The Relationship between Executive Function and the Integrity of Cingulum Bundle in Patients with Mild Cognitive Impairment and Patients withMild Alzheimer’s Disease

背景與目的:執行功能的表現是預測輕度知能障礙患者惡化為阿茲海默症的重要因子之一。扣帶迴神經束則是聯絡執行功能神經網絡主要神經纖維束之一。然而，扣帶迴神經束(cingulum bundle)之結構完整性在輕度知能障礙患者以及輕度阿茲海默症患者中退化的程度，以及扣帶迴神經束結構完整性與此兩種患者執行功能(executive function)表現間的相關性仍未有定論。因此本研究主要目的有二：(一)利用腦部擴散頻譜造影(diffusion spectrum imaging)之影像，探討輕度知能障礙、輕度阿茲海默症患者與與年齡相當之健康成人的扣帶迴神經束結構完整性差異；(二)探討輕度知能障礙與輕度阿茲海默症患者之執行功能與扣帶迴神經束結構完整性間之相關性。 方法: 本研究原本共徵召34位受試者，但其中2位受試者(一位輕度知能障礙患者及一位健康成年人)之腦部影像因品質較差而無法納入分析，因此資料可分析人數總共為32位，包含健康控制組15位(平均年齡71.1±7.1歲)，輕度知能障礙患者8位(平均年齡73.7±8.2歲)以及輕度阿茲海默症患者9位(平均年齡74.7±8.2歲)。每位受試者接受腦部磁振造影及臨床神經心理測驗，測驗內容含「彩色路徑描繪測驗A部分與B部分」 (Color Trails Test- Part A and Part B)與尼爾森修訂版卡片分類測驗 (Modified Card Sorting Test)兩個臨床執行功能測驗，及評估整體認知功能之迷你心智量表(Mini-Mental State Examination)。對擴散頻譜造影資料，採特定神經纖維束分析法(tract-specific analysis)與興趣區域分析法(region of interest (ROI) analysis)，計算整段、前段、中段及後段扣帶迴神經束之普不等向性擴散分數(generalized fractional anisotropy, GFA)，並以這些值代表扣帶迴神經束整段及分段之結構完整性，GFA值越高代表扣帶迴神經束整段及分段之結構越完整。在統計分析方面，本研究以克-瓦二氏單因子等級變異數分析(Kruskal-Wallis one-way analysis of variance by ranks)，並以曼惠特尼U檢定(Mann-Whitney U test)作事後檢定，比較三組在神經心理測驗表現與扣帶迴神經束結構完整性上之差異。另以斯皮爾曼等級相關係數(Spearman''s rank correlation coefficient)探討兩組患者中，其執行功能表現與扣帶迴神經束結構完整性間之相關性。 結果: 組間比較結果發現：輕度阿茲海默症患者在尼爾森修訂版卡片分類測驗之完成組數(p=0.008)、固著性錯誤(p=0.003)以及彩色路徑描繪測驗A部分(p=0.001)與B部分(p=0.003)的表現顯著低於健康控制組；而輕度知能障礙患者之執行功能表現則介於阿茲海默症患者及健康控制組之間，但與此兩組相較未達顯著差異(p= 0.041~0.964)。而以特定神經纖維束分析法所得之結果顯示，輕度阿茲海默症組之左側整段(p=0.001)以及左側後段(p=0.006)扣帶迴神經束之GFA值顯著低於健康控制組。此外，輕度知能障礙患者與輕度阿茲海默患者完成彩色路徑描繪測驗B部分的時間與以特定神經纖維束分析法所得之左側整段 (rs= -0.628, p= 0.007)及左側後段(rs= -0.613, p= 0.009)扣帶迴神經束之GFA值具有中度負相關，與右側中段之GFA值亦有低度負相關(rs= -0.482, p= 0.05)，代表完成彩色路徑描繪測驗B部份所需的時間越久(亦即表現越差)的患者，其左側整段、左側後段及右側中段扣帶迴神經束之GFA值越低，即這些神經束段落之結構完整性越差。此外，尼爾森修訂版卡片分類測驗結果顯示，兩組患者之非固著性錯誤個數與以特定神經纖維束分析法所得之右側中段扣帶迴神經束GFA值有顯著中度負相關(rs= -0.500, p= 0.04)，代表非固著性錯誤個數越多(即表現越差)的患者，其右側中段扣帶迴神經束GFA值越低，即此段神經束結構完整性越差。然而，以興趣區域分析法所得之結果則發現：不論是三組間扣帶迴神經束結構完整性的比較，或是扣帶迴神經束結構完整性與執行功能表現間的相關性，皆未達到統計上顯著的差異(p=0.106~0.903)。 結論: 總結而言，本研究發現輕度阿茲海默症患者之執行功能表現以及採特定神經纖維束分析法所得之左側整段及左側後段扣帶迴神經束完整性較健康控制組的為差。此外，以特定神經纖維束分析法所得之結果顯示，輕度知能障礙患者與輕度阿茲海默患者之執行功能表現與其左側整段、左側後段及右側中段之扣帶迴神經束結構完整性有低至中度的相關性。因此，以特定神經纖維束分析法分析扣帶迴結構完整性確實能反應出輕度知能障礙患者與輕度阿茲海默症患者腦部與執行功能退化相關之扣帶迴結構完整性退化現象。Backgroundand Purposes: Executive function is one of the most important predictors for conversion to Alzheimer’s disease (AD) from mild cognitive impairment (MCI). Cingulum bundle (CB) is one of the main associative fibers connecting the “executive control network” in the brain. However, it remains controversial regarding whether the degree of degeneration of the CB in patients with MCI and patients with AD, and concerning whether there is a correlation between the integrity of CB and the executive function of these patients. Therefore, the two purposes of this study were: (1) to compare the differences in the integrity of CB among patients with MCI, patients with mild AD, and age-matched healthy controls using diffusion spectrum imaging (DSI) of the brain and (2) to investigate the relationship between executive function and the integrity of CB in patients with MCI and patients with mild AD. Methods: We originally recruited 34 subjects. Due to the poor quality of brain image data of one MCI subject and one healthy subject, we only analyzed data from the remaining 32 subjects, including 15 healthy controls (mean age= 71.1 ± 7.1 years), 8 MCI (mean age= 73.7 ± 8.2 years), and 9 mild AD (mean age= 74.7 ± 8.2 years), were analyzed. All subjects received the DSI MR scan of the brain and clinical neuropsychological tests. The latter included the Color Trails Test- Parts A and B (CTT-A and CTT-B, respectively) and the Nelson Modified Card Sorting Test (MCST) for assessing executive function; and the Mini-Mental State Examination (MMSE) for assessing overall cognitive function. In DSI data analysis, we used tract-specific analysis method and region of interest (ROI) analysis method to calculate the generalized fractional anisotropy (GFA) values of the entire CB and the anterior (aCB), middle (mCB), and posterior (pCB) segments of the CB of each hemisphere to serve as the quantitative measures of the CB integrity for each subject. The higher the GFA values are, the better the integrity of CB is.For statistical analyses, we compared group differences in GFA values and performance on executive function tests using the Kruskal-Wallis analysis of variance by ranks test. The Mann-Whitney U test was used for post-hoc analysis. The relationships between the performance on executive function tests and the GFA values were analyzed by using the Spearman''s rank correlation coefficients. Results: Statistical results showed that patients with mild AD performed significantly poorer than the healthy control group on the number of completed set (p=0.008) and number of perseverative errors (p=0.003) of the MCST test, as well as on the CTT-A (p=0.001) and CTT-B (p=0.003). Performance on these executive function tests of the MCI group was better than that of the mild AD group and poorer than that of the healthy control group, but there were no significant group differences (p= 0.041~0.964)。Results of the tract-specific analysis method showed that the GFA values of the entire left CB (p=0.001) and left pCB(p=0.006) significantly smaller in the mild AD group compared to those of the healthy control group (p< 0.017). Results of the correlation analyses for the two patient groups showed that the time to complete the CTT-B was highly correlated with the GFA values of the entire left CB (rs= -0.628, p= 0.007), left pCB(rs= -0.613, p= 0.009), and right mCB(rs= -0.482, p= 0.05) calculated by using the tract-specific analysis method. This finding suggests that patients who performed poorer on CTT-B also had poorer structural integrity of their left entire CB, left pCB, and right mCB. In addition, patients’ number of non-perseverative errors on the MCST was significantly correlated with the GFA value of the right mCB (rs= -0.500, p= 0.04), suggesting that patients who presented a greater number of non-perseverative errors on the MCST also showed poorer integrity of the right mCB. Results of analyses using the GFA values obtained from the ROI method showed no significant group differences in any GFA value and no significant correlations between the GFA values and executive function performance (p=0.106~0.903)。 Conclusion.We concluded thatbased on the structural integrity measures derived from the tract-specific analysis method, patients with mild AD presented poorer structural integrity of the entire left CB and left pCB than the healthy controls. The executive function of patients with mild AD and patients with MCI was significantly correlated with the structural integrity of the entire left CB, left pCB, and right mCB. These findings suggest that the structural integrity of CB analyzed by using the tract-specific method could reveal CB fiber integrity degeneration that is associated with decline in executive function