Untargeted metabolomics yields insight into ALS disease mechanisms

Abstract

ObjectiveTo identify dysregulated metabolic pathways in amyotrophic lateral sclerosis (ALS) versus control participants through untargeted metabolomics.MethodsUntargeted metabolomics was performed on plasma from ALS participants (n=125) around 6.8 months after diagnosis and healthy controls (n=71). Individual differential metabolites in ALS cases versus controls were assessed by Wilcoxon rank-sum tests, adjusted logistic regression and partial least squares-discriminant analysis (PLS-DA), while group lasso explored sub-pathway-level differences. Adjustment parameters included sex, age and body mass index (BMI). Metabolomics pathway enrichment analysis was performed on metabolites selected by the above methods. Finally, machine learning classification algorithms applied to group lasso-selected metabolites were evaluated for classifying case status.ResultsThere were no group differences in sex, age and BMI. Significant metabolites selected were 303 by Wilcoxon, 300 by logistic regression, 295 by PLS-DA and 259 by group lasso, corresponding to 11, 13, 12 and 22 enriched sub-pathways, respectively. ‘Benzoate metabolism’, ‘ceramides’, ‘creatine metabolism’, ‘fatty acid metabolism (acyl carnitine, polyunsaturated)’ and ‘hexosylceramides’ sub-pathways were enriched by all methods, and ‘sphingomyelins’ by all but Wilcoxon, indicating these pathways significantly associate with ALS. Finally, machine learning prediction of ALS cases using group lasso-selected metabolites achieved the best performance by regularised logistic regression with elastic net regularisation, with an area under the curve of 0.98 and specificity of 83%.ConclusionIn our analysis, ALS led to significant metabolic pathway alterations, which had correlations to known ALS pathomechanisms in the basic and clinical literature, and may represent important targets for future ALS therapeutics.

Metabolomic Biomarkers Are Associated With Area of the Pons in Fragile X Premutation Carriers at Risk for Developing FXTAS

“…The energy and phospholipid metabolism have also been found to be impaired in patients with HD that ultimately affects the function of neurons (53,69). Glucose metabolism is dysregulated in AD patients (70) and in area of the pons and cerebellum of MSA patients (71,72), while an association of fatty acid metabolism with the development of ALS was observed (73). Finally, in our recent study we reported on the identification of metabolic biomarkers of early diagnosis and progression of FXTAS and on their association with altered lipid metabolism including free fatty acids, acylcarnitine, sphingolipids, diacylglycerol, and phospholipids, in individuals who developed the symptoms of FXTAS over time (25).…”

Amyotrophic Lateral Sclerosis: A Diet Review

“…Indeed, a study conducted by Nakken and colleagues showed that high early-aged levels of BMI are associated with low ALS risk several decades later [ 169 ]. Moreover, a study conducted by Goutman and colleagues showed that higher premorbid BMI is associated with slower ALS progression [ 170 ]. A high BMI at diagnosis is also associated with a better survival suggesting it as a marker of disease severity [ 170 ].…”

“…Moreover, a study conducted by Goutman and colleagues showed that higher premorbid BMI is associated with slower ALS progression [ 170 ]. A high BMI at diagnosis is also associated with a better survival suggesting it as a marker of disease severity [ 170 ].…”

Altered Metabolic Profiles of the Plasma of Patients with Amyotrophic Lateral Sclerosis

“…Derived from the high-energy product creatine, blood creatinine is widely used as a biomarker of kidney function. Previous studies have demonstrated decreased creatinine levels in those with motor neuron diseases, including ALS [ 10 , 12 , 31 ], spinal muscular atrophy (SMA) [ 32 ], and spinal and bulbar muscular atrophy (SBMA) [ 31 ]. Consistent with our study, lower levels of creatinine have been observed in the plasma [ 10 , 12 , 31 ], serum [ 32 ], and CSF [ 14 ] of ALS patients.…”

“…The profiles of metabolites are produced by catabolic and anabolic processes in different tissues, serving to reflect dysregulated cellular and metabolic processes. In ALS, the metabolic profiles revealed by various metabolomics platforms show a disturbance of a number of ALS-associated metabolic pathways, including amino acid, pyruvate, and lipid metabolism [ 7 , 8 , 9 , 10 ]. Altered levels of sphingolipids have been reported in the plasma of ALS patients [ 11 , 12 , 13 ].…”