Biomarkers of Metabolism in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the deterioration of motor neurons. However, this complex disease extends beyond the boundaries of the central nervous system, with metabolic alterations being observed at the systemic and cellular level. While the number of studies that assess the role and impact of metabolic perturbations in ALS is rapidly increasing, the use of metabolism biomarkers in ALS remains largely underinvestigated. In this review, we discuss current and potential metabolism biomarkers in the context of ALS. Of those for which data does exist, there is limited insight provided by individual markers, with specificity for disease, and lack of reproducibility and efficacy in informing prognosis being the largest drawbacks. However, given the array of metabolic markers available, the potential exists for a panel of metabolism biomarkers, which may complement other current biomarkers (including neurophysiology, imaging, as well as CSF, blood and urine markers) to overturn these limitations and give rise to new diagnostic and prognostic indicators.

Blood biomarkers and prognosis of amyotrophic lateral sclerosis

“…These results provide further evidence for a dysregulation of glycolytic metabolism in ALS patients. As previously reported, a substantial proportion of ALS patients have glucose intolerance [27] and insulin resistance [28]. The associations noted between a higher glucose level at diagnosis and an increasing level of glucose after ALS diagnosis with a higher mortality risk might suggest that the dysregulation is more pronounced amongst patients with worse survival compared to patients with better survival.…”

Genome-wide Meta-analysis Finds the ACSL5-ZDHHC6 Locus Is Associated with ALS and Links Weight Loss to the Disease Genetics

“…In the interpretation of these results, it is important to recognize that given the size of the effect of our SNPs on fat-free mass in the MEND-MND cohorts, the dataset provided insufficient statistical power to reliably reject the null hypothesis. Furthermore, BMI and weight do not always accurately reflect changes in fat-free mass in ALS (Ioannides et al, 2017b;Kirk et al, 2019).…”

“…In this case cohort, we observed no association between the SNPs and weight (rs58854276 p = 0.97 and rs3828599 p = 0.50) or BMI (rs58854276 p = 0.47 and rs3828599 p = 0.33) at first visit. It is important to recognize that BMI and weight do not always accurately reflect changes in fat-free mass in ALS (Ioannides et al, 2017b;Kirk et al, 2019) and that in the case cohorts, individuals have weight measurements taken at cross-sectional times relative to their personal disease trajectory. Here, including time since diagnosis in the analysis did not offer further clarity.…”

Peripheral Glycolysis in Neurodegenerative Diseases

“…This dysfunction of the mitochondrial ETC is accompanied by an increased dependence on glycolysis or lipid metabolism, hypothesised to be in compensation for impaired ATP production [ 88 , 89 ]. These metabolic adaptations offer potential therapeutic targets, in addition to opportunities for biomarker development [ 90 ].…”