臺灣老年人代謝質體特徵及認知功能缺損之關聯性研究

Abstract

研究背景 全球的老化速度不斷上升，老年人口相關議題逐漸備受重視，伴隨認知功能退化的疾病─失智症，已成為老年族群中重要的健康議題。一維氫譜核磁共振儀是探討代謝質體中快速且簡易的分析平台，過去曾用來探討慢性疾病之致病機轉，然而，過去探討認知功能缺損其病理變化的代謝體學研究有限。因此，本研究運用一維氫譜核磁共振儀評估老年人血漿中代謝物與認知功能缺損之間的關聯性。 材料與方法 此橫斷性研究於2011至2013年間招募574位參加臺大醫院老人健檢且年齡介於65至84歲的長者。整體性認知功能利用台灣版蒙特利爾認知評估量表（MoCA-T）進行評估；其他特定的認知範疇則分別用魏氏記憶量表第三版（WMS-III）中邏輯記憶測驗一、二，及空間記憶廣度測驗，語意流暢度測驗，及路徑描繪測驗A、B與兩者之比值（B:A）進行評估。血液檢體則用來決定代謝物特徵及載脂蛋白E（APOE ε4）之基因型。代謝物圖譜均透過500兆赫（mHz）的核磁共振儀及一維NOESY脈衝進行分析。透過多變項邏輯斯迴歸模型探討代謝物與認知功能缺損之間的關聯性，並針對重要的干擾因子進行分層分析，例如：年齡分組（65至74歲、75至84歲）、性別、APOE ε4狀態。 研究結果 當acetate（調整勝算比＝0.11，95%信賴區間＝0.02-0.77）、lipid（CH2CH2C=C，調整勝算比＝0.03，95%信賴區間＝0.003-0.39）及creatine（調整勝算比＝0.78，95%信賴區間＝0.61-0.99）增加一個單位時，可降低記憶功能的缺損（魏氏記憶量表中邏輯記憶測驗部分）。此外，當tyrosine（調整勝算比＝0.36，95%信賴區間＝0.17-0.76）、creatine（調整勝算比＝0.03，95% CI = 0.002-0.41）及valine（調整勝算比＝0.13，95%信賴區間＝0.03-0.53）增加一個單位時，可降低執行功能的缺損（路徑描繪測驗B及路徑描繪測驗B:A之比值）有關。針對重要的干擾因子進行分層分析後，發現上述關係在老老人（年齡介於75至84歲，調整勝算比介於0.001至0.58）及非APOE ε4帶因者（調整勝算比介於0.02至0.75）依舊維持統計顯著。此外，此研究發現認知功能表現存在性別差異，在男性長者中，當acetate（調整勝算比＝0.02）、lipid（CH2CH2C=C，調整勝算比＝0.002）及creatine（調整勝算比＝0.62）增加一個單位時，可降低記憶功能的缺損；在女性長者中，當tyrosine（調整勝算比＝0.27）、creatine（調整勝算比＝0.009）及valine（調整勝算比＝0.07）增加一個單位時，可降低執行功能的缺損。 結論 血漿中acetate及lipid (CH2CH2C=C)相對濃度上升時，與較佳之記憶功能表現有關（曲線下面積＝0.69，95%信賴區間＝0.64-0.73），這個關係特別在老老人及非APOE ε4帶因者依舊存在。由本研究結果可知，代謝體特徵也許可用於長者認知功能缺損的早期偵測，對於此研究的發現需要更進一步的驗證。

Abstract Background: As the aging rate increases rapidly worldwide, dementia, which is characterized with cognitive impairment, has become a critical health issue in the elderly.Past studies exploring metabolome and cognitive impairment are limited. Proton nuclear magnetic resonance (1H NMR) is a fast and easy platform for assessing metabolome, which has been used to explain the pathogenesis of some chronic diseases. Therefore, this study utilized this platform to assess the association between metabolome and cognitive impairment. Methods: This cross-sectional study recruited 574 elderly aged 65 to 84 years from the annual Elderly Health CheckupProgram at National Taiwan University Hospitalfrom 2011 to 2013. Cognitive function wasassessed by Montreal Cognitive Assessment-Taiwan version for global cognition,and logical memory and digit span parts in Wechsler Memory Scale-third version (WMS-III), verbal fluency tests, and trail making tests for cognitive domain-specificvariables. Blood samples were collected to determine metabolic profile and apolipoprotein E (APOE) ε4 diplotype. All 1H NMR spectra of the plasma samples were acquired at 500.13MHzspectrometer with 1D nuclear overhauser effect spectroscopy sequence. Multivariable logistic regression was performed to explore the association between metabolites and cognitive impairment. Stratification analyses wereperformed by important confounders,e.g., age groups (65-74 and 75-84 years old), sex, and APOE ε4 status. Results:Elevated acetate[adjusted odds ratio (AOR) = 0.11, 95% CI = 0.02-0.77], lipid (CH2CH2C=C, AOR = 0.03, 95% CI = 0.003-0.39), and creatine (AOR = 0.78, 95% CI = 0.61-0.99) level protected against impaired memory function (logical memory tests in WMS-III). Moreover, elevated tyrosine (AOR = 0.36, 95% CI = 0.17-0.76), creatine (AOR = 0.03, 95% CI = 0.002-0.41), and valine (AOR = 0.13, 95% CI = 0.03-0.53) protected against impaired executive function (trail making test B and trail making test B:A). After stratification by important confounders, similar findings were observed in the old old (75-84 years old, AOR = 0.001-0.58) and APOE ε4 non-carriers (AOR = 0.02-0.75). Sexdifference on cognition was observed in this study. That is, the association between some metabolites [acetate, AOR = 0.02; lipid (CH2CH2C=C), AOR = 0.002; creatine, AOR = 0.62]protected againstimpaired memory function in men, while other metabolites (tyrosine, AOR = 0.27; creatine, AOR = 0.009; valine, AOR = 0.07) protected against impaired executive function in women. Conclusion: Elevated plasma acetate and lipid (CH2CH2C=C) protected against impaired memory function (area under the curve = 0.69, 95% CI = 0.64-0.73) especially in the old old, men, and APOE ε4 non-carriers.The metabolome profile may be useful for early detection of cognitive impairment in the elderly. More studies are warranted to confirm our findings.