Cross-sectional analysis of plasma and CSF metabolomic markers in Huntington's disease for participants of varying functional disability: a pilot study

Abstract

Huntington's Disease (HD) is a progressive, fatal neurodegenerative condition. While generally considered for its devastating neurological phenotype, disturbances in other organ systems and metabolic pathways outside the brain have attracted attention for possible relevance to HD pathology, potential as therapeutic targets, or use as biomarkers of progression. In addition, it is not established how metabolic changes in the HD brain correlate to progression across the full spectrum of early to late-stage disease. In this pilot study, we sought to explore the metabolic profile across manifest HD from early to advanced clinical staging through metabolomic analysis by mass spectrometry in plasma and cerebrospinal fluid (CSF). With disease progression, we observed nominally significant increases in plasma arginine, citrulline, and glycine, with decreases in total and D-serine, cholesterol esters, diacylglycerides, triacylglycerides, phosphatidylcholines, phosphatidylethanolamines, and sphingomyelins. In CSF, worsening disease was associated with nominally significant increases in NAD⁺, arginine, saturated long chain free fatty acids, diacylglycerides, triacylglycerides, and sphingomyelins. Notably, diacylglycerides and triacylglyceride species associated with clinical progression were different between plasma and CSF, suggesting different metabolic preferences for these compartments. Increasing NAD⁺ levels strongly correlating with disease progression was an unexpected finding. Our data suggest that defects in the urea cycle, glycine, and serine metabolism may be underrecognized in the progression HD pathology, and merit further study for possible therapeutic relevance.

Figure 1

Correlations between metabolites in plasma and clinical outcomes. r-value correlations of − 0.7 to − 1.0 ( ) , − 0.4 to − 0.69 ( ) , 0.7 to 1.0 ( ) and 0.4–0.69 ( ) are shown; nominal p values represented as follows: *0.01 < p < 0.05; **0.001 < p < 0.01 and ***p < 0.001.

Figure 2

Correlations between metabolites in CSF and clinical outcomes. r-value correlations of − 0.7 to − 1.0 ( ), − 0.4 to − 0.69 ( ), 0.7 to 1.0 ( ) and 0.4–0.69 ( ) are shown; nominal p values are represented as follows: *0.01 < p < 0.05; **0.001 < p < 0.01 and ***p < 0.001.

Figure 3

Overview of glycine (A), arginine (B), and creatine (C) metabolism in HD. Pathways with multiple metabolic changes are shown, including the urea cycle, nitrous oxide cycle and creatine synthesis. Arrows are red (plasma) or yellow (CSF), and indicate correlation with clinical state: up indicates circulating concentrations increase with progression, down indicates decrease with progression.