本节目由艾莫利大学荣誉出品 This program is brought to you by Emory University
主持人:欢迎大家来到本学期第一期 Host: Welcome to the first of this semester's
心灵生活系列讲座 Life of the Mind lecture
这一系列由教务处支持推出 This series is sponsored by the Provost office
我是来自教务处的汤姆·詹金斯 And my name is Tom Jenkins in the Provost office
这一系列旨在探索 The goal of this series is to explore an accessible way
深藏于研究进程这个制度的核心的 some things that, is that in the core of this institution
一种可开拓的方法 and that is the research process
可以说 就是发现新知识的过程 Literally, that on how new knowledge is found
探寻新知识的动力 and what motivates the discoveries of that knowledge
还有如何探寻 and how they do it
其中我们最感兴趣的就是 And one of the things we are especially interested in
本系列展现了贯穿众多重要领域的 that comes across in this series is the variety of ways
相同点与不同之处 and also the similarities across the great great range of fields
在大家座位上的宣传单上可以看到都有 and you can see some of those range of fields on the flyer
哪些涉及领域 on your chair
下一场讲座在2月19日 The next talk is on February 19th
主讲人是法学院的维多利亚·诺里斯 down with Victoria Nourse from the law school
她会和大家分享她的近期工作 who will be speaking about on her current research
是基于她对政治方面的研究 which grows out of her work on the political series
这项工作是她与乔·拜登在国会共事时完成的 where she worked down with Joe Biden on the Hill
可以说非常具有趣味性和时效性 So it should be to put them especially interesting and also timely
说到时效性 今天的这次讲座 But when speaking of timely, this first lecture
是为这一系列揭幕的最好方式 I think is really the best way to start this down series
当我们思考心智的活动时 because when you think of the life of the mind
就应当深入到思想的基础去 you're really now going to down the foundation of the mind
也就是大脑 which is the brain
大脑可能是目前科学中最伟大的不解之谜 and probably one of the greatest and the mysteries still of science
但是它也是最具戏剧性的 and but the one with really the most dramatic
有着改变人类生命的潜力 and the potential to change our lives
某些关于大脑的研究就是在 and some of that work is here in
艾莫利大学孕育的 今天也在不断进行 and it's happening down right here at Emory
在艾莫利大学 我们的神经学研究 We have one of the premier Neurology
是目前世界最前沿的神经科学项目之一 that neuroscience programs now in the world here at Emory
我们今天非常幸运地 And we're specially fortunate today
能请来两位世界级的专家 to have really two of the world's experts
他们在神经学领域非常杰出 the greatest experts in the field of neurology
欢迎主讲人艾伦·利维博士 Our feature speaker, Dr. Allan Levey
以及介绍人马伦·德朗博士 and to introduce him, Dr. Mahlon DeLong
现在将讲台交给他们 并感谢大家的到来 So, I will turn over them and thank you for coming
马伦:能在这里向大家介绍艾伦·利维 Mahlon: That was really really nice opportunity
实在是太荣幸了 to say some nice things about a very nice person
他对神经学做出了巨大的贡献 whose done tremendous things here, Allan Levey
艾伦是我的熟人 I happen to know Allan
我们相识已经很多年了 I have known Allan for many years
最初相遇的时候是1986年 Actually we met 1986 somewhere in there
那时 他刚加入霍普金斯大学的 when he joined the faculty
神经学部门教职员工 at Hopkins Department Neurology
作为神经学实习医生 as a resident in Neurology
之后 又成为了实习医生主管 When to the ranks, became chief resident
然后在教职员部又工作了一小段时间 and then stayed on for a short time on the faculty
初来时 艾伦的资历已经相当丰富了 Prior to that, actually, Allan came really pre-packaged
他通过对大脑类胆碱功能系统的出色研究 He had already done a PhD with an outstanding research
获得了博士学位 in cholinergic systems of the brain
这项研究是一次非常大的奠基和突破 Done really fundamental ground breaking research
他为我们带来了 So came into this was a very mature perspective
非常独到和成熟的视角 on what he was doing
之后他担任了几年研究员 and then spent some years in fellowship
做得也相当不错 and got very well around it
艾伦就是这样的理想人选 and Allan is a sort of the ideal candidate
我1990年离开霍普金斯 and when I left Hopkins in 1990
开始细心地挑选应聘者 I looked carefully for people to try to recruit
这是一个有趣的工作 which became kind of fun thing to do
我想挑选最优秀最有才华的 Always picking the best, brightest
最终我们成功说服艾伦加入 and we were able to persuade Allan to come
他不久之后便加入了艾莫利的教职员部 He joined the faculty here shortly thereafter
那是1991年 It was 1991
我给大家讲个小故事 I'll just tell you a little story
不会占用很多时间 and I am going to make it very brief
艾伦那个时候 So, Allan at that time
我没有告诉别人我要离开霍普金斯的事情 you don't have to talk to people about leaving Hopkins
可是最后我也得去找院长谈 and eventually I have to talk to the Dean
那时的院长是迈克尔·约翰斯 At that time it was Michael Johns
我想迈克尔也使出了九牛二虎之力说服他 I think Michael was using every sort of persuasion he could
我告诉他南下也许是错误的 I told him that it might be rather serious mistake to go down south
你可能会迷失或者失败 and you know get lost, fall off the table
或者其他的挫折 or something you know in those terms
艾伦最终被我们说服了 and Allan nonetheless was persuaded in
从此以后 就是一个经典 圆满的成功案例 and it has been a wonderful, remarkable success story
艾伦是我们的核心雇员 Allan as a key recruit at that time
我绝对没有夸张 I say that not likely lightly
他是部门的中流砥柱 Allan was a cornerstone of the department
在临床研究与教学的每个领域都有涉猎 and worked in every area in clinical research
也在开发一些项目 and teaching to develop programs there
他开创了老年痴呆症研究中心 He's set up the Alzheimer's Disease Research Center
从国立卫生研究院拿到了研究基金 Obtained funding from that from the NIH
自2001创始起 中心运转至今 and that has been in existence since 2001
艾伦同时也成为 and also became director of the center for neurologic
并成为神经组织退化失调疾病研究中心的主任 for neurologic degeneration neurodegenerative disorders
他训练了大量优秀的博士生 He's trained numerous PhD's
带过很多博士生候选人 supervised PhD candidates
在大脑皮层研究和研究生项目上也颇有影响 been very involved in the MST program, graduate program
并且他也会继续领导这些研究 对么 and you know continuous to direct that I think, is that right?
艾伦:我退居幕后了 Allan: I stepped down
马伦:是的 你退居幕后了 Mahlon: No. You stepped down
你最终还是从第一线退下来了 You stepped down finally
没错 我记起来了 that's right, I remember
2003年我退休之际 艾伦接手了我的工作 In 2003, Allen took over where I had when I stepped down
并持续不断的注入新鲜血液 新的能量 and you know has continued to bring new blood, new energy
以及新的资源到部门中来 and new resources into the department
都是不可忽视的成功 remarkable in his success
还有更令人赞叹的成就 我就不冗述了 I won't bore you with all of the successes
他是许多协会和机构的成员 he has had in multiple societies and organizations
建议报告 国立卫生研究院 研究部门 advised reports, NIH, study section
诸如此类 and all those things
任何一个位置上 他都做得非常出色 He's punched his ticket in every all of the right places
作为一名热情 乐于助人并出色的研究者 and has really earned a tremendous reputation
也作为一名杰出的老师 as compassionate, caring physician, outstanding researcher
艾伦赢得了众多敬重 and a teacher
如果用四个字来形容艾伦的话 I can describe Allan in two words
我们总是这么开玩笑 但事实也是如此 We use this kind of jokingly sometimes, but it's a real thing
那就是三重威胁 Triple threat
大多数人应该明白我的意思 And many of you know what that means
那就是出众 出众再出众 that means just outstanding, outstanding, outstanding
在这里除了艾伦我想不到更优秀的人了 And Allan I can't think of anybody better here
更没有别人有资格谈论这样的话题了 or anywhere to talk to you
即心智产生的 about the foundations of the mind
基础 从大脑开始 and that really does start in the brain
艾伦 现在把时间交给你 So, Allan I turn this over to you
欢迎你到讲台上来 as great opportunity to welcome my chair as well
艾伦:谢谢你 马伦 Allan: Well, thanks Mahlon
首先 大家能听到我的声音么 First of all, can everybody hear me on the microphones
调高一点 再高一点 再高一点 Higher, higher, higher
现在呢 How's that?
好的 Good
如果听不到 请举手示意 Just raise your hand if you can't hear me
马伦 谢谢你 Well Mahlon, thank you
感谢你多年前将我带到艾莫利大学 Thank you for bringing me here many years ago now
这些事情仿如昨日啊 It still seems like it was yesterday
这里每天都快速地演变着 Since this place continuous to evolve at rapid pace
并且一天比一天好 and gets better every day
对我而言 这次演讲是非常好的机会 This is actually going to be really fun opportunity for me to talk
能面对这群了不起的 多样化的听众 just looking at this incredibly diverse group
我眼前的人都是我的老师 I am looking at people that I learn from every day
都是我无比敬佩的人 People that I respect every day
我眼前的都是杰出的神经学家 I am looking at people who are outstanding neurologist
杰出到的神经科学家以及其他领域的领头羊 outstanding neuroscientist, outstanding in all walks of life
我以为这次演讲应该不会有大量受众 So I think this might be a challenge to hit a very broad audience
因此 深入研究神经科学 So, those of you involved in the depths of neuroscience
还有研究老年痴呆症的人们 in the research on Alzheimer's disease
如果我说的不对 你们可以随时打断 Feel free to chime in because I don't have to hit some high points
另外 这里温度比较高 Others, it's also warm in here
又是傍晚时分 At the end of the day
需要激活大家的脑部细胞 and encourage everybody's brain activating systems
保持脑部的运动防止睡着 to keep turned on and keep from falling asleep
因此我鼓励大家的参与 and I encourage your participation
因为大家来自不同领域 I love questions
欢迎各位随时提问 and since I particularly sense it's a broad audience
如果我讲得不清楚 Feel free to interrupt along the way
请直接打断我 if I am not making anything clear
我今天想要做的 What I thought I would do though
就是把握机会和你们聊聊心智的活动 is take the opportunity to talk about the life of the mind
我想讲讲心智上的疾病 This is a what I want to talk about are disorders of the mind
更准确的说 是老年痴呆症 and one in particular, Alzheimer's disease
这是最令人们惊恐的A字打头的疾病 This is the one the big A the thing that scares a lot of us
不幸的是 它影响了太多人 Unfortunately, it touches too many of us
他就在我们身边 It touches us personally
有时就在我们教职员工队伍里 Sometimes in our own faculty
看到世界上最聪明的头脑 to see the greatest minds in the world
被老年痴呆病夺去自己的心智 become afflicted with the disorder that robs them of their thoughts
这是非常惨痛的 It's pretty tragic
所以这种疾病我们都非常熟悉 了解 So, it's certainly one that we all know and aware of
同时我还想通过这次演讲 and what I want to do during the talk is also
我会强调 well I hit high points
我要特别强调一点的是 I am going to in particular try to hit high points of
我认为艾莫利大学的研究机构 where I think bright spots here at Emory
这里的研究已经到达了一个比较高的水平 Where some of the progress is occurring here from a high level
因此 首先 So first of all
我想告诉大家 for those of you
中间一些还没有意识到这个问题的人 who aren't aware of what we are talking about
老年痴呆症是一种全球性的危机 This is a worldwide crisis obviously
并且会成为一种流行病 and it's going to become an epidemic
真的 在过去的几个月里 Gosh, over the last several months
我们经历了许多重大灾难 there are lot of major catastrophes upon us
经济危机 战争 where there is economy, war
还有其他的全球性威胁 and all sorts of global threats
老年痴呆症也会成为其中一项 This is going to be one that got to be added to the list
也许影响还会不断增加 Probably increasingly
因为越来越多的人都会 because many people are gonna have become
更明显地意识到这个问题 more and more aware of the problem
我们今天要说的是老年痴呆症 We are going to talk about Alzheimer's disease today
但其实还有其他疾病 but there are actually a variety of different diseases
也通过骇人的方式影响人的心智 that can affect the mind in pretty tragic ways
在这张图表中不难发现 and as you can see here
在往后的几十年中 we are expecting over a hundred million people
我们估计 将有上百万人遭受 affected with disorders of the mind
各类心智疾病的影响 over the next few decades
因此 我们必须引起大家的关注 So, we have to say we have to do something about it
而其中老年痴呆就是最好的例子 and Alzheimer's disease is really the best example
它是最常见的 It's the most common
占了全部失智症的三分之二 It accounts for about two thirds of all the dementing disorders
因为社会的老龄化 and it's a disease that we're gonna see more and more of
老年痴呆症的病例也会越来越多 because of the aging of society
一项研究指出 This is from one study
老年痴呆的发病率随着年龄增长而增长 you can say that the rates of Alzheimer's disease increases with age
而患病的几率 and the chances
对那些年龄超过85岁的老人而言 start approaching nearly 50% chance of getting Alzheimer's disease
罹患老年痴呆症的几率是50% for those people who lived past the age of 85
这一疾病趋于蔓延的原因 and the reason we really have an epidemic upon us is
是因为活过85岁的人越来越多 because of the number of people living past the age of 85
如图所示 as shown on this figure
这张图向我们展示了 This graph shows you that
仅在美国 in the US alone
预计会活过85岁的人群的人群数目 the number of millions of people who are gonna predicted
以百万人计 to live past the age of 85
再取这个数字的一半 and take that number by about 50%
就是可能患老年痴呆症的人数 and that's the number that we might see with Alzheimer's disease
我们必须行动起来 unless we do something about this
正如下面的文字显示 Of course we had, and you can see the text on the bottom
仅在美国 So in the US alone
现在就有超过五百万人已经超过了85岁 we have over 5 million people out of the current estimates
而在婴儿潮时期出生的七千万人 and the 70 million Baby Boomers on this country
也陆续到了领社保的年龄 have just hit age of social security
因此 经济真正会开始受到疾病的影响了 So, this is now really gonna begin to hit the economy as well
以今天的美元面值计 Currently, in today's dollars
估计老年痴呆症在美国造成的开销是 it's estimated that Alzheimer's disease cost in the United States
每年一千五百亿 a hundred and fifty billion dollars a year
在这里我要指出 and I was pointing out during the talk
很不幸 most of their money is
当这部分钱真正投入应用的时候 unfortunately
很多人的心智都已经无法挽救了 after the most of the mind has been lost
所以钱都花在晚期疾病 So, it's late in the disease
对那些没有自理能力的病人的护理上了 taking care of people who really can't take care of themselves
同时 我想再次强调 And again, I wanted to try and highlight
艾莫利大学在老年痴呆症的现阶段工作中 a little bit of the work that's going on at Emory
一些研究概况 in this overview of Alzheimer's disease today
凯尔·斯汀蓝是公共健康学院的教授 And Kyle Stinland is a professor in the School of Public Health
同时也负责艾莫利大学 He is the head of our data management
老年痴呆症研究中心的生物学统计与数据管理 and biostatistics score in our Alzheimer's disease center
和生物统计数据的负责人 here at Emory
他一直在研究死亡率的变化 So, he's been looking at mortality data
不仅有多年前的 He has the last couple years
也有现今的能够买到的数据 He has today if we could purchase it
他也分析这些可用数据的可行性 but what he has done is analyzed the data if it's been available
鉴于大约2000年的时候 since there is a new coding classification system
一种全新的医学分类系统推行开来 that went into effect in about year 2000
如图所示 As you can see here
仅在过去几年中 the mortality rates even over the last several years
美国因老年痴呆症 are seem to be increasing with about and over 30% increase
而导致的有报告的死亡率 in the reported mortality rates
就增长了30% for Alzheimer's disease in this country
这样的结果有许多原因 There are lots of reasons
来源于活组织取检报告等等 this could be from reporting biopsies and all sort of things
但这些报告数据是真实可靠的 but these are the numbers as they are reported
同时 凯尔还研究了美国老年痴呆症的 He also, Kyle also looked to the geographical distribution
地理分布情况 of Alzheimer's disease in United States
得到一张有趣的患病地图 and it's a very interesting map
灰色阴影部分的地区 The area shaded here in gray are areas
死亡率较高 where there is a higher mortality rate
大家也不难看到 东南部地区这一片 and what you can see is down here in the southeast
有几个州 是较高的死亡率集中的地方 we have a cluster of a states with a higher rate
西北部也受到一定的影响 On the northwest also is particularly affected
如果你们了解中风事件的几率 and those of you who are aware of stroke incidents rates
就明白这张地图反映了 realized this map basically mirrors
并且同时真实显示了 and lays right on top of the mortality rate
心血管疾病和中风的死亡率 for cardiovascular and stroke deaths
在中风的领域 So, in a stroke field
我们将亚特兰大称为中风带的扣环 we call Atlanta here the buckle of stroke belt
而东南地区就是中风带 and the southeast being the stroke belt
老年痴呆症也是如此 We can say the exact same thing about Alzheimer's disease
如此说来 在心血管疾病和老年痴呆之间 and as we talk about, there are actually growing commonalities
的确存在许多相似之处 between cerebrovascular disease and Alzheimer's disease
也存在着许多共同的风险因素 with many shared risk factors
我们怀疑 说不定还存在共同的治疗前景 and we suspect perhaps even shared treatments ahead
现在我们就简单聊聊老年痴呆症 So let's talk a little bit then about Alzheimer's disease
通常情况下 我们把这种疾病看作 On the average, we think about these diseases
一种能持续上十年的疾病 a disease that goes on over by a ten year course
就像人类各有特色一样 It's highly variable
本疾病面貌也比较多样 just like all of us are very different
发病之前 Before we have a disease
本疾病对不同的人有不同的影响 this is a disease that affects people differently
有时几年的时间内很快发病 sometimes very rapidly over a couple of years
有时有超过20年的潜伏期 sometimes protracted course is over 20 years
但对所有病患而言 But for all people though
基本都是一个这样的发展过程 eventually there is a progression
从轻微的失忆到严重的失智症 from very mild memory loss to severe dementia
然后是完全丧失自理能力 were people are unable to really help themselves at all
最后终日躺在床上依靠护理院的护理 End up in bed bound in the nursing home dependent
喂食 如厕等等 for eating, toileting, you name it
并且大多数的护理 And most of their cares
都出现在这条致病曲线的终点 are meant to really at this end of the curve
世界范围内 我们关注的都是患病的早期阶段 Worldwide, we are really focusing now on the earliest stages
所出现的临床症状 wether there are any clinical symptoms apparent
这样我们就能更早一步行动 So that we can begin to move the focus earlier
我们现在有一个通用术语 We now have a term that is generally accepted
那就是 轻度认知障碍 called mild cognitive impairment
这是一种临床证据 Which is really a clinically evident condition
主要表现是 病人偶尔会抱怨记忆丧失 where patients will complain of memory loss on occasion
家人则明显意识到失忆状况 Families will certainly be aware of memory loss
我们则客观衡量失忆状况 and we can objectively measure memory loss
很明显有东西改变了记忆 There is clearly something going on with some change in memory
也改变了高层次的认知功能 and other types of higher cognitive functioning
轻度认知障碍只是老年痴呆最早的 So, mild cognitive impairment is the first prodromal stage
前期征兆 of Alzheimer's disease
我想指出 它不一定会无可避免地 I need to point out though it's not inevitable
导致老年痴呆 that it will lead to Alzheimer's disease
因为还存在其他众多状况 There're many other conditions
都可能导致这种轻微认知障碍所导致的状况 that will lead to that mild cognitive impairment
这就跟失智症是存在众多导因的一样 could lead to, just like there's many different causes of dementia
不过上述它们的症状也许都很类似 All of those might have a similar type of syndrome
因此我们接下来要说的是 So much more of what we are going to talk about also is
我们是否能扭转这条曲线的方向 focusing on moving this curve back
我们也发现这一疾病 and we're also now aware that the disease actually begins
事实上早在一二十年前就开始了 what we expect probably a decade or two
这早在前期失忆症状发作之前 before even the first symptoms of memory loss are apparent
这里显示了实际变化的证据 So, as will show you there is evidence that the actual changes
大脑的神经退化 the neurodegeneration that occurs in the brain
病理改变的积累 the accumulation of some pathological changes
往往是在症状出现之前的 are actually present maybe 10 or 20 years
10到20年间产生的 before symptoms begin
我也逐渐变老 As my hair is gray
因此我总会思考我的大脑里都在发生些什么 I've always wondered what's going on inside my brain
想办法改变老年痴呆症的路线 So, to change this course of Alzheimer's disease
想办法将曲线扭转 To really move this back
使我们以后能提前预防这不可避免的未来 so we can prevent the future that otherwise will be ahead of us
现在我们的关注焦点主要是两大挑战 There are really two major challenges that are the focus of attention
第一点就是早期侦测 In the first is early detection
由于变化是 since the changes do occur
早在失忆症状出现之前就产生的 before symptoms of memory loss are present
在大脑真正开始出现明显的临床衰退的之前 What can we do to actually identify and recognize
我们该如何识别和判断 who actually have the first changes occurring in the brain?
哪些病人出现了这种早期的脑部改变呢 Before the brain starting to fail clinically in evident manner
第二个挑战就是 在侦测到之后 and the second thing is obviously then, after we detect it
我们要有能力及时处理 we need to be able to do something about it
并从根本上改变疾病的走向 and modify the actual course of the disease
首先 In the first goal is
如果我们能改变这条疾病的曲线 if we can just sort of shift the curve as shown here
如图虚线所示 on the dotted line
如果能将这条曲线往回回溯 If we can push the curve back
这样症状出现的年龄就能继续往后推 so that symptoms begin at a later age for many people
我们已经可以在公共卫生的角度上 We can actually begin to have a great impact on the disease
很好地影响这一疾病 from a public health point of view
而在从个人出发的角度上 obviously on an individual level
我们明显还需要做得更多 We need to do more
我们最高的目标就是老年痴呆症的预防 and our ultimate goal is disease prevention
因此今天主要的内容 So, I am going to focus to talk today
就是围绕早期侦测和疾病改造这两方面 around these two themes of early detection, disease modification
以及艾莫利大学一些研究工作的亮点 and some of the highlights what's happening at Emory
作为序言 As a prologue to that
我先给大家讲点背景知识 let me now just give a little bit of background about
例如我们所了解的发病机理 病因 what we know about the pathogenesis, the cause of the disease
以及我们是如何发现的 还有艾莫利的研究 and how we got there, and again what's happening at Emory
首先 大家都同意 First of all, so we're on the same page
老年痴呆症是一种原发型神经退行性疾病 Alzheimer's disease is a prototypical neurodegenerative disease
也就是脑细胞产生了退化 meaning brain cells are degenerating
如右边所示 and as you can see on the right
是死于老年痴呆症一名病人的大脑解剖图 from an autopsy brain of a person who died with Alzheimer's disease
大脑上部可见大面积的收缩 There is tremendous shrinkage of the upper parts of the brain
箭头指向的大脑皮层的这块地方 The cerebral cortex here where the arrow is
出现大量萎缩 shows a lot of atrophy
褶皱部分与认知功能完整 The folds are wide apart
这和死于非认知性疾病的病人相比 compared to a somebody
脑皮层间距离极远 who has cognitively intact and died of other causes
这里 大脑物质要多得多 As you can see, there is much more of a brain substance
灰质是饱满的 The gray matter is full
因此 老年痴呆症中有某种现象 So, there's something that goes on Alzheimer's disease
导致了脑组织的退化 that leads to this degeneration of brain tissue
是什么呢 What is it?
约百年前 阿尔兹海默 Well, Alzheimer himself a little over a hundred years ago
指出了大脑产生的这种变化现象 really recognized what is going on in the brain
并将此称为早老性痴呆症 He identified what was called this presenile dementia
又称早老性阿尔兹海默症 老年痴呆症 or Alzheimer's disease as presenile form of senility
他当时护理了一位叫做奥古斯特的病人 and what he did is he took care of a patient, Auguste
50岁刚刚出头 who was in the early 50's
有妄想症状 记忆出现问题 had some paranoid delusions, developed memory problems
四处漫游 走失 wandering, got lost
虽然经过多年住院治疗 She was hospitalized in over several years
最终难免一死 Died
她死后 阿尔兹海默解剖了她的大脑 When she died, he dissected her brain
加入新型染剂放在显微镜下观察 looked it at under a microscope with some new special stains
那是一百多年前发明的一种染色剂 that were developed a hundred years ago
他当时所看到的景象 请看这里的显微照片 and what he saw is depicted down here in the photo micrographs
他描述了两大主要的病理改变 He described two major pathological changes
今天我们仍然认为是 that we still recognize
老年痴呆症的病理特点 as the pathological hallmarks of Alzheimer's disease
这里出现老年斑 The senile plaques which are shown here
是一种蛋白质的沉淀 These are accumulations of a proteinaceous substance
不断累积在大脑中 环绕着脑细胞 that accumulate in the brain, around the brain cells
环绕着神经元 around the neurons
这种蛋白质沉淀又称为淀粉质 So this is an accumulation of a protein substance called amyloid
我们稍后也会提到 that we're gonna be talking about
阿尔兹海默也指出了脑细胞内部的第二种变化 And he also described the second change within the brain cells
他发现了神经原纤维缠结 He found these things called neurofibrillary tangles
这一丝状的缠绕就像火车轨一样 So this twisted filaments through like the train tracks
在脑细胞中缠绕起来 干扰了脑细胞中的 that got twisted up within the brain cell that transport machinery
传输机理 within the brain cells is disrupted
他详细地描述了这些变化 So, he described this changes
我们依然视这些为老年痴呆的病理特征 and we still use this as the pathological signature
直到现在 of Alzheimer's disease that is, has been until recently
我们确知老年痴呆症的唯一方法 the only way that we can really confirm Alzheimer's disease
就是通过解剖或者活体组织取检 is present at autopsy or occasionally biopsy
因此 近15年来发展 So, the research that has been going on that has really
和迅猛发展起来的研究 exploded over the last fifteen years
趋于了解脑细胞死亡的根本原因 has been to understand that the root causes of
大脑老年斑形成的原因 what lead to brain cell death, what lead to senile plaques to form
以及神经原纤维缠结的形成原因 and accumulate, and what lead to the neurofibrillary tangles to form
我们接下来会谈到这些问题 So, we're going again talk a little bit about some of those things
以及它们为什么最后会导致神经退化 and why it is that they lead eventually to this neurodegeneration
首先 对究竟是什么导致了 The first step in really getting clues as to
老年痴呆症的第一阶段的理解 what types of things might lead to Alzheimer's disease
来自流行病学研究 have come from epidemiological studies
我们知道老年痴呆症 We know that Alzheimer's disease is a disease
具有一个复杂的特点 That has one of this complex traits as we call them results
我们称其为 基因易感性 from a combination of our genetic susceptibility as well as
与某些我们仍然没有判明的 from some environmental factors
环境因素的综合的结果 that are really as yet unidentified
流行病学研究指出的线索表明 There are clues from epidemiologic studies that there're both
存在保护性的因素 也存在风险因素 some factors that are protective and others are at a risk factors
红色的阴影部分就是风险因素 and I have shaded here in red the risk factors
是由流行性病学研究 that have come out from have been reproduced
指出来的 from multiple epidemiological studies as well as
这些则是保护性因素 those that are protective
因此 红色的风险因素部分 and so you can on the list in red
它们指的是头部损伤 抑郁 高血压 there are things like head trauma, depression, hypertension
高胆固醇 高半胱酸铵 低B12维生素 high cholesterol levels, high homocysteine levels, and low B12
以及低叶酸这些因素 and low foliate levels which well has been associated
都跟老年痴呆症的高发风险有关系 with an increased risk of developing Alzheimer's disease
值得一提的好消息是 艾莫利的团队发现 In contrast, the good news is, those of us who are here at Emory
高等教育是预防 higher education is a very protective factor
老年痴呆症的保护性因素之一 over developing Alzheimer's disease
我们最近的研究发现 We have learned recently
身体锻炼也是保护性因素之一 that exercise seems to be a protective factor
我们通过流行病学研究可以发现 We've learn from epidemiologic studies that people
使用非类固醇抗炎药的人 who take nonsteroidal anti-inflammatory drugs
例如患有关节炎的人 for things like arthritis
患老年痴呆症的风险较小 also have a lower risk associated with Alzheimer's disease
服用降低胆固醇药物的人患病几率也比较小 People who take cholesterol lowering drugs are protected
还有对我来说是个好消息 and also good news for me
红酒也能降低患病风险 red wine is very protective
这就是我们的发现和部分相关因素 So, those are clues, there associations
我们不能说有什么因果关系 We certainly can't say there cause and effect
媒体总是喜欢高调关注这一方面 People in the news often like to highlight these things
并让人们对还未确定的治疗抱以过高希望 and encourage people that this were gonna be cures which there not
媒体需要多做点功课 They need a lot more study
不幸的是 Unfortunately
我们知道大部分疾病都是遗传性的 we know that the vast majority of diseses is genetic
因此估计可能有 So probably, it's estimated
80%到90%的老年痴呆症都属于遗传紊乱 80 to 90% of Alzheimer's disease is really genetic disorder
我们认识上的最大的进步就是 and the really the greatest advances in understanding
大多数老年痴呆症是 what goes on have come from families where many individuals
和家庭的因素息息相关 are affected by Alzheimer's disease
我想和你们分享我们在艾莫利大学 This is one family that I like showing that we identified
研究的的一个家庭 here at Emory
我们现在收集了这个家族族谱中 which is we now have over a hundred individuals
超过100个个人案例 in this pedigree that have been that we've collected
并请他们来艾莫利大学参与研究 and recruited to come to Emory to study
这一疾病 This is the disease
困扰了他们家族好几代人 that's affected their family for several generations
这是我们收诊的初始病人 This was the initial patient who came to see us
黄色箭头指示的地方 where the yellow arrow is
她的父亲 Her father
和父亲的每位兄弟姐妹都患有老年痴呆 and every one of his siblings had Alzheimer's disease
我们手头有这个家族的9名成员的解剖资料 and we'd have autopsies now on nine members of this family
并进行了遗传研究 and we have done genetic studies
并且发现 and we know that
没有能够识别的基因突变 there is no known genetic mutation that can be identified
很明显是一种新生成的基因引起的 There's clearly a new gene that's responsible
遗传学院院长史蒂夫·沃纳 that were actively searching for with Steve Warner
及其小组的研究正在积极地寻找这种基因 with his group and the chairman of in the Department of Genetics
不过其他家族也出现了这样的问题 But there are other families like this
引导我们判定了这些基因 that have led to identification of a genes
正是这些(听不清)的家族 and it's really this (INAUDIBLE) families
改变了我们对这种疾病的认知 that have changed our understanding
这些家庭属于 These are families that have
我们所称的 家族型老年痴呆症 what we called familial Alzheimer's disease
也就是 单个基因中产生的单型突变 where there's a single mutation in a single gene
不可避免地导致了老年痴呆 that inevitably leads to the disease
这些家族中的首次患病记录 and when this disease starts on these families
可以出现在很年轻的阶段 it comes out at a very early age
这些都属于老年痴呆症的高活跃型形式 As these are highly aggressive forms of Alzheimer's disease
他们的子孙遗传疾病的几率是50% where 50% of their children who will inherit the disease by chance
也就是说 他们靠遗传获取了患病染色体 if they get the affected chromosome
好在这样的情况不多 and fortunate they're rare
这样的家庭数量在整个世界中都不算很多 They're only really a handful of families around the world with this
但也让我们发现到了 and has led to the identification of the responsible
肇事基因的存在 the culprit genes
我们从早先发病的 and there are actually three different genes
多个家庭中 that you account for almost all of the families
发现了三种不同的致病基因 that have early onset Alzheimer's disease
一个是染色体21号上的APP基因 Those are the APP gene on chromosome 21
另外两个是早老素基因 and two genes called presenilins
他们的分布位置不重要 their location doesn't matter
我们了解到了这些基因的生物特性 But what we've learned about the biology of these genes
和它们改变脑细胞功能的方式 and how they change brain cell function
我会一一讲解这些内容 I will show you
因为它真正为我们 because it's really given us the road map to
了解老年痴呆的病因 what we think this is the cause of the disease
探寻治病的方法 以及早期侦测 and ideas about how we might modify the disease
指明了一条道路 and detect it earlier
与这种罕见的家族病例不同 In contrast to this rare families though
有90%的老年痴呆症都转变成了 about 90% of people with Alzheimer's disease developed
散发型老年痴呆 what we call sporadic Alzheimer's disease
他们发病的年龄较晚 They get it in a later age
可能有患病的家人 例如叔叔阿姨 They may have a family member affected, an aunt or uncle
有时是父母 Sometimes the parent
但是这种情况下家族成员患病几率是50% but it's clearly not the case
这种情况是完全不存在的 where 50% of the individuals in the family are getting the disease
因此老年痴呆症的散发型 So the sporadic form of the disease
主要取决于一种遗传因素 there's one major genetic association
即载脂蛋白Apo E 4等位基因 and that's a the Apo E 4 gene
这种基因也是导致心脏疾病的风险因素 It's a gene that also is a risk factor for heart disease
它和胆固醇代谢息息相关 It's involved in cholesterol metabolism
并且占全部型老年痴呆症案例的 and it accounts for 40 to 50 percent
40%到50% of all cases of Alzheimer's disease
这是整体上的估计 sort of the general estimates
它也不是一种因果关系 It's not a cause and effect though
这一点和我们谈到的其他基因不同 and it's a major difference from the other genes we've talked about
在座多数人 So in this case, many of us in the room
都有载脂蛋白Apo E 4等位基因 have an Apo E 4 gene
但并不意味着我们会得老年痴呆 It doesn't mean we have Alzheimer's disease obviously
我们不一定会患病 and it doesn't mean we will get it
只是说我们患病的几率比别人大 It just means our chances are increased that we will get it
我们了解 可能还存在5到10种其他的基因 and then we there probably about five or ten other genes out there
会不同程度地导致老年痴呆症 that are responsible for the other contribution to Alzheimer's disease
我们和其他研究人员正努力研究 and we and others are actively searching
希望知道这些基因是什么 for what some of those genes are
我会向你们展示其中一种 and I'll show you a little bit about one of the genes
它是我们在艾莫利的研究所得 that's recently been identified as a result of some work here at Emory
我们怎么知道这些基因会导致老年痴呆呢 So, how do these genes inform us about what causes this disease?
我想通过这个动画 This is a cartoon that I put together
解释我们如何由对基因的认识 to try and explain how we can go from understanding a gene
进而知道脑细胞是否出现机能障碍 to understanding how a brain cell functions and dysfunctions
这里展示的就是这些家族的患病基因 What I'm showing you here is the protein or the structural substance
如何对蛋白质和结构物质 that is encoded by the relevant gene that causes Alzheimer's disease
进行编码 in some families
这种淀粉样前体蛋白基因 and this amyloid precursor protein gene
我们大脑中大多细胞都会制造 that is made in most of our brain cells
在正常的大脑运作过程中 and during the course of our normal brain functioning
我们每天都形成新蛋白质 We make new proteins every day
再由身体进行分解 and our bodies degrade the protein
进而替换 and turn them over
蛋白质分解的方式 and the way this protein gets degraded
是非常典型的 it gets degraded in a very stereotypical manner
它被分为一小块一小块的 So it gets cut up into little pieces
其中一小块蛋白质 and one of the little pieces of this protein
被称为β淀粉样肽 is called amyloid peptide or A beta
另外两种是β淀粉样肽40和42 and one of the forms is called A beta 40 and one of them is 42
我们都在制造这种小块的蛋白质断片 So, all of us are making these little peptide fragments as we speak
它由人体产生然后又排出人体 It's getting made in our body as fortunately getting rid of it
因此它并不会累积起来造成老年痴呆 So it doesn't accumulate and cause Alzheimer's disease
随着年龄的增长 As we age
会出现一些常见的清除问题 there seems to be some generally some clearance problems
或者是清除率下降的问题 or some slowing down of clearance
这些肽的碎片开始堆积 Some of these little peptides begin to aggregate
它们是很难对付的 It's a sticky little peptide
一旦它们开始堆积起来 They accumulate and once they start accumulating
会造成很大的毒性 that is believe to be what's really toxic
对脑细胞造成伤害 and what really injures brain cells
随着这种物质积聚的增多 and the substance further aggregate
就会在脑组织中形成沉积物 and clamps and forms a deposit in the brain tissue
这就是我要分享的大致路线 So, that's the road map I'm gonna talk about
希望它能引导我们更好地早期侦测疾病 as really the guide for how we can move towards early detection
发现更优秀的疗法 and better treatments
我也提到过 同时载脂蛋白等位基因 I also mentioned that Apo E is a major susceptibility gene
是致病的主要易感性基因 for Alzheimer's disease
就它在老年痴呆症中的角色 and there are lots of questions about
存在很多疑问 how it places a role on the disease
某种层面上 我们对此的了解并不够 We really don't understand at a level that we need to
我们只知道它能影响淀粉质 We know that it somehow can affect amyloid
也就是β淀粉样肽的粘性 The little beta peptide that can be evolved in its stickiness
过去几年中 and there's been a lot of research
也有大量相关研究 I think over the last couple years
这一领域的兴趣都转向于此 Most of the excitement in the field has sort of shifted to this
(听不清)小段肽的堆积和形成 (INAUDIBLE) the little aggregates of this peptide that formed
由于认识到了它形式上的高毒性 and there's a lot interest in this since it's been realized that
人们的研究兴趣也越来越大 it's a toxic, it's of highly toxic form of it
艾莫利大学的一些研究 Some of the research at Emory has actually
就占有非常重要的席位 been playing an important role
化学学院的大卫·林恩 David Lynn in the Chemistry Department here
与神经退化疾病中心的 formed a collaboration
毛子胥 音 合作进行了一项研究 with Zixu Mao in the Center of for Neurodegenerative Disease
他们的研究 and they were funded
由老年痴呆症研究中心的示范项目资助 by a pilot project on Alzheimer's disease center
大卫对淀粉质结构的研究已经有十几年了 David has been working on the structure of amyloid for over a decade
现在则致力于研究 now with very high resolution trying to understand
肽形成积淀的原因 why this little peptide forms aggregates
他运用了高分辨率结构的方法 and he has used high-resolution structural approaches
他发现 特定的金属离子 例如铜和锌 and learned that certain metal ions like copper and zinc
他们是大脑运作非常重要的因素 They are important elements in normal brain function
同时对肽积淀的催化 also play a very important role
也起到了重要的作用 in catalyzing the aggregation of this peptide
这项发现对类似研究 This has been a very important finding
也有很大的帮助 that others have seen similar things
同时也产生了一系列相关的治疗研究 and there's been a whole field of therapeutics
关注如何将这些研究运用起来 that's been arising about how to learn with
将这些发现 used what's been learn from this information
运用到制药开发当中 to actually think about drug development
他们可能阻止疾病的发生 They could block this process
在澳大利亚有一项临床试验 There's been a clinical trial for example in Australia
使用含有某些上述金属的螯合药物 using chelate drugs that actually combined some these metals
来阻止疾病进程 and block the process
以上是一个小故事 Such as one little snippet
在艾莫利大学还有一个令人激动的研究领域 Another I think very exciting area at Emory
过去的四五年间 over the last 4 to 5 years
吉姆·拉和团队研究发现了 has come from the work of Jim Lah and others
一种叫做LR11或者SorLA的蛋白质 identifying a protein called LR11 or SorLA
让我来跟大家略讲一讲 And let me just tell you a little bit about
这一发现 what's been learned about this
因为这作为治疗老年痴呆的 Since this has actually gotten a lot of attention
潜在制药靶标 over the last a year or 2
在近一两年已经引起了不少关注 as another potential drug target for Alzheimer's disease
是我们的一名神经学研究员 It's actually one of our neurology residents
在四五年前做了一项研究 About 4 to 5 years ago did a study
他从老年痴呆症研究中心的 He took blood cells from our patients
病人身上提取血液细胞 in the Alzheimer's Disease Center
然后提出一个非常简单的问题 and asked a very simple question
哪些基因是不同的 Which genes are different?
这些从病人身上提取的血液细胞 How much of every gene that he could measure
和正常人相比 was present in blood cells from patient with Alzheimer's disease
到底有多少基因是不同的呢 versus control individuals
他只发现了几种 and he found only a handful of genes
不同的基因 that were different
于是决定研究LR11这一种 and decided to study this one called LR11
这个基因引起他的注意是因为他意识到 and the reason it caught his attention because he realized
这种基因与载脂蛋白等位基因受体族相关 that it was related to the Apo E receptor family
我们预测这种蛋白质受体 So this was a protein that we would predict
能够中和载脂蛋白等位基因 that would be able to bind Apo E
后者是老年痴呆症的主要风险因素 the major genetic risk factor for Alzheimer's disease
克莱门兹的研究 What Clemens learned is that
指出这一基因在特定脑细胞中 in fact this gene is expressed in very high levels
有很高的表达 in certain brain cells
尤其是在老年痴呆症 precisely those brain cells that degenerate early
早期退化的脑细胞中 on Alzheimer's disease
在老年痴呆症的案例中 and in Alzheimer's disease cases
脑细胞死亡之前 it seems before the brain cells die
就已经失去生产这种蛋白质的能力了 they start losing their ability to make this protein
许多研究生接下去做了许多研究 Many graduate students has subsequently taken this on
理查·康恩参与了淀粉质形成过程中的 Rick Kahn has been involved in the collaborations on
LR11蛋白质功能的研究协作 how this is LR11 protein function in the process of amyloidogenesis
该研究的一项发现是 One of the things that's been learned is that it
LR11是结合剂 this is a binding partner
它能将淀粉样前体蛋白基因 It actually combined the amyloid precursor protein directly
直接在脑细胞中结合 in brain cells
并且改变了 and it can actually change the way
淀粉样前体蛋白基因在脑细胞内部的运行方式 that amyloid precursor protein gets handled within brain cells
并改变其新陈代谢的方式 and how it gets metabolized
事实上 我们能证明 In fact, we've been able to show that
脑细胞和其他细胞中的LR11数量 the amount of LR11 present in brain cells or other cells
直接影响所产生的淀粉质的数量 directly influences the amount of amyloid that gets made
这张图表就是较高水平的LR11 So showing this little graph here is that the higher the level of LR11
这里LR11的水平越高 you can see here there's higher levels of LR11
由细胞产生和庇护的 The lower the amount of amyloid beta protein
β淀粉样肽就越少 made and secreted by cells
因此 我们预期 老年痴呆症中 So, we expect in Alzheimer's disease
LR11水平越低 if there's lower levels of LR11
脑细胞就会产生越多的淀粉质 brain cells will be making more amyloid
这样我们就能把这一点和发病机理联系起来 So we began to be able to link this to the disease pathogenesis
艾莫利大学另一名神经科学研究生 One of our other neuroscience graduate students here at Emory
克里斯汀·赛杰 Christian Sager
和我们的小组一同合作 formed a collaboration with us with a group
针对修女进行了研究 at Rush using a nun studies
在芝加哥 他们对修女进行研究 So in Chicago, they've been studying these nuns
让修女们每年进行记忆测试 Getting them, having them, had memory test every year
修女都决定死后自愿捐出自己的大脑 and when they die, they've all decided to donate their brains
根据生前最后一次评估 Well, many of these nuns have had mild cognitive impairment
大多数修女都出现了轻微的认知障碍 When they were last assessed before they died
克里斯汀记录下了 and Christian has been able to measure
他们大脑中的LR11产生数量 the amount of this LR11 protein present in their brains
如图所示 Showing here
她研究出了 she developed some methods
测算大脑LR11含量的方法 so we can measure within individual brain cells the amount of LR11
并对其量化 and quantify it
这里就是不同个体的大脑 and this shows you individual different brains
死时认知功能完善的人 People who were cognitively healthy at the time of their death
与患有老年痴呆症的人比较 versus people with Alzheimer's disease
重复一次 一项研究指出 Again, there was a finding that
在老年痴呆患者中 there's remarkably lower amount of LR11
LR11的含量相对显著较低 present in Alzheimer's disease
有趣的是 那些具有轻微认知障碍的人 but really interesting was people with mild cognitive impairment
也就是发病的早期时候 again the very earliest stages
有些患者和真正罹患老年痴呆症的人一样 some people have very low level of LR11
LR11水平都较低 just like Alzheimer's disease
其他病人则有着较高的水平 接近常人 Other patients have higher levels much like normal
同时 我们也证实 LR11的数量 Also, we were able to show that the amount of LR11
和认知能力也是相关的 actually correlates with the cognitive ability
这是在轻度认知障碍阶段 This is actually the first biomarker that I am aware of
我所了解的 第一个和临床状态直接相关的 that actually shows a direct correlation with clinical status
生理标记 at mild cognitive impairment stages
不久前 也有研究 指出了 and then most recently, to directly link
LR11的表现数量 the amount of LR11 expression
和实际淀粉质沉积之间存在直接关系 to actual amyloid deposition
克里斯汀 凯瑟琳和萨拉在实验室 Christian and Katherine and Sara in the laboratory
运用老年痴呆症的动物模型 used an animal model of Alzheimer's disease
这些实验转基因老鼠 These are little transgenic mice
带有导致老年痴呆的 that have incorporated human mutation
人类突变基因 that causes Alzheimer's disease
随着老鼠年龄的增加 and as this mice aged
他们脑内也产生了淀粉质沉淀 they too get amyloid deposits in their brain
在老鼠大脑的显微图片中的亮点 and this was one of bright spots here
就是沉淀 in this photo micrograph of the mouse brain
如果我们测量一下老年斑的数量 and if you measure the amount of this senile plaques
患病者的LR11不足 when LR11 is deficient as occurs in Alzheimer's disease
而老年斑的数量也较多 there are higher levels of senile plaques
我们认为它是目前几项基本研究得出的 So we think this is a potentially new target
一个潜在的新靶点 from some of the basic work that has been done here
在过去几年中 and then over the last couple of years
首次进行了一次遗传学研究 there has also been the first genetic studies
将产生LR11的基因的多态性变化联系起来 Linking changes in polymorphisms in the gene that makes LR11
因此遗传获得了这一基因变种的人 so that people who have certain genetic variance of this gene
更容易患上老年痴呆症 actually have a higher risk of Alzheimer's disease
这点也补充了人们的认识 So this has been added
这也是 and this is actually been
过去几年老年痴呆症研究中 one of the most widely confirmed genetic associations
最广受承认的的基因联系 in the Alzheimer's disease field over the last couple of years
因此染病基因 So it's clearly the diseased gene
直接与发病机理有关 that's directly implicated in the disease pathogenesis
我们也认为这个基因 and it's also a gene
是可以成为制药靶点的 for which we think it may be a druggable target
因此吉姆和他的团队尝试(听不清) so Jim and others have begun working out trying to (INAUDIBLE)
开始研究我们是否能研发相关药物 began a project and see if we can get some drugs developed
在艾莫利大学制造出这一分子 for this molecule here at Emory
我要提醒大家 这个遗传变量 I should also say this gene, the genetic variance
似乎和认知的老化有关 seem to correlate with cognitive aging
所以忘了老年痴呆症这回事吧 So forget Alzheimer's disease
我们直接来谈心智的活动 We're just all about the life of the mind
最睿智的心智的活动 The life of the brightest mind
一些遗传变量 似乎 it seems that certain genetic variants
与高智商有着特别的联系 are associated with higher intelligence
据弗拉明翰的一项队列研究指出 In a Framingham cohorts study
看来这个基因 还有不同的原因 This is a gene that maybe we will be interested
值得我们去对它关注 to keep an eye on for other reasons as well
我们现在已经大致讲过了 So, we've talked now about what our current understanding is
对老年痴呆症成因的普遍认识的现状 in a very general way about what causes Alzheimer's disease
接下来的内容将集中于 Let me and the remaining parts of the talk now focus
我们如何破译这些信息 on how we can begin to translate that information
运用到早期侦测中 into early detection
并最终回到 and then ultimately we would come back and talk about
疾病缓解的相关研究上 where we going in terms of disease modification
轻度认知障碍对临床学家而言是一次挑战 So mild cognitive impairment is a real challenge
特别是如何发现这一病症 for us as clinicians on how to recognize this condition
这是一个非常高危的状况 It turns out that it's a very high risk condition
每年都有10%患有轻度认知障碍的病人 about 10% of people with this mild cognitive impairment will
实际患上老年痴呆症 actually developed Alzheimer's disease each year
比照而言 健康老人患病的几率 and that's compared about 1 to 2%
只有1%到2% of a healthy elderly controlled individuals
因此 如果你患有轻度认知障碍 So if you have mild cognitive impairment
患上老年痴呆的机会 your chances of developing Alzheimer's disease
就高了5到10倍 go up 5 or 10 folds
这个状况非常值得注意 It's obviously an important condition
以便于我们及早进行干预 so that we can begin to intervene early
我之前也提到了 这个问题很常见 As I mentioned, It's really a popular
是老年痴呆症研究中目前临床研究的主要课题 It's a major topic on Alzheimer's disease, clinical research currently
也是重要的公共卫生问题 It's also a huge public health problem
正如这里显示的 只有10%的患者 As shown here, only 10% of patients
前去就诊时 when they go to their doctor
只有10%患有轻微认知障碍 and actually having more than MCI
甚至是早期失智症的患者 even early stages of dementia
能够得到确诊 will be recognized as having their condition
一项全科医师从业调查指出 In a general practitioner practice study
只有3%的人 only 3% of individuals were
得到了确诊 actually identified as having a problem
因此 我认为这场疾病的海啸 So, as I see this tsunami
这一老年痴呆症变为流行病的浪潮中 this big epidemic coming of Alzheimer's disease
如何让这个问题达到 How we're gonna get this out
初级护理医生的掌握范围内 into our primary care doctor's hands
将是我们所面临的最大挑战 It's gonna be a major challenge for us
这并不是医生的过错 and it's not the doctors' fault
而是太花费时间了 This is something that takes time
必须要盘问家人 取得统一 You have to talk to families, getting informants
需要仔细调查病史 这是一个需时很长的流程 This is just, it's a careful history and the process takes time
我们现在的医疗系统 that our current medical system is
还不能很好的应对这一问题 really not well, equipped to deal with
艾莫利的一些其他研究指出 Some of the other research at Emory has been addressing
我们应该寻找更好的侦测方法 how can we developed better way to detect it
凯尔·斯汀蓝和公共卫生学院 Again, Kyle Steenland and the School of Public Health
与以吉姆为首的临床核心联合起来 hooked up with Jim and our clinical core to actually see
看能否开发一种低技术含量的方式 帮助医生 if we could develop a very low-tech way of helping doctors
来确诊轻度认知障碍 identify mild cognitive impairment
最终他们发现了一个非常简单的方法 and it turns out their very simple way
只用在医生办公室花上三分钟 that take about three minutes in a doctor's offices
做一个 迷你认知测试 to do something called the, mini cog test
让病人画一个这样的钟表 Have the patient draw a clock as shown here
并让他们重复三个单词 Ask them to repeat three words
等他们画好钟的时候 When they're done drawing the clock
让他们回忆这三个词 ask them to remember the three words
结果就显而易见了 and then you see how they did
同时 询问病人的护理人员 Simultaneously, you ask your caregiver
病人在家中表现如何 how that individuals functioning at home
他们的银行账户等 这样的 Are they having any extra needs to help with banking
各式日常行为是否需要协助 and other types of activities of daily living
凯尔从卫斯理伍兹的上百名病人 See, Kyle took the information
身上得到了这样的信息 from several hundred patients here at Wesley Woods
老年医学临床的基层部门给这些病人做了测试 that were given this test in the primary in the Geriatric clinics
然后想出了一种基本的筛查方法 and figured out basically a screening strategy
这样就能减少误诊率 so he could get a cut-off
可检出85%到90%的易感或特定人群 that was over 85 to 90% sensitive and specific
只要用这种简单的测试 just using this simple test
这样 我们就能区别轻度认知障碍 So you can distinguish people with mild cognitive impairment
和更晚期的老年痴呆 from those who had more advanced stages of Alzheimer's disease
也能区别出身体健康的人 from those who are just health elderly individuals
这个方法技术要求不高 So this is a very low-tech way
当然也有些高技术含量的方法 There are also some higher-tech ways
斯图尔特·左拉领导 Stuart Zola headed
艾莫利大学灵长类研究中心 the Primate Center here at Emory
研究灵长类的记忆力多年 has been studying memory in primates for many years
他在对一个方案进行改造 He has been adapting a task
以前用这个方案来衡量灵长类的记忆 that has been used in primates for measuring memory
这个测试方案被证明在测试灵长类记忆方面 and has been shown to be exquisitely sensitive
非常敏感有效 for measuring memory in primates
现在试图用于人类 To humans
这个方案很简单 我们观察事物 人类 it's a simple task where you look at objects and humans
和其他动物 and all other animals
它们的大脑都具有一种共同的天生特质 have this innate feature of their brain
即我们都喜欢新奇 that we love novelty
如果给你看两个东西 So, if you've seen two things
而其中一个是你见过的 and one of those things you've seen before
你就会花更多的时间 you'll spend most of your time
观赏研究新事物 gazing and searching the novel object
因此这是一个固有的生理现象 So it's just a biological phenomenon that's there
是可测的 and you can measure that
我们可以运用这一点来测试记忆力 and that's the way to measure memory in people
不论是人类的还是灵长类还是其他动物 or primates of any other animal
斯图尔特研究小组 and what Stuart and his group found
在轻度认知障碍的病人身上发现 in patients with mild cognitive impairment that
通过这个测试来观察人们看哪个物品 in fact you can use this test to see where they're looking
对照组的健康人群 三分之二的时间里 and control individual will look at the novel object
会观察新事物 about two thirds of the time
而患有老年痴呆症的人 Patients with Alzheimer's disease
他们两分钟前才看过的物体 they've seen an object and then two minutes later
等回来再看的时候 they come back and they're seeing the object
完全是靠几率 他们还是会看同一个物体 They basically will look at the object the same just by chance
也就是说 只有50%的时间里 about 50% of the time
他们会观察新物体 they'll look at the novel object
这也说明老年痴呆患者都具有 showing that the Alzheimer's patient basically is having a problems
记性差的问题 with their memory
由于斯图尔特实验中的 and what Stuart found in mild cognitive impairment patients
轻度认知障碍者只有50人 since we have about 50 in that group at this point
测试结果不够有说明性 This test seems to be pretty sensitive
因此斯图尔特开始研究 So Stuart has been interested in now moving this out
这一点它是否能跟大脑功能成像结合起来 and correlating this with functional imaging as well
因此 在高科技研究的这一边 Then on the other end of the spectrum
我们认为很快就能出台新方法 the highest-tech ways, that we think are gonna be available soon
能够通过脑功能成像确诊轻度认知障碍 to detect mild cognitive impairment are through brain imaging
对这一研究领域的人来说是值得期待的 and this has really been I think exciting to all of us in the field
如果说这个方法能以成本有效的方式推行 because we really think this is gonna change the paradigm
那么就能改变一直以来的范式 if ever it could be implemented in a cost-effective manner
也有些新的化合物被开发出来 There have been compounds that have been developed
能够通过脑功能成像的方法 that allow brain imaging methods
探测老年斑的数量 to detect the amount of senile plaques
以前 正常人大脑产生的淀粉质 The amyloid present in brains of living human people
是我们能通过解剖中诊断出来的唯一的东西 used to be that we can only diagnose this at autopsy
现在 我们还能断定淀粉质的数量 Well now, we can measure how much amyloid is present
就像阿尔兹海默一百年前在显微镜下看到的 just like Alzheimer did under a microscope a hundred years ago
放射学主任凯罗琳·梅尔泽 Carolyn Meltzer here is Chair of Radiology
是匹兹堡小组的一员 She was part of the group at Pittsburgh
他们发现了 匹兹堡合成物B that developed was called Pittsburgh Compound B
最终制成了第一个能测量淀粉质的 which has really become the first PET imaging agent
PET显像剂 to measure amyloid
这些就是凯罗琳在艾莫利制出的图像 and these are some images that Carolyn obtained here at Emory
这是老年痴呆研究中心的一位健康长者的图像 This is a healthy elderly individual from the Alzheimer's Center
这是患有老年痴呆症的病人的对照图 and patient with Alzheimer's disease
甚至是轻度认知障碍阶段 and even in mild cognitive impairment stages
某些患者体内就已经开始积聚淀粉质了 you can see some people are beginning to accumulate amyloid
这是我们从世界各地所进行的研究工作中 This is just one example what we're learning very quickly
所了解到的一个案例 from studies going on around the world now is
60岁以上的健康长者 that amyloid is present
大概三分之一的人 in about a third of healthy elderly individuals
脑内都有淀粉质 over the age of 60
他们都没有失忆的问题 These are people that don't have memory problems
但他们都似乎 and that these people seem to be the ones
在向轻度认知障碍转变 that are converting to mild cognitive impairment
那些有轻度认知障碍的人 If you look at people with mild cognitive impairment
那些脑内具有淀粉质的人 those with amyloid often have levels of amyloid
淀粉质水平达到老年痴呆症水平的人 that are full blown Alzheimer's disease levels
这些人就已经开始向轻度认知障碍转化了 and those are the same individuals are beginning to convert
这些都是进行中的研究 So these are studies that are ongoing
我们离最终数据还相当遥远 We're certainly far from having the data
但我们坚信这很有可能会成为 but many of us think this is extremely likely to be
老年痴呆症的一个非常敏感 basically a very exquisitely sensitive predictor
的预测变量 of Alzheimer's disease
使我们能在患者生存阶段便能够 and would really be away for us to diagnose it with virtual certainty
做出确诊 while people are living
以上就是疾病早期侦测的领域 So that's where I see the field for early detection
后面的时间里 我会主要讲讲疾病缓解 In a last few minutes now, let me focus on disease modification
这是我们面临的最大问题 Which is gonna be our greatest challenge
在开始之前 Before going to where we're headed
请允许我向大家介绍一下目前的现状 let me just bring everybody up with for this where we are right now
可以说 and basically
我们可用的药物种类比较少 we have a few different types of medications which are used
而且治标不治本 and they're really symptomatic medications
其中一种叫做乙酰胆碱酯酶抑制剂 One is a group of drugs called, acetylcholinesterase inhibitors
它的设计原理是 增加大脑中的 Which are designed to enhance the levels of acetylcholine
乙酰胆碱水平 in the brain
另一种叫做美金刚胺 Another second class is Memantine
是一种较弱的NMDA 谷氨酸受体拮抗剂 which is a weak NMDA, glutamate receptor antagonist
一些研究也指出维他命E and vitamin E has been shown in some studies
可能可以减缓 to be able to perhaps slow down
老年痴呆症的发病过程 the progression of Alzheimer's disease
第一种基于多项研究的药物原理是 So, the first drug that really came from much research was
脑中含有乙酰胆碱的神经元 because as neurons on the brain that contain acetylcholine
就是脑细胞退化发生的神经元群 are one of the groups of brain cells that degenerate
这是20世纪70年代中期的一项发现 and this was found in the mid 1970's
最终在20年后被人们应用 and it was finally translated twenty years later
制成第一类药物 也就是胆碱酯酶抑制剂 into the first class of drugs that are this cholinesterase inhibitors
这种药物依然治标不治本 These drugs so are really symptomatic
它们只能增强记忆和认知 They're designed to help memory and cognition
即使最乐观的情况下 They're at best very mildly effective
也只能对某些人起较小的疗效 for some people
首先 也是最重要的 The first, I think one of the most important
第一 药物的临床研究 first clinical studies of drugs
似乎又将我们带回了 that are sort of moving the needle back towards
轻度认知障碍的研究中 mild cognitive impairment was done
这是几年前 罗恩·彼得森领导的研究 Headed up by Ron Peterson a couple years ago
研究了患有轻度认知障碍的 and this was a study of hundreds of individuals
几百名病患 with mild cognitive impairment
几年内 他们只服用以下一种药物 They were treated for several years with one of the drugs
胆碱酯酶抑制剂 或维他命E或安慰剂 that cholinesterase inhibitors, or vitamin E or placebo
然后对这些人群进行跟踪 以观察 and these were individuals were followed to see
在跟踪观察的三年内 how frequently they converted to Alzheimer's disease
他们罹患老年痴呆症的几率 over the 3-year period
究竟有多大 that they were followed
三年内 这些轻度认知障碍患者的表现 And if you look at individuals with mild cognitive impairment
形成了这样的曲线 over a 3-year period
展示了发病率 this curve just shows you their rate of progression
在临床研究初始 So at the beginning of their clinical trial
没人患上老年痴呆 nobody had Alzheimer's disease
18个月后 载脂蛋白等位基因检测 After 18 months, those who are Apo E 4 positive
呈阳性的高危人群 开始发病 had the genetic risk factor, had begun to convert
20%的人会转变为老年痴呆症 等等 about 20% had converted to Alzheimer's disease, etc.
这里还存在一点不同 As we can see, there's a difference
带有致病风险的载脂蛋白等位基因的人 Those with a genetic risk factor ApoE4
和不带这一遗传的人群相比 convert to Alzheimer's disease at a faster rate
最后转变成老年痴呆症的过程速度更快 than those who don't have the genetic risk factor
仔细观察实验结果 So, if you look at the results of the trial
一年内 服用了药物的病人 overall it showed no different in the delay after a year
没有表现出什么差异 for all individuals treated with these drugs
但再看看携带载脂蛋白等位基因的人群 But if you look at the ApoE4 group
也就是基因风险高位人群 those who are genetically, the high risk group
接受胆碱酯酶抑制剂治疗的人 The people that were treated with cholinesterase inhibitor
和服用维他命E与安慰剂的人相比 had a significantly delayed rate of conversion to Alzheimer's disease
极大的推迟了发展为老年痴呆症的发病时间 compared to those who took vitamin E or placebo
原因可以有多种 There are lots of reasons this could be
并不能说明这种药物能保护神经 It's certainly doesn't mean that it's neuroprotective
还可能是因为一些潜在的症状受益 It could have been some potentially symptomatic benefits
但这终究是朝着正确的方向迈出的第一部 but again it was sort of a the first step on the right direction
我想我们有机会来减缓疾病的进程 I think that we might be able to modify the disease process
事实上 这一实验的三年中 In fact, it was significant over the full 3 years that trial
载脂蛋白等位基因群组发病时间的延缓 for the ApoE4 group in terms of their delay
是非常显著的 to Alzheimer's disease
有小部分生物学证据说明 There's a little bit of biological evidence that actually
这些药物不仅能治疗症状 these drugs might be neuroprotective
还能保护神经 more than just symptomatic drugs
英国几年前有一项病理研究 There is a pathological study done in England several years ago
对那些参与了 looking at people who had actually
乙酰胆碱酯酶抑制剂实验的人进行研究 participated in a acetylcholinesterase inhibitor trials
在他们死后 and then when they died
分析他们的大脑 their brains were analyzed
对他们脑中淀粉质进行了量化 and the amount of amyloid present in their brains was quantified
在试验中接受药物治疗的人 and those individuals who had been receiving drug in the trials
与服用安慰剂或历史对照组的人相比 overall had less of these amyloid plaques
接受了药物治疗的人 than the individuals
脑中的淀粉样蛋白质斑较少 who have been placebo-treated or historical controls
这一发现非常重要 and again that was significant
也有研究显示 There are other studies showing
受到药物治疗的人的大脑萎缩状况 that actual amount of brain atrophy
比其他群组的人要好一些 in people treated with these drugs may be less
其他研究也表明 萎缩的速度要慢一些 The rate of atrophy is less in some studies as well
所以我们目前的药物 如果给药较早的话 So there's potential from even drugs that we have
也是有潜力的 that if we begin them early
能让我们有可能减缓发病的过程 we might be able to modify the disease progression
另一点 制药开发方面 One of the other things that we've been working on
我们正在努力研发更好的药物 in terms of drug development is better drugs
以更好地利用乙酰胆碱酯酶 that can actually take advantage of the proper
调节淀粉质的形成的这个自身特质 the ability of acetylcholine to modulate amyloidogenesis
这方面我们研究了多年 This is an area that we've been working on for many years
艾莫利大学的一位旧同事杰夫·康恩 One of our ex-Emory faculty member is Jeff Conn
他现在在范德比尔特 who's now at Vanderbilt
是研发第一种特效药的 has really been one of the leaders
先驱之一 这种药物是针对 in developing the first highly specific drugs
某种乙酰胆碱受体的 受体叫做M1 for one of the acetylcholine receptors that we call M1
我们认为它很有可能是一种关键受体 Which we think it's probably gonna be a key receptor
能调节淀粉质 if any of them are in terms of regulating amyloid
和杰弗里的合作展示了 and working with Jeffrey been able to show that
受体上有一个新部位 称作变构部位 there's a new site on this receptors that's called an allosteric site
这里细节不是最重要的 The details are not important for this purpose
这一类药物是第一种高选择性药物 But it's really the first class of drugs which is highly selective
只能跟M1起作用 which can react with M1
而不跟其他乙酰胆碱受体亚型起作用 but not the other acetylcholine receptor subtypes
我们证实了 这种药物能够有效并积极地调控 and we've been able show in fact that this drug potently modulates
脑细胞产生的 And in a positive way the amount of amyloid
淀粉质的数量 that gets made by brain cells
以上是为关注细节的各位提供的生化观点 These are just biochemical grasp for those interested in the details
它展示了 It shows that it actually can
这些新药能够减少β淀粉样肽的数量 These new drugs can decrease the amount of amyloid beta peptide
产生和积聚的淀粉样肽 that're actually get made and secreted
这些药物也能被大脑吸收 The drug also are able to penetrate the brain
他们还有另一个作用 They also have another property that we know
基于这类毒蕈碱型乙酰胆碱受体M1 that due to this muscarinic acetylcholine receptor m1
能够有效激活谷氨酸酯受体 that actually activates glutamate receptors
和NMDA谷氨酸酯受体 and NMDA glutamate receptors in a very potent way
这种化学物质对学习和记忆有关键性的作用 that's a type of chemical that's critical for learning and memory
我们知道这些药物有一定 We know that these drugs have behavioral effects
有利的行为影响 that are beneficial
我们也认识到 and we also have been learning that actually
这些药物还有许多独特的 they have some other properties that are very seem very unique
有利于药物研发前景的特性 and very promising for drug development
他们并不是用同样的方式 and that they don't lead to activation of the receptors
激活所有受体 in the same way
以前总是一种药物激活一种受体 so that usually one of drug activates the receptor
然后受体逐渐脱敏 关闭回应 the body sort of desensitizes and turns off the response
而这些新药的做法是不同的 These newer drugs seem to not do that
这又能让我们思考长期治疗的问题 so that we think about chronic application
我们想从这些药物的优点中获益 We think about these drugs having some beneficial features
除了药物 In addition to drugs though
艾莫利还有其他正在研究中的 there are also some extremely other interesting ways
有趣独特的方法 that are under research
看来很有前景 And appear promising here at Emory
克丽丝·塞斯娅 托尼·斯特林格 Krish Sathian, Tony Stringer
他们属于康复神经学院 at Rehab and Neurology departments
和年轻教员本·汉普斯特德有一项联合研究 have been working with Ben Hampstead, a junior faculty member
他们在过去一年做了一些有趣的研究 Have done some really exciting work over the past year
其中一个示范项目已经要进入下一阶段了 Again, a pilot project that is now ready to go to another level
托尼多年来都在和 and Tony for years has been working with patients
受过脑部创伤的病人打交道 with traumatic brain injury
即有静态脑创伤的病人 patients that have a static injury
并应用如何进行认知康复的范例 and giving them paradigm to how to do cognitive rehab
训练脑损伤患者提高记忆力 how to train individuals with brain injury to improve their memory
这一小组选择了一些患轻度认知障碍的人 So this group took some patients with mild cognitive impairment
并研究如何训练提高他们记忆力的方法 and asked what can we increase memory training in this group
他们的研究结果是 and what they found is at indeed they could
他们可以教会病人如何更好地记忆人名 They could teach people how to better remember names
跟我一样年纪大的人应该都很清楚 Those of you who are becoming more senior like me realized
最可怕也是最早的记忆衰退就是 that one of the greatest, the first failings of memory is
你想不起别人的名字 you can't remember somebody's name
你参加聚会的时候 人们认出了你 You go to a party and people go, I know you
和你亲切的打招呼 and hi guy how are you doing?
你只能回应对方我很好 I'm alright
其实记名字是有一套有效的方法的 Well, you can actually teach people how to remember names
方法很有效 本及其工作小组发现 That's pretty effective and what Ben and the group learned is that
训练效果可以持续 this training persisted
即使过了十二个月 十八个月 so even after about twelve to eighteen months
也有不少良好效果能够持续 因此 There are some lasting benefits so that this might be
如果我们能够将记忆放慢 这也许是很有用的 actually a promising thing if we can slow memory down
甚至对神经元退化疾病的患者来说很有用 even for a person with a neurodegenerative disease
更好的是 他们对有反应的一组人 More exciting, when they actually did functional brain imaging
进行脑功能成像的研究 in a group of people that actually responded
他们发现训练过的人 They found that those
在做记忆测试的时候 who are trained had increased brain activation
大脑活动更活跃 而且更活跃的正是那些 when they were doing memory tasks and these were precisely
在老年痴呆症中 as the areas of the brain
首先开始退化的区域 that are the first to degenerate in Alzheimer's disease
因此也许存在某些比药物更简单的方式 So it turns out may be some simpler things other than medicines
我们现在手头就有的一些方式 may actually be available at our hands currently
就能够帮助提高记忆力 that could help memory function
还有一点有趣的看法 Another highly interesting here is
锻炼身体的作用是怎样的? what's the role of exercise?
我跟大家展示过 流行病学研究显示 I showed you that epidemiologic studies are linked to people
锻炼越多的人得老年痴呆的风险就越低 who have more exercise, have a lower risk of Alzheimer's disease
在这一方面 第一项以科学方法进行的 The first really prospective trial that tested this
前瞻性实验 in a scientific manner
结果刚刚发表出来 该实验研究了锻炼是否 whether exercise could have some impact on cognition
能对认知功能有所影响 was published not too long ago
这个澳大利亚的研究小组 This was a group in Australia
挑选了一些患有轻度认知障碍的病人 who took a bunch of individuals who have mild cognitive impairment
为他们制定了严格的锻炼日程表 and they gave them a rigorous exercise regimen
甚至量化了他们一天走了多少步路 They quantified how many steps they were walking
以及是否做了些额外的激烈锻炼 and if they were doing more vigorous exercise
研究结果是 and what they found is that
这些轻度认知障碍的病人 in these patients with mild cognitive impairment
是可以通过锻炼身体提高认知能力的 they could actually improve cognition through exercise
并且效果是持久的 and again the effects were enduring
因此甚至是在实验结束之后18个月 So, even after the end of the trial, after about 18 months
依然显现出持续的益处 There seem to be some persistent benefits
所以锻炼也许能够 So, exercise perhaps is immediately available
让我们瘫痪在床的病人重新站起来 as well if we can get our sedentary groups going again
我没有时间把 I don't have time to get into all the other
全部的可能制药标靶讲完 sort of drug druggable targets
但我们现在对 but our roadmap for understanding
老年痴呆症的发病原理有了大概的理解 how Alzheimer's disease actually occurs now
我们相信 as we generally believe
这给了我们一些新的药理目标 gives us many new targets for drug development
这里展示了所有的种类 which are shown here, and they're all sorts of them
其中大部分都在艾莫利大学进行试验 and many of them are under trial at Emory
这里不能一一介绍这些研究人员 And I don't have time to get into many of their basic researchers
他们在各种新药上的 They are working at different steps along the path here
研究进度都不一样 trying to develop newer drugs
这是我们首次 And for the first time
拥有一批数量日益增长的试验阶段药物 we have a really growing pipeline of drugs in trial
如图所示 在去年 Over the last year, for example is this graph shows you
我们开发了50种药物 We have over 50 drugs
并都处于人类临床试验的第三和第四阶段 that were in phase 3 or phase 4 clinical trials of humans
对我这样的本领域研究者来说 This is really for someone like myself who came into this field
当我们从无药可医 when we had no medications
到形成药物试验规划 to actually have a growing pipeline of drugs
是非常令人欣慰的 is really extraordinarily promising
最大的瓶颈就是将药物带入临床试验时 The greatest bottle neck that I see is we bring drugs to clinic is
我们必须进行仔细的筛选 that we've got to choose really carefully
看哪种药物对人有效 which drugs gonna do in human
之前那张幻灯片展示的制药靶点中 All those targets I showed you on the previous slide
大多数都在患有老年痴呆症的老鼠实验中 Almost all of them have been shown to be beneficial
显现出一定的疗效 in a little mouse model with Alzheimer's disease
但是对象换成人情况就不一样了 but when things get into a human that's another
完全是另一个样子 it's a whole another game
因此必须仔细筛选 and one has to choose very carefully
一类药物要通过人类临床试验 It can cost hundreds of millions of dollars
可能要花费几百万美元 to get a drug through clinical trials in humans
在动物模型中最激动人心的进展就是 and I think one of the most exciting advances in animal models
我们能通过灵长类试验对疾病有着更好的理解 how we can actually learn from primates more about the disease
并找到相应的应对方法 and how about how to treat them
这同样也来自艾莫利大学的研究 It's really coming from work here at Emory as well
世界非人类灵长类转基因之父 Anthony Chan is the father of
安东尼·陈 the world's first transgenic non-human primates
他的第一例研究是 He published his first studies
关于亨廷顿舞蹈症的 刚刚发表 in Huntington's disease
我们与安东尼合作 not too long ago, and working with Anthony
将老年痴呆症的突变引入了研究中 we've been able to introduce Alzheimer's disease mutations
拉瑞·沃克 吉姆·拉 我 还有斯图尔特 Lary Walker, Jim Lah, myself, Stuart
一直想将老年痴呆症的突变带入灵长类研究 all been working to put Alzheimer's disease mutations into primates
安东尼成功地开发出了 and Anthony is the proud father of some Alzheimer's
一些基因组里带有基因型老年痴呆症的灵长类 some primates who have genetic forms of Alzheimer's disease
目前研究正在进行 in their genome now and ongoing studies
如果我们能更好的运用这类动物模型 We'll see if we can use animal models like this more wisely
就能在早期临床阶段实现药物控制 to help get different drugs into clinic earlier
我希望这次演讲 So, I hope I've given you
让大家对我们的现状有个大致的了解 an overview then of where we are
包括艾莫利大学正在进行的一些研究 including many of the things on going at Emory
我们一定能找到治疗的新方法 I certainly see a day where we have new tools available
我对此相当乐观 and I'm very optimistic
我们也一定能在症状出现前 we're gonna be able to predict Alzheimer's disease well
就预知老年痴呆症 before symptoms begin
同时 知道我们手上 and I'm also very encouraged
也许就有一些有效疗法 让我感到倍受鼓舞 that we have even some things on hand that might be effective
我们可以肯定的告诉病人 We certainly have things we can suggest the patients
不用太多痛苦 只要加强锻炼 健康饮食 that don't hurt like exercise, watch your diet
控制威胁心血管的因素 control your cardiovascular risk factors
进行一定的心智刺激训练 do mentally stimulating things
运用这些我们知道的方法 and using these approaches we know
就算只能达到一半疗效 也是不错的 that even if we can have a partial success
如果我们能制定相应的策略 if we have strategies that could have
打造一些治疗计划 If we could begin a some treatment regimens
并能成功将老年痴呆症的发病推迟五年 that had ability to delay the onset of Alzheimer's disease five years
如图所示 将对老年痴呆症的发病率 This graph shows you that it would have a huge impact
产生极大的影响 on the occurrence of Alzheimer's disease
这张图中红色的部分代表的是 So, showing for example in red in this graph is
将受疾病影响的人数 以百万人计 the number of millions of people that would be affected
这个数字将从8百万人降至4百万人 would go down from about 8 to about 4 million individuals
如果我们能将发病时间推迟五年 if we could delay the disease onset for 5 years
就是这个结果能对公共卫生 so that the public health impact
有着非常可观的影响 is gonna be huge
时间原因我就不深讲了 I think I'm going to stop there for the sake of time
我希望大家能鼓励自己的国会议员 I just want to encourage all of you to talk to your Congressman
对相关研究提供更多资金支持 Raise money for researches
因为目前是一个非常重要的时间 because this is really important in time
我们有许多可以实现的期待 We have a lot of promise
我们还有许多研究要继续 We have a lot things going on
却因为资金问题碰到了瓶颈 and really the bottleneck in all of it is research money
为了让大家更明了 and just to put things in perspective
我要提醒大家 I want to remind you
目前就我们在老年痴呆症的研究 that we currently have it about 600 million dollars of research
从全国卫生研究院得到了60亿资金 from the NIH for Alzheimer's disease
等你向代表们提出 So remember to compare these figures
为全国卫生研究院筹资的时候 when you talk to your representatives
请对比一下这个数据 about raising money for the NIH
我们都知道最近的大规模救市的事儿 So we all know there's been a huge bail-out
救市费用跟投在老年痴呆症上的 which is well more than the money
费用相比 是有非常大的出入的 that goes to Alzheimer's disease research
刚刚也提到了 We've spent, I told you
我们对晚期老年痴呆症患者的护理 about a 150 billion dollars
就需要1500亿 on care of patients with end-stage Alzheimer's disease
远远超过了60亿 versus a 600 million
在防御疾病的研究上 You know that's not very much dollar for dollar
和护理患者方面 that actually goes into research for prevention
花费是不能斤斤计较的 versus caring for people with the disease
仅在佐治亚州这里就有一大笔开销 There are a lot of that there's a huge expenses in Georgia alone
有一些好人 Some wonderful members
我的朋友约翰·特罗杨瑙斯基不无困难地算出 My friend John Trojanowski has drudged up
我们在抗衰老化妆品的研究上一年 We spend 53 billion dollars
就需要530亿元 a year on anti-aging balms
研究所涉及的东西 and related the things
没有任何科学确凿的有效证据 that has no other shred of scientific evidence
但他们自己说有用 that they said they work
我们在性生活援助上每年花50亿元 We spend 5 billion dollars a year on sexual aids
在爆玉米花上头一年花20亿元 We spend 2 billion dollars a year on popcorn
我觉得尤其不可思议 that's my favorite
法国人在这上面 and the French even spend more per person
比我们的人均开销多得多 than we do here in America
我们面前还有许多世界性的挑战 So we have, we have a great challenge ahead of us worldwide
因此我们和在座各位都还要付出巨大的努力 So there's a lot we can do and there's a lot you can do
谢谢各位 So, thank for your attention
大家可以随意提问 维克多 Happy to answer any questions, Victor
听众:在(听不清)之前 Audience: So the insights to take before (INADUBILE)
能够加强心血管健康 of cardiovascular health can enhance
也许是我过于乐观 but I was so optimistically
我不能理解消除淀粉样肽 I don't understand the mechanistic relationship
和心血管健康之间的 between try to eliminate within the amyloids peptide
机械关系 and cardiovascular health
还有一点我不能理解 and then I was struck by the fact that
人们所用的药物 you know the drugs that people I used into
也能改善心血管健康么 trying to prevent the disease have included cardiovascular
艾伦:心血管健康 Allan: Cardiovascular health?
这个问题很好 Well it's a good question
简单而言 我们不理解 The short answer is we really don't understand
跟风险有关的具体的细胞机理 the precise cellular mechanisms that linked the risks
许多可能性正在研究中 There are a lots of possibilities that are being explored
这个过程中 各种关系的大量证据 and there's a lot of pieces of evidence
得到了发现 from many links along the way
胆酰酯酶是一个很明显的关系 Cholesterol is one obvious link
它在神经元细胞中的地位非常重要 Cholesterol plays a key role in neural cells
如果调控神经中胆酰酯酶的数量 and when one modulates the amount of cholesterol in a neuron
也就调控了淀粉样前蛋白的 you actually modulate the processing and trafficking
产生和运输 of the amyloid precursor protein itself
例如他汀类药物 Statins for example
一个效用就是降低胆碱酯酶的含量 one benefit of lowering cholesterol
增加心血管健康 for cardiovascular health
也可能降低了 You also might be lowering
脑细胞中淀粉质的产生 the amount of amyloid that gets made in brain cells
其他研究表面 他汀类药物也对 Statins also seem to have an effect on seen on some studies
β-基质分泌酶分解APP有着影响 and actual beta-secretase enzyme that actually cleaves the APP
因此还存在其他关联 So there may be other links
也存在其他种类的细胞机能 and other variety of other cellular mechanism
现在全球都正在进行研究 at play on a more sort of a global level
血液循环这方面有许多值得探索的地方 There are all sorts interesting things about blood flow
刚开始 人们以为老年痴呆症 initially, Alzheimer's disease was thought to be
血液循环疾病 a disease of blood flow
于是有许多治疗方法 and there were all sorts of treatment approaches
都旨在增加血流量 that were aimed in increasing blood flow
我们知道 We still know that
如果我们从大脑的新陈代谢方面来看 some of the earliest changes in the brain from peptides
那么脑内肽的一些早期变化 if you look at cerebral metabolism
明显是跟血液循环的早期异常有关系的 that clearly are abnormalities in blood flow
但是这一发现的基础原理并不被人们理解 that occur early and really the basis for that is not yet understood
甚至有人证明了 淀粉样前蛋白 There are people that have shown that amyloid precursor protein
和淀粉质是由心脏产生的 and amyloid actually even occur on the heart
因此有人从完全不同的角度研究老年痴呆症 Some people studying cardio
他们关注的是心脏的问题 the certainly opposite end of the spectrum as Alzheimer's disease
将心血管健康与之联系起来 linked to cardiovascular health
这方面又有许多不同的联系 So there are interesting links at that level as well
听众:所以如果已经患病 Audience: And so once you have Alzheimer's
再用他汀类药物治疗就太迟了是么 it's too late to use a Statins in treating the disorder
艾伦:你问的这个问题 Allan: You asked it
非常值得思考 It was a good question
它大概是最终答案吧 大部分试验 and it's probably the final answer, most of the trial
有些以他汀类药物为基础的 there been a couple trials now with statins
人类老年痴呆症实验 in people with Alzheimer's disease
结果并不尽如人意 and they haven't been positive
还有些在进行过程中 Others are ongoing
我之前也提到了 Yes I showed you
在轻微认知障碍的早期 In mild cognitive impairment stages
病理表现基本就成熟了 the pathology is pretty much there
也许已经完全成熟了 maybe even full blown
因此 我们成功的 So, we think really to be our greatest chance
最大机会就在于 of demonstrating a success is gonna be
更早阶段开始临床实验 the earlier we can start clinical trials
开始得更早 成功的机会就越大 By farther greater likelihood, we'll gonna have success
尽管目前老年痴呆症病人的研究结果 So, the trials have been negative
都是不令人满意的 for patients with Alzheimer's disease so far
但是放弃这个研究方向 and that could be too early
还言之尚早 just to throw out the approaches more globally
郝文和马伦 你们说呢 Herwin and Mahlon
听众:艾伦 帕金森综合症 Audience: Allan, the common
和老年痴呆症之间的 on the relationship between
联系和共同点 the link of Parkinson's disease to Alzheimer's disease
更准确的说让我们 and more specifically as this led to a serious
更深入思考相同点等等 about the common and the others
艾伦:是的 这个问题也是 Allan: Yeah. Well that question is
我最近的重点关注之一 one of my pet passions lately
研究老年痴呆症和帕金森综合症的联系 It's the link between Alzheimer's and Parkinson's
这项工作非常鼓舞人心 and it's been a passion
因为有许多世界级的帕金森综合症专家 because we have the Parkinson's experts of the world
像马伦及在座各位一样 with Mahlon and the rest of the group here
我们原本以为这是完全不同的两种病 You know we classically think about these are very different diseases
事实上 患有帕金森综合症的人 In fact, the sort of patients with Parkinson's disease
或多或少都表现出老年痴呆症的病理 if you look at them, they more or less have Alzheimer's pathology
可能比想象的还要多 probably more
流行病学研究指出 Now, I think that the epidemiologic study suggest
70%到80%的帕金森病人 maybe 70 to 80% of patients with Parkinson's disease
会在患病之后的7到8年发展为失智症 will develop dementia in over a 7 to 8-year period
反过来看 From the other side, Alzheimer's disease
三分之一或更多的老年痴呆症患者 about a third or more patients with Alzheimer's disease
会发展出帕金森综合症 从病理学上来讲 actually developed Parkinson's disease and pathologically
帕金森患者脑中 they have some nucleins
有一些蛋白核 是这种疾病的 the pathological hallmark of Parkinson's disease
标记性病理特征 present in their brains
我们对这两类不同的疾病 We've become very interested in the possibility
非常感兴趣 that these various spectrums of disorder
我们都知道 以前这些 and we've all known that they are patients
患有两种疾病的人 that actually have both very clearly
我们称之为体液型失智症 that we call dementia with fluid bodies
我们不知道是这两种病 It's been unclear whether that's just people with both
还是说是另一种病的不同表现 or sort of another aspect of a different disease
与之相关 that might be related
我们尝试从遗传学的角度来研究 We've asked this from a genetic point of view
结果发现我们收诊的 it turns out that about a third of individuals
三分之一病人 that just come to clinic
都有老年痴呆症的家族病史 will have a family history of Alzheimer's disease
而在接受检查的帕金森病人中 and a little bit less about 25% of patients
只有不到25%的人 that come to clinic with Parkinson's disease
有这方面的家族病史 will have a family history of Parkinson's disease. It turns out
根据我们的研究 at least from our study we've looked at about
基于韦斯利·伍兹研究所 I think about a thousand of individuals
收诊的一千名研究个体 who came to the clinics at Wesley Woods
患有老年痴呆和帕金森症的患者 with Alzheimer's and Parkinson's
并追溯他们家族的病史 just look to their families
基本上患这两种疾病的人 It's in the same families, basically
都是家族遗传的问题 where you get Alzheimer's and Parkinson's
因此 这个问题似乎和基因遗传相关 So there seems to be a link genetically
在冰岛的研究发现 we are able to look at this in Iceland and find that
还存在染色体的问题 there is a chromosomal association
LOD值超过4 A LOD score of over four
那些老年痴呆症和帕金森综合症的家族 If we look at families with Alzheimer's and Parkinson's
都有相同的显型 that has a same phenotype
这就对共享的一种基因易感性 So we actually have genetic evidence
提供了遗传学上的证据 that there's a share genetic susceptibility as well
因此我们正在进一步研究 So for sure we are now doing some more
寻找更多遗传的联系 refined genetic associations
如果我们能够发现 that he's trying to figure out, if we can, you know
这些联系的所在 where that lies
相似性在哪里 是什么 Where the commonality lies and what it is
它们只是同一个范畴的两个方面而已 So it might be that these are just two ends of the same spectrum
马伦:关于他汀类药物 Mahlon: Statins
一个学士研究是这样的 I met a BA study that
我们研究过成百上千的病人 I looked at patients, thousands of them
不论是用立普妥还是用辛戈他丁 Either on protocol for Lipitor or Zocor
用立普妥的效果并不大 So once on Lipitor again, you have no benefit
用辛戈他丁和他汀类来改变大脑 Those on Zocor and protocol to brain epinephrines statins
成效非常明显 其他研究也有印证 had remarkably done and those clearly associated studies
我每次(听不清) (INAUDIBLE) as soon as I bring myself every time
对我而言 那是最有用的数据 For me, that was the most relevant data
再把研究结果带入试验 and have this study to these trials
之后再看对肾上腺素的影响 and then looking at the effects really done to use brain epinephrine
因为这种情况很多 because there's a lot
我依然持怀疑态度 I mean, I'm just being skeptical
艾伦:或许我不该说 Allan: Yeah, I probably shouldn't answer
但是我由此想到 that account remember every time I have
戴夫 你想就此说两句吗？ Dave, do you wanna comment on that?
我的胆固醇高是医生的问题 We have, my doctor takes care of my high cholesterol
听众:一些神经学家 Audience: Because there are certain neurologist
致力于(听不清) that are taking care of (INAUDIBLE)
我也不记得最后的答案了 and I don't remember the answer to that
我和戴夫一样 I have the same with Dave
我想问的问题是 The question that I have is coming back around to that is
我有一些病人 很怕他汀类药物 I've got patients who were dropping statins like crazy
因为有报告称这会导致认知障碍 because of a report that it causes cognitive impairment
我认为在(听不清)之前 I think it was (INAUDIBLE) before did
他们因此无论好坏都要阻止我们 So now they're stopping us whether the protective benefits
我们认为 没错 We think, yeah
有解决认知问题的好方法了 there is this acute sort of acquiring cognitive function
但人们却害怕它的作用 that thing everybody afraid of
还需要一个漫长的过程 it's gonna be all long turning back
因此这个问题 我没有答案 So I have no answer to that question
我也在问自己 I'm also gonna ask myself
很明显我们有不同的 Obviously there are different sort of
(听不清)的方法 we guys gave a measure of those (INAUDIBLE)
我很想想知道 and somehow I differentiate
初期认知障碍和长期防御之间的利弊权衡 that the initial cognitive impairment versus long time of protection
教授:是的 那个发表了 Professor: Yeah, that website that's publicizing
他汀类药物和认知障碍关系的网站 the link with statins and cognitive impairment
是不可以出现在我的研究所的 is a bane in my existence in clinic
因为无法查证 所以对我们是很大的挑战 You know, it's really challenging because we don't see it
我不知道这些联系有没有科学证明 I don't know of any real scientific evidence if there's a link
因为从个体的感受性来看 You know, obviously, anecdotally, you know
是不可思议的 in individual susceptibility
你必须听病人的 不是么 You know you gotta listen to the patient right?
病人告诉用药后你出现了问题 Patients tell you they started and they're having a problem
尽管我们也可以推荐继续用药 You know we can recommend trying
但我最终还是没有继续 and that's what I just try stopping
但是在我有限的了解范围内 and see, but I really haven't ever seen any cases, you know
我确实没见过这样的案例 in my limited number
从神经病理学上看 that I've actually measured neuropsychologically
在停药前后 before and after stopping
从没发现他们的联系 never really seen any link, but you know
所以这一点应该是杜撰的 that's just totally anecdotal
马伦:(听不清)的联系 Mahlon: It's just that the link between (INAUDIBLE)
其他脑组织由维他命E得益 the other brain benefit issue is the vitamin E
因为它不是植入脑中 because it often approaches which is not getting in the brain
而是使大脑有所得益 and it's the gamma that is used to give brain benefits
因此大多数维他命E的研究 so all this study of vitamin E most of them
都变成了(听不清) have become (INAUDIBLE)
艾伦:我赞成 Allan: I agree
我还等着你 You know I was hoping you're gonna
来说维他命D的问题呢 马伦 ask your vitamin D questions, Mahlon
马伦:我等会再说这个问题 Mahlon: Well I'm saving it for a while
艾伦:好的 你有要补充的么 Allan: Okay. You want to ask your question?
上周 So just last week
最新的全基因组研究协会 the latest Genome Wide Association Study
宣布说 was reported
有关老年痴呆症和维他命D受体的研究 for Alzheimer's disease and vitamin D receptors
引起了很多专家学者的关注 seems to be at a hotspot
并成为治疗老年痴呆症的新方法 as a new possible susceptibility locus for Alzheimer's disease
等等一些类似的内容 studies like that
马伦:有些人可能不知道 Mahlon: For those of you who may have not know
在帕金森患者和老年痴呆患者中 Vitamin D deficiency seems to be a major finding
大多数人都缺乏维生素D in patients both with Parkinson's and Alzheimer's
而且他们的缺乏状况 Also with normal, but more so, definitely more so
和普通人相比也多得多 in the Parkinson's and the Alzheimer's
听众:难道(听不清) Audience: Do you not (INAUDIBLE)
马伦:几年的(听不清) Mahlon: Few years in (INAUDIBLE)
维生素E Vitamin E
太阳光照合成的维他命 Sunshine vitamin
但没有人服用 None of us taking
听众:(听不清)这一数据 Audience: (INAUDIBLE) this data
我们每个人都是这样 that's in all of us too
总是记得药用的可怕一面 that was the scary part of the incidence
我们总是看到健康的另一面 We thought of a different view over here exact the health of imaginary
正常人大概有60% We have over 60% of our normal
都存在维他命D不足的问题 that are by definition low in vitamin D
因此我也不知道有多少 So I don't have the association on how much
(听不清) you know, (INAUDIBLE)
大概5%到6%都趋于肥胖 that were to 5 to 6% of normal obese that are
马伦:我们的生活方式如此 Mahlon: You know our life style especially
除非常出去晒太阳 if we do not have many source of vitamin D
我们是没有其他维他命D来源的 unless we go out into the sun
饮食上(听不清) The dietary, you know, is (INAUDIBLE)
额外的工作则不适合(听不清) and supplements works truly inadequate that (INAUDIBLE)
我们面临很大的麻烦 so we're in deep trouble
而且很多人把它看做世界性的流行病 and you know people many people view this as a worldwide epidemic
没错 它标志了国家的(听不清) Certainly, it symbolized the nation's (INAUDIBLE)
还有生活方式的(听不清) and the lifestyle (INAUDIBLE)
维他命D并不是一种维他命 Vitamin D is not a vitamin
而是皮肤产生的一种类固醇激素 it's a steroid hormone made in the skin
无管怎样 那是另一个领域的问题了 Anyway, that's another call
研究的新希望 Promising line of study
艾伦:这是很让人期待的 Allan: It is very promising
观众:我想接着上面的问题 Audience: I have a question to that, this is a follow up on that
维他命D的缺乏和老年痴呆症的发病 How good is the correlation
这之间到底有多大的联系呢 between vitamin D deficiency and onset of Alzheimer
艾伦:这方面确实有些联系 Allan: There really is any correlation at this point
听众:我的问题和(听不清)数据有关 Audience: My question will have to do with (INAUDIBLE) figures
你提到美国的老年痴呆症 where you told that there are 5 million novel cases
大概有5百万新案例 of Alzheimer's diagnosed in the US
世界范围大概是两千六百万 I think you said something about 26 million worldwide
难道不是由更少的发病率得出的 which had to result from a much much smaller incidence
例如这个数据的四分之一 is that just, it's not a quarter?
艾伦:这个问题很好 Allan: Yeah, that's a good question
我确信这是分开研究的 I'm sure it is partly reporting
同样也有着不同的数据库 It's also very different data sets
估计的数量要大一些 The estimates are wider quite very
世界卫生组织做了一些世界范围的估计 World Health Organization has done some worldwide estimates
奇怪的是 哪怕在美国 You know, it's remarkable there hasn't really been a careful study
也没有一个非常严谨的研究指出精确的数值 even in this country what the real rates are
人们认为它应该成为 Some people are arguing that's a should be a real priority
公共卫生方案的首位工作 for Public Health Planning
听众:是的 Audience: Certainly
艾伦:所以我们也不知道 Allan: So we really don't know
人们只是 People are just…
听众:这是国与国之间的问题(听不清) Audience: It's country to country (INAUDIBLE)
艾伦:有一个小组做了一些跨国调研 Allan: There have been some studies across… by a group
但有一点很清楚 那就是没有人能逃得过去 and one of the things that's clear is it's nobody's spared
年岁增长是最重要的风险因素 Age is so, you know, so such a predominant risk factor
区别就是不同国家 that really it depends more on the longevity differences
人的预期寿命不尽相同 across different countries
这也解释了大部分的区别 that really is what explains most of the differences
观众:是的(听不清)有一个研究者 Audience: Yeah. (INAUDIBLE) Is there a researcher by
(听不清)年龄是如何影响的 (INAUDIBLE) how age is the factor
为什么人们不能变年轻 Why don't people get younger
我们可以由此研究 and from that can we learn something
什么是心智的活动 literally about the life of the mind
以及心智如何变老 How the mind aged, ages
记忆如何退化 and why is it that memory may be less
(听不清)和其他脑部疾病 (INAUDIBLE) and other kinds of mental functions
艾伦:是的 这个问题非常好 Allan: Yeah, that's a great question and you know
老年痴呆症 it's sort of been a holy grail of
和其他神经退行性疾病的各项研究中 much of the Alzheimer's disease
这一点就是各个研究所致力追求的最终目标 and that neurodegenerative disease research
这个概念就是 有选择性的脆弱性 This concept is selective vulnerability
为什么有些脑细胞退化了 有些却没有呢 Why there's certain brain cells degenerate and others don't?
这好像就是我们手头掌握着的 You know it seems like that will hold a major clue
解决这些疾病的关键 as to really what's causing the disease
几十年来它却依旧始终未能得到解决 and it's remained a mystery despite as, you know, decades
也有成百上千的研究者 And hundreds of thousands of researchers
想回答这个问题 trying to answer that question
为什么年龄本身是最大的风险因素？ You know why age itself is clearly the greatest risk factor also
同时 you know
它仍然是一个未解决的问题 It fundamentally remains an unanswered question
很多研究老龄化指出 Lots of theories from oxidative stress as a major theory of aging
氧化应激是主要的因素 that may link, you know
(听不清)基本上这个问题还没有答案 (INAUDIBLE) basically it's an unanswered
显而易见 and you know it think that obviously
如果能回答这个问题 我们所知就不止如此了 If we could answer that we would know a lot
感谢各位的支持和参与 Well thank you very much for your attention
谢谢大家 Thank you so much
本节目由艾莫利大学版权所有 The preceding program is copyrighted by Emory University