Cortical metabolites as biomarkers in the R6/2 model of Huntington's disease

Lori Zacharoff, Ivan Tkac, Qingfeng Song, Chuanning Tang, Patrick J. Bolan, Silvia Mangia, Pierre Gilles Henry, Tongbin Li, Janet M. Dubinsky

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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 1H 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.

Original languageEnglish (US)
Pages (from-to)502-514
Number of pages13
JournalJournal of Cerebral Blood Flow and Metabolism
Volume32
Issue number3
DOIs
StatePublished - Mar 2012

Keywords

  • biomarker
  • in-vivo H MR spectroscopy
  • metabolite profiles
  • metabolomics
  • principal-least square discriminant analysis

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