臺灣博碩士論文加值系統

背景: 物質戒斷係與成癮現象有密切相關，探討酒精戒斷時期相關之神經毒性與神經適應性，可協助了解酒精之成癮機轉。震顫性譫妄乃為酒精戒斷症候群中最嚴重的表現，目前認為具有震顫性譫妄的個案因其較差預後而被視為一特異族群。腦神經滋養因子(Brain-derived neurotrophic factor，BDNF)在成癮發展過程之神經塑性與學習扮演重要角色，同時，目前證據顯示長期飲酒和生物節律異常有明顯相關，生物節律乃由數個生物節律基因所調控，包括hClock1, hBmal1, hPer1, hPer2, hCry1, hCry2。然而有關長期飲酒導致生物節律基因的表現改變，多以動物研究呈現，尚未有人體證據。因此，我們將探討酒癮患者血中的BDNF濃度表現以及周邊淋巴球的生物節律基因mRNA表現量，以及在停酒一週後，亦即早期戒斷後之表現，同時比較患者有無併發譫妄現象在這兩個指標上的差別表現。並且探討和併發譫妄之關聯。
方法： 65位符合精神科診斷準則第四版中酒精依賴的住院患者，與39位健康控制組加入研究。患者在住院治療期間依其呈現譫妄現象與否而分組為譫妄組(25位)與非譫妄組(40位)。所有的個案在早上9到10點間接受抽血，但酒癮者則抽血兩個時間點，亦即住院隔天早上一次（基準值）與住院第七天（第一週）。血清中BDNF濃度則由sandwich enzyme-linked immunosorbent assay (ELISA）檢測。其中，我們由全血中分離並收集22 位男位酒精依賴患者與12位控制的周邊淋巴球，以定量real-time PCR測定hClock1, hBmal1, hPer1, hPer2, hCry1, hCry2 的基因表現量。
結果: 血清中BDNF濃度在控制組、非譫妄組、譫妄組在統計上呈現顯著的組間差異，分別是14.8 ± 4.7 ng/mL, 12.3 ± 3.3 ng/mL與6.2 ± 2.6 ng/mL (p < 0.001). 在一週的戒斷後，酒精依賴患者的兩組血清中BDNF濃度有顯著增加，雖然非譫妄組的BDNF濃度已和控制組無差異(13.4 ± 3.5 ng/mL)，但譫妄組個案則仍然顯著低於控制組 (8.9 ± 4.4 ng/mL)。至於生物節律基因的表現量方面, 兩組酒精依賴個案均遠低於控制組個案(p < 0.001)，即使經過一週之戒斷時間，兩組酒精依賴個案生物節律基因mRNA表現仍少有改善，並且有無譫妄發生僅有小幅影響兩組之間的表現差異。
討論: 我們的研究指出長期飲酒會造成酒精依賴患者體內的BDNF濃度下降，同時我們發現具有更為低下的BDNF濃度和併發譫妄可能有關。此外，適當的戒斷治療會協助BDNF濃度的回復。這指出BDNF 可能與酒精戒斷症候群中不同表現型有關，並參與相關神經適應性的調控。但我們卻發現無論有無併發譫妄，幾乎每個指標生物節律基因表現量在所有酒精依賴個案的皆呈嚴重不足，這個現象並且在戒斷一週後並無太大改變。雖然本研究呈現人體長期飲酒後生物節律基因表現量變化的首次發表，但我們的檢測為單點研究，未來仍需佐以其他生物節律指標的資料，以提供酒精破壞生物節律型態更為直接有力的證據。由於 BDNF也參與生物節律基因的調控，從而影響神經塑性，所以亦將進一步探討其與指標生物節律基因表現量之相關性。

Background: Alcohol withdrawal-enhanced neuroadaptation contributes to the addictive process. Delirium tremens (DTs) is the most serious complication of alcohol withdrawal syndrome (AWS) and postulated to be a clinically distinct phenotype among AWS. Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity and learning related to addiction. Meanwhile, current evidence indicated a clear interaction between chronic alcohol consumption and disrupted circadian rhythmicity which is regulated by several circadian clock genes including hClock1, hBmal1, hPer1, hPer2, hCry1, hCry2. Studies exploring the altered expressions of these genes in alcohol addiction have been mainly described in animals. Therefore, we assessed the differences in serum BDNF levels as well as the mRNA expression of circadian clock genes, measured at baseline and one week after alcohol withdrawal among alcoholic patients with and without DT.
Methods: Sixty-five inpatients, fulfilling the DSM-IV criteria of alcohol dependence and admitted for alcohol detoxification, as well as 39 healthy control subjects were enrolled. The alcoholic patients were further divided by the appearance of DTs into the DT group (n = 25) and non-DT group (n = 40). All the participants received blood withdrawal at 9-10 a.m. while the AD patients had blood collection for twice: on the next morning of admission (baseline) and on the 7th day. Among them, the PBMCs of 22 male alcoholics and 12 comparison control subjects were collected from the whole blood. Serum BDNF levels were measured by sandwich enzyme-linked immunosorbent assay while the mRNA expression profiles of hClock1, hBmal1, hPer1, hPer2, hCry1, hCry2 in PBMCs were determined by quantitative real-time PCR.
Results: Serum BDNF levels differed significantly among the three groups: (1) control group 14.8 ± 4.7 ng/mL; (2) non-DT group 12.3 ± 3.3 ng/mL; (3) DT group 6.2 ± 2.6 ng/mL (p < 0.001). After one week after alcohol withdrawal, BDNF levels increased significantly for both alcoholic groups. While non-DT group had comparable BDNF levels (13.4 ± 3.5 ng/mL) with controls, the DT group still exhibited lower levels (8.9 ± 4.4 ng/mL). Regarding to the expression of circadian clock genes, baseline mRNA levels were markedly lower in AD patients than in control subjects. After one week of alcohol detoxification, there were very limited restorations of discrete circadian gene expressions. DT group did not differ in the expression patterns of circadian clock genes from non-DT group.
Conclusions: The present study suggests chronic drinking leads to a reduction in BDNF levels and patients with more deficient BDNF expression are vulnerable to the development of DTs. BDNF levels elevated after prompt alcohol detoxification treatment. Therefore BDNF could involve modifying the phenotypes of AWS as well as the pertinent neuroadaptive processes of AD. In addition, we first demonstrated the overall lowering of circadian clock genes among AD patients. But, the expression pattern is comparable between patients with and without DTs. Though preliminary with data at only one single time point, the observation of strikingly reduced mRNA levels supports the association between circadian clock gene dysregulation and chronic alcohol intake.

頁數
中文摘要..………………………………………………………………………….1~2
(Abstract in Chinese)
英文摘要..………………………………………………………………………….3~5
(Abstract in English)
緒論………………………………………………………………………………...6-13
(Introduction)
研究目的…………………………………………………………………………......14
(Study Aims)
研究材料與方法…………………………………………………………………15~20
(Materials and Methods)
實驗結果…………………………………………………………………………21~25
(Results)
討論………………………………………………………………………………26~36
(Discussion)
結論與展望………………………………………………………………………37~38
(Conclusion and Perspective)
參考文獻…………………………………………………………………………39~48
(References)
圖表………………………………………………………………………………49~70
(Tables and Figures)
Table 1. Demographic characteristics and Chinese version of Delirium Rating Scale-Revised-98 (DRS-R-98-C) scores of four diagnostic patients. …..49

Table 2. Internal consistency of Chinese version of Delirium Rating Scale-Revised-98 (DRS-R-98-C) scale in 28 delirious patients. …..50
Table 3. Cutoffs, Sensitivity, and specificity of Chinese version of Delirium Rating Scale-Revised-98 (DRS-R-98-C) when comparing delirious group with all non-delirious groups, based on Receiver Operating Characteristic analysis. …..52
Table 4. Baseline demographic characteristics and biological parameters in control subjects and alcoholic patients. …..53
Table 5. The demographic and clinical characteristics and laboratory data in healthy controls and patients with alcohol dependence (AD) divided by the appearance of DTs (delirium tremens). …..55
Table 6. Target genes, symbols, assay identifications numbers (ID), reference sequence (accession numbers). …..56
Table 7. The comparison of hClock1, hBmal1, hPer1, hPer2, hCry1, hCry2 mRNA expressions in two AD groups and healthy controls at baseline as well as the comparison in two AD groups one week after detoxification (Week 1). …..57
Fig. 1. The distribution of Chinese version of Delirium Rating Scale- Revised-98 (DRS-R-98-C) severity and total scores in quartiles (middle 50% in the box) and median scores (in solid black lines) of four patient groups. …..58
Fig. 2. Regression plot between Chinese version of Delirium Rating Scale-Revised-98 (DRS-R-98-C) total scores and Mini-Mental State Examination (MMSE) in 28 delirious patients. …..59
Fig. 3. Serum BDNF levels (mean ± SD) of alcohol patients (n = 25) at baseline and after one-week alcohol withdrawal as well as of the healthy controls (n = 22). ….60
Fig. 4. The correlation between baseline serum BDNF levels and the average of first-day CIWA-Ar scores in alcoholic patients. …..61
Fig. 5. Comparison of the baseline serum BDNF levels between groups (gray) and the changes after one week of detoxification among alcoholic patients (shadowed). …..62
Appendix 1. Chinese version of Clinical Institute Withdrawal Assessment Scale for Alcohol, Revised (CIWA-Ar-C). …..63
Appendix 2. Chinese version of Delirium Rating Scale-R-98. …..66

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