Brain, Vol. 123, No. 9, 1845-1849,
September 2000
© 2000 Oxford University Press
Regional axonal loss in the corpus callosum correlates with cerebral white matter lesion volume and distribution in multiple sclerosis
1 Centre for Functional Magnetic Resonance Imaging of the Brain, John Radcliffe Hospital and 1 Department of Clinical Neurology, University of Oxford, Oxford, UK
Correspondence to:
Professor P. M. Matthews, Centre for Functional Magnetic Resonance Imaging of the Brain, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK E-mail: paul{at}fmrib.ox.ac.uk
 |
Abstract |
|---|
 Top Abstract IntroductionMaterial and methodsResultsDiscussionReferences |
|---|
Previous imaging studies have suggested that there is substantial axonal loss in the normal-appearing white matter (NAWM) of brains from multiple sclerosis patients and that this axonal loss may be an important determinant of disability. Recently, substantial axonal loss in the NAWM has been confirmed directly in post-mortem tissue. Whether the NAWM changes occur as a consequence of damage to axons traversing lesions or to a more diffuse injury process is uncertain. Using formalin-fixed brains of eight multiple sclerosis patients and eight age-matched controls, we examined the relationship between demyelinating lesion load in three volumes of the cerebral white matter and the loss of axons in NAWM of the corresponding three projection regions (anterior, middle, posterior) in the corpus callosum (CC). There was a significant loss of calculated total number of axons crossing the CC in each of the three regions relative to the non-multiple sclerosis controls. Strong correlations were found between the regional lesion load and both the axonal density (r = –0.673, P = 0.001) and the total estimated number of axons crossing the corresponding projection area in the CC (r = –0.656, P = 0.001) for the patients. This suggests that Wallerian degeneration of axons transected in the demyelinating lesions makes a major contribution to the substantial, diffuse loss of axons in the NAWM in multiple sclerosis. These findings emphasize the need to consider the consequences of multiple sclerosis lesions in terms of both local and distant effects in functionally connected regions of the brain.
multiple sclerosis; neuropathology; axon; corpus callosum; Wallerian degeneration
CC = corpus callosum; NAWM = normal-appearing white matter
|
Introduction |
|---|
|
TopAbstractIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
While less prominent than demyelination, loss of axons in multiple sclerosis lesions is well described in the neuropathological literature (Greenfield and King, 1936
). The importance of axonal loss in the pathogenesis of the symptoms of multiple sclerosis has recently become the focus of attention (Matthews et al., 1998). Using magnetic resonance spectroscopy to measure levels of N-acetylaspartate, more specific evidence for the role of axonal dysfunction in axon loss has been found both in multiple sclerosis lesions and in the normal-appearing white matter (NAWM) of living multiple sclerosis patients (Arnold et al., 1990; Fu et al., 1998).
Studies of post-mortem brains first confirmed the early loss of axons in acute multiple sclerosis lesions (Ferguson et al., 1997; Trapp et al., 1998). We reported recently a quantitative pathological study of axonal loss in the NAWM, which demonstrated a reduction of >50% in the total number of axons passing through the corpus callosum (CC) in multiple sclerosis patients compared with controls who died of unrelated diseases (Evangelou et al., 2000). The cause of the axonal loss was hypothesized to be Wallerian degeneration of the axons transected in multiple sclerosis lesions, but the possibility of a more generalized axonopathy could not be discounted.
To investigate this hypothesis, we extended our pathological studies in order to examine the relationship between the regional multiple sclerosis lesion load in the cerebral hemispheres and distant axonal loss in the corresponding projection areas of NAWM in the CC. We reasoned that, if Wallerian degeneration of the axons that are transected in demyelinating lesions is a dominant mechanism of axon loss in NAWM, then a strong relationship should be found between these measures.
|
Material and methods |
|---|
|
TopAbstractIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
Using the archival material of the Department of Neuropathology at the Radcliffe Infirmary, we examined the brains of the most recent eight patients to have died with multiple sclerosis and to have had an autopsy examination, and eight brains from subjects as closely matched as possible for age and sex who died of non-neurological conditions. All brains were fixed in formalin.
We bisected each brain in the mid-sagittal plane and measured the cross-sectional area of the CC as described previously (Evangelou et al., 2000). The CC was divided into three sections for analysis. The first section included the rostrum, the inferior genu and the superior genu, the second section included the posterior genu and the mid-body, and the third section included the isthmus and the splenium (Aboitiz et al., 1992). Sections of the CC (10 µm) were stained either for myelin with luxol fast blue and cresyl violet or for axons with the Palmgren silver stain (Fig. 1). After regions of the corpus callosum with demyelinating lesions had been excluded (fewer than ~5% of the total CC studied), we measured the axonal density in each of the three regions of the CC using a previously validated automated method (Evangelou et al., 2000). The total estimated number of axons crossing the CC was calculated for each region by multiplying the density of the fibres by the cross-sectional area.
|
We sectioned the cerebral hemispheres coronally every 1 cm. We identified and then measured the cross-sectional area of all of the macroscopically identified multiple sclerosis lesions using the stereological technique of point counting (Howard and Reed, 1998
). The volume of the lesions was calculated by multiplying the surface area by the depth of the section (1 cm). We then calculated the separate lesion loads in each of three cerebral white matter volumes (anterior, middle and posterior) projecting into the corresponding regions of the CC. The results are reported as mean ±1 SD unless otherwise noted. Comparisons between groups were performed using the Wilcoxon signed rank test, and one-tailed Pearson correlations were calculated (assuming that volume or axon number increases were not possible in the patient group). The relationship between relative changes in lesion volumes and regional NAWM axon counts was tested by multiple regression analysis. All statistical calculations were performed with SPSS for Windows version 8.
|
Results |
|---|
|
TopAbstractIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
Individual results for patients and mean values for controls are given in Table 1
. The ages of the normal controls (median 63 years, range 40–77 years, n = 8) and the multiple sclerosis patients (median 58 years, range 30–71 years, n = 8) at death were similar. Two patients had relapsing–remitting multiple sclerosis and the other six had secondary progressive disease. The median duration of disease was 21 years (range 5–34 years).
|
The mean cross-sectional areas were smaller in the multiple sclerosis brains than in control brains in each of the three anatomical regions of the CC [in mm2, median (range): anterior, multiple sclerosis patients 152 (96–304), controls 232 (176–352); middle, multiple sclerosis patients 230 (154–267), controls 315 (240–465); posterior, multiple sclerosis patients 182 (111–338), controls 297 (260–349)]. The mean axonal densities in the multiple sclerosis brains were also reduced in all three regions compared with controls [in axons/mm2: anterior, multiple sclerosis patients 9.2 x 104 (2.0–15 x 104), controls 1.4 x 105 (1.1–1.9 x 105); middle, multiple sclerosis patients 7.8 x 104 (2.1–18 x 104), controls 1.3 x 105 (0.8–1.6 x 105); posterior, multiple sclerosis patients 7.7 x 104 (2.7–18 x 104), controls 1.2 x 105 (1.0–1.8 x 105)]. The calculated total numbers of axons crossing the CC in the multiple sclerosis brains were therefore reduced significantly in each region relative to normal controls (anterior: patients, median 1.7 x 107, controls 3.3 x 107, P < 0.01; middle: patients, median 2.0 x 107, controls 3.5 x 107, P < 0.04; posterior: patients, median 1.6 x 107, controls 3.8 x 107, P < 0.01). There were no significant differences between patients and controls in the relative regional reductions in CC area or axon density, or in calculated numbers of axons crossing the CC.
The patients had a median lesion load of 10.2 cm3 (range 0.2–31.2 cm3). Similar lesion loads were found in each of the three volumes of cerebral white matter defined on the basis of the region of projection through the CC [median (range): anterior 2.1 (0.1–9.6) cm3; middle 4.3 (0–13.8) cm3; posterior 3.5 (0–9.8) cm3]. The multiple sclerosis lesion loads in each cerebral white matter volume (anterior, middle and posterior) correlated with both the axonal density (r = –0.673, P = 0.001) (Fig. 2A) and the total number of axons crossing the CC in the corresponding region (r = –0.656, P = 0.001) (Fig. 2B). We found that when the relationship between lesion loads in the different cerebral white matter volumes and regional CC axon changes was tested for data from individual patients by multiple regression analysis, this correlation remained strong (r = 0.620, P = 0.001), excluding the possibility that the patients just with higher lesion loads might be biasing the group results.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
It has long been known that there can be extensive axonal loss in gliotic lesions with chronic multiple sclerosis (Greenfield and King, 1936
). More modern post-mortem studies have demonstrated injury and loss of axons in acute lesions (Ferguson et al., 1997; Trapp et al., 1998) also, confirming the earlier magnetic resonance spectroscopic studies (Arnold et al., 1990). Evidence has emerged recently for a substantial loss of axons in areas of the brain that do not appear to be affected by the disease, this loss being associated with signal intensity changes on conventional MRI of the brain (Narayanan et al., 1997; Fu et al., 1998; De Stefano et al., 1999) or on direct neuropathological examination (Evangelou et al., 2000). There is evidence that the extent of axonal loss in the NAWM plays an important role in determining the clinical disability (De Stefano et al., 1998; Fu et al., 1998; Matthews et al., 1998). Two possible pathogenetic mechanisms have been proposed for the decrease of axonal numbers in the NAWM. One possibility is that there is a diffuse axonopathy in multiple sclerosis. Although such a process might be particularly important in primary progressive disease (in which the inflammatory lesion load is low), it may also contribute to axon loss in more typical disease. Secondly (and not mutually exclusively), loss of axons in the NAWM might simply be the result of Wallerian degeneration of axons that are transected in multiple sclerosis lesions.
The results of our study are most consistent with the second hypothesis. Despite the variation in the number of axons across the CC of neurologically normal controls, we found a significant and strong correlation between regional hemispheric lesion volume and axonal density in the corresponding projection region of the CC in multiple sclerosis patients. Supportive results have been presented recently in a study of the cervical cord of multiple sclerosis patients (Ganter et al., 1999), but the CC offers advantages for the quantitative assessment of axon loss. Although many of the fibres are unmyelinated (and the smallest cannot be visualized in paraffin-embedded material, potentially contributing to underestimation of axon loss) (Aboitiz et al., 1992), the high degree of order in axon orientation within the CC allows them to be counted accurately in transverse sections.
Quantitative relationships between more distant white matter lesions and axon loss in the CC is also possible. Most of the axons of the CC appear to connect homologous areas of the two cerebral hemispheres (de Lacoste et al., 1985; Pandya and Seltzer, 1986). In the adult corpus callosum the genu connects the prefrontal cortices, the midbody connects the motor, sensory and auditory cortices, and the splenium carries temporal, parietal and occipital fibres (de Lacoste et al., 1985; Pandya and Seltzer, 1986). Therefore, estimates of regional axonal densities and total fibres can be related to the volume of multiple sclerosis lesions within the regions from which these fibres arise.
Wallerian degeneration follows quickly after axonal transection. Imaging studies after cerebral infarction have demonstrated that the earliest changes occur within 72 h to 14 days (Igarashi et al., 1998; Castello et al., 2000), with subsequent evolution over up to 4 months after injury (Orita et al., 1994).
If disability in multiple sclerosis is caused predominantly by injury to axons traversing inflammatory lesions, then efforts to minimize damage to and loss of axons should work in cooperation with current efforts directed at reducing the frequency and extent of inflammation. Pharmacological targeting of potentially toxic inflammatory factors (Rothwell and Hopkins, 1995) or the use of neurotrophic agents may be helpful (Skaper and Walsh, 1998). Potential genetic markers of increased susceptibility to more severe disease may provide further new targets for treatment, as may the identification of genes specifically determining Wallerian degeneration.
|
Acknowledgments |
|---|
P.M.M. wishes to thank the Medical Research Council (MRC) and the Multiple Sclerosis Society of Great Britain and Northern Ireland for their generous support of this work and the MRC for personal support.
|
References |
|---|
|
TopAbstractIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
Aboitiz F, Scheibel AB, Fisher RS, Zaidel E. Fiber composition of the human corpus callosum. Brain Res 1992; 598: 143–53.[Web of Science][Medline]
Arnold DL, Matthews PM, Francis G, Antel J. Proton magnetic resonance spectroscopy of human brain in vivo in the evaluation of multiple sclerosis: assessment of the load of disease. Magn Reson Med 1990; 14: 154–9.[Web of Science][Medline]
Castillo M, Mukherji SK, Isaacs D, Smith JK. Cerebral infarctions: evaluation with single-axis versus trace diffusion-weighted MR imaging. AJR Am J Roentgenol 2000; 174: 853–7.
de Lacoste MC, Kirkpatrick JB, Ross ED. Topography of the human corpus callosum. J Neuropathol Exp Neurol 1985; 44: 578–91.[Web of Science][Medline]
De Stefano N, Matthews PM, Fu L, Narayanan S, Stanley J, Francis G, et al. Axonal damage correlates with disability in patients with relapsing–remitting multiple sclerosis: results of a longitudinal magnetic resonance spectroscopy study. Brain 1998; 121: 1469–77.
De Stefano N, Narayanan S, Matthews PM, Francis GS, Antel JP, Arnold DL. In vivo evidence for axonal dysfunction remote from focal cerebral demyelination of the type seen in multiple sclerosis. Brain 1999; 122: 1933–9.
Evangelou N, Esiri MM, Smith S, Palace J, Matthews PM. Quantitative pathological evidence for axonal loss in normal appearing white matter in multiple sclerosis. Ann Neurol 2000; 47: 391–5.[Web of Science][Medline]
Ferguson B, Matyszak MK, Esiri MM, Perry VH. Axonal damage in acute multiple sclerosis lesions. Brain 1997; 120: 393–9.
Fu L, Matthews PM, De Stefano N, Worsley KJ, Narayanan S, Francis GS, et al. Imaging axonal damage of normal-appearing white matter in multiple sclerosis. Brain 1998; 121: 103–13.
Ganter P, Prince C, Esiri MM. Spinal cord axonal loss in multiple sclerosis: a post mortem study. Neuropathol Appl Neurobiol 1999; 25: 459–67.[Web of Science][Medline]
Greenfield JG, King LS. Observations on the histopathology of the cerebral lesions in disseminated sclerosis. Brain 1936; 59: 445–58.
Howard CV, Reed MG. Unbiased stereology: three dimensional measurement in microscopy. Oxford: BIOS Scientific; 1998.
Igarashi H, Katayama Y, Tsuganezawa T, Yamamuro M, Terashi A, Owan C. Three-dimensional anisotropy contrast (3DAC) magnetic resonance imaging of the human brain: application to assess Wallerian degeneration. Intern Med 1998; 37: 662–8.[Web of Science][Medline]
Matthews PM, De Stefano N, Narayanan S, Francis GS, Wolinsky JS, Antel JP, et al. Putting magnetic resonance spectroscopy studies in context: axonal damage and disability in multiple sclerosis. Semin Neurol 1998; 18: 327–36.[Web of Science][Medline]
Narayanan S, Fu L, Pioro E, De Stefano N, Collins DL, Francis GS, et al. Imaging of axonal damage in multiple sclerosis: spatial distribution of magnetic resonance imaging lesions. Ann Neurol 1997; 41: 385–91.[Web of Science][Medline]
Orita T, Tsurutani T, Izumihara A, Kajiwara K. Early, evolving Wallerian degeneration of the pyramidal tract in cerebrovascular diseases: MR study. J Comput Assist Tomogr 1994; 18: 943–6.[Web of Science][Medline]
Pandya DN, Seltzer B. The topography of commissural fibers. In: Lepore F, Ptito A, Jasper HH, editors. Two hemispheres—one brain. New York: Alan R. Liss; 1986. p. 47–73.
Rothwell NJ, Hopkins SJ. Cytokines and the nervous system, II: actions and mechanisms of action. [Review]. Trends Neurosci 1995; 18: 130–6.[Web of Science][Medline]
Skaper SD, Walsh FS. Neurotrophic molecules: strategies for designing effective therapeutic molecules in neurodegeneration. [Review]. Mol Cell Neurosci 1998; 12: 179–93.[Web of Science][Medline]
Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998; 338: 278–85.
Received January 31, 2000. Revised April 11, 2000. Accepted April 18, 2000.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J Furby, T Hayton, D Altmann, R Brenner, J Chataway, K. Smith, D. Miller, and R Kapoor Different white matter lesion characteristics correlate with distinct grey matter abnormalities on magnetic resonance imaging in secondary progressive multiple sclerosis Multiple Sclerosis, June 1, 2009; 15(6): 687 - 694. [Abstract] [PDF]
|
|
|
|
 |
|
 Y. He, A. Dagher, Z. Chen, A. Charil, A. Zijdenbos, K. Worsley, and A. Evans Impaired small-world efficiency in structural cortical networks in multiple sclerosis associated with white matter lesion load Brain, May 12, 2009; (2009) awp089v1. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. C. Tallantyre, L. Bo, O. Al-Rawashdeh, T. Owens, C. H. Polman, J. Lowe, and N. Evangelou Greater loss of axons in primary progressive multiple sclerosis plaques compared to secondary progressive disease Brain, May 1, 2009; 132(5): 1190 - 1199. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Kezele, D. Arnold, and D. Collins Atrophy in white matter fiber tracts in multiple sclerosis is not dependent on tract length or local white matter lesions Multiple Sclerosis, July 1, 2008; 14(6): 779 - 785. [Abstract] [PDF]
|
|
|
|
 |
|
 L. Bonzano, A. Tacchino, L. Roccatagliata, G. Abbruzzese, G. L. Mancardi, and M. Bove Callosal Contributions to Simultaneous Bimanual Finger Movements J. Neurosci., March 19, 2008; 28(12): 3227 - 3233. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Rocca, E. Pagani, M. Absinta, P. Valsasina, A. Falini, G. Scotti, G. Comi, and M. Filippi Altered functional and structural connectivities in patients with MS: A 3-T study Neurology, December 4, 2007; 69(23): 2136 - 2145. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Agosta, E. Pagani, D. Caputo, and M. Filippi Associations Between Cervical Cord Gray Matter Damage and Disability in Patients With Multiple Sclerosis Arch Neurol, September 1, 2007; 64(9): 1302 - 1305. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Pulizzi, M. Rovaris, E. Judica, M. P. Sormani, V. Martinelli, G. Comi, and M. Filippi Determinants of Disability in Multiple Sclerosis at Various Disease Stages: A Multiparametric Magnetic Resonance Study Arch Neurol, August 1, 2007; 64(8): 1163 - 1168. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Agosta, M. Absinta, M. P. Sormani, A. Ghezzi, A. Bertolotto, E. Montanari, G. Comi, and M. Filippi In vivo assessment of cervical cord damage in MS patients: a longitudinal diffusion tensor MRI study Brain, August 1, 2007; 130(8): 2211 - 2219. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Audoin, G. Davies, W. Rashid, L. Fisniku, A.J. Thompson, and D.H. Miller Voxel-based analysis of grey matter magnetization transfer ratio maps in early relapsing remitting multiple sclerosis Multiple Sclerosis, May 1, 2007; 13(4): 483 - 489. [Abstract] [PDF]
|
|
|
|
 |
|
 F. Lin, C. Yu, T. Jiang, K. Li, and P. Chan Diffusion Tensor Tractography-Based Group Mapping of the Pyramidal Tract in Relapsing-Remitting Multiple Sclerosis Patients AJNR Am. J. Neuroradiol., February 1, 2007; 28(2): 278 - 282. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Tsunoda, T. Tanaka, E. J. Terry, and R. S. Fujinami Contrasting Roles for Axonal Degeneration in an Autoimmune versus Viral Model of Multiple Sclerosis: When Can Axonal Injury Be Beneficial? Am. J. Pathol., January 1, 2007; 170(1): 214 - 226. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J H Simon Brain atrophy in multiple sclerosis: what we know and would like to know Multiple Sclerosis, November 1, 2006; 12(6): 679 - 687. [Abstract] [PDF]
|
|
|
|
|
|
M. Rovaris, E. Judica, A. Gallo, B. Benedetti, M. P. Sormani, D. Caputo, A. Ghezzi, E. Montanari, A. Bertolotto, G. Mancardi, et al. Grey matter damage predicts the evolution of primary progressive multiple sclerosis at 5 years Brain, October 1, 2006; 129(10): 2628 - 2634. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ge Multiple Sclerosis: The Role of MR Imaging AJNR Am. J. Neuroradiol., June 1, 2006; 27(6): 1165 - 1176. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. C. DeLuca, K. Williams, N. Evangelou, G. C. Ebers, and M. M. Esiri The contribution of demyelination to axonal loss in multiple sclerosis Brain, June 1, 2006; 129(6): 1507 - 1516. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Oreja-Guevara, A. Charil, D. Caputo, R. Cavarretta, M. P. Sormani, and M. Filippi Magnetization transfer magnetic resonance imaging and clinical changes in patients with relapsing-remitting multiple sclerosis. Arch Neurol, May 1, 2006; 63(5): 736 - 740. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Audoin, K. T. M. Fernando, J. K. Swanton, A. J. Thompson, G. T. Plant, and D. H. Miller Selective magnetization transfer ratio decrease in the visual cortex following optic neuritis Brain, April 1, 2006; 129(4): 1031 - 1039. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Imitola, T. Chitnis, and S. J. Khoury Insights Into the Molecular Pathogenesis of Progression in Multiple Sclerosis: Potential Implications for Future Therapies Arch Neurol, January 1, 2006; 63(1): 25 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rovaris, A. Gass, R. Bammer, S. J. Hickman, O. Ciccarelli, D. H. Miller, and M. Filippi Diffusion MRI in multiple sclerosis Neurology, November 22, 2005; 65(10): 1526 - 1532. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rovaris, A. Gambini, A. Gallo, A. Falini, A. Ghezzi, B. Benedetti, M. P. Sormani, V. Martinelli, G. Comi, and M. Filippi Axonal injury in early multiple sclerosis is irreversible and independent of the short-term disease evolution Neurology, November 22, 2005; 65(10): 1626 - 1630. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kutzelnigg, C. F. Lucchinetti, C. Stadelmann, W. Bruck, H. Rauschka, M. Bergmann, M. Schmidbauer, J. E. Parisi, and H. Lassmann Cortical demyelination and diffuse white matter injury in multiple sclerosis Brain, November 1, 2005; 128(11): 2705 - 2712. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Oral Presentations Multiple Sclerosis, September 1, 2005; 11(5_suppl): S1 - S182. [PDF]
|
|
|
|
|
|
A. Gallo, M. Rovaris, R. Riva, A. Ghezzi, B. Benedetti, V. Martinelli, A. Falini, G. Comi, and M. Filippi Diffusion-Tensor Magnetic Resonance Imaging Detects Normal-Appearing White Matter Damage Unrelated to Short-term Disease Activity in Patients at the Earliest Clinical Stage of Multiple Sclerosis Arch Neurol, May 1, 2005; 62(5): 803 - 808. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Oreja-Guevara, M. Rovaris, G. Iannucci, P. Valsasina, D. Caputo, R. Cavarretta, M. P. Sormani, P. Ferrante, G. Comi, and M. Filippi Progressive Gray Matter Damage in Patients With Relapsing-Remitting Multiple Sclerosis: A Longitudinal Diffusion Tensor Magnetic Resonance Imaging Study Arch Neurol, April 1, 2005; 62(4): 578 - 584. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G R W. Moore MRI Correlates of MS Pathologic Subtypes Multiple Sclerosis, February 1, 2005; 11(1): 103 - 105. [PDF]
|
|
|
|
|
|
J. A. Kamholz, J. Y. Garbern, O. Gonen, Y. Ge, M. Inglese, and R. I. Grossman Neuronal cell injury precedes brain atrophy in multiple sclerosis Neurology, January 11, 2005; 64(1): 176 - 176. [Full Text] [PDF]
|
|
|
|
|
|
N. Evangelou, G. C. DeLuca, T. Owens, and M. M. Esiri Pathological study of spinal cord atrophy in multiple sclerosis suggests limited role of local lesions Brain, January 1, 2005; 128(1): 29 - 34. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J Oh, R G Henry, C Genain, S J Nelson, and D Pelletier Mechanisms of normal appearing corpus callosum injury related to pericallosal T1 lesions in multiple sclerosis using directional diffusion tensor and 1H MRS imaging J. Neurol. Neurosurg. Psychiatry, September 1, 2004; 75(9): 1281 - 1286. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. D Coombs, A. Best, M. S Brown, D. E Miller, J. Corboy, M. Baier, and J. H Simon Multiple sclerosis pathology in the normal and abnormal appearing white matter of the corpus callosum by diffusion tensor imaging Multiple Sclerosis, August 1, 2004; 10(4): 392 - 397. [Abstract] [PDF]
|
|
|
|
|
|
J. Oh, D. Pelletier, and S. J. Nelson Corpus Callosum Axonal Injury in Multiple Sclerosis Measured by Proton Magnetic Resonance Spectroscopic Imaging Arch Neurol, July 1, 2004; 61(7): 1081 - 1086. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Filippi, M. Rovaris, and M. A Rocca Imaging primary progressive multiple sclerosis: the contribution of structural, metabolic, and functional MRI techniques Multiple Sclerosis, June 1, 2004; 10(1_suppl): S36 - S45. [Abstract] [PDF]
|
|
|
|
|
|
G. C. DeLuca, G. C. Ebers, and M. M. Esiri Axonal loss in multiple sclerosis: a pathological survey of the corticospinal and sensory tracts Brain, May 1, 2004; 127(5): 1009 - 1018. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Filippi, M. Rovaris, and M. A Rocca Imaging primary progressive multiple sclerosis: the contribution of structural, metabolic, and functional MRI techniques Multiple Sclerosis, May 1, 2004; 10(3_suppl): S36 - S45. [Abstract] [PDF]
|
|
|
|
|
|
J. A. Frank, N. Richert, C. Bash, L. Stone, P. A. Calabresi, B. Lewis, R. Stone, T. Howard, and H. F. McFarland Interferon-{beta}-1b slows progression of atrophy in RRMS: Three-year follow-up in NAb- and NAb+ patients Neurology, March 9, 2004; 62(5): 719 - 725. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J P Ranjeva, J Pelletier, S Confort-Gouny, D Ibarrola, B Audoin, Y Le Fur, P Viout, A A. Cherif, and P J Cozzone MRI/MRS of corpus callosum in patients with clinically isolated syndrome suggestive of multiple sclerosis Multiple Sclerosis, December 1, 2003; 9(6): 554 - 565. [Abstract] [PDF]
|
|
|
|
 |
|
 A. S. Weinstein, R. B. Goldstein, and A. J. Barkovich In Utero Disappearance of the Corpus Callosum Secondary to Extensive Brain Injury J. Ultrasound Med., August 1, 2003; 22(8): 837 - 840. [Full Text] [PDF]
|
|
|
|
|
|
H Lassmann Axonal injury in multiple sclerosis J. Neurol. Neurosurg. Psychiatry, June 1, 2003; 74(6): 695 - 697. [Full Text] [PDF]
|
|
|
|
|
|
A. Castriota-Scanderbeg, F. Fasano, G. Hagberg, U. Nocentini, M. Filippi, and C. Caltagirone Coefficient Dav Is More Sensitive Than Fractional Anisotropy in Monitoring Progression of Irreversible Tissue Damage in Focal Nonactive Multiple Sclerosis Lesions AJNR Am. J. Neuroradiol., April 1, 2003; 24(4): 663 - 670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. N. Mitchell, S. L. Free, M. Merschhemke, L. Lemieux, S. M. Sisodiya, and S. D. Shorvon Reliable Callosal Measurement: Population Normative Data Confirm Sex-Related Differences AJNR Am. J. Neuroradiol., March 1, 2003; 24(3): 410 - 418. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. M. Medana and M. M. Esiri Axonal damage: a key predictor of outcome in human CNS diseases Brain, March 1, 2003; 126(3): 515 - 530. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Filippi, M. Bozzali, M. Rovaris, O. Gonen, C. Kesavadas, A. Ghezzi, V. Martinelli, R. I. Grossman, G. Scotti, G. Comi, et al. Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis Brain, February 1, 2003; 126(2): 433 - 437. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R Leigh, J Ostuni, D Pham, A Goldszal, B K Lewis, T Howard, N Richert, H McFarland, and J A Frank Estimating cerebral atrophy in multiple sclerosis patients from various MR pulse sequences Multiple Sclerosis, October 1, 2002; 8(5): 420 - 429. [Abstract] [PDF]
|
|
|
|
|
|
T. Kuhlmann, G. Lingfeld, A. Bitsch, J. Schuchardt, and W. Bruck Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time Brain, October 1, 2002; 125(10): 2202 - 2212. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. B. Rao, N. Richert, T. Howard, B.K. Lewis, C.N. Bash, H.F. McFarland, and J. A. Frank Methylprednisolone effect on brain volume and enhancing lesions in MS before and during IFN{beta}-1b Neurology, September 10, 2002; 59(5): 688 - 694. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rovaris, M. Bozzali, G. Iannucci, A. Ghezzi, D. Caputo, E. Montanari, A. Bertolotto, R. Bergamaschi, R. Capra, G. L. Mancardi, et al. Assessment of Normal-Appearing White and Gray Matter in Patients With Primary Progressive Multiple Sclerosis: A Diffusion-Tensor Magnetic Resonance Imaging Study Arch Neurol, September 1, 2002; 59(9): 1406 - 1412. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. H. Miller, F. Barkhof, J. A. Frank, G. J. M. Parker, and A. J. Thompson Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance Brain, August 1, 2002; 125(8): 1676 - 1695. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C M Griffin, J Dehmeshki, D T Chard, G J. Parker, G J Barker, A J Thompson, and D H Miller T1 histograms of normal-appearing brain tissue are abnormal in early relapsing-remitting multiple sclerosis Multiple Sclerosis, June 1, 2002; 8(3): 211 - 216. [Abstract] [PDF]
|
|
|
|
|
|
M. Filippi and R. I. Grossman MRI techniques to monitor MS evolution: The present and the future Neurology, April 23, 2002; 58(8): 1147 - 1153. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Inglese, A. Ghezzi, S. Bianchi, S. Gerevini, M. P. Sormani, V. Martinelli, G. Comi, and M. Filippi Irreversible Disability and Tissue Loss in Multiple Sclerosis: A Conventional and Magnetization Transfer Magnetic Resonance Imaging Study of the Optic Nerves Arch Neurol, February 1, 2002; 59(2): 250 - 255. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rovaris, M. Bozzali, G. Santuccio, A. Ghezzi, D. Caputo, E. Montanari, A. Bertolotto, R. Bergamaschi, R. Capra, G. Mancardi, et al. In vivo assessment of the brain and cervical cord pathology of patients with primary progressive multiple sclerosis Brain, December 1, 2001; 124(12): 2540 - 2549. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Evangelou, D. Konz, M. M. Esiri, S. Smith, J. Palace, and P. M. Matthews Size-selective neuronal changes in the anterior optic pathways suggest a differential susceptibility to injury in multiple sclerosis Brain, September 1, 2001; 124(9): 1813 - 1820. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||