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Abstract

Background:

Sphingolipids are important components of neurons and the myelin sheath whose levels are altered in multiple sclerosis (MS).

Objectives:

We aimed to determine if cerebrospinal fluid (CSF) sphingolipids can be used as markers of MS disease progression.

Methods:

Using liquid chromatography tandem mass spectrometry, we analysed sphingolipids in CSF from 134 individuals. The MS group included 65 patients divided into 41 relapsing–remitting MS (RRMS) and 24 progressive MS (ProgMS). In addition, a group of 13 early MS/clinically isolated syndrome (EarlyMS) and two control groups consisting of 38 individuals with other neurological diseases (OND) and 18 OND with signs of inflammation (iOND) were analysed. A follow-up study included 17 additional RRMS patients sampled at two time points 4.7±1.7 years apart.

Results:

Levels of sphingomyelin (SM)- and hexosylceramide (HexCer)-derived sphingolipids increased in the CSF of patients with MS independently of the fatty acid chain length in RRMS (p<0.05). Levels of palmitic acid (16:0)-containing HexCer (HexCer16:0) increased significantly in ProgMS compared with the OND (p<0.001), iOND (p<0.05) and EarlyMS (p<0.01) groups and correlated with Expanded Disability Status Scale in RRMS in both studies (p=0.048; p=0.027).

Conclusion:

HexCer16:0 is a promising candidate marker of disease progression in MS, especially in RRMS.

Keywords

Multiple sclerosis cerebrospinal fluid inflammation axonal damage demyelination mass spectrometry

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References

Compston

Coles

. Multiple sclerosis. Lancet 2008; 372: 1502–1517.

Comabella

Montalban

. Body fluid biomarkers in multiple sclerosis. Lancet Neurol 2014; 13: 113–126.

Genain

Cannella

Hauser

. Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nat Med 1999; 5: 170–175.

Goverman

. Autoimmune T cell responses in the central nervous system. Nat Rev Immunol 2009; 9: 393–407.

Kanter

Johnson

. Identification of naturally occurring fatty acids of the myelin sheath that resolve neuroinflammation. Sci Transl Med 2012; 4: 137ra173.

Quintana

Yeste

Weiner

. Lipids and lipid-reactive antibodies as biomarkers for multiple sclerosis. J Neuroimmunol 2012; 248: 53–57.

Hannun

Obeid

. Many ceramides. J Biol Chem 2011; 286: 27855–27862.

Miller

Barkhof

Montalban

. Clinically isolated syndromes suggestive of multiple sclerosis, part I: Natural history, pathogenesis, diagnosis, and prognosis. Lancet Neurol 2005; 4: 281–288.

McDonald

Compston

Edan

. Recommended diagnostic criteria for multiple sclerosis: Guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50: 121–127.

10.

Sullards

Liu

Chen

. Analysis of mammalian sphingolipids by liquid chromatography tandem mass spectrometry (LC-MS/MS) and tissue imaging mass spectrometry (TIMS). Biochim Biophys Acta 2011; 1811: 838–853.

11.

Davison

Wajda

. Cerebral lipids in multiple sclerosis. J Neurochem 1962; 9: 427–432.

12.

Tourtellotte Ww

HAF

. Lipids in cerebrospinal fluid: XII. In multiple sclerosis and retrobulbar neuritis. Arch Neurol 1969; 20: 605–615.

13.

Seidel

Buck

Heipertz

. Cerebrospinal fluid lipids in demyelinating disease. J Neurol 1980; 222: 171–176.

14.

Seppälä

Nerg

Koivisto

. CSF biomarkers for Alzheimer disease correlate with cortical brain biopsy findings. Neurology 2012; 78: 1568–1575.

15.

Schiffmann

Ferreiros

Birod

. Ceramide synthase 6 plays a critical role in the development of experimental autoimmune encephalomyelitis. J Immunol 2012; 188: 5723–5733.

16.

Vidaurre

Haines

Katz Sand

. Cerebrospinal fluid ceramides from patients with multiple sclerosis impair neuronal bioenergetics. Brain 2014; 137: 2271–2286.

17.

Grösch

Schiffmann

Geisslinger

. Chain length-specific properties of ceramides. Prog Lipid Res 2012; 51: 50–62.

18.

Haghighi

Lekman

Nilsson

. Myelin glycosphingolipid immunoreactivity and CSF levels in multiple sclerosis. Acta Neurol Scand 2012; 125: 64–70.

19.

Podbielska

Hogan

. Molecular and immunogenic features of myelin lipids: Incitants or modulators of multiple sclerosis? Mult Scler 2009; 15: 1011–1029.

20.

Lou

HOC

Matzke

. Cerebroside and other polar lipids of the cerebrospinal fluid in neurological diseases. Acta Neurol Scand 1965; 41: 445–447.

21.

Wheeler

Bandaru

Calabresi

. A defect of sphingolipid metabolism modifies the properties of normal appearing white matter in multiple sclerosis. Brain 2008; 131: 3092–3102.

22.

Doorn

Nijland

Dekker

. Fingolimod attenuates ceramide-induced blood–brain barrier dysfunction in multiple sclerosis by targeting reactive astrocytes. Acta Neuropathol (Berl) 2012; 124: 397–410.

23.

Hla

Brinkmann

. Sphingosine 1-phosphate (S1P): Physiology and the effects of S1P receptor modulation. Neurology 2011; 76: S3-S8.

24.

Van Doorn

Van Horssen

Verzijl

. Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions. Glia 2010; 58: 1465–1476.

25.

Kulakowska

Zendzian-Piotrowska

Baranowski

. Intrathecal increase of sphingosine 1-phosphate at early stage multiple sclerosis. Neurosci Lett 2010; 477: 149–152.

26.

Teunissen

Dijkstra

Polman

. Biological markers in CSF and blood for axonal degeneration in multiple sclerosis. Lancet Neurol 2005; 4: 32–41.

27.

Salzer

Svenningsson

Sundström

. Neurofilament light as a prognostic marker in multiple sclerosis. Mult Scler 2010; 16: 287–292.

28.

Zohren

Toutzaris

Klärner

. The monoclonal anti-VLA-4 antibody natalizumab mobilizes CD34+ hematopoietic progenitor cells in humans. Blood 2008; 111: 3893–3895.

29.

Chataway

Miller

. Natalizumab therapy for multiple sclerosis. Neurotherapeutics 2013; 10: 19–28.

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