Brain, Vol. 125, No. 10, 2202-2212,
October 2002
© 2002 Oxford University Press
Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time
1 Department of Neuropathology, Charité, Humboldt-Universität, Berlin and 2 Department of Neurology, Ruppiner Kliniken GmbH, Neuruppin, Germany
Correspondence to: Professor Dr med Wolfgang Brück, Institut für Neuropathologie, Charité, Campus Virchow-Klinikum, Augustenburger Platz 1, D-13353 Berlin, Germany E-mail: wolfgang.brueck{at}charite.de*Present address: Institüt für Neuropathologie, Georg-August-Universität, Robert-Koch-Str 40, 37075, Göttingen, GermanyE-mail: wbrueck{at}med.uni-goettingen
Multiple sclerosis is characterized morphologically by the key features demyelination, inflammation, gliosis and axonal damage. In recent years, it has become more evident that axonal damage is the major morphological substrate of permanent clinical disability. In our study, we investigated the occurrence of acute axonal damage determined by immunocytochemistry for amyloid precursor protein (APP) which is produced in neurones and accumulates at sites of recent axon transection or damage. The numbers of APP-positive axons in multiple sclerosis lesions were correlated with the disease duration and course. Most APP-positive axons were detected within the first year after disease onset, but acute axonal damage was also detected to a minor degree in lesions of patients with a disease duration of 10 years and more. This effect was not due to the lack of active demyelinating lesions in the chronic disease stage. Late remyelinated lesions (so-called shadow plaques) did not show signs of axon destruction. The number of inflammatory cells showed a decrease over time similar to that of the number of APP-positive axons. There was a significant correlation between the extent of axon damage and the numbers of CD8-positive cytotoxic T cells and macrophages/microglia. Our results indicate that a putative axon-protective treatment should start as early as possible and include strategies preventing T cell/macrophage-mediated axon destruction and leading to remyelination of axons.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  N. Melzer, S. G. Meuth, and H. Wiendl CD8+ T cells and neuronal damage: direct and collateral mechanisms of cytotoxicity and impaired electrical excitability FASEB J, November 1, 2009; 23(11): 3659 - 3673. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Garcea, A. Villa, F. Caceres, T. Adoni, M. Alegria, R. Barbosa Thomaz, R. Buzo, L. Llamas Lopez, and M. Rivera Kindel Early treatment of multiple sclerosis: a Latin American Experts Meeting Multiple Sclerosis, October 1, 2009; 15(3_suppl): S1 - S12. [Abstract] [PDF]
|
|
|
|
|
|
D. Goodin and D. Bates Review: Treatment of early multiple sclerosis: the value of treatment initiation after a first clinical episode Multiple Sclerosis, October 1, 2009; 15(10): 1175 - 1182. [Abstract] [PDF]
|
|
|
|
 |
|
 J. M. Frischer, S. Bramow, A. Dal-Bianco, C. F. Lucchinetti, H. Rauschka, M. Schmidbauer, H. Laursen, P. S. Sorensen, and H. Lassmann The relation between inflammation and neurodegeneration in multiple sclerosis brains Brain, May 1, 2009; 132(5): 1175 - 1189. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. D. Duncan, A. Brower, Y. Kondo, J. F. Curlee Jr., and R. D. Schultz Extensive remyelination of the CNS leads to functional recovery PNAS, April 21, 2009; 106(16): 6832 - 6836. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Huizinga, R. Q. Hintzen, K. Assink, M. van Meurs, and S. Amor T-cell responses to neurofilament light protein are part of the normal immune repertoire Int. Immunol., April 1, 2009; 21(4): 433 - 441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y Benesova, A Vasku, H Novotna, J Litzman, P Stourac, M Beranek, Z Kadanka, and J Bednarik Matrix metalloproteinase-9 and matrix metalloproteinase-2 as biomarkers of various courses in multiple sclerosis Multiple Sclerosis, March 1, 2009; 15(3): 316 - 322. [Abstract] [PDF]
|
|
|
|
|
|
P Coyle, B Arnason, B Hurwitz, and F Lublin Optimizing Outcomes in Multiple Sclerosis - A Consensus Initiative Multiple Sclerosis, February 1, 2009; 15(2_suppl): S5 - S35. [Abstract] [PDF]
|
|
|
|
|
|
A Wilkins and N Scolding Protecting axons in multiple sclerosis Multiple Sclerosis, September 1, 2008; 14(8): 1013 - 1025. [Abstract] [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]
|
|
|
|
 |
|
 D Horakova, J L Cox, E Havrdova, S Hussein, O Dolezal, D Cookfair, M G Dwyer, Z Seidl, N Bergsland, M Vaneckova, et al. Evolution of different MRI measures in patients with active relapsing-remitting multiple sclerosis over 2 and 5 years: a case-control study J. Neurol. Neurosurg. Psychiatry, April 1, 2008; 79(4): 407 - 414. [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. A. Nash, O. Stuve, J. D. Bowen, E. M. Frohman, L. M. Griffith, G. J. Hutton, G. H. Kraft, U. Popat, M. K. Racke, and P. A. Muraro Autologous HSCT for advanced MS: Is the glass half-empty or really half-full? Brain, February 1, 2008; 131(2): e89 - e89. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Chandran, D. Hunt, A. Joannides, C. Zhao, A. Compston, and R. J.M Franklin Myelin repair: the role of stem and precursor cells in multiple sclerosis Phil Trans R Soc B, January 12, 2008; 363(1489): 171 - 183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Rejdak, A. Petzold, Z. Stelmasiak, and G. Giovannoni Cerebrospinal fluid brain specific proteins in relation to nitric oxide metabolites during relapse of multiple sclerosis Multiple Sclerosis, January 1, 2008; 14(1): 59 - 66. [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]
|
|
|
|
|
|
D. Centonze, M. Bari, S. Rossi, C. Prosperetti, R. Furlan, F. Fezza, V. De Chiara, L. Battistini, G. Bernardi, S. Bernardini, et al. The endocannabinoid system is dysregulated in multiple sclerosis and in experimental autoimmune encephalomyelitis Brain, October 1, 2007; 130(10): 2543 - 2553. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Dutta and B. D. Trapp Pathogenesis of axonal and neuronal damage in multiple sclerosis Neurology, May 29, 2007; 68(22_suppl_3): S22 - S31. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. W. Yong, F. Giuliani, M. Xue, A. Bar-Or, and L. M. Metz Experimental models of neuroprotection relevant to multiple sclerosis Neurology, May 29, 2007; 68(22_suppl_3): S32 - S37. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Hamamcioglu and A. Reder Interferon-{beta} regulates cytokines and BDNF: greater effect in relapsing than in progressive multiple sclerosis Multiple Sclerosis, May 1, 2007; 13(4): 459 - 470. [Abstract] [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]
|
|
|
|
|
|
B. Banwell, M. Shroff, J. M. Ness, D. Jeffery, S. Schwid, B. Weinstock-Guttman, and for the International Pediatric MS Study Group MRI features of pediatric multiple sclerosis Neurology, April 17, 2007; 68(16_suppl_2): S46 - S53. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W Rashid, G R Davies, D T Chard, C M Griffin, D R Altmann, A J Thompson, and D H Miller Relationship of triple dose contrast enhanced lesions with clinical measures and brain atrophy in early relapsing-remitting multiple sclerosis: a two-year longitudinal study Multiple Sclerosis, March 1, 2007; 13(2): 178 - 185. [Abstract] [PDF]
|
|
|
|
|
|
K. J. Smith Axonal protection in multiple sclerosis--a particular need during remyelination? Brain, December 1, 2006; 129(12): 3147 - 3149. [Full Text] [PDF]
|
|
|
|
|
|
J. A. Black, S. Liu, B. C. Hains, C. Y. Saab, and S. G. Waxman Long-term protection of central axons with phenytoin in monophasic and chronic-relapsing EAE Brain, December 1, 2006; 129(12): 3196 - 3208. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Kappos, C. H. Polman, M. S. Freedman, G. Edan, H. P. Hartung, D. H. Miller, X. Montalban, F. Barkhof, L. Bauer, P. Jakobs, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes Neurology, October 10, 2006; 67(7): 1242 - 1249. [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]
|
|
|
|
|
|
D Merkler, B Schmelting, B Czeh, E Fuchs, C Stadelmann, and W Bruck Myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in the common marmoset reflects the immunopathology of pattern II multiple sclerosis lesions Multiple Sclerosis, August 1, 2006; 12(4): 369 - 374. [Abstract] [PDF]
|
|
|
|
|
|
B Casanova, I Bosca, S Parra, A Pascual, and F Coret Letter to the Editor Multiple Sclerosis, August 1, 2006; 12(4): 521 - 522. [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]
|
|
|
|
|
|
L. A. Boven, M. Van Meurs, M. Van Zwam, A. Wierenga-Wolf, R. Q. Hintzen, R. G. Boot, J. M. Aerts, S. Amor, E. E. Nieuwenhuis, and J. D. Laman Myelin-laden macrophages are anti-inflammatory, consistent with foam cells in multiple sclerosis Brain, February 1, 2006; 129(2): 517 - 526. [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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
G R Davies, D R Altmann, W Rashid, D T Chard, C M Griffin, G J Barker, R Kapoor, A J Thompson, and D H Miller Emergence of thalamic magnetization transfer ratio abnormality in early relapsing--remitting multiple sclerosis Multiple Sclerosis, June 1, 2005; 11(3): 276 - 281. [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]
|
|
|
|
 |
|
 A. Schneider, G. W. Araujo, K. Trajkovic, M. M. Herrmann, D. Merkler, E.-M. Mandelkow, R. Weissert, and M. Simons Hyperphosphorylation and Aggregation of Tau in Experimental Autoimmune Encephalomyelitis J. Biol. Chem., December 31, 2004; 279(53): 55833 - 55839. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. J. Fox Immunopathology of multiple sclerosis Neurology, December 28, 2004; 63(12_suppl_6): S3 - S7. [Abstract] [Full Text]
|
|
|
|
|
|
L. Kappos, B. Weinshenker, C. Pozzilli, A. J. Thompson, F. Dahlke, K. Beckmann, C. Polman, H. McFarland, and for the European and North American Interferon b Interferon beta-1b in secondary progressive MS: A combined analysis of the two trials Neurology, November 23, 2004; 63(10): 1779 - 1787. [Abstract] [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]
|
|
|
|
|
|
M. S. Deloire, T. Touil, B. Brochet, V. Dousset, J.-M. Caille, and K. G Petry Macrophage brain infiltration in experimental autoimmune encephalomyelitis is not completely compromised by suppressed T-cell invasion: in vivo magnetic resonance imaging illustration in effective anti-VLA-4 antibody treatment Multiple Sclerosis, October 1, 2004; 10(5): 540 - 548. [Abstract] [PDF]
|
|
|
|
|
|
G R Davies, L Ramio-Torrenta, A Hadjiprocopis, D T Chard, C M B Griffin, W Rashid, G J Barker, R Kapoor, A J Thompson, and D H Miller Evidence for grey matter MTR abnormality in minimally disabled patients with early relapsing-remitting multiple sclerosis J. Neurol. Neurosurg. Psychiatry, July 1, 2004; 75(7): 998 - 1002. [Abstract] [Full Text] [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]
|
|
|
|
|
|
M. Kerschensteiner, C. Stadelmann, B. S. Buddeberg, D. Merkler, F. M. Bareyre, D. C. Anthony, C. Linington, W. Bruck, and M. E. Schwab Targeting Experimental Autoimmune Encephalomyelitis Lesions to a Predetermined Axonal Tract System Allows for Refined Behavioral Testing in an Animal Model of Multiple Sclerosis Am. J. Pathol., April 1, 2004; 164(4): 1455 - 1469. [Abstract] [Full Text] [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
C. Malmestrom, S. Haghighi, L. Rosengren, O. Andersen, and J. Lycke Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS Neurology, December 23, 2003; 61(12): 1720 - 1725. [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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 M. Samsam, W. Mi, C. Wessig, J. Zielasek, K. V. Toyka, M. P. Coleman, and R. Martini The Wlds Mutation Delays Robust Loss of Motor and Sensory Axons in a Genetic Model for Myelin-Related Axonopathy J. Neurosci., April 1, 2003; 23(7): 2833 - 2839. [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]
|
|