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Association of a Marker of N-Acetylglucosamine With Progressive Multiple Sclerosis and Neurodegeneration

Educational Objective
To determine whether serum concentration of N-acetylglucosamine (GlcNAc) is altered in patients with multiple sclerosis.

1 Credit CME

JAMA Neurology

Published Online: May 10, 2021

Original Investigation

Article Information and Disclosures

Alexander U. Brandt, MD^1,2,3;

Michael Sy, MD, PhD²;

Judith Bellmann-Strobl, MD^1,3;

et al

Barbara L. Newton, MD²;

Judy Pawling⁴;

Hanna G. Zimmermann, PhD^1,3;

Zhaoxia Yu, PhD⁵;

Claudia Chien, MSc^1,3;

Jan Dörr, MD^1,3;

Jens Th. Wuerfel, MD^1,6;

James W. Dennis, PhD^4,7;

Friedemann Paul, MD^1,3;

Michael Demetriou, MD, PhD^2,8

Author Affiliations

¹Experimental and Clinical Research Center, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Max Delbrück Center for Molecular Medicine, Berlin, Germany
²Department of Neurology, University of California, Irvine, Irvine
³NeuroCure Clinical Research Center, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
⁴Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Toronto, Ontario, Canada
⁵Department of Statistics, University of California, Irvine, Irvine
⁶Medical Image Analysis Center, Department of Biomedical Engineering, University Basel, Basel, Switzerland
⁷Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
⁸Department of Microbiology and Molecular Genetics, University of California, Irvine, Irvine

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Key Points

Question Is the serum concentration of N-acetylglucosamine (GlcNAc) altered in patients with multiple sclerosis?

Findings This cross-sectional study found that patients with a progressive multiple sclerosis subtype and more severe disease have reduced serum levels of a marker of GlcNAc. In addition, GlcNAc is a rate-limiting substrate for N-glycan branching, which has been shown to regulate immunoactivity and myelination.

Meaning This study suggests that GlcNAc and N-glycan branching are associated with multiple sclerosis in general and progressive multiple sclerosis in particular.

Abstract

Importance N-glycan branching modulates cell surface receptor availability, and its deficiency in mice promotes inflammatory demyelination, reduced myelination, and neurodegeneration. N-acetylglucosamine (GlcNAc) is a rate-limiting substrate for N-glycan branching, but, to our knowledge, endogenous serum levels in patients with multiple sclerosis (MS) are unknown.

Objective To investigate a marker of endogenous serum GlcNAc levels in patients with MS.

Design, Setting, and Participants A cross-sectional discovery study and cross-sectional confirmatory study were conducted at 2 academic MS centers in the US and Germany. The discovery study recruited 54 patients with MS from an outpatient clinic as well as 66 healthy controls between April 20, 2010, and June 21, 2013. The confirmatory study recruited 180 patients with MS from screening visits at an academic MS study center between April 9, 2007, and February 29, 2016. Serum samples were analyzed from December 2, 2013, to March 2, 2015. Statistical analysis was performed from February 23, 2020, to March 18, 2021.

Main Outcomes and Measures Serum levels of GlcNAc plus its stereoisomers, termed N-acetylhexosamine (HexNAc), were assessed using targeted tandem mass spectroscopy. Secondary outcomes (confirmatory study) comprised imaging and clinical disease markers.

Results The discovery cohort included 66 healthy controls (38 women; mean [SD] age, 42 [20] years), 33 patients with relapsing-remitting MS (RRMS; 25 women; mean [SD] age, 50 [11] years), and 21 patients with progressive MS (PMS; 14 women; mean [SD] age, 55 [7] years). The confirmatory cohort included 125 patients with RRMS (83 women; mean [SD] age, 40 [9] years) and 55 patients with PMS (22 women; mean [SD] age, 49 [80] years). In the discovery cohort, the mean (SD) serum level of GlcNAc plus its stereoisomers (HexNAc) was 710 (174) nM in healthy controls and marginally reduced in patients with RRMS (mean [SD] level, 682 [173] nM; P = .04), whereas patients with PMS displayed markedly reduced levels compared with healthy controls (mean [SD] level, 548 [101] nM; P = 9.55 × 10⁻⁹) and patients with RRMS (P = 1.83 × 10⁻⁴). The difference between patients with RRMS (mean [SD] level, 709 [193] nM) and those with PMS (mean [SD] level, 405 [161] nM; P = 7.6 × 10⁻¹⁸) was confirmed in the independent confirmatory cohort. Lower HexNAc serum levels correlated with worse expanded disability status scale scores (ρ = –0.485; P = 4.73 × 10⁻¹²), lower thalamic volume (t = 1.7; P = .04), and thinner retinal nerve fiber layer (B = 0.012 [SE = 7.5 × 10⁻¹¹]; P = .008). Low baseline serum HexNAc levels correlated with a greater percentage of brain volume loss at 18 months (t = 1.8; P = .04).

Conclusions and Relevance This study suggests that deficiency of GlcNAc plus its stereoisomers (HexNAc) may be a biomarker for PMS. Previous preclinical, human genetic, and ex vivo human mechanistic studies revealed that N-glycan branching and/or GlcNAc may reduce proinflammatory responses, promote myelin repair, and decrease neurodegeneration. Combined, the data suggest that GlcNAc deficiency may be associated with progressive disease and neurodegeneration in patients with MS.

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Article Information

Accepted for Publication: March 11, 2021.

Published Online: May 10, 2021. doi:10.1001/jamaneurol.2021.1116

Corresponding Author: Michael Demetriou, MD, PhD, Department of Neurology, University of California, Irvine, 208 Sprague Hall, Irvine, CA 92697 (mdemetriou@uci.edu).

Author Contributions: Drs Brandt and Demetriou had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Brandt, Sy, Dennis, Paul, Demetriou.

Acquisition, analysis, or interpretation of data: Brandt, Bellmann-Strobl, Newton, Pawling, Zimmermann, Yu, Chien, Dörr, Wuerfel, Dennis, Paul, Demetriou.

Drafting of the manuscript: Brandt, Sy, Yu, Chien, Demetriou.

Critical revision of the manuscript for important intellectual content: Sy, Bellmann-Strobl, Newton, Pawling, Zimmermann, Chien, Dörr, Wuerfel, Dennis, Paul, Demetriou.

Statistical analysis: Brandt, Yu.

Obtained funding: Brandt, Paul, Demetriou.

Administrative, technical, or material support: Bellmann-Strobl, Newton, Zimmermann, Chien, Dörr, Wuerfel, Dennis, Paul.

Supervision: Brandt, Sy, Wuerfel, Dennis, Paul, Demetriou.

Conflict of Interest Disclosures: Dr Brandt reported receiving grants and personal fees from Guthy Jackson Foundation, Einstein Foundation, BMB, and Deutsche Forschungsgemeinschaft Exc 157 during the conduct of the study; being cofounder and receiving shares from Motognosis GmbH and Nocturne GmbH outside the submitted work; and having a patent for GlcNAc as Serum Biomarker for Multiple Sclerosis issued. Dr Sy reported having an ownership stake in Glixis Therapeutics LLC outside the submitted work. Dr Bellmann-Strobl reported receiving nonfinancial support from Biogen Idec; personal fees from Bayer Healthcare, Merck Serono, Teva Pharmaceuticals, Roche, and Novartis; and personal fees and nonfinancial support from Sanofi Genzyme outside the submitted work. Dr Zimmermann reported receiving grants from Novartis and personal fees from Bayer Healthcare outside the submitted work. Ms Chien reported receiving speaking fees from Bayer and research funding from Novartis unrelated to this study. Dr Dörr reported receiving grants from Bayer during the conduct of the study; and personal fees from Bayer, Biogen, Novartis, Roche, Merck Serono, Sanofi, and Teva outside the submitted work. Dr Wuerfel reported receiving grants from the EU (Horizon2020) and the Swiss National Science Foundation; and serving on advisory boards for Actelion, Genzyme-Sanofi, Idorsia, InmuneBio, Novartis, and Roche. Dr Dennis reported holding a patent pending for PCT/US16/15807 N-Acetyl Glucosamine as a Biomarker of MS Disease Course and being an inventor on this patent, a patent on methods and compositions for preventing and treating a disease related to glycan dysregulation issued to Wellsley Therapeutics, and a patent on Analogs of N-acetylglucosamine pending; and being a cofounder of and holding shares in Glixis Therapeutics LLC. Dr Paul reported receiving grants from Celgene, Novartis, BMBF, Alexion, Guthy Jackson Foundation, Falck-Foundation, Roche, Almirall, Deutsche Forschungsgemeinschaft, Einstein Foundation, Biogen, and Merck Serono; research support and personal fees from UCB, Roche, Alexion, Sanofi Genzyme, Mitsubishi Tanabe, Bayer, Merck Serono, and Viela Bio outside the submitted work. Dr Demetriou reported receiving grants from the National Institute of Allergy and Infectious Disease and the National Center for Complementary and Integrative Health during the conduct of the study; having a patent for US9775859B2 issued, a patent for US10495646B2 issued, and a patent pending for US20170042919A1; and being a cofounder and shareholder of Glixis Therapeutics. No other disclosures were reported.

Funding/Support: The UC Irvine discovery cohort was supported by grant R01AI108917 from the National Institute of Allergy and Infectious Disease and grant R01AT007452 from the National Center for Complementary and Integrative Health (Dr Demetriou). The confirmation cohort study was supported by DFG grant Exc. 257 (Dr Paul).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Cynthia Kraut, Technical Radiology Assistant, Charité–Universitätsmedizin Berlin, and Susan Pikol, Technical Radiology Assistant, Charité–Universitätsmedizin Berlin, for MRI assistance and Bibiane Seeger, Laboratory Assistant, Charité–Universitätsmedizin Berlin, and Carey F. Li, PhD, University of California, Irvine, for laboratory assistance. They were all compensated for their work as employees of their respective institutions. We thank Claudia Kawas, for access to participants from the 90+ Cohort.

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Association of a Marker of N-Acetylglucosamine With Progressive Multiple Sclerosis and Neurodegeneration

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