matthews,et al.  Accelerated evolution of brain atrophy and “black holes” in MS patients with APOE‐ε4 , 2004, Annals of neurology.

[124]  Rohit Bakshi,et al.  Prediction of neuropsychological impairment in multiple sclerosis: comparison of conventional magnetic resonance imaging measures of atrophy and lesion burden. , 2004, Archives of neurology.

[125]  R. Zivadinov,et al.  HLA genotypes and disease severity assessed by magnetic resonance imaging findings in patients with multiple sclerosis , 2003, Journal of Neurology.

[126]  B D Trapp,et al.  Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration , 2003, Multiple sclerosis.

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

[128]  F. Barkhof,et al.  Longitudinal brain volume measurement in multiple sclerosis: rate of brain atrophy is independent of the disease subtype. , 2002, Archives of neurology.

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

[130]  David H. Miller,et al.  Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. , 2002, Brain : a journal of neurology.

[131]  Rohit Bakshi,et al.  Bicaudate ratio as a magnetic resonance imaging marker of brain atrophy in multiple sclerosis. , 2002, Archives of neurology.

[132]  R. Bakshi,et al.  Frontal cortex atrophy predicts cognitive impairment in multiple sclerosis. , 2002, The Journal of neuropsychiatry and clinical neurosciences.

[133]  B. Trapp,et al.  Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions , 2001, Annals of neurology.

[134]  G Cazzato,et al.  A longitudinal study of brain atrophy and cognitive disturbances in the early phase of relapsing-remitting multiple sclerosis , 2001, Journal of neurology, neurosurgery, and psychiatry.

[135]  C. Lucchinetti,et al.  Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. , 2001, Trends in molecular medicine.

[136]  G J Barker,et al.  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. , 2000, Brain : a journal of neurology.

[137]  A M Dale,et al.  Measuring the thickness of the human cerebral cortex from magnetic resonance images. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[138]  Karl J. Friston,et al.  Voxel-Based Morphometry—The Methods , 2000, NeuroImage.

[139]  R. Rudick,et al.  Axonal transection in the lesions of multiple sclerosis. , 1998, The New England journal of medicine.

[140]  G. Gasbarrini,et al.  Neuroimaging of cerebral and cerebellar atrophy in anorexia nervosa , 1997, Psychiatry Research: Neuroimaging.

[141]  Nick C. Fox,et al.  The boundary shift integral: an accurate and robust measure of cerebral volume changes from registered repeat MRI , 1997, IEEE Transactions on Medical Imaging.

[142]  M. Reveley,et al.  EFFECTS OF ACUTE DEHYDRATION ON COMPUTERISED TOMOGRAPHIC ASSESSMENT OF CEREBRAL DENSITY AND VENTRICULAR VOLUME , 1982, The Lancet.

[143]  B. Brownell,et al.  The distribution of plaques in the cerebrum in multiple sclerosis , 1962, Journal of neurology, neurosurgery, and psychiatry.

[144]  Frederik Barkhof,et al.  Cortical atrophy patterns in multiple sclerosis are non-random and clinically relevant. , 2016, Brain : a journal of neurology.

[145]  J. Karakaya,et al.  Assessment of the effect of cigarette smoking on regional brain volumes and lesion load in patients with clinically isolated syndrome. , 2016, The International journal of neuroscience.

[146]  C. Besada,et al.  Brain Atrophy in Radiologically Isolated Syndromes , 2015, Journal of neuroimaging : official journal of the American Society of Neuroimaging.

[147]  S J Nelson,et al.  Genotype-Phenotype correlations in multiple sclerosis: HLA genes influence disease severity inferred by 1HMR spectroscopy and MRI measures. , 2009, Brain : a journal of neurology.

[148]  V. M. Anderson BSc,et al.  Detecting treatment effects on brain atrophy in relapsing remitting multiple sclerosis: Sample size estimates , 2007, Journal of Neurology.

[149]  Rohit Bakshi,et al.  Role of MRI in multiple sclerosis II: brain and spinal cord atrophy. , 2004, Frontiers in bioscience : a journal and virtual library.

[150]  F Barkhof,et al.  Qualitative Assessment of Cerebral Atrophy on MRI: Inter- and Intra-Observer Reproducibility in Dementia and Normal Aging , 1997, European Neurology.