Changes in 24(S)-Hydroxycholesterol Are Associated with Cognitive Performance in Early Huntington’s Disease: Data from the TRACK and ENROLL HD Cohorts

• Published in: Journal of Huntington's disease Vol. 13; no. 4; pp. 449 - 465
• Main Authors: Gray, Sarah M., Dai, Jing, Smith, Anne C., Beckley, Jacob T., Rahmati, Negah, Lewis, Michael C., Quirk, Michael C.
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.11.2024; Sage Publications Ltd
• Subjects: Adult; Allosteric properties; Cholesterol; Cognition; Cognitive ability; Cognitive Dysfunction - blood; Cognitive Dysfunction - etiology; Cohort Studies; Correlation analysis; Female; Glutamate receptors; Glutamic acid receptors (ionotropic); Homeostasis; Humans; Huntington Disease - blood; Huntington Disease - complications; Huntington Disease - psychology; Huntington's disease; Huntingtons disease; Hydroxycholesterols - blood; Liquid chromatography; Male; Mass spectroscopy; Middle Aged; N-Methyl-D-aspartic acid receptors; Plasma; Plasma levels; Receptors, N-Methyl-D-Aspartate - metabolism; Huntington’s disease; cognition; NMDA receptor; Oxysterols
• ISSN: 1879-6397; 1879-6397; 1879-6400
• DOI: 10.3233/JHD-240030

Background: There is evidence for dysregulated cholesterol homeostasis in Huntington’s disease (HD). The brain-specific cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-OHC) is decreased in manifest HD. 24(S)-OHC is an endogenous positive allosteric modulator (PAM) of the N-methyl-D-aspartate (NMDA) receptor, suggesting lower 24(S)-OHC may contribute to NMDA receptor hypofunction in HD. We hypothesized changes in 24(S)-OHC would be associated with cognitive impairment in early HD. Objective: To determine the interactions between oxysterols (24(S)-OHC, 25-OHC, and 27-OHC) at the NMDA receptor, the plasma levels of these oxysterols, and how these levels relate to cognitive performance. Methods: An in vitro competition assay was used to evaluate interactions at the NMDA receptor, liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) was used to measure plasma 24(S)-OHC, 25-OHC, and 27-OHC levels, and correlation analyses investigated their relationship to performance on cognitive endpoints in TRACK and ENROLL-HD (NCT01574053). Results: In vitro, 25-OHC and 27-OHC attenuated the PAM activity of 24(S)-OHC on the NMDA receptor. Lower plasma 24(S)-OHC levels and 24(S)/25-OHC ratios were detected in participants with early HD. Moderate and consistent associations were detected between plasma 24(S)/25-OHC ratio and performance on Stroop color naming, symbol digit modality, Trails A/B, and emotion recognition. Little association was observed between the ratio and psychiatric or motor endpoints, suggesting specificity for the relationship to cognitive performance. Conclusions: Our findings support growing evidence for dysregulated CNS cholesterol homeostasis in HD, demonstrate a relationship between changes in oxysterols and cognitive performance in HD, and propose that NMDA receptor hypofunction may contribute to cognitive impairment in HD.