Brain Advance Access published online on September 4, 2008
Brain, doi:10.1093/brain/awn212
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Plasma 24S-hydroxycholesterol and caudate MRI in pre-manifest and early Huntington's disease
1Unit Biochemistry and Genetics, Fondazione-IRCCS Istituto Neurologico Carlo Besta, Milan, Italy, 2Department of Neurodegenerative Disease and Dementia Research Centre, Institute of Neurology, University College London, UK, 3Department of Pharmacological Sciences and Centre for Stem Cell Research, University of Milan, 4Unit of Neuroradiology, Fondazione-IRCCS Istituto Neurologico Carlo Besta, 5Department of Bioengineering, Politecnico di Milano, Milan, Italy and 6Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska University Hospital, Stockholm, Sweden
Correspondence to:
Stefano Di Donato, MD, Fondazione-IRCCS Istituto Neurologico Carlo Besta, via Celoria, 11-20133 Milan, Italy. E-mail: didonato{at}istituto-besta.it
Huntington's disease (HD) is a hereditary neurodegenerative disorder for which biological indicators of disease progression, or disease stage, would be especially important for therapeutic trials. 24S-hydroxycholesterol (24OHC) is a brain-generated cholesterol metabolite which has been associated with neurodegeneration, and alterations of cholesterol metabolism in murine HD models and patients’ tissues have been recently identified. On these grounds, and with the aim of identifying putative biomarkers in HD, we studied cholesterol metabolism through the analysis in vivo of plasma 24OHC and cholesterol in two independent cohorts of controls and patients of Italian and British origin. We analysed a total of 62 controls, 96 HD symptomatic patients at different disease stages (stage 1–3), and 33 HD gene-positive pre-manifest subjects [pre-manifest HD (pre-HD)]. Cholesterol and 24OHC plasma levels were comparable in both the British and Italian subjects, and were not influenced by fasting or post-meal status. Cholesterol levels did not show differences between controls, pre-HD subjects and HD patients. In contrast, the plasma levels of 24OHC were significantly higher in controls than in HD patients at all disease stages (P < 0.001). Interestingly, in pre-HD subjects plasma 24OHC concentrations were similar to those of controls, and thus significantly greater than those of HD patients at any disease stage (P < 0.001). As expected, significant differences in caudate volumes between stage 1–2 HD patients and pre-HD subjects, and pre-HD subjects and controls were found. The pre-HD cohort of subjects was heterogeneous as to 24OHC levels, since subjects closer to predicted development of motor signs of disease had lower 24OHC levels than those far from onset. Our data indicate that the brain-generated cholesterol metabolite 24OHC measured in plasma was significantly depleted in HD patients at any disease stage, and it could discriminate pre-manifest subjects from patients with overt motor disease. However, 24OHC levels failed to mark further disease progression in patients with manifest HD. Overall, we demonstrate that 24OHC levels parallel the large decrease in caudate volumes observed in gene-positive subjects from pre-manifest to HD stage 1, thus reflecting a critical phase characterized by neuronal loss. We conclude that that 24OHC levels complement MRI morphometry as a valuable tool to follow neurodegenerative changes in the early stages of Huntington disease.
Key Words: gas chromatography-mass spectrometry; oxysterol; biomarker; 24S-hydroxycholesterol; caudate volume; MRI
Abbreviations: HD, Huntington's disease; 24OHC, 24S-hydroxycholesterol; pre-HD, pre-manifest HD; CAG, Cytosine–Adenine–Guanine
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Received February 5, 2008. Revised July 17, 2008. Accepted August 1, 2008.
*These authors contributed equally to this work.
These authors contributed equally to this work.