Ginkgo biloba for Prevention of Dementia: A Randomized Controlled Trial

1. Ginkgo biloba for Prevention of Dementia: A RandomizedControlled Trial JAMA. 2008 November 19; 300(19): 2253–2262. doi:10.1001/jama.2008.683. 張秋密營養師 99.8.22

2. 銀杏果與銀杏葉的效果大不同 • 在東方，銀杏自古就被中醫視為止咳平喘的良藥，不過這種銀杏採用的是「銀杏果」的部位，真正發現「銀杏葉」的醫療功效，則是在歐洲。 • 拜天然藥草萃取技術發達所賜，歐洲的植物研究專家發現，從「銀杏葉」中萃取的有效物質，具有重大的醫療功效─改善末梢血液循環障礙。 提醒一般民眾，目前在台灣銀杏葉製劑屬於藥品，消費者必須在藥局才能購買到，一般被列為食品的銀杏產品，專業認定並無療效。

3. The prevention of disabling chronic diseases in elderly individuals is a major clinical and public health goal. • Dementia, especially Alzheimer disease (AD), is a prevalent chronicdisease currently affecting more than 5 million people in the United Statescause of age-related disability and long-term care placement. • The herbal product Ginkgobiloba is prescribed in some areas of the world for preservation of memory; however, there are no medications approved for primary prevention of dementia. • In the United States,worldwide sales of G biloba exceed $249 million annually.

4. Oxidative stress may accelerate the cascade of AD pathological changes that can lead to dementia and cerebrovascular disease. • A major mechanism by which G biloba is proposed to exert its effect is by action of multiple antioxidants. • More recently, an in vitro study indicated that ginkgo extract has an anti-amyloid aggregation effect, suggesting another mechanism whereby G biloba may be beneficial in dementia prevention

5. Clinical trials of efficacy of G biloba have focused primarily on patients with dementia. In1998, a meta-analysis of early trials reported a small benefit, but a Cochrane CollaborationReview in 2007 found that the evidence for benefit of G biloba on cognition in individuals with dementia was not convincing. • An intention-to-treat analysis from one trial involving individuals already diagnosed with AD showed a small positive effect size over 52 weeks but also experienced a dropout rate approaching 50%. • Several small, short-termrandomized trials have had mixed results.

6. Objective • To determine effectiveness of G biloba vs placebo in reducing the incidence of all cause dementia and Alzheimer disease (AD) in elderly individuals with normal cognition and those with mild cognitive impairment (MCI).

7. METHODS

8. Design, Setting, and Participants • Randomized, double-blind, placebo-controlled clinical trial conducted in 5 academic medical centers in the United States between 2000 and 2008 with a median follow-up of 6.1 years. • Three thousand sixty-nine community volunteers aged 75 years or older with normal cognition (n=2587) or MCI (n=482) at study entry were assessed every 6 months for incident dementia.

9. MCI的定義： • 一種持續性的記憶受損，跟相同教育程度與年齡相仿的人比較有記憶力的減退現象，但語言及注意力尚未受影響。 • 65歲以上的老年人約占10%盛行率。Mayo Clinic之 Petersen等人所設計的MCI診斷標準被廣泛運用。長期的追蹤研究顯示, MCI病患每年約有10%至15%轉變成失智症，遠超過正常對照組的1%到2%，因此MCI可視為退化成失智症的過渡期、或是其危險因素。另外有相關研究指出，APOE4的存在、某些特殊記憶功能障礙、腦部影像中海馬迴（hippocampus）的大小，或是扣帶回皮質層之低灌注影像(Huang 2002,2:9 BMC Neurology)都是相關的阿茲海默氏病預測因子。

10. MCI的症狀如下： • (1) 重覆欲回想至親好友的名字有困難。 • (2) 回憶談話內容的細節很吃力。 • (3) 時常忘記赴約會。 • (4) 重覆再重覆地說相同的笑話。 • (5) 常找不到東西所放置的位子，或找來找去，卻忘了自己在找什麼，但自己有警覺到此困擾。 • (6) 上街買東西，到了店裡卻忘記要買什麼。 • (7) 主觀自覺到記憶力變差，而會使用筆記本、日曆等協助記憶。 • (8) 社交活動能力及一般日常生活活動，如洗衣、購物、沐浴、嗜好、處理財務等仍完好，但執行較複雜、精細技巧之日常事務或計劃有困難。 • (9) 無法仔細回憶剛剛看過的節目或計劃表。 • (10) 說出日常生活常用物品之名字稍有困難。

11. Participants • Individuals with prevalent dementia (meeting Diagnostic and Statistical Manual of Mental • Disorders [Fourth Edition] [DSM-IV] criteria for dementia18 or a score >0.5 on the Clinical Dementia Rating scale19 [CDR]) were excluded from participation.

12. THE CLINICAL DEMENTIA RATING SCALE Score only as decline from previous usual level due to cogntive loss, not impairment due to other factors.Morris, J.C. (1993) The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology, 43, 2412-4.

13. 簡短智能評估已成為全球最廣泛使用之簡短認知功能量表，涵括個認知領域：時間、空間、訊息登錄、專注力與計算能力、記憶力、語言能力、視覺建構力。畫時鐘也是有效評估認知功能的工具，包括聽力理解、動作規劃、數字常識、特別是視覺空間及建構性方面的評估。簡短智能評估已成為全球最廣泛使用之簡短認知功能量表，涵括個認知領域：時間、空間、訊息登錄、專注力與計算能力、記憶力、語言能力、視覺建構力。畫時鐘也是有效評估認知功能的工具，包括聽力理解、動作規劃、數字常識、特別是視覺空間及建構性方面的評估。

14. excluded wereindividuals meeting any of the following criteria • currently taking the anticoagulant warfarin • taking cholinesterase inhibitors for cognitive problems or dementia (memantine had not been approved for use in the United States when the study began); (3)unwilling to discontinue taking over-the-counter G biloba for the duration of the study (4)currently being treated with tricyclic antidepressants, antipsychotics, or other medications with significant psychotropic or centralcholinergic effects (the anticholinergic effects of selective serotonin reuptake inhibitors were not believed to be substantial enough to warrant exclusion); (5) daily use of more than 400-IU vitamin E or unwillingness to reduce intake to this level (6) history of bleeding disorders (7) hospitalization for depression within the last year or electroconvulsive therapy within last 10 years

15. excluded wereindividuals meeting any of the following criteria (8) history of Parkinson disease or taking anti-Parkinson medications (9) abnormal thyroid tests, serum creatinine level greater than 2.0 mg/dL (to convert to μmol/L, multiply by 88.4), or liver function tests more than 2 times the upper limit of normal at baseline (10) baseline vitamin B12 levels 210 pg/mL or lower (to convert to pmol/L, multiply by 0.7378) (11) hematocrit level less than 30% (12)platelet count lower than 100 ×103/Μl (13) disease-related life expectancy of less than 5 years (14) known allergy to G biloba.

16. The recruitment procedures for the GEM Study have been described elsewhere. • Participants with mild cognitive impairment (MCI) werenot excluded. The criteria for classification of MCI at baseline in the GEM Study were based on guidelines set forth by the International Working Group on Mild Cognitive Impairment. • In brief, individuals defined as having baseline MCI met both of the following 2 criteria: (1) impaired at or below the 10th percentile of Cardiovascular Health Study normative data, stratified by age and education, on at least 2 of 10 selected neuropsychological test scores from each cognitive domain, including memory, language, visuospatial abilities, attention, and executive function; and (2) CDR global score of 0.5.

17. Study Intervention • Participants were randomized to twice-daily doses of either 120-mg G biloba extract (EGb761; Schwabe Pharmaceuticals, Karlsruhe, Germany) or an identically appearing placebo. • The formulation EGb 761 is used in many of the branded ginkgo products sold in the United States. • Selection of the specific formulation of G biloba to be used in the study was made following a separate NCCAM “Request for Product” for a company to provide G biloba product of consistent prespecified composition in blister pack format with equal amounts of identically packaged, identically appearing placebo tablets, sufficient to complete the study. • The 240-mg dose of EGb 761 was chosen based on information from prior clinical studies suggesting a dose-response relationship up to 240 mg Moreover, this dose is commonly used. • The composition of the placebo and active tablets was confirmed by independent laboratory analysis for each lot of tablets used during the trial (eTable 1;http://www.jama.com).

18. Treatment adherence and participant retention were a particular focus in this trial because of the age of the study population. • For treatment adherence monitoring, participants returned all blister packs at each 6-month visit, and adherence was calculated using the number of pills taken vs number of days since previous visit. • Additionally, an adherence and retention subcommittee led by a geriatrician met monthly to review and discuss challenges to adherence and retention with field center staff and to provide study-specific adherence and retention tracking data to each field center. • Annual site visits to all clinics and a midstudy retreat for field center staff focused extensively on strategies for participant adherence and retention specific to this age group.

19. Study Outcomes • Results from the full NPB and all clinical assessments were then reviewed by an expert panel blinded to treatment assignment. • The panel consisted of 2 neurologists with expertise in dementia diagnosis; 2 neuropsychologists experienced in cognitive assessment of dementia; and a psychometrician with extensive experience in training, administration, and scoring of the CDR. • Based on the test battery listed in the Box, participants were considered to have reached dementia outcome in the GEM Study if any of the following applied: 1. Incident abnormal scores were made on 5 or more tests, and at least 1 of the abnormal scores was on a memory test. 2. Incident abnormal scores were made on 4 tests, at least 1 of the abnormal scores was on a memory test, and the participant failed to complete 1 or more of the other neuropsychological tests. 3. Incident abnormality in 2 or more cognitive domains (participant scored below cutoff for age- and education-adjusted norms in both tests of that domain) and 1 of those domains was memory.

21. Participants classified as reaching dementia end point at this point were then referred for a full neurological evaluation and a magnetic resonance imaging (MRI) scan at the clinical site to confirm that the participant met clinical criteria for dementia and assess for atypical causes of dementia. 海馬迴大小

22. Sample Size • In the calculation of the sample size, it was assumed that in the placebo group, the rate of dementia would be 4%per year and that the combined mortality and dropoutrate would be 6% per year based on limited data from observational studies. • With the use of these estimates, the planned sample size of 3000 with an average follow-up of 5.0 years results in 96% power to detect a 30% reduction in the rate of dementia at a 2-sided significance level of .05. • Under these assumptions, the expected total number of dementia cases at the conclusion of the trial would be 439. • The sample size also provided adequate power (86%) to detect a 25% reduction in risk. • Because of the uncertainties of the estimate of the dementia rate, the study protocol contained a provision allowing the continuation of the study beyond 5 years until the total of 439 dementia cases occurred, if approved by the DSMB of the study and the funding agency.

23. Statistical Analyses • Analyses were conducted using an intention-to-treat approach. • The Cox proportional hazards model was used to compute hazard ratios (HRs) and log-rank tests • Testing for proportional hazards used Schoenfeld residuals. • The cumulative event curves were estimated by the product-limit (Kaplan-Meier) method. • t Tests for the continuous variables and χ2 tests for the discrete variables were used in the non–time-to-event analyses shown in the tables. • P<.05 was considered significant and all testing was 2-sided. • The few subgroup analyses were not adjusted for multiple comparisons. • Analyses were done using Stata version 10 (StataCorp, College Station, Texas).

24. Figure 1. Flow of Participants Through the Ginkgo Evaluation of Memory (GEM) Study PD indicates Parkinson disease.

25. enrollment period from September 2000 to June 2002 • Because of a lower-than-expected dementia rate early in the trial, study follow-up was extended in 2006. • After reaching the required number of dementia outcomes (n=439),participant closeout was initiated in October 2007 and completed in April 2008 • Median follow-up at closeout was 6.1 years (maximum, 7.3 years). • Although the dementia rate was extremely low during the first year (<1% in both treatment groups), the rate steadily increased over the remainder of the study follow-up.

26. 79.1y/o 46％

29. The 195 participants who declined to continue the study after randomization did not differ from the 2874 who remained in the study by age,sex, minority race/ethnicity, baseline disease categories (eg, myocardial infarction,stroke,heart failure, cancer), or smoking status. • However, a difference in MCI status at baseline was found with 22.6% of dropouts classified with this condition compared with 15.2% of those who completed the study (P=.01).

30. 60.3﹪ Figure 2. Cumulative Adherence to Assigned Study Tablets by Scheduled 6-Month Follow-up Visit (Excluding Death and Incident Dementia) Study visit No. 3 was the first 6-month follow-up visit after randomization.

31. Figure 3. Cumulative Dementia Rates by Treatment CI indicates confidence interval; HR, hazard ratio.

34. COMMENT • The results from the GEM Study did not show that G biloba is effective in preventing or delaying the onset of all-cause dementia in participants older than 75 years. • G biloba also had no effect on the risk for developing AD in this age group. • G biloba showed no benefit for reducing all-cause dementia or dementia of the Alzheimer type. • G biloba cannot be recommended for the purpose of preventing dementia.

35. 失智症的分類： 參考資料:失智症的臨床診斷流程 台中榮民總醫院  精神部 卓良珍 （一）原發性失智症（中樞神經瀰漫性的腦實質疾病）： （二）次發性失智症： 1.新陳代謝疾病：如黏液水腫、甲狀腺或副甲狀腺病，Wilsons病、肝病、血糖過低、血鈣過低、血鈉過低、血鈣過高、尿毒症、Cushings症候群、體液缺失、癌症的遠處效應、血液透析、成人異染性的白色素萎縮症、腦下垂體功能不足等。 2.心臟血管疾病：如動脈硬化症、心律不整、充血性心臟衰竭，血管栓塞性血管炎、主動脈弓症候群、全身性紅斑狼瘡（腦血管炎症反應）、大腦皮質下動脈性硬化腦病變、動靜脈畸形等。 3.缺氧或低氧：如貧血或缺血性的缺氧、無氧性缺氧、停滯性缺氧、組織細胞性缺氧（如低血糖、氰化物、酒精等物質干擾腦細胞的氧氣利用），慢性胸腔疾病所致的低氧或二氧化碳過高症等。 4.正常腦壓的水腦症：可由腦腫瘤、慢性腦膜炎、蜘蛛膜下腔出血、外傷等所引起。 5.營養失調症：如Wernicke-Korsakoffs症候群（酒癮等引起缺乏維他命B1），糙皮病（缺乏Niacin），吃素者的維他命12及Folate缺乏症（如胃癌、胃酸過低、胃切除後）等。 6.腦腫瘤：約有50—70％出現精神及行為的改變。有原發性與轉移來的次發性。 7.腦外傷：如開放性及封閉性的腦外傷，拳擊選手的敲碎症候群（Punch-Drunk syndrome），硬腦膜下出血、熱中暑（約10％生還者有癡呆症）等。 8.感染疾病：如腦膿瘍、細菌性腦膜炎、黴菌性腦膜炎、腦炎、亞急性硬化性的瀰漫性腦炎、進行性多發病灶性腦白質炎、庫魯症（Kuru），Behcets症候群（Virus所致），梅毒、肺結核、心內膜炎、Creutzfeldt-Jakob病等。 9.中毒及藥物：如一氧化碳中毒、有機物質、重金屬（如砷、汞、鉛），及其他藥物等的中毒。 10.憂鬱症：長期的憂愁煩惱、心力交瘁，對環境事物及活動缺乏興趣，而導致知覺及認知功能的減退。 11.感覺剝奪：如聾、盲所產生的認知功能減低，致使智力功能因少刺激反應，產生用盡廢退的失智症狀。     12.慢性疼痛：造成憂鬱症，再引發失智現象。 13.住院（麻醉、手術後）或環境改變、孤立等，造成憂鬱及感覺剝奪等。 14.其他：例如多發性硬化症、肌肉萎縮症、肉芽腫性脂肪消耗病、集中營症候群（因營養失調），成人青盲性白痴（adult amaurotic idiocy，及Kuf’s病），家族性的基底核蓋化症等。

36. 依照病症之分佈比率分成： 1. Alzheimers Disease約佔50—55％。 2.血管性失智症約佔20—25％。 3.混合型占10—15％。 4.其他則占10％左右，大多是有原因的，屬於次發型的癡呆症，且是較容易復原的。

37. 控制以上的身體疾病相當重要。 • 少吃鹽類、內臟食物、多喝開水，適度之運動 • 預防高血壓、心臟病、糖尿病、高血脂、少抽煙 • 血管性失智症患者之鑑別診斷，除了使用哈親氏缺血性量表分數高於7分以上之外，陣發性、起起伏伏之變化情緒或痴呆症狀，今天好兩天，後天又變得不好，早上好好的，下午、晚上又不好。尤其天氣悶熱、氣壓低、通風不良、耗氧量增加而氧氣缺乏之時，例如暴風雨之前、空氣不流通之時，特別容易煩躁、發脾氣及坐立不安等是血管型失智症的特殊表現。

38. 表二、退化性癡呆症與血管性失智症的區別 • 退化性失智症                   血管性失智症 • Alzheimer’s disease             Vascular  dementia • ＿＿＿＿＿＿＿＿＿＿＿     ＿＿＿＿＿＿＿＿＿＿＿ • （1）緩慢發作               （1）急性發作 • （2）女性 ＞ 男性           （2）男性 ＜ 女性 • （3）年齡較高               （3）年齡較輕 • （4）呈下坡線狀進行性的     （4）斷續性、下梯階狀頹退 • （5）無局部性神經缺陷症狀    （5）局部或偏側神經缺陷 • （6）無合併特殊疾病         （6）有糖尿病或高血壓心臟病 • （7）無假性延髓麻痺症狀    （7）時常有 • （8）表情冷漠平淡           （8）情緒起伏不定

39. 預防失智症的原則 （一）預防與控制身體及病的發生：       例如 高血壓、心臟病、糖尿病、肝腎疾病、巴金森氏 症等病情之控制可以減緩失智症之發生。 （二）生活及飲食習慣之調整： • 抽香菸是占血管型失智症發生的危險因子之第三位占35％，必須下定決心戒除煙癮。 • 從年輕時代即培養運動和正常休閒、藝術、交友等生活習慣。 • 少吃油膩及內臟、鹼鹽類食物、充足的睡眠及休息。 • 每天可服用約1 / 3 片的阿斯匹林片，減少血小板之凝集沈澱在血管壁上，保持血流的暢通。 • 若是吃素者而缺乏維他命B12之攝取者，必須補充維他命B12，必須靠口服片劑或注射維他命B12針劑補充之，預防因維他命B12缺乏之癡呆症。 • 至於含有麩酸之味精、味素是否可以間接刺激膽鹼激素之形成（Acetylcholine）而預防退化型失智症尚可以研究。

40. （三）生活上復健的照顧： 1.隨時給予現實感的定向力 2.環境要光亮、鮮明、活潑 3.注意個人衛生的維護 4.營養的攝取要足夠、均衡 5.多做身體的活動 6.預防意外傷害 7.鼓勵參加社團活動 8.安撫與陪伴 9.趁早培養正當的嗜好

41. 敬請批評指教