老年人基因多型性、憂鬱、睡眠與認知間的關聯性研究

Abstract

目的 這篇論文包含兩部分。第一部分(即論文第二章)的研究旨在探討CISD2 (CDGSH iron sulfur domain 2) 基因的多型性變異與罹患阿茲海默症 (Alzheimer's disease, AD) 風險之間的關聯。 第二部分(即論文第三章)的研究旨在探討居住在社區的臺灣老年人的憂鬱和睡眠與認知之間的關係。

方法 第一部分：這是一項病例對照研究。於2007年至2010年期間，從臺灣三所教學醫院總共招募了276名AD患者；同期從老年健檢和醫院志工中招募460名對照者。所有參與者年齡均在60歲或以上。從CISD2基因中選擇兩個單倍型標記的單核苷酸多型性 (haplotype-tagging single nucleotide polymorphism, htSNP) (rs223330和rs223331)，以檢視它們的多型性與失智風險之間的關聯，以及探究脂蛋白酶元 (apolipoprotein E, APOE) ε4狀態、性別、高血壓和第二型糖尿病如何影響其關聯。 第二部分：這個為期四年的前瞻性世代研究 (2015-2019) 包括379名65歲或以上的參與者，這些參與者來自台大醫院的年度老年健康檢查，之後每兩年進行一次追蹤。使用經過驗證的神經心理學測驗評估整體和領域認知功能。自變項部分，使用流行病學研究中心憂鬱 (CES-D) 量表評估憂鬱症狀，以匹茲堡睡眠品質指數 (PSQI) 評估睡眠品質，採用Epworth嗜睡量表 (ESS) 評估白天過度嗜睡。廣義線性混合模型用於探索亞臨床憂鬱症狀和睡眠與認知的關聯，並調整重要的共變項。並依睡眠變項進行分層分析。

結果 第一部分：rs223330 變異與AD風險無關 [TT 比 CC：調整勝算比 (AOR)=0.98，95% 信賴區間 (CI)=0.59-1.62；TC 比 CC：AOR=0.72，95% CI=0.47-1.11]。 rs223331 也觀察到類似的結果（AA 比 TT：AOR=1.12；AT 比 TT：AOR=0.99）。此外，高血壓顯著影響了rs223331與AD風險之間的關聯（P=0.005）。CISD2有三種常見的單倍型 (TT,CA,CT) (累積頻率=99.8%）。而CISD2常見單倍型與AD風險無關。 第二部分：隨著時間的推移，兩年後追蹤，發現亞臨床憂鬱症狀與整體認知 (β = -1.25, P=0.007) 和執行功能 (Trail Making Test A: β = -0.35, P=0.007; Trail Making Test B: β = -0.46, P=0.006) 表現不佳相關。睡眠品質差（PSQI分數較高）與記憶力差相關 (β = -0.04, P=0.04)。白天過度嗜睡 (ESS分數較高）與記憶力 (β = -0.03, P=0.02) 和執行功能 (β = -0.02, P=0.002) 表現不佳有關。在基線時較好的睡眠品質和白天沒有過度嗜睡，與較好的記憶力相關。

結論 第一部分：我們的研究結果顯示CISD2 單倍型標記的單核苷酸多型性與AD風險無關。 第二部分：亞臨床憂鬱症狀、較差的睡眠品質量和白天過度嗜睡，與認知領域 (主要是記憶和執行功能) 的障礙相關。本研究的結果對預防和治療策略具有公共衛生意義，可以治療亞臨床憂鬱症狀以預防認知功能的下降，以及使用適當的認知功能測驗來篩檢處於失智症臨床前階段有睡眠障礙之老年人。

總結 第一部分的研究結果並未如期待地與研究假說相符。第二部分的研究結果與我們的研究假設相符。 第一部分研究的貢獻在於發現CISD2多型性可能並未參與阿茲海默症的致病機轉。第二部分研究結果的貢獻在於對認知功能障礙的預防和治療具有公共衛生意涵，可以治療亞臨床憂鬱症狀以預防認知功能的下降，以及使用適當的認知功能測驗來篩檢處於失智症臨床前階段有睡眠障礙之老年人。 第一部分研究的主要局限性在於樣本數較小；因此，未來需要更大規模的研究來確認我們的發現。第二部分世代研究的局限性可能是樣本數相對較小；但與全世界過去相似議題的研究相比，本研究的參與者已明顯相對較多。且此世代也仍在追蹤中，可利於未來後續研究。

Objectives This dissertation includes two parts. Part 1 (i.e., chapter 2 in the dissertation) aimed to explore the association between sequence variants of the CISD2 (CDGSH iron sulfur domain 2) gene and risk for Alzheimer’s disease (AD). Part 2 (i.e., chapter 3 in the dissertation) aimed to explore the association of subclinical depressive symptoms and sleep with cognition in community-dwelling Taiwanese older adults.

Methods Part 1: This was a case-control study. A total of 276 AD patients were recruited from three teaching hospitals in Taiwan from 2007 to 2010; 460 controls were recruited from elderly health checkups and volunteers of the hospital during the same period of time. All participants aged 60 and older. Two haplotype-tagging single nucleotide polymorphisms (htSNPs), rs223330 and rs223331, were selected from the CISD2 gene to test the association between their polymorphisms and the risk of dementia, and how APOE ε4 status, gender, hypertension and type 2 diabetes mellitus modify this association. Part 2: This four-year prospective cohort study (2015-2019) included 379 participants aged 65 years or older from the annual senior health checkup program at National Taiwan University Hospital who were followed up two years later. Global and domain cognitive functions were assessed using validated neuropsychological tests. Depressive symptoms were evaluated using the Center for Epidemiologic Studies Depression (CES-D) Scale. Sleep quality was evaluated using the Pittsburg Sleep Quality Index (PSQI). Excessive daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS). Generalized linear mixed models were used to explore the associations of subclinical depressive symptoms and sleep variables with cognition, adjusting for important covariates. Stratification analyses were performed using the sleep variables.

Results Part 1: The rs223330 variant carriers were not associated with the risk of AD [TT vs. CC: adjusted odds ratio (AOR)=0.98, 95% confidence interval (CI)=0.59-1.62; TC vs. CC: AOR=0.72, 95% CI=0.47-1.11]. Similar findings was observed for rs223331 (AA vs. TT: AOR=1.12; AT vs. TT: AOR=0.99). In addition, hypertension significantly modified the association between rs223331 and the risk of AD (P=0.005).Three common haplotypes (frequency=99.8%) were observed for CISD2. CISD2 common haplotypes were not associated with the risk of AD. Part 2: Over time, depressive symptoms were associated with poor performance of global cognition (β = -1.25, P=0.007) and executive function (Trail Making Test A: β = -0.35, P=0.007; Trail Making Test B: β = -0.46, P=0.006). Poor sleep quality (elevated PSQI score) was associated with poor memory performance (β = -0.04, P=0.04). Excessive daytime sleepiness (elevated ESS score) was associated with poor performance of memory (β = -0.03, P=0.02) and executive function (β = -0.02, P=0.002). At baseline, better sleep quality and no excessive daytime sleepiness were associated with better memory performance.

Conclusions Part 1: The findings suggested that CISD2 htSNPs were not associated with AD risk. Part 2: Subclinical depressive symptoms, worse sleep quality, and excessive daytime sleepiness were differentially associated with impairment of cognitive domains.

Summary The results of Part 1 were not consistent with the research hypotheses as expected. The contribution of Part 1 is that CISD2 polymorphism may not be involved in the pathogenesis of AD. The limitation of Part 1 is the small sample size; therefore, future larger studies are needed to confirm our findings. The results of Part 2 were consistent with our hypotheses. The contribution of Part 2 is public health implications for the prevention of cognitive decline by treatment of subclinical depression, and the use of cognitive tests suitable for screening for older adults with sleep disturbances in the preclinical stage of dementia. The limitation of Part 2 may be that the sample size is relatively small; however, compared with previous studies on similar topics around the world, the number of participants in this study is significantly large. This cohort is still being followed up, which can benefit future research.