Biochemical Differences in Cerebrospinal Fluid between Secondary Progressive and Relapsing–Remitting Multiple Sclerosis

Abstract

To better understand the pathophysiological differences between secondary progressive multiple sclerosis (SPMS) and relapsing-remitting multiple sclerosis (RRMS), and to identify potential biomarkers of disease progression, we applied high-resolution mass spectrometry (HRMS) to investigate the metabolome of cerebrospinal fluid (CSF). The biochemical differences were determined using partial least squares discriminant analysis (PLS-DA) and connected to biochemical pathways as well as associated to clinical and radiological measures. Tryptophan metabolism was significantly altered, with perturbed levels of kynurenate, 5-hydroxytryptophan, 5-hydroxyindoleacetate, and N-acetylserotonin in SPMS patients compared with RRMS and controls. SPMS patients had altered kynurenine compared with RRMS patients, and altered indole-3-acetate compared with controls. Regarding the pyrimidine metabolism, SPMS patients had altered levels of uridine and deoxyuridine compared with RRMS and controls, and altered thymine and glutamine compared with RRMS patients. Metabolites from the pyrimidine metabolism were significantly associated with disability, disease activity and brain atrophy, making them of particular interest for understanding the disease mechanisms and as markers of disease progression. Overall, these findings are of importance for the characterization of the molecular pathogenesis of SPMS and support the hypothesis that the CSF metabolome may be used to explore changes that occur in the transition between the RRMS and SPMS pathologies.

Impact of Exercise on Immunometabolism in Multiple Sclerosis

“…From a clinical standpoint, identifying the risk of developing a more progressive form of MS is vital. In this context, Lim et al found that Kyn metabolite levels are a significant indicator of MS disease course: Changes in levels of Kynurenic acid (KynA) in the CSF occurred between RRMS patients in relapse versus recovery, as well as between RRMS and SPMS patients [ 167 , 168 , 169 ]. Furthermore, individuals with SPMS and RRMS also revealed different responses of Trp metabolism to acute aerobic exercise and training: In contrast to RRMS, the training interventions did not change Trp and Kyn/Trp ratio in persons with SPMS [ 167 ].…”

Circulating Metabolites as Potential Biomarkers for Neurological Disorders—Metabolites in Neurological Disorders

“…However, these same studies have also found decreased citrate levels, mannose, acetate, and phenylalanine when comparing patients with MuS and healthy controls [ 103 , 104 ]. Recently, an MS-based metabolomics study identified differences in tryptophan, phenylalanine, and pyrimidine metabolism in the CSF from patients with MuS, progressive, and relapsing-remitting disease, in comparison with controls [ 105 ].…”

Targeted metabolomics of CSF in healthy individuals and patients with secondary progressive multiple sclerosis using high-resolution mass spectrometry

“…Due to its proximity to the central nervous system (CNS), CSF is better for study diseases affecting the brain. Today, more than 450 metabolites have been identified and quantified in human CSF (Wishart et al 2008) and several of these have been found altered in neurological diseases, such as Alzheimer's disease (Wilkins and Trushina 2018), Parkinson's disease (Willkommen et al 2018), Huntington's disease (Herman et al 2019b) and multiple sclerosis (MS) (Herman et al 2018(Herman et al , 2019aReinke et al 2014).…”

“…We have previously used non-targeted metabolomics methods of CSF to increase understanding of SPMS (Herman et al 2019a) and provided a methodology to integrate multiple layers of information to improve early detection of transitioning patients (Herman et al 2018).…”