24S-Hydroxycholesterol: A potential brain-derived biomarker of Huntington’s Disease

Huntington’s disease (HD) arises from of an expanded polyglutamine-coding trinucleotide repeat in exon 1 of the huntingtin gene. Despite considerable research, a successful disease modifying therapy has yet to be confirmed. Cholesterol homeostasis in brain is considered one of the biological processes to be disturbed in HD. In the current study we show that non-esterified 24S-hydroxycholesterol (24S-HC), the stereo-specific brain-derived cholesterol metabolite that can cross the blood brain barrier, is at a lower concentration in plasma of a group of people with manifest HD than in groups of people with premanifest HD or healthy controls. Although our data does not indicate that 24S-HC is a prognostic biomarker at the individual level, it could potentially be used to monitor a pharmacodynamic response for groups of patients, or perhaps of disease progression in individuals. In addition, by exploiting binary classification techniques we show that a diagnostic model can be developed giving a good to very good performance according to the area under the curve (AUC) in receiver operating characteristic (ROC) curves to distinguish people with premanifest HD from people with manifest HD. This will be tested in future studies and could be valuable in monitoring therapeutic response. Notably, the most important metabolites in the binary classification models were plasma levels of 24S-HC and of the cholesterol precursor 7-dehydrocholesterol, both of which showed statistical changes in the manifest HD group, reinforcing the involvement of cholesterol metabolism in HD.