We investigated the relationship between 24(S)-HC and cognitive performance in samples from TRACK-HD, a longitudinal biomarker study of pre-manifest and early-stage HD. 

24(S)-hydroxycholesterol (24(S)-HC) is an endogenous, brain specific, cholesterol metabolite that acts as a positive allosteric modulator (PAM) of the NMDA receptor. Alterations in plasma and/or brain levels of 24(S)-HC have been identified in several diseases, including Smith-Lemli-Opitz syndrome, Niemann Pick, Huntington’s disease (HD), and some forms of dementia. Although a broad range of pathology and core symptomology is observed across these different disorders, all manifest some degree of behavioral, cognitive, and psychiatric symptoms. One important question is whether 24(S)-HC is associated with these symptoms and which features are most directly associated with decreased glutamatergic tone. Cognitive deficits are a hallmark of HD and precede the onset of motor impairments by decades. Previous work has established that levels of 24(S)-HC are decreased in plasma and brain in HD patients, suggestive of decreased NMDA receptor function.

Plasma samples from the TRACK-HD study (60 control; 60 Pre-HD; 60 HD) were analyzed for 24(S)-HC via liquid-liquid extraction and analyzed with LC-MS/MS. Regression analysis was performed between oxysterol levels and performance on a number of cognitive and motor endpoints.

We found that levels of 24(S)-HC positively correlated with several cognitive tasks including the Stroop test, Trails A and B, symbol digit modality and processing of negative emotion in the Eckman faces task across all years of the TRACK-HD study. 24(S)-HC levels were not correlated with motor performance tasks and associations were not found for other oxysterols (25- and 27-HC) supporting a specific role for 24(S)-HC/NMDA dysfunction in non-motor aspects of HD.

These data support a critical role for NMDA-receptor function in cognitive performance in HD. We are currently evaluating the safety and tolerability of an NMDA-PAM (SAGE-718) in early HD patients.