Cortical Metabolites as Biomarkers in the R6/2 Model of Huntington's Disease

Abstract

To improve the ability to move from preclinical trials in mouse models of Huntington's disease (HD) to clinical trials in humans, biomarkers are needed that can track similar aspects of disease progression across species. Brain metabolites, detectable by magnetic resonance spectroscopy (MRS), have been suggested as potential biomarkers in HD. In this study, the R6/2 transgenic mouse model of HD was used to investigate the relative sensitivity of the metabolite profiling and the brain volumetry to anticipate the disease progression. Magnetic resonance imaging (MRI) and 1 H MRS data were acquired at 9.4 T from the R6/2 mice and wild-type littermates at 4, 8, 12, and 15 weeks. Brain shrinkage was detectable in striatum, cortex, thalamus, and hypothalamus by 12 weeks. Metabolite changes in cortex paralleled and sometimes preceded those in striatum. The entire set of metabolite changes was compressed into principal components (PCs) using Partial Least Squares-Discriminant Analysis (PLS-DA) to increase the sensitivity for monitoring disease progression. In comparing the efficacy of volume and metabolite measurements, the cortical PC1 emerged as the most sensitive single biomarker, distinguishing R6/2 mice from littermates at all time points. Thus, neurochemical changes precede volume shrinkage and become potential biomarkers for HD mouse models.

The neurochemical profile quantified by in vivo 1H NMR spectroscopy

“…Glutamine and glutamate alterations suggest the impaired neurotransmission and glutamate-glutamine cycling, while increased creatine and phosphocreatine are the reflection of impaired mitochondrial bioenergetics and reduced oxidative phosphorylation (Oliveira, 2010). Recently, an elegant study in the R6/2 model of HD demonstrated that neurochemical alterations measured by MRS anticipate structural deterioration detectable in MR images (Zacharoff et al, 2011), indicating that the neurochemical profile may be used as biomarker for early therapeutic decisions.…”

“…Transgenic mice models have been created with mutated huntingtin to study the mechanisms of the disease and definitively suggest compromised mitochondrial dysfunction as a hallmark of HD (reviewed in Oliveira, 2010). The neurochemical profile of such mice reveal consistent modifications (Jenkins et al, 2000(Jenkins et al, , 2005Tkáč et al, 2007;Zacharoff et al, 2011). In the R6/2 transgenic mouse model of HD, striatal concentrations of creatine, glycerophosphorylcholine, glutamine and glutathione were found to be increased and NAA levels decreased (Jenkins et al, 2000;Tkáč et al, 2007).…”

Longitudinal neurochemical modifications in the aging mouse brain measured in vivo by 1H magnetic resonance spectroscopy

“…This supports the use of the neurochemical profile as region-and time-specific biomarker and, indeed, its noninvasive detection by magnetic resonance spectroscopy (MRS) has emerged as an important research tool in translational neuroscience. Neurochemical profiling has thus been successfully used to reliably probe brain biochemical modifications upon disease and/or treatment monitoring in mice (Berthet et al, 2011;Zacharoff et al 2012), rats Rao et al, 2011), or humans (Bustillo et al, 2009;Seaquist et al, 2005). Each neuropathology has different etiology, is region specific and occurs with most prominence at a particular age range.…”

Porcine Model of Huntington's Disease

“…1 H MRS has previously been considered as a biomarker method in pre-manifest and early stages of HD [35][36][37]. In order to evaluate in vivo brain metabolite differences, single-voxel spectroscopy (SVS) has been primarily used [35,38,39]. However, several studies have also used two-dimensional chemical shift imaging (2D-CSI) [33,40,41].…”