Brain Advance Access published online on February 7, 2006
Brain, doi:10.1093/brain/awl027
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1 Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK; Suffolk Mental Health Partnership NHS Trust, Department of Psychiatry, Wedgwood House, West Suffolk Hospital, Bury St Edmunds, UK
* To whom correspondence should be addressed. There has been considerable progress recently towards developing therapeutic strategies for Huntington's disease (HD), with several compounds showing beneficial effects in transgenic mouse models. However, human trials in HD are difficult, costly and time-consuming due to the slow disease course, insidious onset and patient-to-patient variability. Identification of molecular biomarkers associated with disease progression will aid the development of effective therapies by allowing further validation of animal models and by providing hopefully more sensitive measures of disease progression. Here, we apply metabolic profiling by gas chromatography-time-of-flight-mass spectrometry to serum samples from human HD patients and a transgenic mouse model in a hypothesis-generating search for disease biomarkers. We observed clear differences in metabolic profiles between transgenic mice and wild-type littermates, with a trend for similar differences in human patients and control subjects. Thus, the metabolites responsible for distinguishing transgenic mice also comprised a metabolic signature tentatively associated with the human disease. The candidate biomarkers composing this HD-associated metabolic signature in mouse and humans are indicative of a change to a pro-catabolic phenotype in early HD preceding symptom onset, with changes in various markers of fatty acid breakdown (including glycerol and malonate) and also in certain aliphatic amino acids. Our data raise the prospect of a robust molecular definition of progression of HD prior to symptom onset, and if validated in a genuinely prospective fashion these biomarker trajectories could facilitate the development of useful therapies for this disease. *These authors contributed equally to the study.
Received November 14, 2005
Revised January 4, 2006
Accepted January 5, 2006
Article
Huntington disease patients and transgenic mice have similar pro-catabolic serum metabolite profiles
Benjamin R. Underwood 1 *,
David Broadhurst 2 *,
Warwick B. Dunn 2 *,
David I. Ellis 2,
Andrew W. Michell 3,
Coralie Vacher 4,
David E. Mosedale 5,
Douglas B. Kell 2 
,
Roger A. Barker 3 ,
David J. Grainger 6 ,
and
David C. Rubinsztein 4 *
2 School of Chemistry, University of Manchester, Manchester, UK
3 Cambridge Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge, UK
4 Department of Medical Genetics, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK
5 Translational Research Unit, Papworth Hospital NHS Trust, Papworth Everard, Cambridge, UK
6 Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK; Translational Research Unit, Papworth Hospital NHS Trust, Papworth Everard, Cambridge, UK
David C. Rubinsztein, E-mail: dcr1000{at}hermes.cam.ac.uk
Abstract The study has four equal senior authors.
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