Brain, Vol. 123, No. 6, 1174-1183,
June 2000
© 2000 Oxford University Press
Acute axonal injury in multiple sclerosis
Correlation with demyelination and inflammation
1 Departments of Neurology and 2 Neuropathology, Georg-August-Universität, Göttingen, and 3 Department of Neuropathology, Charité, Campus Virchow-Klinikum Berlin, Germany
Correspondence to:
Professor Dr Wolfgang Brück, Institut für Neuropathologie Charité, Campus Virchow-Klinikum, Augustenburger Platz 1, D-13353 Berlin, Germany E-mail: wolfgang.brueck{at}charite.de
Damage to axons is taken as a key factor of disability in multiple sclerosis, but its pathogenesis is largely unknown. Axonal injury is believed to occur as a consequence of demyelination and was recently shown to be a feature even of the early disease stages. The present study was aimed at characterizing the association of axonal injury and histopathological hallmarks of multiple sclerosis such as demyelination, cellular infiltration and expression of inflammatory mediators. Therefore, axon reduction and signs of acute axonal damage were quantified in early lesion development of chronic multiple sclerosis and correlated with demyelinating activity and inflammation. Patients with secondary progressive multiple sclerosis revealed the most pronounced axonal injury, whereas primary progressive multiple sclerosis patients surprisingly showed relatively little acute axonal injury. Acute axonal damage, as defined by the accumulation of amyloid precursor protein (APP), was found to occur not only in active demyelinating but also in remyelinating and inactive demyelinated lesions with a large inter-individual variability. Only few remyelinating lesions were adjacent to areas of active demyelination. In this minority of lesions, axonal damage may have originated from the neighbourhood. APP expression in damaged axons correlated with the number of macrophages and CD8-positive T lymphocytes within the lesions, but not with the expression of tumour necrosis factor-alpha (TNF-
) or inducible nitric oxide synthase (iNOS). Axonal injury is therefore, at least in part, independent of demyelinating activity, and its pathogenesis may be different from demyelination. This has major implications for therapeutic strategies, which aim at preventing both demyelination and axonal loss.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A Wilkins and N Scolding Protecting axons in multiple sclerosis Multiple Sclerosis, September 1, 2008; 14(8): 1013 - 1025. [Abstract] [PDF]
|
|
|
|
 |
|
 J. M. Anderson, D. W. Hampton, R. Patani, G. Pryce, R. A. Crowther, R. Reynolds, R. J. M. Franklin, G. Giovannoni, D. A. S. Compston, D. Baker, et al. Abnormally phosphorylated tau is associated with neuronal and axonal loss in experimental autoimmune encephalomyelitis and multiple sclerosis Brain, July 1, 2008; 131(7): 1736 - 1748. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Irvine and W. F. Blakemore Remyelination protects axons from demyelination-associated axon degeneration Brain, June 1, 2008; 131(6): 1464 - 1477. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Pirko, T. K. Nolan, S. K. Holland, and A. J. Johnson Multiple Sclerosis: Pathogenesis and MR Imaging Features of T1 Hypointensities in Murine Model Radiology, March 1, 2008; 246(3): 790 - 795. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Hoftberger, F. Garzuly, H.P. Dienes, J. Grubits, B. Rohonyi, G. Fischer, Z. Hanzely, H. Lassmann, and H. Budka Fulminant central nervous system demyelination associated with interferon-{alpha} therapy and hepatitis C virus infection Multiple Sclerosis, November 1, 2007; 13(9): 1100 - 1106. [Abstract] [PDF]
|
|
|
|
|
|
K.M. Mitchell, A.L. Dotson, K.M. Cool, A. Chakrabarty, S.H. Benedict, and S.M. LeVine Deferiprone, an orally deliverable iron chelator, ameliorates experimental autoimmune encephalomyelitis Multiple Sclerosis, November 1, 2007; 13(9): 1118 - 1126. [Abstract] [PDF]
|
|
|
|
 |
|
 I. Tsunoda, T. Tanaka, Y. Saijoh, and R. S. Fujinami Targeting Inflammatory Demyelinating Lesions to Sites of Wallerian Degeneration Am. J. Pathol., November 1, 2007; 171(5): 1563 - 1575. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. T. Mars, J. Bauer, D. A. Gross, F. Bucciarelli, H. Firat, D. Hudrisier, F. Lemonnier, K. Kosmatopoulos, and R. S. Liblau CD8 T Cell Responses to Myelin Oligodendrocyte Glycoprotein-Derived Peptides in Humanized HLA-A*0201-Transgenic Mice J. Immunol., October 15, 2007; 179(8): 5090 - 5098. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Galea, M. Bernardes-Silva, P. A. Forse, N. van Rooijen, R. S. Liblau, and V. H. Perry An antigen-specific pathway for CD8 T cells across the blood-brain barrier J. Exp. Med., September 3, 2007; 204(9): 2023 - 2030. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. P. Amato, E. Portaccio, B. Goretti, V. Zipoli, M. Battaglini, M. L. Bartolozzi, M. L. Stromillo, L. Guidi, G. Siracusa, S. Sorbi, et al. Association of Neocortical Volume Changes With Cognitive Deterioration in Relapsing-Remitting Multiple Sclerosis Arch Neurol, August 1, 2007; 64(8): 1157 - 1161. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Metz, C. F. Lucchinetti, H. Openshaw, A. Garcia-Merino, H. Lassmann, M. S. Freedman, H. L. Atkins, B. Azzarelli, O. J. Kolar, and W. Bruck Autologous haematopoietic stem cell transplantation fails to stop demyelination and neurodegeneration in multiple sclerosis Brain, May 1, 2007; 130(5): 1254 - 1262. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Chitnis, J. Imitola, Y. Wang, W. Elyaman, P. Chawla, M. Sharuk, K. Raddassi, R. T. Bronson, and S. J. Khoury Elevated Neuronal Expression of CD200 Protects Wlds Mice from Inflammation-Mediated Neurodegeneration Am. J. Pathol., May 1, 2007; 170(5): 1695 - 1712. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Stagi, P. Gorlovoy, S. Larionov, K. Takahashi, and H. Neumann Unloading kinesin transported cargoes from the tubulin track via the inflammatory c-Jun N-terminal kinase pathway FASEB J, December 1, 2006; 20(14): 2573 - 2575. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L Leocani, M Rovaris, F M Boneschi, S Medaglini, P Rossi, V Martinelli, S Amadio, and G Comi Multimodal evoked potentials to assess the evolution of multiple sclerosis: a longitudinal study J. Neurol. Neurosurg. Psychiatry, September 1, 2006; 77(9): 1030 - 1035. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. P. Shriver and B. N. Dittel T-Cell-Mediated Disruption of the Neuronal Microtubule Network: Correlation with Early Reversible Axonal Dysfunction in Acute Experimental Autoimmune Encephalomyelitis Am. J. Pathol., September 1, 2006; 169(3): 999 - 1011. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Wang, R. Allie, K. Conant, N. Haughey, J. Turchan-Chelowo, K. Hahn, A. Rosen, J. Steiner, S. Keswani, M. Jones, et al. Granzyme B mediates neurotoxicity through a G-protein-coupled receptor FASEB J, June 1, 2006; 20(8): 1209 - 1211. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J Brettschneider, A Petzold, A Junker, and H Tumani Axonal damage markers in the cerebrospinal fluid of patients with clinically isolated syndrome improve predicting conversion to definite multiple sclerosis Multiple Sclerosis, April 1, 2006; 12(2): 143 - 148. [Abstract] [PDF]
|
|
|
|
 |
|
 E. M. Frohman, M. K. Racke, and C. S. Raine Multiple sclerosis--the plaque and its pathogenesis. N. Engl. J. Med., March 2, 2006; 354(9): 942 - 955. [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]
|
|
|
|
 |
|
 K. Rostasy, E. Withut, D. Pohl, P. Lange, B. Ciesielcyk, R. Diem, J. Gartner, and M. Otto Tau, Phospho-Tau, and S-100B in the Cerebrospinal Fluid of Children With Multiple Sclerosis J Child Neurol, October 1, 2005; 20(10): 822 - 825. [Abstract] [PDF]
|
|
|
|
|
|
E. M. Frohman, O. Stuve, E. Havrdova, J. Corboy, A. Achiron, R. Zivadinov, P. S. Sorensen, J. T. Phillips, B. Weinshenker, K. Hawker, et al. Therapeutic Considerations for Disease Progression in Multiple Sclerosis: Evidence, Experience, and Future Expectations Arch Neurol, October 1, 2005; 62(10): 1519 - 1530. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Krapf, S. P. Morrissey, O. Zenker, T. Zwingers, R. Gonsette, H. -P. Hartung, and the MIMS Study Group Effect of mitoxantrone on MRI in progressive MS: Results of the MIMS trial Neurology, September 13, 2005; 65(5): 690 - 695. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Frohman, M. Filippi, O. Stuve, S. G. Waxman, J. Corboy, J. T. Phillips, C. Lucchinetti, J. Wilken, N. Karandikar, B. Hemmer, et al. Characterizing the Mechanisms of Progression in Multiple Sclerosis: Evidence and New Hypotheses for Future Directions Arch Neurol, September 1, 2005; 62(9): 1345 - 1356. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Friese and L. Fugger Autoreactive CD8+ T cells in multiple sclerosis: a new target for therapy? Brain, August 1, 2005; 128(8): 1747 - 1763. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Minneboo, B. M. J. Uitdehaag, H. J. Ader, F. Barkhof, C. H. Polman, and J. A. Castelijns Patterns of enhancing lesion evolution in multiple sclerosis are uniform within patients Neurology, July 12, 2005; 65(1): 56 - 61. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J Brettschneider, M Maier, S Arda, A Claus, S D Sussmuth, J Kassubek, and H Tumani Tau protein level in cerebrospinal fluid is increased in patients with early multiple sclerosis Multiple Sclerosis, June 1, 2005; 11(3): 261 - 265. [Abstract] [PDF]
|
|
|
|
|
|
M. Tiberio, D. T. Chard, D. R. Altmann, G. Davies, C. M. Griffin, W. Rashid, J. Sastre-Garriga, A. J. Thompson, and D. H. Miller Gray and white matter volume changes in early RRMS: A 2-year longitudinal study Neurology, March 22, 2005; 64(6): 1001 - 1007. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A Petzold, M J Eikelenboom, G Keir, D Grant, R H C Lazeron, C H Polman, B M J Uitdehaag, E J Thompson, and G Giovannoni Axonal damage accumulates in the progressive phase of multiple sclerosis: three year follow up study J. Neurol. Neurosurg. Psychiatry, February 1, 2005; 76(2): 206 - 211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Stagi, P. S. Dittrich, N. Frank, A. I. Iliev, P. Schwille, and H. Neumann Breakdown of Axonal Synaptic Vesicle Precursor Transport by Microglial Nitric Oxide J. Neurosci., January 12, 2005; 25(2): 352 - 362. [Abstract] [Full Text] [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. Norgren, P. Sundstrom, A. Svenningsson, L. Rosengren, T. Stigbrand, and M. Gunnarsson Neurofilament and glial fibrillary acidic protein in multiple sclerosis Neurology, November 9, 2004; 63(9): 1586 - 1590. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Rejdak, M. J. Eikelenboom, A. Petzold, E. J. Thompson, Z. Stelmasiak, R. H.C. Lazeron, F. Barkhof, C. H. Polman, B. M.J. Uitdehaag, and G. Giovannoni CSF nitric oxide metabolites are associated with activity and progression of multiple sclerosis Neurology, October 26, 2004; 63(8): 1439 - 1445. [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]
|
|
|
|
|
|
H. Pellkofer, A. S. Schubart, R. Hoftberger, N. Schutze, M. Pagany, M. Schuller, H. Lassmann, R. Hohlfeld, R. Voltz, and C. Linington Modelling paraneoplastic CNS disease: T-cells specific for the onconeuronal antigen PNMA1 mediate autoimmune encephalomyelitis in the rat Brain, August 1, 2004; 127(8): 1822 - 1830. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Amato, M. L. Bartolozzi, V. Zipoli, E. Portaccio, M. Mortilla, L. Guidi, G. Siracusa, S. Sorbi, A. Federico, and N. De Stefano Neocortical volume decrease in relapsing-remitting MS patients with mild cognitive impairment Neurology, July 13, 2004; 63(1): 89 - 93. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F G Maggs and J Palace The pathogenesis of multiple sclerosis: is it really a primary inflammatory process? Multiple Sclerosis, June 1, 2004; 10(3): 326 - 329. [Abstract] [PDF]
|
|
|
|
|
|
H. J. Kim, I. Ifergan, J. P. Antel, R. Seguin, M. Duddy, Y. Lapierre, F. Jalili, and A. Bar-Or Type 2 Monocyte and Microglia Differentiation Mediated by Glatiramer Acetate Therapy in Patients with Multiple Sclerosis J. Immunol., June 1, 2004; 172(11): 7144 - 7153. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Lucchinetti and W. Bruck The pathology of primary progressive multiple sclerosis Multiple Sclerosis, June 1, 2004; 10(1_suppl): S23 - S30. [Abstract] [PDF]
|
|
|
|
|
|
R. R. Kreitman and F. Blanchette On the horizon: possible neuroprotective role for glatiramer acetate Multiple Sclerosis, June 1, 2004; 10(1_suppl): S81 - S89. [Abstract] [PDF]
|
|
|
|
 |
|
 M. J. Craner, J. Newcombe, J. A. Black, C. Hartle, M. L. Cuzner, and S. G. Waxman Molecular changes in neurons in multiple sclerosis: Altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger PNAS, May 25, 2004; 101(21): 8168 - 8173. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Lucchinetti and W. Bruck The pathology of primary progressive multiple sclerosis Multiple Sclerosis, May 1, 2004; 10(3_suppl): S23 - S30. [Abstract] [PDF]
|
|
|
|
|
|
R. R. Kreitman and F. Blanchette On the horizon: possible neuroprotective role for glatiramer acetate Multiple Sclerosis, May 1, 2004; 10(3_suppl): S81 - S89. [Abstract] [PDF]
|
|
|
|
|
|
C. Skulina, S. Schmidt, K. Dornmair, H. Babbe, A. Roers, K. Rajewsky, H. Wekerle, R. Hohlfeld, and N. Goebels Multiple sclerosis: Brain-infiltrating CD8+ T cells persist as clonal expansions in the cerebrospinal fluid and blood PNAS, February 24, 2004; 101(8): 2428 - 2433. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Nau, J. Gerber, S. Bunkowski, and W. Bruck Axonal injury, a neglected cause of CNS damage in bacterial meningitis Neurology, February 10, 2004; 62(3): 509 - 511. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Lily, J. Palace, and A. Vincent Serum autoantibodies to cell surface determinants in multiple sclerosis: a flow cytometric study Brain, February 1, 2004; 127(2): 269 - 279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Craner, B. C. Hains, A. C. Lo, J. A. Black, and S. G. Waxman Co-localization of sodium channel Nav1.6 and the sodium-calcium exchanger at sites of axonal injury in the spinal cord in EAE Brain, February 1, 2004; 127(2): 294 - 303. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. L. Oleszak, J. R. Chang, H. Friedman, C. D. Katsetos, and C. D. Platsoucas Theiler's Virus Infection: a Model for Multiple Sclerosis Clin. Microbiol. Rev., January 1, 2004; 17(1): 174 - 207. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Bar-Or, R. K. Nuttall, M. Duddy, A. Alter, H. J. Kim, I. Ifergan, C. J. Pennington, P. Bourgoin, D. R. Edwards, and V. W. Yong Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis Brain, December 1, 2003; 126(12): 2738 - 2749. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Schroeter, G. Stoll, R. Weissert, H.-P. Hartung, H. Lassmann, and S. Jander CD8+ Phagocyte Recruitment in Rat Experimental Autoimmune Encephalomyelitis: Association with Inflammatory Tissue Destruction Am. J. Pathol., October 1, 2003; 163(4): 1517 - 1524. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Frohman, D. S. Goodin, P. A. Calabresi, J. R. Corboy, P. K. Coyle, M. Filippi, J. A. Frank, S. L. Galetta, R. I. Grossman, K. Hawker, et al. The utility of MRI in suspected MS: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology Neurology, September 9, 2003; 61(5): 602 - 611. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Vegeto, S. Belcredito, S. Etteri, S. Ghisletti, A. Brusadelli, C. Meda, A. Krust, S. Dupont, P. Ciana, P. Chambon, et al. Estrogen receptor-{alpha} mediates the brain antiinflammatory activity of estradiol PNAS, August 5, 2003; 100(16): 9614 - 9619. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Barkhof, W. Bruck, C. J. A. De Groot, E. Bergers, S. Hulshof, J. Geurts, C. H. Polman, and P. van der Valk Remyelinated Lesions in Multiple Sclerosis: Magnetic Resonance Image Appearance Arch Neurol, August 1, 2003; 60(8): 1073 - 1081. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. G. Geurts, G. Wolswijk, L. Bo, P. van der Valk, C. H. Polman, D. Troost, and E. Aronica Altered expression patterns of group I and II metabotropic glutamate receptors in multiple sclerosis Brain, August 1, 2003; 126(8): 1755 - 1766. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Giuliani, C. G. Goodyer, J. P. Antel, and V. W. Yong Vulnerability of Human Neurons to T Cell-Mediated Cytotoxicity J. Immunol., July 1, 2003; 171(1): 368 - 379. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Wolswijk and R. Balesar Changes in the expression and localization of the paranodal protein Caspr on axons in chronic multiple sclerosis Brain, July 1, 2003; 126(7): 1638 - 1649. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H Lassmann Axonal injury in multiple sclerosis J. Neurol. Neurosurg. Psychiatry, June 1, 2003; 74(6): 695 - 697. [Full Text] [PDF]
|
|
|
|
|
|
N. De Stefano, P. M. Matthews, M. Filippi, F. Agosta, M. De Luca, M. L. Bartolozzi, L. Guidi, A. Ghezzi, E. Montanari, A. Cifelli, et al. Evidence of early cortical atrophy in MS: Relevance to white matter changes and disability Neurology, April 8, 2003; 60(7): 1157 - 1162. [Abstract] [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]
|
|