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NEUROLOGY 2009;72:1322-1329
© 2009 American Academy of Neurology

Combination of CSF N-acetylaspartate and neurofilaments in multiple sclerosis

C. E. Teunissen, PhD, E. Iacobaeus, MD, M. Khademi, PhD, L. Brundin, PhD, N. Norgren, PhD, M.J.A. Koel-Simmelink, PhD, M. Schepens, MD, F. Bouwman, PhD, H. A.M. Twaalfhoven, BSc, H. J. Blom, PhD, C. Jakobs, PhD and C. D. Dijkstra, PhD

From NUBIN, Department of Molecular Cell Biology and Immunology (C.E.T., M.J.A.K.-S., M.S., C.D.D.), Department of Neurology (F.B.), and Department of Clinical Chemistry (H.A.M.T., H.J.B., C.J.), VUMC, Amsterdam, the Netherlands; Centre of Molecular Medicine (E.I., M.K., L.B.), Neuroimmunology Unit, Karolinska Institutet Stockholm; and UmanDiagnostics AB (N.N.), Umeå Biotech Incubator, Sweden.

Address correspondence and reprint requests to Dr. Charlotte E. Teunissen, Molecular Cell Biology and Immunology, VU University Medical Center, FdG, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands c.teunissen{at}vumc.nl.

Objective: Axonal degeneration is the likely cause of disease progression in multiple sclerosis (MS). Our previous results indicated that neuron-specific N-acetylaspartate (NAA) is a candidate CSF biomarker for disease progression in MS. The aim of this study was to explore the potential of NAA as an early biomarker of axonal damage in MS. Next, we wanted to know the additional value of measurement of NAA compared to other candidate markers for axonal damage, such as neurofilament subunits and tau protein.

Methods: Levels of NAA, neurofilament light, neurofilament heavy, and tau were determined in CSF of patients with clinically isolated syndrome (CIS, n = 38), relapsing-remitting MS (RRMS, n = 42), secondary progressive MS (SPMS, n = 28), and primary progressive MS (PPMS, n = 6); patients without neurologic disease (ND, n = 28); noninflammatory neurologic controls (n = 18); and inflammatory neurologic controls (n = 39).

Results: CSF NAA levels were decreased in patients with SPMS compared to ND controls, patients with CIS, and patients with RRMS. CSF NAA levels in patients with CIS and RRMS were similar to those in ND subjects. All axonal damage proteins showed specific patterns of changes and relations with disease activity measures. The neurofilament light chain levels were already increased in patients with CIS, especially in patients who converted to MS. The neurofilament heavy chain levels were highest in the patients with SPMS. Tau levels were similar in MS and ND.

Conclusions: CSF N-acetylaspartate (NAA) levels were not different from patients without neurologic disease in early stages of multiple sclerosis, though decreased as the disease progressed. Combining CSF NAA and neurofilament levels yields information on different phases of axonal pathology.

Abbreviations: CIS = clinically isolated syndrome; EDSS = Expanded Disability Status Scale; FLAIR = fluid-attenuated inversion recovery; FSE = fast spin echo; IEF = isoelectric focusing; IND = inflammatory neurologic disease; MRS = magnetic resonance spectroscopy; MS = multiple sclerosis; NAA = N-acetylaspartate; ND = patients without neurologic disease; Nf = neurofilament; NIND = noninflammatory neurologic diseases; OCB = oligoclonal bands; PPMS = primary progressive multiple sclerosis; RRMS = relapsing-remitting multiple sclerosis; SLE = systemic lupus erythematosus; SPMS = secondary progressive multiple sclerosis; TE = echo time; TR = repetition time.

Supplemental data at www.neurology.org

Supported by the Dutch Brain Foundation [13F05.(2)46], Dutch Research Council [NWO/VENI (016.056.024)], Swedish Medical Research Council.

Disclosure: The authors report no disclosures.

Medical Devices: High-performance ELISA buffer (Sanquin; Amsterdam, Netherlands); INNOTEST® hTAUAg (Innogenetics; Ghent, Belgium); purified porcine axonal Nf 200 (Chemicon International; Temecula, CA); reagents for the Nf light determination (UmanDiagnostics AB; Umeå, Sweden); General Electric scanner (GE Chalfont, St. Giles, UK).

Received September 25, 2008. Accepted in final form January 30, 2009.






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