{"paper_id":"e76663fb-36a2-4675-bea0-218511311b45","body_text":"Abstract\nHuntington’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.\nCompeting Interest Statement\nRL is employed by CHDI Management, Inc., the company that manages the scientific activities of CHDI Foundation, Inc. WJG and YW are listed as inventors on the patent \"Kit and method for the quantitative detection of steroids\" US9851368B2. WJG and YW are shareholders in CholesteniX Ltd.\nFunding Statement\nThis work was funded by CHDI Foundation, Inc., a nonprofit biomedical research organization exclusively dedicated to developing therapeutics that will substantially improve the lives of those affected by Huntington's disease. Additional funding was received from UKRI (grant no BB/L001942/1, BB/I001735/1, BB/S019588/1, MR/X012387/1, MR/Y008057/1); the European Union through European Structural Funds (ESF), as part of the Welsh Government funded Academic Expertise for Business project; by a BRAIN Unit Infrastructure Award (Grant no UA05) and the Advanced NeuroTherapies Centre both funded by the Welsh Government through Health and Care Research Wales.\nAuthor Declarations\nI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.\nYes\nThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:\nCamberwell St Giles Research Ethics Committee (IRAS 185506) gave ethical approval for this work.\nI confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.\nYes\nI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).\nYes\nI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.\nYes\nData Availability\nAll data produced in the present study are available upon reasonable request to the authors.","source_license":"CC-BY-4.0","license_restricted":false}