Sarah M Gray, Jing Dai, Anne C Smith, Jacob T Beckley, Negah Rahmati, Michael C Lewis, Michael C Quirk
{"title":"24(S)-羟基胆固醇的变化与早期亨廷顿氏症患者的认知能力有关:来自 TRACK 和 ENROLL HD 队列的数据。","authors":"Sarah M Gray, Jing Dai, Anne C Smith, Jacob T Beckley, Negah Rahmati, Michael C Lewis, Michael C Quirk","doi":"10.3233/JHD-240030","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":null,"pages":null},"PeriodicalIF":2.1000,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Changes in 24(S)-Hydroxycholesterol Are Associated with Cognitive Performance in Early Huntington's Disease: Data from the TRACK and ENROLL HD Cohorts.\",\"authors\":\"Sarah M Gray, Jing Dai, Anne C Smith, Jacob T Beckley, Negah Rahmati, Michael C Lewis, Michael C Quirk\",\"doi\":\"10.3233/JHD-240030\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>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. 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引用次数: 0
摘要
背景:有证据表明亨廷顿氏病(HD)中胆固醇平衡失调。脑特异性胆固醇代谢物 24(S)-羟基胆固醇(24(S)-OHC)在显性 HD 中减少。24(S)-OHC是N-甲基-D-天冬氨酸(NMDA)受体的内源性正异位调节剂(PAM),这表明24(S)-OHC的降低可能会导致HD中NMDA受体功能减退。我们假设 24(S)-OHC 的变化与早期 HD 的认知障碍有关:目的:确定氧基甾醇(24(S)-OHC、25-OHC 和 27-OHC)与 NMDA 受体之间的相互作用、这些氧基甾醇的血浆水平以及这些水平与认知能力的关系:方法:使用体外竞争试验评估 NMDA 受体的相互作用,使用液相色谱耦合串联质谱 (LC-MS/MS) 测量血浆中 24(S)-OHC、25-OHC 和 27-OHC 的水平,并通过相关性分析研究它们与 TRACK 和 ENROLL-HD (NCT01574053) 中认知终点表现的关系:结果:在体外,25-OHC和27-OHC削弱了24(S)-OHC对NMDA受体的PAM活性。早期 HD 患者的血浆 24(S)-OHC 水平和 24(S)/25-OHC 比率较低。血浆中的24(S)/25-OHC比率与Stroop颜色命名、符号数字模型、Trails A/B和情绪识别能力之间存在中度和一致的联系。该比值与精神或运动终点之间几乎没有关联,这表明该比值与认知能力的关系具有特异性:我们的研究结果支持越来越多的证据表明 HD 患者中枢神经系统胆固醇平衡失调,证明了羟基甾醇的变化与 HD 患者认知能力之间的关系,并提出 NMDA 受体功能低下可能会导致 HD 患者认知能力受损。
Changes in 24(S)-Hydroxycholesterol Are Associated with Cognitive Performance in Early Huntington's Disease: Data from the TRACK and ENROLL HD Cohorts.
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.