Axonal damage accumulates in the progressive phase of multiple sclerosis: three year follow up study

A Petzold, M J Eikelenboom, G Keir, D Grant, R H C Lazeron, C H Polman, B M J Uitdehaag, E J Thompson, G Giovannoni, A Petzold, M J Eikelenboom, G Keir, D Grant, R H C Lazeron, C H Polman, B M J Uitdehaag, E J Thompson, G Giovannoni

Abstract

Background: Neurofilament phosphoforms (Nf) are principal components of the axoskeleton released during axonal injury. Cerebrospinal fluid (CSF) levels of Nf phosphoforms might be useful surrogate markers for disability in multiple sclerosis (MS), aid in distinguishing clinical subtypes, and provide valuable prognostic information.

Method: Thirty four patients with MS were included in a three year follow up study along with 318 controls with other non-inflammatory neurological diseases. CSF levels of two Nf heavy chain (NfH) phosphoforms (NfH(SMI35), NfH(SMI34)) were quantified at baseline and three year follow up using new ELISA techniques. Levels of NfH phosphoforms, the degree of phosphorylation (NfH(SMI34):NfH(SMI35) ratio), and changes in NfH levels between baseline and follow up (Delta NfH) were related to the clinical phenotype (RR or SP/PP), to three clinical scales (Kurtzke's EDSS, ambulation index (AI), and nine hole peg test (9HPT)), and to progression of disability.

Results: A significantly higher proportion (59%) of patients with SP/PPMS experienced an increase in NfH(SMI35) levels between baseline and follow up compared with those with RRMS (14%, p<0.05). CSF NfH(SMI34) levels at baseline were higher in patients with SP/PP (11 pg/ml) compared with RR (7 pg/ml, p<0.05) and NfH(SMI35) levels were higher at follow up in SP/PP (129 pg/ml) compared with levels below assay sensitivity in RR (p<0.05). NfH(SMI35) correlated with the EDSS (r(s) = 0.54, p<0.01), the AI (r(s) = 0.42, p<0.05), and the 9HPT (r(s) = 0.59, p<0.01) at follow up.

Conclusion: The increase in NfH during the progressive phase of the disease together with the correlation of NfH(SMI35) with all clinical scales at follow up suggests that cumulative axonal loss is responsible for sustained disability and that high NfH(SMI35) levels are a poor prognostic sign.

References

    1. Ann Neurol. 1999 Nov;46(5):747-54
    1. Neurology. 1983 Nov;33(11):1444-52
    1. J Cell Sci. 2000 Feb;113 ( Pt 3):401-7
    1. J Cell Biol. 2000 May 29;149(5):1157-66
    1. Ann Neurol. 2000 Jun;47(6):707-17
    1. Brain. 2000 Jun;123 ( Pt 6):1174-83
    1. Am J Pathol. 2000 Jul;157(1):267-76
    1. J Cell Biol. 2000 Jul 10;150(1):165-76
    1. N Engl J Med. 2000 Nov 16;343(20):1430-8
    1. N Engl J Med. 2000 Nov 16;343(20):1486-7
    1. Ann Neurol. 2001 Jul;50(1):121-7
    1. J Neurocytol. 2000 Nov-Dec;29(11-12):843-72
    1. Ann Neurol. 2001 Aug;50(2):169-80
    1. J Neuroimmunol. 1987 Mar;14(2):149-60
    1. Biochem J. 1988 Dec 1;256(2):665-8
    1. Neuropathol Appl Neurobiol. 1992 Aug;18(4):319-34
    1. Brain. 1993 Feb;116 ( Pt 1):117-34
    1. J Neurochem. 1995 Sep;65(3):1282-9
    1. Brain. 1996 Jun;119 ( Pt 3):701-8
    1. J Neurosci. 1996 Sep 1;16(17):5425-36
    1. Neurology. 1996 Apr;46(4):907-11
    1. Neurology. 1996 Dec;47(6):1469-76
    1. Brain. 1996 Dec;119 ( Pt 6):2009-19
    1. Brain. 1997 Mar;120 ( Pt 3):393-9
    1. J Neurosci. 1997 May 15;17(10):3455-66
    1. N Engl J Med. 1998 Jan 29;338(5):278-85
    1. N Engl J Med. 1998 Jan 29;338(5):323-5
    1. J Neurol Neurosurg Psychiatry. 1998 Mar;64(3):402-4
    1. J Neurochem. 1999 Jun;72(6):2248-55
    1. Radiology. 2001 Sep;220(3):606-10
    1. Brain. 2001 Oct;124(Pt 10):1978-88
    1. Neurology. 2001 Oct 9;57(7):1248-52
    1. Neurology. 2001 Oct 9;57(7):1253-8
    1. J Neuroimmunol. 2002 Jan;122(1-2):132-9
    1. Neuron. 2002 Mar 14;33(6):861-75
    1. Curr Opin Neurol. 2002 Jun;15(3):239-45
    1. Brain. 2002 Jul;125(Pt 7):1462-73
    1. Brain. 2002 Oct;125(Pt 10):2202-12
    1. Neurology. 2003 Jan 28;60(2):219-23
    1. Ann Neurol. 2003 Feb;53(2):150-3
    1. Ann Neurol. 2003 Feb;53(2):174-80
    1. J Cell Biol. 2003 May 12;161(3):489-95
    1. J Neuroimmunol. 2003 May;138(1-2):45-8
    1. Brain. 2003 Jul;126(Pt 7):1590-8
    1. Brain. 2003 Aug;126(Pt 8):1755-66
    1. Neuron. 2003 Jul 17;39(2):217-25
    1. J Immunol Methods. 2003 Jul;278(1-2):179-90
    1. Brain. 2003 Oct;126(Pt 10):2191-202
    1. Brain Res. 2003 Nov 7;989(2):196-204
    1. Neurology. 2003 Dec 23;61(12):1720-5
    1. Mult Scler. 2004 Jun;10(3):261-5
    1. J Neurol Sci. 1975 Jun;25(2):165-82
    1. Ann Neurol. 1978 Oct;4(4):337-44
    1. Proc Natl Acad Sci U S A. 1983 Oct;80(19):6126-30
    1. Nat Med. 2000 Jan;6(1):67-70

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe