1H-NMR-Based Metabolomic Profiling of CSF in Early Amyotrophic Lateral Sclerosis

Abstract

BackgroundPathophysiological mechanisms involved in amyotrophic lateral sclerosis (ALS) are complex and none has identified reliable markers useful in routine patient evaluation. The aim of this study was to analyze the CSF of patients with ALS by 1H NMR (Nuclear Magnetic Resonance) spectroscopy in order to identify biomarkers in the early stages of the disease, and to evaluate the biochemical factors involved in ALS.MethodologyCSF samples were collected from patients with ALS at the time of diagnosis and from patients without neurodegenerative diseases. One and two-dimensional 1H NMR analyses were performed and metabolites were quantified by the ERETIC method. We compared the concentrations of CSF metabolites between both groups. Finally, we performed principal component (PCA) and discriminant analyses.Principal FindingsFifty CSF samples from ALS patients and 44 from controls were analyzed. We quantified 17 metabolites including amino-acids, organic acids, and ketone bodies. Quantitative analysis revealed significantly lower acetate concentrations (p = 0.0002) in ALS patients compared to controls. Concentration of acetone trended higher (p = 0.015), and those of pyruvate (p = 0.002) and ascorbate (p = 0.003) were higher in the ALS group. PCA demonstrated that the pattern of analyzed metabolites discriminated between groups. Discriminant analysis using an algorithm of 17 metabolites revealed that patients were accurately classified 81.6% of the time.Conclusion/SignificanceCSF screening by NMR spectroscopy could be a useful, simple and low cost tool to improve the early diagnosis of ALS. The results indicate a perturbation of glucose metabolism, and the need to further explore cerebral energetic metabolism.

NMR analysis of the CSF and plasma metabolome of rigorously matched amyotrophic lateral sclerosis, Parkinson’s disease and control subjects

“…Elevated levels of glucose and lactic acid in CSF were also detected in a recent longitudinal study (Gray et al 2015). The observed changes for alanine and glucose are in agreement with the recent MS-based study on the same patient cohort (Wuolikainen et al 2016), while two other studies did not observe similar changes (Blasco et al 2010(Blasco et al , 2013.…”

“…4a; Table 2). Elevated CSF-and plasmalevels of glutamate and pyruvate have previously been observed in ALS patients (Blasco et al 2010(Blasco et al , 2013Lawton et al 2012;Kumar et al 2010;Wuolikainen et al 2016). The increased level of glutamate in plasma/serum has previously been attributed to either the glutamate excitotoxicity in ALS or to an imbalance in the glutamate/ glutamine conversion (Kumar et al 2010).…”

Power of a Metabonomic Approach to Investigate an Unknown Nervous Disease

“…For example, ultra performance liquid chromatography/mass spectroscopy (UPLC/MS) metabolic profiles from serum collected on cerebral infarction patients have been analyzed using a metabonomic approach (Jiang et al, 2011). Quantitative analysis of human cerebrospinal fluid using NMR spectroscopy has been performed in multiple sclerosis (Lutz et al, 2007a), to identify biomarkers in the early stages of the amyotrophic lateral sclerosis (Blasco et al, 2010). Plasmatic metabolic disruptions between healthy and old persons with Alzheimer's disease were investigated using UPLC/MS-based metabonomic approach (Li et al, 2010).…”

“…The interest of brain extracts coming from an animal model has been also illustrated to investigate epilepsy, for which the pharmacologically-induced animal model was obtained using pentylenetetrazole, a drug that induces seizures (Carmody and Brennan, 2010). Plasma from an experimental animal model of the spinal cord injury (Blasco et al, 2010) has been analyzed by 1 H NMR to get fingerprint profiles of this pathology (Jiang et al, 2010). Other cerebral alterations like brain tumors (Tate et al, 1996;Tate et al, 1998), schizophrenia and meningitis (Holmes et al, 2006;Lutz et al, 2007a) have also been investigated.…”

Magnetic Resonance Spectroscopy (MRS) in Kidney Transplantation: Interest and Perspectives

“…Currently, in biology, Magnetic Resonance Spectroscopy (MRS) is widely used in metabonomics for diagnosis and prognostication in a wide range of studies from brain (Blasco et al, 2010) to leg (Borel et al, 2009) pathologies. Between both, the topic of interest in this section: the kidney.…”