Plasma 24S-hydroxycholesterol and caudate MRI in pre-manifest and early Huntington's disease

• Published in: Brain (London, England : 1878) Vol. 131; no. 11; pp. 2851 - 2859
• Main Authors: Leoni, Valerio, Mariotti, Caterina, Tabrizi, Sarah J., Valenza, Marta, Wild, Edward J., Henley, Susie M. D., Hobbs, Nicola Z., Mandelli, Maria Luisa, Grisoli, Marina, Björkhem, Ingemar, Cattaneo, Elena, Di Donato, Stefano
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.11.2008; Oxford Publishing Limited (England)
• Subjects: 24S-hydroxycholesterol; Adult; Biological and medical sciences; biomarker; Biomarkers - blood; Brain Mapping - methods; Caudate Nucleus - pathology; caudate volume; Cholesterol - blood; Cohort Studies; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Progression; Female; gas chromatography-mass spectrometry; Gas Chromatography-Mass Spectrometry - methods; Humans; Huntington Disease - blood; Huntington Disease - pathology; Hydroxycholesterols - blood; Magnetic Resonance Imaging - methods; Male; Medical sciences; Middle Aged; MRI; Neurology; oxysterol; Prognosis; Young Adult; oxysterol; gas chromatography-mass spectrometry; 24S-hydroxycholesterol; biomarker; caudate volume; MRI; Nervous system diseases; Huntington disease; Nuclear magnetic resonance imaging; Genetic disease; Cerebral disorder; Gas chromatography; Central nervous system disease; Degenerative disease; Mass spectrometry; Extrapyramidal syndrome
• ISSN: 0006-8950; 1460-2156; 1460-2156
• DOI: 10.1093/brain/awn212

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.