title: Plasma 24S-hydroxycholesterol and caudate MRI in pre-manifest and early Huntington's disease.
abstract: 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.
authors.affiliation: Unit Biochemistry and Genetics, Fondazione-IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Leoni
authors.forename: Caterina
authors.initials: C
authors.lastname: Mariotti
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Tabrizi
authors.forename: Marta
authors.initials: M
authors.lastname: Valenza
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Wild
authors.forename: Susie M D
authors.initials: SM
authors.lastname: Henley
authors.forename: Nicola Z
authors.initials: NZ
authors.lastname: Hobbs
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Mandelli
authors.forename: Marina
authors.initials: M
authors.lastname: Grisoli
authors.forename: Ingemar
authors.initials: I
authors.lastname: Björkhem
authors.forename: Elena
authors.initials: E
authors.lastname: Cattaneo
authors.forename: Stefano
authors.initials: S
authors.lastname: Di Donato
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D001931:Brain Mapping / Q000379:methods; D002421:Caudate Nucleus / Q000473:pathology*; D002784:Cholesterol / Q000097:blood; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D006801:Humans; D006816:Huntington Disease / Q000097:blood* / Q000473:pathology*; D006888:Hydroxycholesterols / Q000097:blood*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D055815:Young Adult
chemical_list: D015415:Biomarkers; D006888:Hydroxycholesterols; C044563:24-hydroxycholesterol; D002784:Cholesterol