Grey matter damage predicts the evolution of primary progressive multiple sclerosis at 5 years.

Reliable prognostic markers of primary progressive (PP) multiple sclerosis evolution are still needed. Diffusion tensor (DT) MRI can quantify normal-appearing white matter (NAWM) and grey matter (GM) damage in multiple sclerosis patients. We investigated whether conventional and DT-MRI-derived measures can predict the long-term clinical evolution of PP multiple sclerosis. In 54 PP multiple sclerosis patients, conventional and DT-MRI scans of the brain and T1-weighted scans of the cervical cord were acquired at baseline and after a median follow-up of 15 months. Another clinical evaluation was performed, 56 months after baseline, in 52 patients. Measures of lesion load, brain and cord atrophy were obtained. Histograms of the mean diffusivity (MD) and fractional anisotropy (FA) values from the NAWM and GM were analysed. At follow-up, 35 patients (65%) experienced a confirmed disability progression. Baseline expanded disability status scale score and average GM MD were independent predictors of subsequent clinical deterioration in a multivariable model (Nagelkerke R2: 0.44; discriminating ability: 81%). A lower level of disability and a more severe GM damage identify PP multiple sclerosis patients with an increased risk of disease progression over the subsequent 5 years. These data may be relevant to select patients for future exploratory phase II trials.

[1]  A. Thompson,et al.  Primary progressive multiple sclerosis: a 5-year clinical and MR study. , 2003, Brain : a journal of neurology.

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

[3]  Marco Rovaris,et al.  Assessment of normal-appearing white and gray matter in patients with primary progressive multiple sclerosis: a diffusion-tensor magnetic resonance imaging study. , 2002, Archives of neurology.

[4]  A J Thompson,et al.  Clinical and Magnetic Resonance Imaging Predictors of Disability in Primary and Secondary Progressive Multiple Sclerosis , 1996, Multiple sclerosis.

[5]  P M Matthews,et al.  Evidence for widespread movement-associated functional MRI changes in patients with PPMS , 2002, Neurology.

[6]  A. Thompson,et al.  Spinal cord atrophy and disability in multiple sclerosis. A new reproducible and sensitive MRI method with potential to monitor disease progression. , 1996, Brain : a journal of neurology.

[7]  F. Barkhof,et al.  The effect of the neuroprotective agent riluzole on MRI parameters in primary progressive multiple sclerosis: a pilot study , 2002, Multiple sclerosis.

[8]  F. Barkhof,et al.  Brain and spinal cord abnormalities in multiple sclerosis. Correlation between MRI parameters, clinical subtypes and symptoms. , 1998, Brain : a journal of neurology.

[9]  F. Barkhof,et al.  Cortical lesions in multiple sclerosis. , 1999, Brain : a journal of neurology.

[10]  P. Matthews,et al.  Normalized Accurate Measurement of Longitudinal Brain Change , 2001, Journal of computer assisted tomography.

[11]  G. Barker,et al.  MRI dynamics of brain and spinal cord in progressive multiple sclerosis. , 1996, Journal of neurology, neurosurgery, and psychiatry.

[12]  A. Thompson,et al.  One year follow up study of primary and transitional progressive multiple sclerosis , 2000, Journal of neurology, neurosurgery, and psychiatry.

[13]  O. Ciccarelli,et al.  Diffusion MRI in multiple sclerosis , 2005, Neurology.

[14]  F. Barkhof,et al.  Long-term clinical outcome of primary progressive MS: Predictive value of clinical and MRI data , 2005, Neurology.

[15]  M. Rovaris,et al.  Axonal injury and overall tissue loss are not related in primary progressive multiple sclerosis. , 2005, Archives of neurology.

[16]  A J Thompson,et al.  Metabolite changes in normal-appearing gray and white matter are linked with disability in early primary progressive multiple sclerosis. , 2005, Archives of neurology.

[17]  Christian M Kerskens,et al.  Progressive change in primary progressive multiple sclerosis normal-appearing white matter: a serial diffusion magnetic resonance imaging study , 2004, Multiple sclerosis.

[18]  A J Thompson,et al.  A comparison of the pathology of primary and secondary progressive multiple sclerosis. , 1994, Brain : a journal of neurology.

[19]  R. Ordidge,et al.  High field MRI correlates of myelin content and axonal density in multiple sclerosis , 2003, Journal of Neurology.

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

[21]  P. Matthews,et al.  Regional axonal loss in the corpus callosum correlates with cerebral white matter lesion volume and distribution in multiple sclerosis. , 2000, Brain : a journal of neurology.

[22]  A J Thompson,et al.  Diagnostic criteria for primary progressive multiple sclerosis: A position paper , 2000, Annals of neurology.

[23]  J. Winn,et al.  Brain , 1878, The Lancet.

[24]  J. Parisi,et al.  Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination , 2000, Annals of neurology.

[25]  D. Chard,et al.  Interferon beta-1a in primary progressive MS: an exploratory, randomized, controlled trial. , 2003, Neurology.

[26]  A. Thompson,et al.  Major differences in the dynamics of primary and secondary progressive multiple sclerosis , 1991, Annals of neurology.

[27]  A. Thompson,et al.  Magnetic resonance imaging in monitoring the treatment of multiple sclerosis: concerted action guidelines. , 1991, Journal of neurology, neurosurgery, and psychiatry.

[28]  A. Thompson,et al.  Patterns of disease activity in multiple sclerosis: clinical and magnetic resonance imaging study. , 1990, BMJ.

[29]  Marco Rovaris,et al.  Conventional and magnetization transfer MRI predictors of clinical multiple sclerosis evolution: a medium-term follow-up study. , 2003, Brain : a journal of neurology.

[30]  D. Miller,et al.  Interferon β-1a in primary progressive MS , 2003, Neurology.

[31]  G. Comi,et al.  In vivo assessment of the brain and cervical cord pathology of patients with primary progressive multiple sclerosis. , 2001, Brain : a journal of neurology.

[32]  M. Filippi,et al.  Correlations between Structural CNS Damage and Functional MRI Changes in Primary Progressive MS , 2002, NeuroImage.

[33]  M Cercignani,et al.  Diffusion tensor magnetic resonance imaging in multiple sclerosis , 2001, Neurology.

[34]  F. Barkhof,et al.  Hypointense lesions on T1-weighted spin-echo magnetic resonance imaging: relation to clinical characteristics in subgroups of patients with multiple sclerosis. , 2001, Archives of neurology.

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

[36]  A. Thompson,et al.  A longitudinal study of cognition in primary progressive multiple sclerosis. , 2005, Brain : a journal of neurology.

[37]  J. Kurtzke Rating neurologic impairment in multiple sclerosis , 1983, Neurology.

[38]  J. Baskerville,et al.  The natural history of multiple sclerosis: a geographically based study. 5. The clinical features and natural history of primary progressive multiple sclerosis. , 1999, Brain : a journal of neurology.

[39]  Massimo Filippi,et al.  Quantification of brain gray matter damage in different MS phenotypes by use of diffusion tensor MR imaging. , 2002, AJNR. American journal of neuroradiology.

[40]  Marco Rovaris,et al.  Short-term accrual of gray matter pathology in patients with progressive multiple sclerosis: an in vivo study using diffusion tensor MRI , 2005, NeuroImage.

[41]  Zografos Caramanos,et al.  Magnetization transfer can predict clinical evolution in patients with multiple sclerosis , 2002, Journal of Neurology.

[42]  J. Baskerville,et al.  The natural history of multiple sclerosis: a geographically based study. 3. Multivariate analysis of predictive factors and models of outcome. , 1991, Brain : a journal of neurology.

[43]  F. Barkhof,et al.  Primary and transitional progressive MS , 1999, Neurology.

[44]  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.

[45]  A. Thompson,et al.  Magnetic resonance imaging predictors of disability in primary progressive multiple sclerosis: a 5-year study , 2004, Multiple sclerosis.

[46]  A. J. Thompson,et al.  Magnetic resonance studies of abnormalities in the normal appearing white matter and grey matter in multiple sclerosis , 2003, Journal of Neurology.

[47]  M Rovaris,et al.  Two-year follow-up study of primary and transitional progressive multiple sclerosis , 2002, Multiple sclerosis.

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

[49]  A J Thompson,et al.  Is inflammation important in early PPMS? a longitudinal MRI study , 2005, Journal of Neurology, Neurosurgery & Psychiatry.

[50]  J. Dehmeshki,et al.  The normal appearing grey matter in primary progressive multiple sclerosis , 2003, Journal of Neurology.

[51]  Frederik Barkhof,et al.  Cortical lesions in multiple sclerosis: combined postmortem MR imaging and histopathology. , 2005, AJNR. American journal of neuroradiology.