Objective: To investigate correlations between plasma levels of 24(S)-Hydroxycholesterol (24[S]-HC) and cognitive performance in participants with Huntington’s disease (HD) using data from ENROLL-HD.

Background: HD is characterized by progressive motor, psychiatric, and cognitive symptoms. Evidence suggests that dysregulated cholesterol metabolism contributes to HD pathogenesis. In the brain, 24(S)-HC is the main cholesterol metabolite and is a potent endogenous positive allosteric modulator (PAM) of N-methyl-D-aspartate receptors (NMDARs). Reduced plasma and brain levels of 24(S)-HC have been observed in all HD stages. In our prior analysis of TRACK-HD study data, correlations between plasma 24(S)-HC levels and cognitive performance were examined in participants with premanifest HD and early HD, and healthy controls (n=60 per group). Results showed that plasma 24(S)-HC levels were reduced in early HD and positively correlated with performance on cognitive measures. These findings were not solely driven by neurodegenerative processes (ie, cell loss) and were specific to 24(S)-HC [1].

Method: We sought to replicate these findings by conducting a separate analysis of the larger ENROLL-HD data set, expanding our analysis to examine the ratios of 24(S)-HC to 25-HC and 27-HC (other metabolites).

Results: In ENROLL-HD, plasma 24(S)-HC levels were significantly reduced in patients with manifest HD (n=149) vs premanifest HD (n=123). 24(S)/25-HC and 24(S)/27-HC ratios were lower in patients with manifest HD vs premanifest HD and controls (n=121). Among participants with HD and premanifest HD, 24(S) ratios were negatively correlated with CAG-Age-Product score. Across all participants, 24(S)-HC (but not 25- or 27-HC) as well as 24(S) ratios were positively correlated with cognitive performance.

Conclusion: These findings align with the prior TRACK-HD analysis and suggest that NMDAR hypofunction due to lower 24(S)-HC and 24(S) ratios may contribute to cognitive impairment in HD. In an effort to understand the potential therapeutic benefit of modulating NMDARs, SAGE-718, a novel NMDAR PAM, is currently under investigation for the potential treatment of cognitive impairment due to HD and other neurodegenerative diseases.

References: 1. Lewis M, et al. Presented at: American Academy of Neurology Annual Meeting; May 4–10, 2019. Philadelphia, Pennsylvania, USA.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/24s-hydroxycholesterol-and-cognition-in-huntingtons-disease-results-from-two-large-patient-cohorts-track-hd-and-enroll-hd/