Nun Study of Aging and Alzheimer's Disease 流行病學研究 天主教若瑟醫院 何旭華 醫師

Beta-amyloid Plaques Beta-amyloid is produced under certain circumstances when the amyloid precursor protein (APP) extending through the brain cells is cut by other proteins into smaller sections.

Amyloid precursor protein (APP) is cut by Secretase into smaller sections. The most common isoforms are Aβ40 and Aβ42, but Aβ42 is the more fibrillogenic and is thus associated with disease states.

Beta-amyloid Peptide 42

Two large Phase 3 studies in mild AD patients with tarenflurbil (R flurbiprofen), a putative γ-secretase modulator, were also completely negative.

Further understanding of the reasons of the failures of these γ-secretase-based drugs in AD may be important for the future research on effective treatments for this devastating disease.

什麼是修女研究（Nun Study)? 一九八六年，斯諾登博士(David Snowdon, Ph.D)和一群住在明尼蘇達州的修女們開始進行修女研究（Nun Study）。 研究問題為：人在早年、中年及老年階段，增加阿茲海默症（老年癡呆症）及其他大腦疾病，例如，中風的變因為何？

研究對象 修女研究針對美國7個聖母學校修女會院之678位成員，研究老化與阿茲海默症的各種關聯，參與修女研究的成員年齡介於78-106歲之間，平均年紀為83歲，其中，超過85%的修女是教師。 她們同意研究者可以使用她們的醫療紀錄與修女會院中的自傳和其它檔案，並從研究開始後便每年接受一次心智與生理測驗，好讓研究者可以了解他們生理與認知功能變化的情形。 這些修女們也都同意在死後捐贈大腦。

大衛．斯諾登（David Snowdon）博士 美國明尼蘇達大學流行病學博士，1986年在明尼蘇達大學展開修女研究(University of Minn)。1990年他將修女研究搬到肯德基大學醫學中心(Kentucky Chandler Medical Center) 的「山德斯－布朗老化研究中心」(Sanders-Brown Center )，並在此擔任神經學教授。 身為全球頂尖的阿茲海默症專家之一，他曾在北美與歐洲各個科學會議中多次發表研究成果，並於重量級醫學期刊，如《美國醫學協會期刊》、《老年醫學期刊》等發表論文。

在修女院中的珍貴研究資料 The convent archives are particularly useful in the study of Alzheimer’s disease because they contain accurate risk factor data spanning the entire lifespan of the participants. Accurate information on early and mid-life risk factors is difficult or impossible to obtain in most other studies on Alzheimer’s disease because individuals with this memory disorder cannot accurately recall their history. The convent archives contain a wealth of information including baptismal records, birth certificates, socioeconomic characteristics of the family, education documentation, autobiographies written in early, mid, and late life, as well as residential, social, and occupational data describing their mid and late lives.

Why do the sisters participate in this study? Most sisters enrolled in the Nun Study because they believed their participation would help other women throughout the world. Many felt that they could continue teaching and helping others in their old age, and even after their death, by participating in this study. The bottom line is that these women are altruistic.

What are the research questions? The primary research question in the Nun Study is “What factors in early, mid, and late life increase the risk of Alzheimer’s disease and other brain diseases such as stroke?” Other research questions relate to the determinants of longevity and the quality of life in the elderly.

University of Kentucky

How is the study funded? The Nun Study is funded by the National Institute on Aging (one of the institutes within the National Institutes on Health). More than $2 million in federal tax dollars have been invested so far in this study. In addition, private foundations including the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation in San Antonio, Texas, have given significant financial support to this endeavor.

老年性癡呆症不是直截了當 Perhaps the single most important conclusion from the study is that Alzheimer disease is not straight forward. In several cases, pathology studies of brain tissue from the deceased nuns did not correlate with their performance on cognitive function tests. Sometimes the pathologist would score a brain as having signs of extremely advanced AD, only to learn later that the nun herself scored extremely well on all cognitive tests.

不一致的大腦病理變化 作者從解剖報告中發現，大腦的病理變化和真正臨床的失智表現似乎並不一致。 有些時候有的修女已經出現許多典型的阿茲海默症狀了，但解剖後卻找不到任何異常。 有些時候生前並未測出有心智功能退化的修女，她們的大腦中卻有著阿茲海默症的病理證據(斑塊與糾結)。

童年時的語言能力 修女們早年寫的自傳，是很好的來分析材料，從自傳中可以看出她們運用語言寫作的能力。 作者發現使用高概念密度(Idea Density) (情感表達豐富與文法較複雜)寫作的修女，她們在晚年時大腦被阿茲海默症所侵犯的機會很小，利用這個方法來預測她們晚年是否會失智，準確度高達八到九成。

語言技能 ( Idea Density ) Another finding from the Nun Study is that participants who had well developed language skills, as demonstrated by analysis of the autobiographies that they wrote as postulates, tended not to develop Alzheimer disease. Autobiographies that could be identified as original and unedited were analyzed for two characteristics: idea density and grammatical complexity. High idea density and to some extent, grammatical complexity, were associated with a decreased likelihood of developing AD . Idea density was measured by calculating the number of individual ideas expressed in ten words, and grammatical complexity was measured by rating sentences on a scale of 0 (simple clause) to 7 (complex sentences with embedded grammatical structures and subordination). By the time the researchers finished the analysis, they were able to predict with 80% accuracy from essays written in a woman’s early twenties whether or not she would develop Alzheimer disease at age 80.

Idea density (語言技能 ) Idea density was defined as the average number of ideas expressed per ten words for the last ten sentences of each autobiography. Ideas corresponded to elementary propositions, typically a verb, adjective, adverb, or prepositional phrase. The following sentence from an autobiography illustrates the method used to compute idea density: "I was born in Eau Claire, Wis., on May 24, 1913 and was baptized in St. James Church." The ideas (propositions) expressed in this sentence were (1) I was born, (2) born in Eau Claire, Wis., (3) born on May 24, 1913, (4) I was baptized, (5) was baptized in church, (6) was baptized in St. James Church, and (7) I was born...and was baptized. There were 18 words or utterances in that sentence. The idea density for that sentence was 3.9 (i.e., 7 ideas divided by 18 words and multiplied by 10, resulting in 3.9 ideas per 10 words).

Here's an example of a sentence packed with ideas, from the one of the sister's diaries: "It was about a half hour before midnight between February 28 and 29 of the leap year 1912 when I began to live, and to die, as the third child of my mother, whose maiden name is Hilda Hoffman, and my father, Otto Schmidt..." And here's an example of less idea-rich sentence: "I was born in Eau Claire, Wisconsin on May 24, 1913, and was baptized in St. James Church..."

findings from the Nun Study Early life linguistic ability, late life cognitive function, and neuropathology: findings from the Nun Study Riley KP1, Snowdon DA, Desrosiers MF, Markesbery WR Early-life idea density was significantly related to the categories of late-life cognitive function, including mild cognitive impairments: low idea density was associated with greater impairment. Neurobiol Aging 2005 Mar;26(3):341-7.

生理疾病因素影響失智症？ 修女研究的結果顯示，雖然血管性失智症相對較少，但當一個人的大腦已經有相當數量的阿茲海默症損傷時，小中風就會成為啟動失智症裝的開關，而不曾中風的大腦有足夠的能力去彌補修復阿茲海默症損傷，來抑制臨床失智症狀的出現。

生理疾病因素如何影響失智症？ 高血壓可能會導致中風與心臟病，而這中風又可能引發血管型失智，當中風或心臟無法供應足夠的血流到腦部時，腦部會貧血缺氧，因而造成損傷，使神經細胞死亡並讓大腦開始發炎，讓損傷加劇，而血管型失智又常和阿茲海默症引發的失智互相糾纏，讓失智症變得更加棘手。

生命早期慢性憂鬱症 The study did provide a hint that people suffering from chronic depression early in life tended to be more likely to show outward signs of AD, even though the actual damage to the brain was minimal , and clinicians recognize today that treating depression in AD patients can improve their function. So, there does appear to be a correlation between depression and developing outward symptoms of AD; however, the mechanism behind this relationship is not understood.

修女研究於一九九一年收到第一個捐贈者的大腦，是一位89歲且神智清楚的Nicolette修女。 這群研究對象中，有的人患有阿茲海默症，有的在極高歲數時頭腦還是相當清楚。研究發現，基因是阿茲海默症的一個重要因素外，生活方式（尤其兒時）也有很大關聯性。 修女研究利用大腦解剖報告與血液樣本比對，也同樣發現血液中的葉酸濃度越高，大腦萎縮的比例就越低。

「修女研究」對失智症的貢獻： 修女在二十多歲時所寫的自傳內容概念密度(idea density )較高者，到了老年時的認知功能較佳，罹患阿茲海默症的機率也較低。 2. 小中風可誘發或加重阿茲海默症的症狀。 3. 100歲的蘿絲修女生前沒有失智症狀，死後的大腦解剖也沒有阿茲海默症或中風的病理變化，可見阿茲海默症不是老年的必然現象。 4. 大腦解剖呈現中到重度阿茲海默症病理變化的68位修女中，1/5在生前並無失智，表示受教育或多動腦可增加腦力存款，使阿茲海默症不發病。 5. 大腦解剖呈現中到重度阿茲海默症病理變化的68位修女中，1/5在生前並無失智，除表示受教育或多動腦可增加腦力存款，固定的生活方式、每天持續有認知與體能的活動、生活在熟悉的環境、與熟悉的人物維持互動、外界刺激因子減少(情緒可穩定)、疾病感染源受控制、飲食清淡、有靈性與知性的生活等，是阿茲海默症不發病的重要因素。

Mysteries of Alzheimer disease Why do some people develop symptoms and not others? Why do some people with advanced brain damage: plaques, tangles and tissue loss, not show any symptoms, while others with minimal brain damage show symptoms of advanced AD?

What happens first in the onset of AD The appearance of plaques, the appearance of tangles? Or is there some other, more subtle, event that triggers the pathology?

Aging with Grace: What the Nun Study Teaches Us about Leading Longer, Healthier, and More Meaningful Lives Book 修女研究的宗旨是希望可以找到預防輕微認知損傷轉變成阿茲海默症的方法，許多科學的方法，像是更精密的儀器、更完善的研究設計，都有助於人類探索這個還有很多未知事物的領域；然而在作者的親身觀察中，發現還有許多沒有辦法用科學解釋的東西，像是修女們的信仰和靈性。 A prescription for hope, Aging with Grace shows that old age doesn’t have to mean an inevitable slide into illness and disability; rather it can be a time of promise and productivity, intellectual and spiritual vigor—a time of true grace.

修女研究 修女研究要問的是，為什麼有些修女能夠如此優雅地老去，持續教書與服事，一直到八十歲、九十歲，甚至超過一百歲，都還維持著完好的心智功能？ 為什麼其他一直都過著如此相似生活的修女，卻似乎會失去自我，忘記自己最親近的朋友、親人，到最後甚至跟身邊的世界完全失去聯繫？

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A wealth of practical findings: Why building linguistic ability in childhood may protect against Alzheimer’s. Which ordinary foods promote longevity and healthy brain function. Why preventing strokes and depression is key to avoiding Alzheimer’s. What role heredity plays, and why it’s never too late to start an exercise program . How attitude, faith, and community can add years to our lives. Aging with Grace

成功老化和長壽的秘訣： 為什麼童年時建立語言能力能預防阿茲海默症？ 哪些常見食物有助於長壽與大腦的功能？ 為何預防中風和憂鬱症是避免阿茲海默症的關鍵？ 遺傳扮演了什麼角色？為什麼規律運動永不嫌遲？ 態度、信仰及社群如何能延年益壽？

來自各界讀後心得 「這本動人的書記錄了聖母學校修女會的修女們如何奉獻自己，幫助我們找出阿茲海默症的病因，其中有值得我們所有人學習的事物。讀完本書，我對信仰的力量，以及人類大腦的美麗與複雜都生出新的敬意。」 ──薇吉妮亞．貝爾（Virginia M. Bell），社工學碩士，《The Best Friend’s Approach to Alzheimer’s Care》作者 「斯諾登博士帶領我們經歷他與聖母學校修女會的修女們一起走過這趟充滿迷人的科學發現，卻又非常私密的旅程。這一路上的發現顯示我們其實可以採取許多行動，來改善自己老化的過程，最終能決定自己的壽命。這是一趟萬萬不可錯過的旅程。」 ──湯瑪斯．波爾（Thomas Perls），醫學博士，哈佛醫學院 「一個美麗的故事。看到這些修女奉獻自己的生命，幫助他人盡可能長久地享受生命的恩賜，病人家屬一定能從中找到希望與支持。」 ──西格蒙．湯卡斯基（Sigmund Tomkalsk），阿茲海默症協會威斯康辛東南分會執行主任