Study Identifies Potential Molecular Biomarker of Progressive MS

N-acetylglucosamine (GlcNAc) and N-glycan branching are associated with multiple sclerosis (MS) in general and progressive MS (PMS), according to results of a cross-sectional study published in JAMA Neurology.

Previous studies have suggested N-glycosylation may hold relevance in MS and that the 2 may be related due to environmental factors or genetic sequence variants. In the first study of its kind, researchers investigated endogenous serum GlcNAc levels in humans with MS.

“N-glycan branching modulates cell surface receptor availability, and its deficiency in mice promotes inflammatory demyelination, reduced myelination, and neurodegeneration,” the authors wrote. “In humans, severe central nervous system hypomyelination results from loss-of-function variants in PGM3, a gene required to generate branched N-glycans from GlcNAc.”

In the current analysis investigators “used a unique targeted liquid chromatography–tandem mass spectroscopy approach with ion pairing to assess serum levels of GlcNAc plus its stereoisomers (N-acetylhexosamine [HexNAc]) in healthy controls and patients with MS.” They also assessed whether serum levels of HexNAc are related to progressive disease course, severity, and disease-related neurodegeneration.

Between April 2010 and June 2013, 54 patients with MS and 66 healthy controls were recruited from centers in California to make up the discovery cohort. Any individual presenting with type 1 or 2 diabetes or kidney disease was excluded from the study.

The confirmatory cohort consisted of 180 patients with MS presenting to a neuroimmunology clinical trial unit in Germany between April 2007 and February 2016. Any patient who suffered acute relapse and/or used corticosteroids within 6 months prior to recruitment was excluded.

All participants underwent clinical examinations, MRI, and optical coherence tomography (OCT) to measure retinal nerve fiber layer thickness (RNFL), and provided serum samples that were reviewed by an analyst blinded to sample origin (patient or control).

Of those in the discovery cohort, 38 were women and the mean (SD) patient age was 42 (20) years. Thirty-three patients had relapsing-remitting MS (RRMS) and 21 presented with PMS. In the confirmatory cohort, 125 patients had RRMS, and 82 were women, while the mean patient age was 40 (9) years. Fifty-five patients had PMS in this cohort.

Analyses revealed:

• In the discovery cohort, the mean serum level of GlcNAc plus stereoisomers (HexNAc) was 710 (174) nM in healthy controls and marginally reduced in patients with RRMS (mean [SD] level, 682 [173] nM; P = .04)
• In this same cohort, patients with PMS displayed significantly 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 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 RNFL (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)

Overall, results show “GlcNAc plus its stereoisomers are markedly reduced in PMS in 2 independent cohorts and that serum HexNAc levels are correlated with clinical disability and neuroimaging markers of neurodegeneration,” the authors wrote.

There are currently few data on biomarkers allowing detection of PMS, while diagnoses rely heavily on clinical observation and potential imaging biomarker candidates. Molecular biomarkers for PMS are scarce. However, “identifying simple molecular biomarkers for PMS that may facilitate early diagnosis, assess treatment effectiveness, and/or promote clinical development of novel treatment approaches is an unmet clinical need,” the researchers explained.

More research ought to be carried out exploring HexNAc levels as a potential biomarker for patients at risk of disease progression and to clarify the impact of potential physiological factors like diet or physical activity. It is also unclear why those with PMS may present with HexNAc deficiency.

Because both cohorts were recruited from academic tertiary referral centers, data may not reflect a real-world distribution, marking a limitation to the study. Cohorts also lacked racial and ethnic diversity and the cross-sectional nature of the study precludes any conclusions regarding the predictive power of HexNAc for MS disease development from being drawn.

“Further studies are required to develop our understanding of the relevance of N-glycan branching and GlcNAc in PMS and of the clinical research and/or clinical management of disease progression in MS,” the authors concluded.

Reference

Brandt AU, Sy M, Bellmann-Strobl J, et al. Association of a marker of N-acetylglucosamine with progressive multiple sclerosis and neurodegeneration. JAMA Neurol. Published online May 10, 2021. doi:10.1001/jamaneurol.2021.1116