有氧運動合併雙項任務訓練對輕度知能障礙患者與早期阿茲海默症患者在身體結構與功能、活動能力與社會參與之療效

Abstract

在高齡化的國家中，失智症是日趨受到重視的疾病之ㄧ。近年來研究顯示，中高強度的有氧運動有助於改善知能障礙患者的整體認知功能，或是以雙項任務（dual-task）模式搭配肌力與平衡訓練，則可以改善其特定的認知功能。但這些療效的機制仍為未知，而運動訓練對於不同程度或不同基因型的知能障礙者療效是否不同，目前亦尚未有研究探討。因此，本研究計畫主要目的為探討：（1）經過3個月的有氧運動合併雙項任務訓練後，對改善輕度知能障礙患者及早期阿茲海默症患者在身體結構與功能（包括胰島素阻抗（insulin resistance）、血中細胞激素（TNF-α（tumor necrosis factor-α）、IL-6（interleukin 6）、CRP（C-reactive protein））、基底動脈（basilar artery）阻力、大腦扣帶迴（cingulate）神經纖維束結構完整性、認知功能、動作功能與憂鬱程度）、活動能力（包括體能活動量（physical activity level）、虛弱（frailty）程度與失能程度）與社會參與（包括生活品質與社會參與度）之療效；（2）探討有氧運動合併雙項任務訓練對於輕度知能障礙患者與早期阿茲海默症患者，或對於帶有APOEε4基因與未帶有APOEε4基因的患者在認知功能與動作功能上是否有不同的療效；（3）探討運動訓練後，輕度知能障礙患者和早期阿茲海默症患者認知功能之改善與胰島素阻抗、血中細胞激素、基底動脈阻力、大腦扣帶迴神經纖維束結構完整性變化之關係，以進一步了解此訓練對改善認知功能之神經解剖與生理機制。 本研究採評估者單盲隨機控制臨床試驗（single-blind randomized controlled trial）。共徵召18位輕度知能障礙或早期阿茲海默症患者，分層（stratified）隨機分配至有氧運動合併雙項任務訓練組（有氧組）或伸展運動訓練組（伸展組），每組9位受試者。有氧組與伸展組均接受為期12週，每週3次，每次90分鐘的運動訓練。有氧組運動訓練內容包括中強度有氧運動合併雙項任務訓練，以及另4天中至少2天做30分鐘的走路運動。伸展組則為每次90分鐘的伸展與坐姿下活動訓練。兩組受試者訓練期維持穩定用藥狀況，並在訓練前、後接受身體結構與功能、活動能力與社會參與之評估。 結果顯示，伸展組的教育程度顯著高於有氧組（P < 0.05）。訓練前，兩組受試者在坐站測試有組間差異（P < 0.05），其餘療效參數訓練前均無顯著差異（P > 0.05）。有氧組在經過3個月的運動訓練後，其上、下肢肌力以及雙項任務行走表現有顯著進步（P < 0.05），而伸展組則是在矩陣推理測驗、阿茲海默症評估量表認知功能部份、與憂鬱程度的得分上有顯著的改善（P < 0.05）。有氧組訓練後在左大腦前扣帶迴與中扣帶迴的GFA值高於伸展組，尼爾森修訂版卡片分類測驗的表現也優於伸展組（P < 0.05）。若依患者之認知功能障礙程度分組則發現，訓練前早期阿茲海默症患者的認知功能較輕度知能障礙患者差，運動訓練對於早期阿茲海默症患者在肌力與記憶功能改善療效較輕度知能障礙患者大（P < 0.05）。若依早期阿茲海默症患者是否有帶APOEε4基因型分組則發現，訓練前未帶APOEε4基因型早期阿茲海默症患者的認知功能較帶APOEε4基因型早期阿茲海默症患者差，運動訓練對未帶APOEε4基因型患者比帶APOEε4基因型患者在矩陣推理方面有顯著的療效（P < 0.05）。 本研究顯示：運動訓練－無論是有氧運動合併雙項任務訓練或伸展運動訓練，皆有助於改善輕度知能障礙患者與早期阿茲海默症患者之認知功能或動作功能，對於早期阿茲海默症患者，尤其是未帶APOEε4基因型的患者有顯著的療效。因此建議應早期以運動訓練介入，以維持或促進輕度知能障礙患者及早期阿茲海默症的認知功能與動作功能。

Recent studies have shown that moderate-to-high intensity aerobic exercises are effective in improving overall cognitive function in patients with cognitive impairment and dementia. Dual-task training programs also show positive effects on enhancing executive function in patients with cognitive impairment. However, the mechanisms through which these training effects are mediated remain largely unknown in humans. It also yet to be explored as to whether patients with different levels of dementia or carrying different apolipoprotein E（APOE）genotypes would benefit from aerobic exercises or dual-task training differentially. Therefore, the purposes of this study were: (1) to investigate the effects of a 3-month moderate intensity aerobic exercises combined with dual-task training on body structure and body function (insulin resistance, tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6, C-reactive protein (CRP), basilar artery resistance, cingulum bundle integrity, cognitive function, motor function, and depression), activity (level of physical activity, physical frailty, level of disability), and participation (quality of life and social participation) in patients with mild cognitive impairment (MCI) and in those with early Alzheimer’s disease (AD); (2) to compare the differences in exercise training effects between patients with MCI and patients with AD, and between patients carrying and not carrying APOEε4 genotype; and (3) to investigate the correlations of changes in cognitive functions with changes in insulin resistance, TNF-α, IL-6, CRP, basilar artery resistance, and cingulum bundle integrity, after training in order to explore the possible neuroanatomical and neurophysiological mechanisms of exercise training effects. We conducted an assessor-blind randomized controlled clinical trial. A total of 18 patients with MCI or AD were recruited. The participants were randomly assigned to the aerobic exercise training group (aerobic group) or the stretch control group (stretch group) using the stratified randomization by matching patient’s diagnosis. The both aerobic and stretch group received health education and exercises training for 12 weeks. The aerobic group received three 90-minuate group exercises sessions, that included aerobic exercises combined with dual-task training, and two 30-minute individual walking exercise sessions at home per week. The stretch group received three 90-minuate group exercise sessions that included stretch exercises and activities in sitting. Both groups received examinations on primary outcomes (including insulin resistance, TNF-α, IL-6, CRP, basilar artery resistance, cingulum bundle integrity, cognitive function, and motor performance) and secondary outcomes (including depression, physical activity level, physical frailty, level of disability, social participation, and quality of life) at baseline (week 0) and post-training (week 12). Differences on the aforementioned outcomes brought by the 12-week exercise training programs were compared between and within the aerobic and stretch groups using Mann-Whitney U Test and Wilcoxon Signed Ranks Test, respectively. Correlations of changes in cognitive functions with changes in insulin resistance, TNF-α, IL-6, CRP, basilar artery resistance, and cingulum bundle integrity were analyzed using Spearman rank correlation coefficient to explore the possible neural or physiological mechanisms mediating the exercise training effects. Exercise effects between patients with MCI versus AD and between patients carrying and not carrying APOEε4 were also examined. The results showed that the educational level of the stretch group was higher than the aerobic group. There were significant differences between the aerobic and stretch group in the time of chair rise test before taining. The aerobic group showed a significant increase in muscle strength of upper and lower extremities and improvement in dual-task walking performance after 3 months of training. The stretch group showed a significant increase in the matrix reasoning score and decrease in Alzheimer’s Disease Assessment Scale -Cognitive Subscale (ADAS-cog) and level of depression after 3 months of training. After 3 months of training, the aerobic group showed greater integrity of anterior and middle cingulum bundles of the left hemisphere and better performance of Modified Card Sorting Test (MCST) than stretch group. Patients with AD had poorer cognitive function than the patients with MCI before training. The effects of exercise training were greater for the early AD subjects than for the MCI subjects, especially in muscle strength and memory function. The APOEε4 noncarriers had poorer cognitive function than the APOEε4 carriers at baseline. The APOEε4 noncarriers had greater improvement in matrix reasoning test than the APOEε4 carriers after exercise training. Both aerobic exercise combined dual-task training and stretch exercise training were effective in improving cognitive or motor function of patients with MCI and early AD. These effects of exercise training were greater in patients with early AD, especially in those APOEε4 noncarriers, than in patients with MCI or AD with APOEε4. Early exercise intervention is therefore suggested to patients with MCI and early AD in order to maintain or improve their cognitive and motor functions.