Brain atrophy in clinically early relapsing-remitting multiple sclerosis.

Brain atrophy measured by MRI is a potentially useful tool for monitoring disease progression in multiple sclerosis. The location, extent and mechanisms of brain atrophy in early disease are not well documented. Using quantitative MRI, this study investigated whole brain, grey and white matter atrophy in clinically early relapsing-remitting multiple sclerosis and its relationship to lesion measures. Data came from 27 normal control subjects (14 females and 13 males, mean age 36.1 years) and 26 subjects with clinically definite multiple sclerosis (18 females and eight males, mean age 35.1 years, mean delay from first symptom to scan 1.8 years, median Expanded Disability Status Scale score 1.0). All had three-dimensional fast spoiled gradient recall (3D FSPGR), T(1)-weighted pre- and post-gadolinium-enhanced and T(2)-weighted scans. The 3D FSPGR images were automatically segmented into grey and white matter and cerebrospinal fluid using SPM99. 3D FSPGR hypo-intense, T(2) hyper-intense, T(1) hypo-intense and T(1) post-gadolinium-enhancing lesion volumes were determined by semi-automatic lesion segmentation. The SPM99 output was combined with the 3D FSPGR lesion segmentations to quantify tissue volumes as fractions of total intracranial volumes, producing values for the brain parenchymal fraction (BPF), white matter fraction (WMF) and grey matter fraction (GMF). Comparing multiple sclerosis with control subjects, BPF, GMF and WMF were significantly reduced (P < 0.001 for all tissue fractions). Using Pearson correlations, T(2) hyper-intense and T(1) hypo-intense lesion volumes were inversely related to BPF (T(2) r = -0.78, P < 0.001; T(1) r = -0.59, P = 0.002) and GMF (T(2) r = -0.73, P < 0.001; T(1) r = -0.53, P = 0.006), but not WMF (T(2) r = -0.30, P = 0.134; T(1) r = -0.26, P = 0.199). T(1) post-gadolinium-enhancing lesion volumes were not correlated with any fractional volumes. These results indicate that significant brain atrophy, affecting both grey and white matter, occurs early in the clinical course of multiple sclerosis. The lack of correlation between lesion load measures and WMF suggests that pathological changes in white matter may occur by mechanisms which are at least partly independent from overt lesion genesis in early multiple sclerosis.

[1]  I. Allen,et al.  A histological, histochemical and biochemical study of the macroscopically normal white matter in multiple sclerosis , 1979, Journal of the Neurological Sciences.

[2]  Caterina Mainero,et al.  Brain atrophy in relapsing-remitting multiple sclerosis: relationship with ‘black holes’, disease duration and clinical disability , 2000, Journal of the Neurological Sciences.

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

[4]  J. Ashburner,et al.  Multimodal Image Coregistration and Partitioning—A Unified Framework , 1997, NeuroImage.

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

[6]  G. Barker,et al.  The effect of section thickness on MR lesion detection and quantification in multiple sclerosis. , 1998, AJNR. American journal of neuroradiology.

[7]  G. Comi,et al.  Increased spatial resolution using a three-dimensional T1-weighted gradient-echo MR sequence results in greater hypointense lesion volumes in multiple sclerosis. , 1998, AJNR. American journal of neuroradiology.

[8]  B. Pakkenberg,et al.  Neocortical neuron number in humans: Effect of sex and age , 1997, The Journal of comparative neurology.

[9]  D.L. Plummer,et al.  DispImage: Un mezzo di analisi e presentazione per iconografia medica , 1992 .

[10]  R. Kikinis,et al.  White matter changes with normal aging , 1998, Neurology.

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

[12]  H. Lassmann,et al.  Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. , 2000, The American journal of pathology.

[13]  M N Rossor,et al.  Progressive cerebral atrophy in MS , 2000, Neurology.

[14]  Virginia M. Y. Lee,et al.  Myelin-Associated Glycoprotein Is a Myelin Signal that Modulates the Caliber of Myelinated Axons , 1998, The Journal of Neuroscience.

[15]  Marco Rovaris,et al.  Reproducibility of Brain MRI Lesion Volume Measurements in Multiple Sclerosis Using a Local Thresholding Technique: Effects of Formal Operator Training , 1999, European Neurology.

[16]  Hans Lassmann,et al.  Inflammatory central nervous system demyelination: Correlation of magnetic resonance imaging findings with lesion pathology , 1997, Annals of neurology.

[17]  Peter Kapeller,et al.  Preliminary evidence for neuronal damage in cortical grey matter and normal appearing white matter in short duration relapsing-remitting multiple sclerosis: a quantitative MR spectroscopic imaging study , 2001, Journal of Neurology.

[18]  Gianpaolo Donzelli,et al.  Catch-Up Growth in Short-at-Birth NICU Graduates , 2000, Hormone Research in Paediatrics.

[19]  J S Wolinsky,et al.  Serial proton magnetic resonance spectroscopic imaging, contrast‐enhanced magnetic resonance imaging, and quantitative lesion volumetry in multiple sclerosis , 1998, Annals of neurology.

[20]  A. Spiegel.  G Protein Defects in Signal Transduction , 2000, Hormone Research in Paediatrics.

[21]  W. Tourtellotte,et al.  Some spaces and barriers in postmortem multiple sclerosis. , 1968, Progress in brain research.

[22]  R. Kinkel,et al.  A Wallerian degeneration pattern in patients at risk for MS , 2000, Neurology.

[23]  A J Thompson,et al.  Progressive cerebral atrophy in multiple sclerosis. A serial MRI study. , 1996, Brain : a journal of neurology.

[24]  R. Herndon,et al.  A longitudinal study of brain atrophy in relapsing multiple sclerosis , 1999, Neurology.

[25]  J. Udupa,et al.  The effect of gadolinium-enhancing lesions on whole brain atrophy in relapsing-remitting MS , 2000, Neurology.

[26]  S J Nelson,et al.  A longitudinal study of ventricular volume in early relapsing-remitting multiple sclerosis , 2000, Multiple sclerosis.

[27]  J. Prineas,et al.  The fine structure of chronically active multiple sclerosis plaques , 1978, Neurology.

[28]  G D Pearlson,et al.  Magnetic resonance imaging evaluation of the effects of ageing on grey–white ratio in the human brain , 1994, Neuropathology and applied neurobiology.

[29]  G. Ratcliff,et al.  Sex differences in brain aging: a quantitative magnetic resonance imaging study. , 1998, Archives of neurology.

[30]  N. Obuchowski,et al.  Volume T1‐Weighted Gradient Echo MRI in Multiple Sclerosis Patients , 1992, Journal of computer assisted tomography.

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

[32]  V. Perry,et al.  Axonal damage in acute multiple sclerosis lesions. , 1997, Brain : a journal of neurology.

[33]  W Steinbrich,et al.  Serial proton MR spectroscopy of contrast-enhancing multiple sclerosis plaques: absolute metabolic values over 2 years during a clinical pharmacological study. , 2000, AJNR. American journal of neuroradiology.

[34]  D D Blatter,et al.  Quantitative volumetric analysis of brain MR: normative database spanning 5 decades of life. , 1995, AJNR. American journal of neuroradiology.

[35]  F. Barkhof,et al.  Histopathologic correlate of hypointense lesions on T1-weighted spin-echo MRI in multiple sclerosis , 1998, Neurology.

[36]  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.

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

[38]  N. Patronas,et al.  Serial gadolinium‐enhanced magnetic resonance imaging scans in patients with early, relapsing‐remitting multiple sclerosis: Implications for clinical trials and natural history , 1991, Annals of neurology.

[39]  D. Silberberg,et al.  New diagnostic criteria for multiple sclerosis: Guidelines for research protocols , 1983, Annals of neurology.

[40]  K O Lim,et al.  Decreased gray matter in normal aging: an in vivo magnetic resonance study. , 1992, Journal of gerontology.

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

[42]  J A Corsellis,et al.  VARIATION WITH AGE IN THE VOLUMES OF GREY AND WHITE MATTER IN THE CEREBRAL HEMISPHERES OF MAN: MEASUREMENTS WITH AN IMAGE ANALYSER , 1980, Neuropathology and applied neurobiology.

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

[44]  A. Compston,et al.  Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis , 1999, Annals of neurology.

[45]  Age and gender effects on brain grey and white matter volumes in normal controls: the reproducibility and sensitivity of an SPM based segmentation methodology. , 2001 .

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

[47]  D. Mathalon,et al.  A quantitative magnetic resonance imaging study of changes in brain morphology from infancy to late adulthood. , 1994, Archives of neurology.

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

[49]  S. Reingold,et al.  Defining the clinical course of multiple sclerosis , 1996, Neurology.

[50]  M Quarantelli,et al.  Measurement of global brain atrophy in alzheimer's disease with unsupervised segmentation of spin‐echo MRI studies , 2000, Journal of magnetic resonance imaging : JMRI.

[51]  M N Rossor,et al.  Intracranial volume and Alzheimer disease: evidence against the cerebral reserve hypothesis. , 2000, Archives of neurology.

[52]  J. Taubenberger,et al.  Correlation between magnetic resonance imaging findings and lesion development in chronic, active multiple sclerosis , 1993, Annals of neurology.

[53]  S. Yamaguchi,et al.  Gender effects on age-related changes in brain structure. , 2000, AJNR. American journal of neuroradiology.

[54]  L D Blumhardt,et al.  Three dimensional MRI estimates of brain and spinal cord atrophy in multiple sclerosis , 1999, Journal of neurology, neurosurgery, and psychiatry.

[55]  Pradeep Rajagopalan,et al.  Age and sex effects on brain morphology , 1997, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

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