Sphingomyelin as a myelin biomarker in CSF of acquired demyelinating neuropathies

Fast, accurate and reliable methods to quantify the amount of myelin still lack, both in humans and experimental models. The overall objective of the present study was to demonstrate that sphingomyelin (SM) in the cerebrospinal fluid (CSF) of patients affected by demyelinating neuropathies is a myelin biomarker. We found that SM levels mirror both peripheral myelination during development and small myelin rearrangements in experimental models. As in acquired demyelinating peripheral neuropathies myelin breakdown occurs, SM amount in the CSF of these patients might detect the myelin loss. Indeed, quantification of SM in 262 neurological patients showed a significant increase in patients with peripheral demyelination (p = 3.81 * 10 − 8) compared to subjects affected by non-demyelinating disorders. Interestingly, SM alone was able to distinguish demyelinating from axonal neuropathies and differs from the principal CSF indexes, confirming the novelty of this potential CSF index. In conclusion, SM is a specific and sensitive biomarker to monitor myelin pathology in the CSF of peripheral neuropathies. Most importantly, SM assay is simple, fast, inexpensive, and promising to be used in clinical practice and drug development.

[1]  L. Lesko,et al.  Use of biomarkers and surrogate endpoints in drug development and regulatory decision making: criteria, validation, strategies. , 2001, Annual review of pharmacology and toxicology.

[2]  R. Wanders,et al.  Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination. , 2014, The Journal of clinical investigation.

[3]  G. Giovannonid,et al.  Guidelines on routine cerebrospinal fluid analysis . Report from an EFNS task force , 2006 .

[4]  F. Lolli,et al.  Consensus recommendations of the Italian Association for Neuroimmunology for immunochemical cerebrospinal fluid examination , 2005, Journal of the Neurological Sciences.

[5]  A. Schenone,et al.  P2X7-mediated Increased Intracellular Calcium Causes Functional Derangement in Schwann Cells from Rats with CMT1A Neuropathy* , 2009, The Journal of Biological Chemistry.

[6]  T. Suhara,et al.  Reconstruction magnetic resonance neurography in chronic inflammatory demyelinating polyneuropathy , 2015, Annals of Neurology.

[7]  D. M. Amundson,et al.  Fluorometric method for the enzymatic determination of cholesterol. , 1999, Journal of biochemical and biophysical methods.

[8]  Jie Zhu,et al.  Biomarkers of Guillain-Barré Syndrome: Some Recent Progress, More Still to Be Explored , 2015, Mediators of inflammation.

[9]  F. Fazekas,et al.  Guidelines for uniform reporting of body fluid biomarker studies in neurologic disorders , 2014, Neurology.

[10]  F. Zipp,et al.  Activation of Microglial Poly(ADP-Ribose)-Polymerase-1 by Cholesterol Breakdown Products during Neuroinflammation , 2003, The Journal of experimental medicine.

[11]  J. Gore,et al.  Proximal nerve magnetization transfer MRI relates to disability in Charcot-Marie-Tooth diseases , 2014, Neurology.

[12]  E. Schuchman,et al.  A fluorescence-based, high-throughput sphingomyelin assay for the analysis of Niemann-Pick disease and other disorders of sphingomyelin metabolism. , 2002, Analytical biochemistry.

[13]  H. Baba,et al.  Sulfatide decrease in myelin influences formation of the paranodal axo‐glial junction and conduction velocity in the sciatic nerve , 2013, Glia.

[14]  H. Reiber.  The discrimination between different blood-CSF barrier dysfunctions and inflammatory reactions of the CNS by a recent evaluation graph for the protein profile of cerebrospinal fluid , 2004, Journal of Neurology.

[15]  P. Bergh,et al.  European Federation of Neurological Societies / Peripheral Nerve Society Guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy : Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society — First Revision Members , 2010 .

[16]  Deepika Agrawal,et al.  Internodal myelination during development quantitated using X-ray diffraction. , 2009, Journal of structural biology.

[17]  K. Nave,et al.  Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models , 2011, Journal of Lipid Research.

[18]  W. Norton,et al.  Isolation of Myelin , 2006, Current protocols in cell biology.

[19]  Dean A Seehusen,et al.  Cerebrospinal fluid analysis. , 2003, American family physician.

[20]  A. Basit,et al.  Rapid evaluation of 25 key sphingolipids and phosphosphingolipids in human plasma by LC-MS/MS , 2015, Analytical and Bioanalytical Chemistry.

[21]  D. Cornblath,et al.  Assessment of current diagnostic criteria for Guillain‐Barré syndrome , 1990, Annals of neurology.

[22]  V. Malhotra,et al.  Sphingomyelin homeostasis is required to form functional enzymatic domains at the trans-Golgi network , 2014, The Journal of cell biology.

[23]  M. Meisler,et al.  Genetic Interaction between MTMR2 and FIG4 Phospholipid Phosphatases Involved in Charcot-Marie-Tooth Neuropathies , 2011, PLoS genetics.

[24]  M. Glaser,et al.  Neuroprotection and enhancement of remyelination by estradiol and dexamethasone in cocultures of rat DRG neurons and Schwann cells , 2008, Brain Research.

[25]  Tom Fawcett,et al.  An introduction to ROC analysis , 2006, Pattern Recognit. Lett..

[26]  Daniel C. Factor,et al.  Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo , 2015, Nature.

[27]  A. Zhang,et al.  Serum metabolomics as a novel diagnostic approach for disease: a systematic review , 2012, Analytical and Bioanalytical Chemistry.

[28]  E. Mohammadi,et al.  Barriers and facilitators related to the implementation of a physiological track and trigger system: A systematic review of the qualitative evidence , 2017, International journal for quality in health care : journal of the International Society for Quality in Health Care.

[29]  N. Gilhus,et al.  Guidelines on routine cerebrospinal fluid analysis. Report from an EFNS task force , 2006, European journal of neurology.

[30]  K. Trinkaus,et al.  Differentiation and quantification of inflammation, demyelination and axon injury or loss in multiple sclerosis. , 2015, Brain : a journal of neurology.

[31]  R. Teraoka,et al.  Specific and sensitive enzymatic measurement of sphingomyelin in cultured cells. , 2012, Chemistry and physics of lipids.

[32]  N. Vanacore,et al.  Peripheral nerve ultrasound changes in CIDP and correlations with nerve conduction velocity , 2015, Neurology.

[33]  J. Pollard,et al.  European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society — First Revision , 2010, European journal of neurology.

[34]  Steffen Jung,et al.  Age-related myelin degradation burdens the clearance function of microglia during aging , 2016, Nature Neuroscience.

[35]  W. J. Dyer,et al.  A rapid method of total lipid extraction and purification. , 1959, Canadian journal of biochemistry and physiology.