鲁白：追忆阿尔兹海默博士——回顾阿尔茨海默症的发现点  撰文 | 鲁白（知识分子主编，清华大学医学院教授）

责编 | 艾维

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想象一下，一位研究阿尔茨海默症的科学家，用当年阿罗伊斯•阿尔茨海默（Alois Alzheimer）博士的显微镜，来观察世界上第一位阿尔茨海默症病人的脑切片，是多么令人兴奋的事情。我正是怀着这份激动与喜悦，参观了一百多年前发现老年痴呆症的阿尔茨海默博士的故乡。

2012年6月24日，2012神经生长因子（NGF）会议结束以后，组织者迈克尔（Michael Sendtner）带我们去了马克特布海特。那是一座位于维尔兹堡南部的小镇，阿尔茨海默正是在那儿诞生的。这里属于德国南方的乡村，此起彼伏的山脉上铺摆着绿油油的农田，草木茂盛，放眼望去，一片碧绿，令人想起了荷兰画派风景画所展示的悠闲。雨后的空气是如此的清新，郁郁葱葱的大地与碧蓝的天空交相辉映，呈现出了安逸宁静的氛围，而就在这份宁静安逸之下，创造出了许多能载入历史的名人轶事。　

迈克尔是维尔兹堡大学（Universität Würzburg）的一位非常有造诣的神经生物学家和精神病医师，也是一位具有  文艺复兴  精神气质的科学家，精通艺术、音乐和历史。从他那儿，我了解到了许多科学历史和维尔兹堡大学的文化。维尔兹堡大学是德国历史最悠久的大学（大约在500年之前建校）。19世纪时，这里聚集了许多著名的科学家，形成了一个浓郁的学术氛围，有不少流芳百世的发现。比如说由于1848年那场革命的缘故，鲁道夫•微尔啸（Rudolf Virchow）被迫离开柏林，来到了维尔兹堡。他与也在柏林的泰奥多尔•施旺（Theodor Schwann）曾围绕神经系统的细胞是起源于流体还是干细胞的问题上，展开过激烈的争论，这一争论导致了神经细胞和胶质细胞的发现及神经系统的现代观。雪旺也因此发现了一种包裹周围神经的胶质细胞后称为施旺氏细胞；而微尔啸则提出了细胞病理学说现已成为了现代细胞生物学的基础。还有阿尔伯特•科立克（Albert Koelliker），他是一位痴迷于显微镜技术的解剖学家，这种兴趣使得他与卡尔•蔡司（Carl Zeiss）成为了好朋友，而如今，蔡司已经成为了显微镜的代名词。科立克同样也是汉斯•斯佩曼（Hans Speemann）的老师和朋友，而斯佩曼后来成为了发育生物学的一位教父般人物。通过在维尔兹堡大学对海胆的研究，西奥多•博韦里（Theodor Boveri）证实了染色体载有遗传物质，重新点燃了人们对孟德尔遗传定律的激情。或许，与阿尔茨海默最有关联的要数弗朗茨•尼氏（Franz Nissl）了，他发明的用苯胺染料对脑切片染色的方法(尼氏染色法) 沿用至今。具有讽刺意味的是，从维尔兹堡附近移居美国加州的李维•斯特劳斯（Levi Strauss），用同样类型的苯胺染料，制造出世界上第一条蓝色Levi’s牛仔裤。谁的发明更有名（有用）呢？

就是在这样一种浓重的学术氛围中，阿尔茨海默开始学医，后来成为了一名精神病医师和神经病理学家。在维尔兹堡大学学习期间，科立克教授通过显微镜的镜头将他引入到了一个神秘而迷人的世界。尼氏对他的影响也很大，他教授阿尔茨海默染色的技巧，最终他们成为了好朋友，并且一起合作了7年之久。阿尔茨海默的许多有关脑病理的难题都是用尼氏的银染色法解决的。除了这些人以外，曾经在那里执教的科学大腕，例如施旺、博韦里，还有科立克的朋友圣地亚哥•拉蒙•卡哈尔（Santiago Ramóny Cajal，神经生物学的开山鼻祖）都或多或少地影响了阿尔茨海默的科学生涯。

1901年11月25日，是医学史上最重要的一天之一。在这一天，奥古斯特•迪特（Auguste Deter），一位51岁的老妇人带着痴呆的表情走进了法兰克福医院，接受了阿尔茨海默的诊治。阿尔茨海默详细地记录了对她的第一次问诊，还给她拍了一张照片，这张照片后来也变成了神经病学中最著名的照片之一。而迪特也成为了第一个得到记载的老年痴呆症的病例。

通过对迪特的观察，阿尔茨海默发现，虽然她表现出理解能力下降、迷惑、偏执、幻听等症状，但她最主要的症状还是记忆力的逐渐衰退。1906年，迪特死后，阿尔茨海默用尼氏的染色方法对她的脑切片进行染色，再通过显微镜进行仔细观察。他发现了迪特脑切片有两个明显特征：小粟粒灶    后来被命名为淀粉样斑块，还有被着上很深颜色的神经原纤维    现在被称为为神经纤维缠结。这项发现后来被普鲁斯尼（Purusini）、克雷佩林（Emil Kraepelin）、费舍尔（Oskar Fischer）等人证实，1910年，克雷佩林教授将这种严重的老年痴呆症命名为  阿尔茨海默症  。

然而和科学史上诸多优秀的天才一样，在当时，阿尔茨海默所提出的这种新的大脑疾病并没有受到医学界的太大关注。1906年，在图宾根（Tuebingen）举行的一次科学会议中，阿尔茨海默首次报告了迪特的病历，还展示了漂亮的神经纤维缠结、淀粉样斑块和活性神经胶质细胞的样本。他原以为在讲述完迪特的病历之后，现场反响会很强烈，可令阿尔茨海默吃惊的是，现场竟然没有人提问。据一本名为《阿尔茨海默：一位医生的一生及其职业生涯》(《Alzheimer: The Life of a Physician & the Career of a Disease》) 的书中记载，当时的会议主席说道：  好吧，尊敬的阿尔茨海默同事，谢谢你的报告，很显然这个病例不需要进行讨论了  。显然，阿尔茨海默当时的发现是超前的，所以整个医学界根本没有意识到他的结果的重要性。

事实上，直到80年以后，这项重大的发现才得到应有的重视。而今天  阿尔茨海默  这个名字早已在医学界和科学界里如雷贯耳，在普通人甚至是政客当中也不会陌生。据估计，如果在2050年之前还没有对该病的治疗措施的话，那么世界人口的5%将会变成该病受害者，而所造成的财政负担会将经济推向崩溃。到2013年，美国国立卫生研究院对阿尔茨海默症的研究投资将达到有史以来的最高点：5.29亿美元。美国总统奥巴马甚至在2011年签署了阿尔茨海默症国家行动计划的法律文件。谁会想到100年以前，一名维尔兹堡的普通医生，会对当今人们的健康生活产生如此巨大的影响！

我们已经再也不能忽视阿尔茨海默症了。不过，要不是有一对夫妇锲而不舍的努力，我们也许不可能对阿尔茨海默博士以及他的科学贡献有深入了解。　

这就是法兰克福大学精神病系的主任康拉德•莫勒（Konrad Maurer）博士和他的太太乌尔丽克（Ulrike）。我很庆幸在参观阿罗伊斯•阿尔茨海默的故居博物馆时遇见了他们。1989年，Ochsenfurter大街15a号的户主以及全世界都得知了这里曾经是阿罗伊斯•阿尔茨海默的住处。这也触发了作为阿尔茨海默粉丝的莫勒博士的兴趣。在他的不懈努力下，终于说服了制药巨头美国礼来公司买下了这栋房子。经过妻子乌尔丽克的改造后，这栋房子变成了科学会议厅和阿尔茨海默博物馆。多年来，由阿尔茨海默博士亲自所写的有关迪特的病史诊断记录遍寻无果。莫勒展开了精疲力竭的搜寻，终于在1995年，一个偶然的机会，他们发现了全部的文件被错放在了精神病科的地下室里。退休以后，莫勒夫妇对阿尔茨海默从学术到生平的研究，变成了俩人的一个新事业。他们从阿尔茨海默的孙辈那儿收集了大量的文物、家具、照片、信件等。他们还说服了慕尼黑大学的梅哈艾因（Parviz Mehraein）教授贡献出了4片迪特的脑切片样本。他们甚至还找到了阿尔茨海默当年用过的显微镜！通过这个显微镜，参观者就可以用阿尔茨海默100年前相同的工具观察迪特女士的淀粉样斑块与神经纤维缠结了。

在我和莫勒博士的谈话中，我问他下一步打算做什么。他告诉我，他们已经确定了迪特的坟墓，并且得到了家属允许证，对她剩余的躯体进行DNA分析，再与他们现有的脑切片样品进行比对。这样就可以观察她的易感基因（如ApoE4、presenilin、Aβ、tau等等）是否有突变。  我兴奋地说：  现在的技术已经可以对迪特做全基因组测序了！是啊，用现代高科技，将重新点燃对这尘封了百年之久的病例的痴迷和好奇。那么阿尔茨海默和莫勒教授的痴迷追索，是否也会对我们今天对医学科学的探索有所启迪呢？

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英文版

Chasing the footsteps of Dr. Alzheimer – Discover how Alzheimer’s disease was discovered

Imaging what a pleasure it would be for a scientist studying Alzheimer disease to have a chance to touch the very microscope with which the Alzheimer’s disease was first discovered? This was exactly the thrill I experienced when I visited the birthplace of Dr. Alois Alzheimer, the person who discovered Alzheimer’s disease.

On June 24, 2012, after the NGF2012 meeting, the organizer Dr. Michael Sendtner took us to Marktbreit, a small town south of Würzburg where Alois Alzheimer was born. This is a beautiful southern Germany countryside, with farmland on wavy hills covered by thick grass, reminding me of Dutch landscape paintings.  The air was incredibly fresh after days of rain wash. The green carpet merged with blue sky, emanating a tranquility that stands the test of history.

Michael is an accomplished neurobiologist/psychiatrist from the Würzburg University, and a   Renaissance   scientist who is well versed in arts, music and history. From him I indulged a high dose of science history and culture of Würzburg Univ., one of the oldest universities (founded more than 500 years ago) in Germany. In the 19th century, many famous scientists gathered here, creating a rich intellectual environment for extraordinary discoveries. The 1848 revolution forced Rudolf Virchow to leave Berlin and come to Würzburg. The debate between Virchow and Theodor Schwann who also had worked in Berlin before 1848 on whether the nervous system is made of cells that are generated feely in fluid or cells that originate from stem cells has led to the discovery of neurons and glial cells and our modern view on the nervous system. Schwann went on to discover the cells that envelope the nerve fibers – now called Schwann cells, and Virchow formulated cell theory, which forms the foundation for modern cell biology. Albert Koelliker also came to Wuerzburg in 1847. He was an anatomist fascinated by microscopic techniques. It was not surprising that he and people trained by him like Ernst Haeckel became friends of Carl Zeiss, whose name is the synonym for microscope today. Through his study of sea urchins at Würzburg, Theodor Boveri demonstrated that chromosomes carry heredity materials, thus connecting Mendel’s law to cell biology. He was also a teacher and friend of Hans Spemann, who later became a paramount figure in developmental biology. Perhaps the most relevant was Franz Nissl, who developed a method of staining brain sections using aniline dye, which is still used today. Ironically, the same type of aniline dye was used by Levi Strauss, who moved from a place not far from Wuerzburg to America and invented the blue jeans.

It was in such a rich intellectual environment that Alois Alzheimer was trained first as a medical student and then as a psychiatrist and neuropathologist. During his doctoral thesis at Würzburg Univ., Prof. Albert Koelliker introduced him to the mysterious but fascinating world through the lens of a microscope. He was also heavily influenced by Franz Nissl, who apparently taught him the staining techniques. They became close friends and collaborated for seven years. Much of Alzheimer’s work on brain pathology made use of Nissl's silver staining method. It is not difficult to imagine that other scientific giants such as Schwann, Boveri, and even Santiago Ramón y Cajal, who as a friend of Koelliker may have an impact on Alzheimer’s scientific career.

Nov. 25, 1901 may turn out to be one of the most important days for the history of medicine! On that day, Auguste D. a 51-year old lady with signs of dementia walked in the Frankfurt Hospital, where she was examined by Dr. Alois Alzheimer. He took detailed notes on the first interview of her, and perhaps even took a picture of her, which became one of the most famous pictures of a patient today. This is what we know the very first case of Alzheimer’s disease. Through his care of Auguste, Alzheimer noticed that although she exhibited reduced comprehension, disorientation, paranoia, and auditory hallucinations, her main symptom was the progressive decline of memory. After her death in 1906, Dr. Alzheimer performed detailed microscopic study of Mrs. Auguste D’s postmortem brain sections using Nissl staining method. This study revealed two distinctive features of Auguste’s brain: small miliary foci which were later known as amyloid plaques, and "deeply stained bundles of neurofibrils" that are now called neuritic tangles. This discovery was confirmed by Purusini, Kraepelin, Fischer, etc. In subsequent years, and Kraepelin named this serious senile dementia "Alzheimer’s disease" in 1910.

Like many geniuses in the history of science, the description of a new brain disease by Alzheimer did not receive much attention by the medical community at the time. In 1906, Alzheimer presented the case of Auguste D. for the first time, with beautiful slides showing neurofibrillary tangles, plaques and activated glia, at a scientific meeting in Tübingen. Expecting lively discussions after his lecture, Dr. Alzheimer was surprised that there were no questions. According to the book   Alzheimer: The Life of a Physician & the Career of a Disease  , the chairman of the conference remarked:   So then, respected colleague Alzheimer, I thank you for your remarks. Clearly there is no desire for discussion.   And clearly, Alzheimer was way ahead of his time, and the medical community did not recognize the importance of his results.  Indeed, the significance of the discovery was not appreciated until 80 years later! Today, the name   Alzheimer   rings thunders not just to medical and scientific community, but to ordinary people and even politicians as well. It is estimated that 5% of the total population will suffer from the disease, if there were not treatment by the year 2050. The investment in research on Alzheimer’s disease by the US National Institutes of Health will reach an all time high of $529 million by 2013. Even the US President Barack Obama signed the National Alzheimer’s Disease Project Act (NAPA) into law in 2011. Who would have thought an ordinary doctor of Würzburg more than 100 years ago would make an impact this big on human health today!

While we can no longer ignore   Alzheimer   as a disease, we would not have known much about Dr. Alzheimer and his scientific contributions, should there not be the relentless effort of a single man, Dr. Konrad Maurer, director of psychiatry department at Frankfurt University, together with his wife, Ulrike. I consider myself fortunate to have the opportunity to get to know this couple during my visit to Alois Alzheimer’s birth house, now. In 1989, the owner of Ochsenfurter Strasse 15a, as well as the world, became aware that this was the birth place of Alois Alzheimer. This triggered the interest of Dr. Maurer, who was a fan of Alois Alzheimer. After tireless effort, Maurer persuaded the Pharmaceutical giant Eli Lilly to purchase the house. Through the hands of Ulrike, the house was transformed into a conference place and an Alzheimer museum. For many years, the medical record of Auguste, with hand-written notes by Dr. Alzheimer, was nowhere to be found. Maurer launched an exhaustive search, and in 1995, they found by accident that the whole file was misplaced in the basement of the department. The Maurers have turned their interest in the work and life of Alzheimer into a new career after their retirement. They collected numerous artifacts, furniture, photographs, letters, etc. from the grandchildren of Alois Alzheimer. They convinced Prof. Mehraein of Munich Univ. to hand over 4 slides of Auguste D’s brain sections. They even managed to find Alzheimer’s original microscope. With that, visitors could look at the plaques and tangles of Mrs. Auguste the same way as what Alzheimer did 100 years ago!

During my conversation with Dr. Maurer, I asked him what’s next for him. He told me that they have now located the burial place of Auguste D, and got the consent to do some DNA analysis of her remains, in comparison with the brain samples they have.   You can look to see if she had mutations in some of the susceptibility genes such as ApoE4, presenilin, and also Aβ, tau, etc.   I got excited.   The current technologies may even allow you to do whole genome sequencing  . I can see that these topics ignite new excitements in a 100-year old case