Targeted biochemical profiling of brain from Huntington's disease patients reveals novel metabolic pathways of interest

Abstract

Huntington's disease (HD) is a devastating, progressive neurodegenerative disease with a distinct phenotype characterized by chorea and dystonia, incoordination, cognitive decline and behavioral difficulties. The precise mechanisms of HD progression are poorly understood; however, it is known that there is an expansion of the trinucleotide cytosine-adenine-guanine (CAG) repeat in the Huntingtin gene. Herein DI/LC-MS/MS was used to accurately identify and quantify 185 metabolites in post mortem frontal lobe and striatum from HD patients and healthy control cases. The findings link changes in energy metabolism and phospholipid metabolism to HD pathology and also demonstrate significant reductions in neurotransmitters. Further investigation into the oxidation of fatty acids and phospholipid metabolism in pre-clinical models of HD are clearly warranted for the identification of potential therapies. Additionally, panels of 5 metabolite biomarkers were identified in both the frontal lobe (AUC = 0.962 (95% CI: 0.85-1.00) and striatum (AUC = 0.988 (95% CI: 0.899-1.00). This could have clinical utility in more accessible biomatrices such as blood serum for the early detection of those entering the prodromal phase of the disease, when treatment is believed to be most effective. Further evaluation of these biomarker panels in human cohorts is justified to determine their clinical efficacy.

Fecal Metabolomics and Potential Biomarkers for Systemic Lupus Erythematosus

“…A stepwise binary logistic-regression was used to establish a combined model. To address the issue of potential over-fitting in generating ROC curves from the combined model, 100-fold cross validation and permutation test were used to calculate the performance by MetaboAnalyst 3.0 via ROC curve based model evaluation (Tester) section (13, 14).…”

Altered Plasma Acylcarnitines and Amino Acids Profile in Spinocerebellar Ataxia Type 7

“…These processes take place in mitochondria, where the role of ACCs is to transport long-chain fatty acids into mitochondria for -oxidation [52]; in fact, fatty acids have been implicated in diverse neurodegenerative diseases [50,51,53]. Furthermore, ACCs have been shown to possess diverse neuroprotective effects, including improvement of mitochondrial function, modulation of gene expression, enhancement of cholinergic neurotransmission, antioxidant activity, and membrane stabilization [18,23,45,54,55]. Thus, metabolic changes in these metabolites could be an indicator of these mechanistic alterations.…”

“…Apart from the CAG repeat length, environmental and genetic modifiers might contribute to SCA7 pathophysiology [8]; thus, identification of sensitive biomarkers will facilitate the monitoring of disease progression and assessing of treatments, which ultimately will improve clinical management of patients. Metabolomics has emerged as a powerful technique to identify potential biomarkers in neurodegenerative diseases [19][20][21] as alterations in brain function can be reflected in the metabolite composition of biofluids such as the serum, plasma, and cerebrospinal fluid (CSF) [22][23][24]. Indeed, recent reports have described the detection of some neurometabolites associated with specific changes in neuronal and astrocytic cells in patients with different SCAs [25].…”

Combinational Biomarkers for Atrial Fibrillation Derived from Atrial Appendage and Plasma Metabolomics Analysis

“…Receiver operating characteristic (ROC) curves have been successfully applied to evaluate the diagnostic accuracy of biomarkers in many studies 22 , 36 . An area under the curve (AUC) greater than 0.7 represents very high diagnostic effectiveness, and the effectiveness is particularly good when the AUC value is greater than 0.9 37 .…”