D14 Plasma levels of 24S-hydroxycholesterol are reduced in Huntington disease subjects: preliminary results of a 2-year longitudinal study

• Published in: Journal of neurology, neurosurgery and psychiatry Vol. 93; no. Suppl 1; p. A25
• Main Authors: Fichera, Mario, Nanetti, Lorenzo, Favagrossa, Monica, Castaldo, Anna, Nigri, Anna, Mongelli, Alessia, Marchini, Gloria, Gellera, Cinzia, Grisoli, Marina, Birolini, Giulia, Valenza, Marta, Bagnati, Renzo, Passoni, Alice, Colombo, Laura, Cattaneo, Elena, Salmona, Mario, Mariotti, Caterina
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.09.2022; BMJ Publishing Group LTD
• Subjects: 24-OHC; Basal ganglia MRI volumes; Biomarker; Cholesterol; D: Wet biomarkers; Huntingtons disease; Longitudinal studies; Longitudinal study; Plasma
• ISSN: 0022-3050; 1468-330X
• DOI: 10.1136/jnnp-2022-ehdn.70

ObjectivesBrain cholesterol is produced in situ and its turn-over is ensured by the conversion into 24S-hydroxycholesterol (24-OHC) which can cross the blood-brain barrier. Brain biosynthesis was shown to be reduced in murine models of Huntington’s disease (HD) and 24-OHC plasma concentrations were found reduced in HD patients. We aimed to investigate 24-OHC longitudinal changes and correlate the plasma levels with disease progression, basal ganglia MRI volumes, and neurofilament concentrations.Participants and MethodsWe conducted a 2-year observational study in 78 HD subjects and 64 healthy controls. Cholesterol and its metabolites were measured using two different in-house developed and validated methods based on liquid chromatography and mass spectrometry. Fifty-eight subjects underwent 3T-MRI for brain morphometry. Neurofilament plasma measures are ongoing. HD subjects were classified using the novel Huntington Disease Integrated Staging System (HD-ISS).ResultsTwenty-one subjects were in stage 0-1; 11 in stage 2; and 46 in stage 3(a-c). Preliminary analyses of baseline data showed 24-OHC significantly reduced in stage 3b and 3c patients in comparison with controls (p=0.03; p<0.02 respectively). We also observed a trend of reduction of 24-OHC from prodromal disease stages (0-1) to the late manifest disease stages. 24-OHC levels were 40.+/-1.9 ng/ml (mean +/- SEM) in controls; 33.6+/-3.8 in HD-stage 0-1; 34.3+/-5.5 in HD-stage 2; 30.9+/-3.9 in HD-stage 3a; 29.3+/-2.5 in HD-stage 3b; and 23.3+/-1.9 in HD-stage 3c.ConclusionsMonitoring 24-OHC plasma concentrations may contribute in following disease progression and may represent a valuable outcome measure in clinical trials testing cholesterol as a candidate drug in HD.