Nature:应开展老年性痴呆一级预防研究

2017-07-23 孙学军 孙学军博客

阿尔茨海默氏症或老年性痴呆这种疾病的一级预防过去很少有人提出,可能是因为对该疾病的发生发展规律认识不全面。最近《自然》杂志发表来自华盛顿大学医学院的神经学博士Eric McDade和Randall J的文章,他们提出应该对阿尔茨海默氏症的研究进一步提前,开展对该疾病的一级预防临床试验,而不是过去发病后治疗或仅仅早期治疗。 2015年,全球阿尔茨海默氏症导致的经济负担为8180亿美元,相对于全

阿尔茨海默氏症或老年性痴呆这种疾病的一级预防过去很少有人提出,可能是因为对该疾病的发生发展规律认识不全面。最近《自然》杂志发表来自华盛顿大学医学院的神经学博士Eric McDade和Randall J的文章,他们提出应该对阿尔茨海默氏症的研究进一步提前,开展对该疾病的一级预防临床试验,而不是过去发病后治疗或仅仅早期治疗。

2015年,全球阿尔茨海默氏症导致的经济负担为8180亿美元,相对于全球第18大经济体的国民生产总值。预计2030年,全球阿尔茨海默氏症患者总数将会超过7千万。如果在治疗方面没有取得突破性进展,85岁以上的老人患病率将会有1/3甚至1/2。哪些幸运逃脱这一厄运的人,会发现至少有1个最亲密的亲朋好友已经不认识自己,这些患者记忆力只有几分钟,彻底失去生活自理能力。

过去临床试验主要是针对哪些已经出现痴呆症状的患者。最近5年,研究人员开始尝试更早期阶段,如当记忆力丧失比较轻微甚至正常,但是大脑扫描显示典型的β淀粉样蛋白斑块。但是有学者提出,这仍然不够早,应该在没有出现病理过程前就进行干预,只有这样才能真正解决问题。

一级预防也称初级预防,就是在问题尚没有发生前便采取措施,减少病因或致病因素,防止或减少疾病的发生。一级预防对预防疾病发生有效的最重要证据是他汀类药物。1980年代早期,发现开始广泛使用他汀类药物能控制一种罕见遗传性高胆固醇血症,这种疾病的人群发病率只有0.005%,会在青少年会刚成年后发展成典型的心血管病症状,不进行治疗的患者30多岁多死于中风或心肌梗塞。给这些患者从儿童时期开始服用他汀类药物,心脏病和中风的发生时间明显延后,寿命平均会延长1530年。我们人类大多数都存在“遗传性高胆固醇血症”,只不过这种表现比较晚,如果希望自己多活30年,一级预防才是根本办法。寻找能预防阿尔茨海默氏症的“他汀类”药物应该是最重要的任务,当然这也是感谢最近关于该疾病病理学的研究,也需要有一群能献身于这一研究的志愿者。当然也需要医药公司、公共和私人机构等提供经费等资源保障。


正确的时间

1980年代,认识到阿尔茨海默氏症威胁灾难迫在眉睫,美国NIH开始在资助全美国的阿尔茨海默病中心。其他如英国也开展了类似投入。随着对阿尔茨海默氏症了解的增加,研究人员和制药行业最终提高了治疗这种疾病的药物效果。

早期努力主要是通过阻断神经递质乙酰胆碱对抗记忆力丢失,尸体解剖发现患者大脑内相关神经严重丢失。1990年代晚期,研究人员开展转向对抗β淀粉样蛋白斑块和Tau蛋白缠结对脑组织的损害。针对不同类型的β淀粉样蛋白斑块清除或阻断的数百种药物临床试验相继开展。但是这些药物并不能阻断患者20年后的典型病理过程。患者晚期神经元开始逐渐死亡,大脑开始萎缩。治疗的阿尔茨海默氏症药物有4种被先后批准,其中三种是基于乙酰胆碱。但这些药物都不能改变疾病发生的病程,也不显著影响患者的症状。针对β淀粉样蛋白斑块的药物候选分子都没有获得成功,部分甚至会导致病情恶化。如一种β淀粉样蛋白疫苗就可以引起许多患者脑组织炎症反应。最近一些临床研究似乎有一些成功的曙光。

过去5年,开始有对症状发生前的病理过程进行干预的临床研究。超过11项这类研究已经开始或计划开始,受试者通过基因检测或大脑扫描发现存在斑块,都是阿尔茨海默氏症高危人群。

有四个方面最新研究结果提示应该在病理损伤出现前开展一级预防才更有价值。

一是科学证据。许多研究提示,在早期阶段使用药物能阻断病理过程,例如小鼠基因模型显示抗淀粉蛋白治疗能阻断斑块形成。另外研究提示老年性痴呆的发病过程存在一个临界点,到了这个临界点,病情会迅速恶化。而且此时再使用药物往往效果很小。所以抗淀粉样蛋白药物只能在临界点前发挥作用。

现在科学家对老年性痴呆发病过程有了更清楚的了解,最早是脑组织代谢紊乱,然后出现淀粉样斑块,进一步出现tau蛋白沉积和炎症反应。这些知识给科学家提供一系列可以说明患者病情的生物标志物,对于研究和判断这一疾病的发病过程提供了知识基础。

二是有合适的研究对象。大约不足1%的阿尔茨海默病患者中属于遗传性疾病,这些患者早在二三十岁大脑内就开始出现淀粉样斑块,这些患者的子女中也有50%的几率患病。这种遗传性阿尔茨海默病患者给一级预防的研究提供了理想的研究对象。研究发现,DIAD基因突变携带者在预期时间会出现阿尔茨海默病症状。科学家可以根据这一特征对这些患者进行早期干预,并确定干预效果。DIAD突变是指能能影响淀粉样蛋白的代谢过程的所有基因突变。不同的基因突变产生的后果一样,都会导致早期发生阿尔茨海默病。

三是有安全有效的治疗方法。淀粉样蛋白是最理想的一级预防目标,许多研究发现,这种蛋白的异常代谢是导致疾病早发的关键原因。大量研究证据显示,一种罕见突变能保护大脑内斑块形成。在爱尔兰,这种能减少β蛋白的基因携带者发生痴呆的几率只有普通人的20%。过去几年,这种遗传效应用各种药物进行模拟。大约12种这种酶的靶向药物发现能将β蛋白水平降低70-80%。重要的是,靶向BACE和伽马分泌酶的药物能口服。且没有发现严重副作用。

 四是机构支持力度增加。由于一级预防研究根据认知和病理过程产生显著差异至少需要经过10年以上的观察周期,这给药物研究带来非常更大的风险,很少有医药公司愿意开展这么长期的临床试验。考虑到这个因素,政府机构尤其是欧美政府,已经开始增加对预防干预研究的支持力度。 

在2014年,Lancet Neurol已发表meta分析结果发现,老年性痴呆的一级预防是有潜力的。研究认为,世界范围内约三分之一的阿尔茨海默病可能归因于潜在的可改变的危险因素。阿尔茨海默病的发病率可能通过改善获得教育机会和使用针对降低心血管危险因素(例如身体缺乏运动,吸烟,中年高血压,中年肥胖和糖尿病)和抑郁症患病率,而有效地减少。

相关文献:

Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne C. Potential for primary prevention of Alzheimer's disease: an analysis of population-based data. Lancet Neurol. 2014;13(8):788-94.

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    2020-12-06 1361ee8c91m

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    2018-06-16 liye789132251
  3. [GetPortalCommentsPageByObjectIdResponse(id=905372, encodeId=8f739053e2fa, content=好, beContent=null, objectType=article, channel=null, level=null, likeNumber=57, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=945e2063969, createdName=1361ee8c91m, createdTime=Sun Dec 06 11:14:04 CST 2020, time=2020-12-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1882304, encodeId=68de1882304f1, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Sat Jun 16 11:52:00 CST 2018, time=2018-06-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=227056, encodeId=193222e0563e, content=疾病,都存在着危险因素,未病先防。, beContent=null, objectType=article, channel=null, level=null, likeNumber=77, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://q.qlogo.cn/qqapp/1103841572/C3426ED027FF661B0C576A5B3127C2E8/40, createdBy=39dc1706090, createdName=QQ25ed180f, createdTime=Fri Jul 28 00:32:16 CST 2017, time=2017-07-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=225582, encodeId=6e84225582c7, content=非常好的文章,学习了,很受益, beContent=null, objectType=article, channel=null, level=null, likeNumber=68, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7LIiaRZTzJ3SEfiauCzTMPW7YvPPYLNJBXG9oh6Al1icq2VQQkIHWxqXehcicTS62YKJVBhxeth3wggw/0, createdBy=7ce01621306, createdName=天涯183, createdTime=Sun Jul 23 23:33:17 CST 2017, time=2017-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=225553, encodeId=ea14225553ce, content=学习了,值得分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20220115/46bcf39c32de4aa6b45c5f9d66c8ee77/6cb4a20c55bb4b7691122f47747bfca2.jpg, createdBy=9dad1662329, createdName=1ddf0692m34(暂无匿称), createdTime=Sun Jul 23 21:08:27 CST 2017, time=2017-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=225543, encodeId=f0b222554336, content=谢谢分享,学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=60, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Sun Jul 23 19:08:39 CST 2017, time=2017-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=225528, encodeId=21e92255281b, content=力帆总是胜过治疗,但是预防确实非常困难,尤其是很难实施, beContent=null, objectType=article, channel=null, level=null, likeNumber=54, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=c4a5105539, createdName=lovetcm, createdTime=Sun Jul 23 18:30:13 CST 2017, time=2017-07-23, status=1, ipAttribution=)]
    2017-07-28 QQ25ed180f

    疾病,都存在着危险因素,未病先防。

    0

  4. [GetPortalCommentsPageByObjectIdResponse(id=905372, encodeId=8f739053e2fa, content=好, beContent=null, objectType=article, channel=null, level=null, likeNumber=57, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=945e2063969, createdName=1361ee8c91m, createdTime=Sun Dec 06 11:14:04 CST 2020, time=2020-12-06, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1882304, encodeId=68de1882304f1, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Sat Jun 16 11:52:00 CST 2018, time=2018-06-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=227056, encodeId=193222e0563e, content=疾病,都存在着危险因素,未病先防。, beContent=null, objectType=article, channel=null, level=null, likeNumber=77, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://q.qlogo.cn/qqapp/1103841572/C3426ED027FF661B0C576A5B3127C2E8/40, createdBy=39dc1706090, createdName=QQ25ed180f, createdTime=Fri Jul 28 00:32:16 CST 2017, time=2017-07-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=225582, encodeId=6e84225582c7, content=非常好的文章,学习了,很受益, beContent=null, objectType=article, channel=null, level=null, likeNumber=68, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7LIiaRZTzJ3SEfiauCzTMPW7YvPPYLNJBXG9oh6Al1icq2VQQkIHWxqXehcicTS62YKJVBhxeth3wggw/0, createdBy=7ce01621306, createdName=天涯183, createdTime=Sun Jul 23 23:33:17 CST 2017, time=2017-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=225553, encodeId=ea14225553ce, content=学习了,值得分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20220115/46bcf39c32de4aa6b45c5f9d66c8ee77/6cb4a20c55bb4b7691122f47747bfca2.jpg, createdBy=9dad1662329, createdName=1ddf0692m34(暂无匿称), createdTime=Sun Jul 23 21:08:27 CST 2017, time=2017-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=225543, encodeId=f0b222554336, content=谢谢分享,学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=60, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Sun Jul 23 19:08:39 CST 2017, time=2017-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=225528, encodeId=21e92255281b, content=力帆总是胜过治疗,但是预防确实非常困难,尤其是很难实施, beContent=null, objectType=article, channel=null, level=null, likeNumber=54, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=c4a5105539, createdName=lovetcm, createdTime=Sun Jul 23 18:30:13 CST 2017, time=2017-07-23, status=1, ipAttribution=)]
    2017-07-23 天涯183

    非常好的文章,学习了,很受益

    0

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    2017-07-23 1ddf0692m34(暂无匿称)

    学习了,值得分享

    0

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    2017-07-23 明月清辉

    谢谢分享,学习了

    0

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    2017-07-23 lovetcm

    力帆总是胜过治疗,但是预防确实非常困难,尤其是很难实施

    0

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