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Lancet Neurology:基因携带者的生物学和临床特征远未达到亨廷顿病青年研究(HD-YAS)预期的发病率:一项横断面分析

2020-12-08 MedSci原创 MedSci原创

亨廷顿病是一种常染色体显性遗传性神经退行性疾病,由HTT基因的CAG扩增引起突变型亨廷顿蛋白的表达,该蛋白被认为是主要的毒性因子。临床上,亨廷顿病的特点是运动和认知功能的逐渐恶化和神经精神障碍。

亨廷顿病是一种常染色体显性遗传性神经退行性疾病,由HTT基因的CAG扩增引起突变型亨廷顿蛋白的表达,该蛋白被认为是主要的毒性因子。临床上,亨廷顿病的特点是运动和认知功能的逐渐恶化和神经精神障碍。

在一个以DNA和RNA为靶点的新疗法时代,亨廷顿病已知的单一遗传原因为此类治疗提供了一个有吸引力的靶点,目前已有几种降低亨廷顿病的药物正在人体试验中。亨廷顿病发病前期的详细描述对于疾病分期、告知开始治疗的最佳时间、以及确定未来对亨廷顿病发病前期(preHD)患者进行试验的生物标志物至关重要。

本文通过利用最新的方法,主要研究了健康对照组和远离预测发病的preHD队列在多个领域的潜在群体差异。这项研究旨在评估如何识别与疾病相关的早期变化(即当存在早期神经变性的可测量生物标志物,但临床功能仍完好无损时),以及哪些指标在早期preHD最敏感。

这项亨廷顿氏病青年研究(HD-YAS)在英国进行。本研究招募了患有preHD的年轻人以及与preHD在年龄、教育程度和性别相匹配的对照组。对照组要求要么有亨廷顿病家族史,但基因检测阴性,要么没有已知的亨廷顿病家族史。所有参与者都接受了详细的神经心理学和认知评估。影像学检查包括MRI,扩散成像和多参数映射。利用血液和CSF检查神经元健康的生物流体标记物。通过使用一般最小二乘线性模型进行横断面分析,以评估组间差异以及与年龄和CAG长度的关系,其与预测的临床发病年龄相关。

数据采集时间为2017年8月2日至2019年4月25日。我们招募了64名患有preHD的年轻人和67名对照组。preHD组和对照组的平均年龄分别为29.0岁(SD 5.6)和29.1岁(5.7)。我们注意到,在预测发病23.6岁(标准差5.8)的preHD参与者中,没有明显的认知或精神障碍的证据(认知测量的FDR为0.22-0.87,神经精神测量的FDR为0.31-0.91)。preHD组的壳核体积稍小(FDR=0.03),但这似乎与预测的发病年龄(FDR=0.54)没有密切关系。其他脑影像学指标无组间差异(FDR>0.16)。与对照组相比,在preHD队列中,CSF神经丝轻蛋白(NfL)、血浆NfL和CSF YKL-40升高(FDR分别<0.0001,=0.01和=0.03)。脑脊液NfL升高更可能发生在接近预期临床发病的个体中(FDR<0.0001)。

综上所述,通过确定一组未检测到功能受损但在某些神经退行性生物学指标中开始表现出微弱升高的preHD个体队列,我们发现了疾病过程早期的关键点。在这一阶段进行干预可能会在功能完整的情况下延迟或预防进一步的神经退化,从而使基因携带者在没有损伤的情况下延长寿命。

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  4. 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status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1617928, encodeId=3529161e928f9, content=<a href='/topic/show?id=e88f6930185' target=_blank style='color:#2F92EE;'>#生物学#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=60, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=69301, encryptionId=e88f6930185, topicName=生物学)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=e44019811593, createdName=12498c32m74暂无昵称, createdTime=Tue Dec 08 08:22:43 CST 2020, time=2020-12-08, status=1, ipAttribution=)]
    2020-12-30 hb2008ye
  5. 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  6. 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status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1617928, encodeId=3529161e928f9, content=<a href='/topic/show?id=e88f6930185' target=_blank style='color:#2F92EE;'>#生物学#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=60, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=69301, encryptionId=e88f6930185, topicName=生物学)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=e44019811593, createdName=12498c32m74暂无昵称, createdTime=Tue Dec 08 08:22:43 CST 2020, time=2020-12-08, status=1, ipAttribution=)]
    2020-12-30 yinhl1978
  7. 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status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1617928, encodeId=3529161e928f9, content=<a href='/topic/show?id=e88f6930185' target=_blank style='color:#2F92EE;'>#生物学#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=60, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=69301, encryptionId=e88f6930185, topicName=生物学)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=e44019811593, createdName=12498c32m74暂无昵称, createdTime=Tue Dec 08 08:22:43 CST 2020, time=2020-12-08, status=1, ipAttribution=)]
    2021-08-12 qblt
  8. 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status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1617928, encodeId=3529161e928f9, content=<a href='/topic/show?id=e88f6930185' target=_blank style='color:#2F92EE;'>#生物学#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=60, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=69301, encryptionId=e88f6930185, topicName=生物学)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=e44019811593, createdName=12498c32m74暂无昵称, createdTime=Tue Dec 08 08:22:43 CST 2020, time=2020-12-08, status=1, ipAttribution=)]
    2020-12-09 Jessie Zhang

    亨廷顿病的特点是运动和认知功能的逐渐恶化和神经精神障碍,原来如此。

    0

  9. 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