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Published in: Journal of Neurology 5/2007

Open Access 01-05-2007 | ORIGINAL COMMUNICATION

N-acetylaspartic acid in cerebrospinal fluid of multiple sclerosis patients determined by gas-chromatography-mass spectrometry

Authors: Bas Jasperse, MD, Cornelis Jakobs, PhD, M. Judith Eikelenboom, MD, Christine D. Dijkstra, MD, PhD, Bernard M. J. Uitdehaag, MD, PhD, Frederik Barkhof, MD, PhD, Chris H. Polman, MD, PhD, Charlotte E. Teunissen, PhD

Published in: Journal of Neurology | Issue 5/2007

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Abstract

Background

Axonal degeneration is considered to play a major role in the development of clinical disability in multiple sclerosis (MS). N-AcetylAspartic Acid (NAA) is a neuron-specific marker constantly identified in MR-spectroscopy studies of the normal and MS brain. To our knowledge there are no studies available that evaluated NAA in cerebrospinal fluid (CSF) as a possible marker for disease severity.

Objective

To evaluate CSF concentrations of NAA in MS in relation to disease phenotype, clinical measures of disability and MRI markers of disease burden.

Methods

NAA concentrations were determined in CSF of 46 patients with MS (26 relapsing remitting (RRMS), 12 secondary progressive (SPMS) and 8 primary progressive (PPMS)). Prior to lumbar puncture, MS-patients underwent MRI and clinical examination, including the Expanded Disability Status Scale (EDSS) and the MS Functional Composite (MSFC). Additionally, CSF concentrations of NAA were determined in 12 patients with other neurological diseases (OND).

Results

Median CSF NAA concentration was 0.74 (IQR: 0.59-.94) in RRMS , 0.54 (IQR: 0.35-.73) in SPMS and 0.83 μmol/l (IQR: 0.56-.03) in PPMS patients. SPMS patients had a significantly lower NAA concentration than RRMS patients. NAA concentrations correlated with EDSS (r = )0.37, p = 0.016), MSFC (r = 0.41, p = 0.010), normalised brain volume (r = 0.49, p = 0.001), T2 lesion load (r = )0.35, p = 0.021) and black hole lesion load (r = )0.47, p = 0.002). No differences were observed between OND (median: 0.57 IQR: 0.28-.73) and MS patients.

Conclusion

CSF NAA concentration in MS patients is related to clinical performance and MRI measures of disease burden and may therefore be an important neuron specific marker of disease severity and possibly progression.
Literature
1.
go back to reference Baslow MH (2003) N-acetylaspartate in the vertebrate brain: Metabolism and function. Neurochem Rese 28:941-53CrossRef Baslow MH (2003) N-acetylaspartate in the vertebrate brain: Metabolism and function. Neurochem Rese 28:941-53CrossRef
2.
go back to reference Bitsch A, Schuchardt J, Bunkowski S, Kuhlmann T, Bruck W (2000) Acute axonal injury in multiple sclerosis - Correlation with demyelination and inflammation. Brain 123:1174-183CrossRefPubMed Bitsch A, Schuchardt J, Bunkowski S, Kuhlmann T, Bruck W (2000) Acute axonal injury in multiple sclerosis - Correlation with demyelination and inflammation. Brain 123:1174-183CrossRefPubMed
3.
go back to reference Bjartmar C, Battistuta J, Terada N, Dupree E, Trapp BD (2002) N-acetylaspartate is an axon-specific marker of mature white matter in vivo: a biochemical and immunohistochemical study on the rat optic nerve. Ann Neurol 51:51-8CrossRefPubMed Bjartmar C, Battistuta J, Terada N, Dupree E, Trapp BD (2002) N-acetylaspartate is an axon-specific marker of mature white matter in vivo: a biochemical and immunohistochemical study on the rat optic nerve. Ann Neurol 51:51-8CrossRefPubMed
4.
go back to reference Bjartmar C, Kidd G, Mork S, Rudick R, Trapp BD (2000) Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann Neurol 48:893-01CrossRefPubMed Bjartmar C, Kidd G, Mork S, Rudick R, Trapp BD (2000) Neurological disability correlates with spinal cord axonal loss and reduced N-acetyl aspartate in chronic multiple sclerosis patients. Ann Neurol 48:893-01CrossRefPubMed
5.
go back to reference Bruck W, Bitsch A, Kolenda H, Bruck Y, Stiefel M, Lassmann H (1997) Inflammatory central nervous system demyelination: correlation of magnetic resonance imaging findings with lesion pathology. Ann Neurol 42:783-93CrossRefPubMed Bruck W, Bitsch A, Kolenda H, Bruck Y, Stiefel M, Lassmann H (1997) Inflammatory central nervous system demyelination: correlation of magnetic resonance imaging findings with lesion pathology. Ann Neurol 42:783-93CrossRefPubMed
6.
go back to reference Cutter GR, Baier ML, Rudick RA, Cookfair DL, Fischer JS, Petkau J, Syndulko K, Weinshenker BG, Antel JP, Confavreux C, Ellison GW, Lublin F, Miller AE, Rao SM, Reingold S, Thompson A, Willoughby E (1999) Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain 122(Pt 5):871-82CrossRefPubMed Cutter GR, Baier ML, Rudick RA, Cookfair DL, Fischer JS, Petkau J, Syndulko K, Weinshenker BG, Antel JP, Confavreux C, Ellison GW, Lublin F, Miller AE, Rao SM, Reingold S, Thompson A, Willoughby E (1999) Development of a multiple sclerosis functional composite as a clinical trial outcome measure. Brain 122(Pt 5):871-82CrossRefPubMed
7.
go back to reference Davie CA, Hawkins CP, Barker GJ, Brennan A, Tofts PS, Miller DH, Mcdonald WI (1994) Serial Proton Magnetic-Resonance Spectroscopy in Acute Multiple-Sclerosis Lesions. Brain 117:49-8CrossRefPubMed Davie CA, Hawkins CP, Barker GJ, Brennan A, Tofts PS, Miller DH, Mcdonald WI (1994) Serial Proton Magnetic-Resonance Spectroscopy in Acute Multiple-Sclerosis Lesions. Brain 117:49-8CrossRefPubMed
8.
go back to reference De Stefano N, Guidi L, Stromillo ML, Bartolozzi ML, Federico A (2003) Imaging neuronal and axonal degeneration in multiple sclerosis. Neurol Sci 24:S283–S286CrossRefPubMed De Stefano N, Guidi L, Stromillo ML, Bartolozzi ML, Federico A (2003) Imaging neuronal and axonal degeneration in multiple sclerosis. Neurol Sci 24:S283–S286CrossRefPubMed
9.
go back to reference De Stefano N, Iannucci G, Sormani MP, Guidi L, Bartolozzi ML, Comi G, Federico A, Filippi M (2002) MR correlates of cerebral atrophy in patients with multiple sclerosis. J Neurol 249:1072-077CrossRefPubMed De Stefano N, Iannucci G, Sormani MP, Guidi L, Bartolozzi ML, Comi G, Federico A, Filippi M (2002) MR correlates of cerebral atrophy in patients with multiple sclerosis. J Neurol 249:1072-077CrossRefPubMed
10.
go back to reference De Stefano N, Matthews PM, Fu LQ, Narayanan S, Stanley J, Francis GS, Antel JP, Arnold DL (1998) Axonal damage correlates with disability in patients with relapsing-remitting multiple sclerosis - Results of a longitudinal magnetic resonance spectroscopy study. Brain 121:1469-477CrossRefPubMed De Stefano N, Matthews PM, Fu LQ, Narayanan S, Stanley J, Francis GS, Antel JP, Arnold DL (1998) Axonal damage correlates with disability in patients with relapsing-remitting multiple sclerosis - Results of a longitudinal magnetic resonance spectroscopy study. Brain 121:1469-477CrossRefPubMed
11.
go back to reference De Stefano N, Narayanan S, Francis GS, Arnaoutelis R, Tartaglia MC, Antel JP, Matthews PM, Arnold DL (2001) Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch Neurol 58:65-0CrossRefPubMed De Stefano N, Narayanan S, Francis GS, Arnaoutelis R, Tartaglia MC, Antel JP, Matthews PM, Arnold DL (2001) Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch Neurol 58:65-0CrossRefPubMed
12.
go back to reference Evangelou N, Konz D, Esiri MM, Smith S, Palace J, Matthews PM (2000) Regional axonal loss in the corpus callosum correlates with cerebral white matter lesion volume and distribution in multiple sclerosis. Brain 123(Pt 9):1845-849CrossRefPubMed Evangelou N, Konz D, Esiri MM, Smith S, Palace J, Matthews PM (2000) Regional axonal loss in the corpus callosum correlates with cerebral white matter lesion volume and distribution in multiple sclerosis. Brain 123(Pt 9):1845-849CrossRefPubMed
13.
go back to reference Ferguson B, Matyszak MK, Esiri MM, Perry VH (1997) Axonal damage in acute multiple sclerosis lesions. Brain 120:393-99CrossRefPubMed Ferguson B, Matyszak MK, Esiri MM, Perry VH (1997) Axonal damage in acute multiple sclerosis lesions. Brain 120:393-99CrossRefPubMed
14.
go back to reference Fu L, Matthews PM, De Stefano N, Worsley KJ, Narayanan S, Francis GS, Antel JP, Wolfson C, Arnold DL (1998) Imaging axonal damage of normalappearing white matter in multiple sclerosis. Brain 121:103-13CrossRefPubMed Fu L, Matthews PM, De Stefano N, Worsley KJ, Narayanan S, Francis GS, Antel JP, Wolfson C, Arnold DL (1998) Imaging axonal damage of normalappearing white matter in multiple sclerosis. Brain 121:103-13CrossRefPubMed
15.
go back to reference Jakobs C, ten Brink HJ, Langelaar SA, Zee T, Stellaard F, Macek M, Srsnova K, Srsen S, Kleijer WJ (1991) Stable isotope dilution analysis of N-acetylaspartic acid in CSF, blood, urine and amniotic fluid: accurate postnatal diagnosis and the potential for prenatal diagnosis of Canavan disease. J Inherit Metab Dis 14:653-60CrossRefPubMed Jakobs C, ten Brink HJ, Langelaar SA, Zee T, Stellaard F, Macek M, Srsnova K, Srsen S, Kleijer WJ (1991) Stable isotope dilution analysis of N-acetylaspartic acid in CSF, blood, urine and amniotic fluid: accurate postnatal diagnosis and the potential for prenatal diagnosis of Canavan disease. J Inherit Metab Dis 14:653-60CrossRefPubMed
16.
go back to reference Kalkers NF, De Groot V, Lazeron RHC, Killestein J, Ader HJ, Barkhof F, Lankhorst GJ, Polman CH (2000) MS Functional Composite - Relation to disease phenotype and disability strata. Neurology 54:1233-239PubMed Kalkers NF, De Groot V, Lazeron RHC, Killestein J, Ader HJ, Barkhof F, Lankhorst GJ, Polman CH (2000) MS Functional Composite - Relation to disease phenotype and disability strata. Neurology 54:1233-239PubMed
17.
go back to reference Kornek B, Storch MK, Weissert R, Wallstroem E, Stefferl A, Olsson T, Linington C, Schmidbauer M, Lassmann H (2000) Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol 157:267-76PubMed Kornek B, Storch MK, Weissert R, Wallstroem E, Stefferl A, Olsson T, Linington C, Schmidbauer M, Lassmann H (2000) Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am J Pathol 157:267-76PubMed
18.
go back to reference Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444-452PubMed Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444-452PubMed
19.
go back to reference Lublin FD, Reingold SC (1996) Defining the clinical course of multiple sclerosis: Results of an international survey. Neurology 46:907-11PubMed Lublin FD, Reingold SC (1996) Defining the clinical course of multiple sclerosis: Results of an international survey. Neurology 46:907-11PubMed
20.
go back to reference Miller DH, Barkhof F, Frank JA, Parker GJ, Thompson AJ (2002) Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain 125:1676-695CrossRefPubMed Miller DH, Barkhof F, Frank JA, Parker GJ, Thompson AJ (2002) Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain 125:1676-695CrossRefPubMed
21.
go back to reference Oestreicher AB, De Graan PN, Gispen WH, Verhaagen J, Schrama LH (1997) B-50, the growth associated protein-43: modulation of cell morphology and communication in the nervous system. Prog Neurobiol 53:627-86CrossRefPubMed Oestreicher AB, De Graan PN, Gispen WH, Verhaagen J, Schrama LH (1997) B-50, the growth associated protein-43: modulation of cell morphology and communication in the nervous system. Prog Neurobiol 53:627-86CrossRefPubMed
22.
go back to reference Poser CM, Paty DW, Scheinberg L, Mcdonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW (1983) New Diagnostic-Criteria for Multiple-Sclerosis - Guidelines for Research Protocols. Ann Neurol 13:227-31CrossRefPubMed Poser CM, Paty DW, Scheinberg L, Mcdonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW (1983) New Diagnostic-Criteria for Multiple-Sclerosis - Guidelines for Research Protocols. Ann Neurol 13:227-31CrossRefPubMed
23.
go back to reference Smith SM, Zhang YY, Jenkinson M, Chen J, Matthews PM, Federico A, De Stefano N (2002) Accurate, robust, and automated longitudinal and cross-sectional brain change analysis. Neuroimage 17:479-89CrossRefPubMed Smith SM, Zhang YY, Jenkinson M, Chen J, Matthews PM, Federico A, De Stefano N (2002) Accurate, robust, and automated longitudinal and cross-sectional brain change analysis. Neuroimage 17:479-89CrossRefPubMed
24.
go back to reference Teunissen CE, Dijkstra C, Polman C (2005) Biological markers in CSF and blood for axonal degeneration in multiple sclerosis. Lancet Neurol 4:32-1CrossRefPubMed Teunissen CE, Dijkstra C, Polman C (2005) Biological markers in CSF and blood for axonal degeneration in multiple sclerosis. Lancet Neurol 4:32-1CrossRefPubMed
25.
go back to reference Teunissen CE, Dijkstra CD, Jasperse B, Barkhof F, Vanderstichele H, Vanmechelen E, Polman CH, Bo L (2006) Growth-associated protein 43 in lesions and cerebrospinal fluid in multiple sclerosis. Neuropathol Appl Neurobiol 32:318-31CrossRefPubMed Teunissen CE, Dijkstra CD, Jasperse B, Barkhof F, Vanderstichele H, Vanmechelen E, Polman CH, Bo L (2006) Growth-associated protein 43 in lesions and cerebrospinal fluid in multiple sclerosis. Neuropathol Appl Neurobiol 32:318-31CrossRefPubMed
26.
go back to reference Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278-85CrossRefPubMed Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278-85CrossRefPubMed
27.
go back to reference Trapp BD, Ransohoff R, Rudick R (1999) Axonal pathology in multiple sclerosis: relationship to neurologic disability. Curr Opin Neurol 12:295-02CrossRefPubMed Trapp BD, Ransohoff R, Rudick R (1999) Axonal pathology in multiple sclerosis: relationship to neurologic disability. Curr Opin Neurol 12:295-02CrossRefPubMed
28.
go back to reference van Walderveen MAA, Barkhof F, Pouwels PJW, van Schijndel RA, Polman CH, Castelijns JA (1999) Neuronal damage in T1-hypointense multiple sclerosis lesions demonstrated in vivo using proton magnetic resonance spectroscopy. Ann Neurol 46:79-7CrossRefPubMed van Walderveen MAA, Barkhof F, Pouwels PJW, van Schijndel RA, Polman CH, Castelijns JA (1999) Neuronal damage in T1-hypointense multiple sclerosis lesions demonstrated in vivo using proton magnetic resonance spectroscopy. Ann Neurol 46:79-7CrossRefPubMed
29.
go back to reference Vrenken H, Barkhof F, Uitdehaag BM, Castelijns JA, Polman CH, Pouwels PJ (2005) MR spectroscopic evidence for glial increase but not for neuro-axonal damage in MS normal-appearing white matter. Magn Reson Med 53:256-66CrossRefPubMed Vrenken H, Barkhof F, Uitdehaag BM, Castelijns JA, Polman CH, Pouwels PJ (2005) MR spectroscopic evidence for glial increase but not for neuro-axonal damage in MS normal-appearing white matter. Magn Reson Med 53:256-66CrossRefPubMed
Metadata
Title
N-acetylaspartic acid in cerebrospinal fluid of multiple sclerosis patients determined by gas-chromatography-mass spectrometry
Authors
Bas Jasperse, MD
Cornelis Jakobs, PhD
M. Judith Eikelenboom, MD
Christine D. Dijkstra, MD, PhD
Bernard M. J. Uitdehaag, MD, PhD
Frederik Barkhof, MD, PhD
Chris H. Polman, MD, PhD
Charlotte E. Teunissen, PhD
Publication date
01-05-2007
Publisher
Steinkopff-Verlag
Published in
Journal of Neurology / Issue 5/2007
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI
https://doi.org/10.1007/s00415-006-0415-5

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