Disease Type- and Status-Specific Alteration of CSF Metabolome Coordinated with Clinical Parameters in Inflammatory Demyelinating Diseases of CNS

Abstract

Central nervous system (CNS) inflammatory demyelinating diseases (IDDs) are a group of disorders with different aetiologies, characterized by inflammatory lesions. These disorders include multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and idiopathic transverse myelitis (ITM). Differential diagnosis of the CNS IDDs still remains challenging due to frequent overlap of clinical and radiological manifestation, leading to increased demands for new biomarker discovery. Since cerebrospinal fluid (CSF) metabolites may reflect the status of CNS tissues and provide an interfacial linkage between blood and CNS tissues, we explored multi-component biomarker for different IDDs from CSF samples using gas chromatography mass spectrometry-based metabolite profiling coupled to multiplex bioinformatics approach. We successfully constructed the single model with multiple metabolite variables in coordinated regression with clinical characteristics, expanded disability status scale, oligoclonal bands, and protein levels. The multi-composite biomarker simultaneously discriminated four different immune statuses (a total of 145 samples; 54 MS, 49 NMOSD, 30 ITM, and 12 normal controls). Furthermore, systematic characterization of transitional metabolic modulation identified relapse-associated metabolites and proposed insights into the disease network underlying type-specific metabolic dysfunctionality. The comparative analysis revealed the lipids, 1-monopalmitin and 1-monostearin were common indicative for MS, NMOSD, and ITM whereas fatty acids were specific for the relapse identified in all types of IDDs.

Inhibition of lactate dehydrogenase A suppresses inflammatory response in RAW 264.7 macrophages

“…There have been reports about the correlation of increased lactate levels and development of various diseases including cancer and rheumatoid arthritis synovitis (9,14). Recent reports have demonstrated that the lactate levels in CSF from clinical patients with NMOSD were elevated (6,7). We hypothesized that the suppression of LDHA would downregulate LPS-induced inflammatory response in RAW 264.7 macrophages.…”

“…Inhibition of lactate dehydrogenase A suppresses expression of cytokines. Lactate is implicated in excessive cell proliferation and autoimmune diseases (6,11). Therefore, we hypothesized that modulation of lactate regulates inflammatory response induced by LPS.…”

“…Reports that LDHA inhibition prevents cancer development have drawn attention for the development of cancer therapeutics, and suggest an important role of lactate in the regulation of cell metabolism and survival (11,21,22). Additionally, metabolomics analyses of clinical CSF samples from NMOSD patients suggest that lactate is a critical regulator in the development of autoimmune diseases (6,7). In contrast, the fact that siLDHA-mediated suppression reduced IL-6 and NO production suggests that LDHA inhibition clearly alleviates LPS-mediated inflammatory response.…”

“…Among them, neuromyelitis optica spectrum disorder (NMOSD) is caused by demyelination in the central nervous system due to the binding of serum autoantibodies to astrocyte water channel aquaporin-4 (5). Recent metabolomic analyses revealed that lactate levels in cerebrospinal fluid (CSF) from clinical patients with NMOSD are elevated (6,7).…”

Technological advances in current metabolomics and its application in tradition Chinese medicine

“…Gas chromatography coupled with mass spectrometry (GC-MS) has been recognized as a primary tool for small molecule analysis, 39 and is still used to detect various metabolic disorders today. 40 Recent interest in metabolomics stems from the ability to carry out more comprehensive metabolome analysis using new liquid chromatography combined with mass spectrometry (LC-MS), which has the potential to discover and identify both disease and pharmaceutical biomarkers, exploring the hidden secrets of the biochemical processes of tissues and cells. 41,42 Advances in LC-MS are very impressive, with recent developments in UPLC, the speed of analysis is further improved.…”