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

IF 2.1 Q3 NEUROSCIENCES Journal of Huntington's disease Pub Date : 2024-09-05 DOI:10.3233/JHD-240030
Sarah M Gray, Jing Dai, Anne C Smith, Jacob T Beckley, Negah Rahmati, Michael C Lewis, Michael C Quirk
{"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. 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":" ","pages":""},"PeriodicalIF":2.1000,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Huntington's disease","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.3233/JHD-240030","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0

Abstract

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.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
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。
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。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
CiteScore
4.80
自引率
9.70%
发文量
60
期刊最新文献
Changes in 24(S)-Hydroxycholesterol Are Associated with Cognitive Performance in Early Huntington's Disease: Data from the TRACK and ENROLL HD Cohorts. Somatic CAG Repeat Stability in a Transgenic Sheep Model of Huntington's Disease. Mono- and Biallelic Inactivation of Huntingtin Gene in Patient-Specific Induced Pluripotent Stem Cells Reveal HTT Roles in Striatal Development and Neuronal Functions. Alterations in Cerebrospinal Fluid Urea Occur in Late Manifest Huntington's Disease. Characterizing Heart Rate Variability Response to Maximal Exercise Testing in People with Huntington's Disease.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1