【引用格式】李宇誠，Julien Baker.輕度認(rèn)知功能障礙的非藥物干預(yù)——體育鍛煉[J]. 中國神經(jīng)精神疾病雜志，2023，49（2）：65-75.

【Cite this article】LI Y C，Julien Baker. Physical exercise： a promising non-pharmacological intervention for patients with mild cognitive impairment[J]. Chin J Nervous Mental Dis，2023，49(2）：65-75.

作者簡介

朱利安貝克教授，哲學(xué)博士及科學(xué)博士，現(xiàn)任香港浸會(huì) 大學(xué)運(yùn)動(dòng)、體育及健康學(xué)系主任。人口健康和醫(yī)學(xué)信息學(xué)研究組負(fù)責(zé)人。 在同行評議期刊上發(fā)表了 650 多篇文章。生理學(xué)學(xué)會(huì)、皇家生物學(xué)會(huì)、生物學(xué)會(huì)和臨床研究機(jī)構(gòu)會(huì)士，美國生理學(xué)會(huì)和生物學(xué)研究學(xué)會(huì)（SSOB）成員，英國藥理學(xué)會(huì)和美國實(shí)驗(yàn)生物學(xué)學(xué)會(huì)聯(lián)合會(huì)（FASEB）會(huì)員。

Professor Julien Baker PhD, DSc, is Head of the Sport, Physical Education and Health Department at Hong Kong Baptist University. He is also the director of the Population Health and Medical Informatics Research group. He has pub? lished over 650 papers in peer reviewed journals. Professor Baker has Fellow? ships with the Physiological Society, the Royal Society of Biology, the Biological Society and the Institute of Clinical Research. Professor Baker is also a member of the American Physiological Society, and the Society for the Study of Biology (SSOB). In addition, he has membership of the British Pharmacological Society, and the Federation of American Societies for Experimental Biology (FASEB).

輕度認(rèn)知功能障礙的非藥物干預(yù)

—— ——體育鍛煉

李宇誠Julien Baker

中山大學(xué)附屬第一醫(yī)院神經(jīng)科；

香港浸會(huì)大學(xué)（Hong Kong Baptist University）

摘 要輕度認(rèn)知功能障礙（mild cognitive impairment，MCI）發(fā)生于阿爾茨海默?。ˋlzheimer disease，AD）的早期階段，非藥物干預(yù)手段是改善MCI患者認(rèn)知功能的途徑之一。在非藥物干預(yù)方式中，體育鍛煉正被越來越多人所關(guān)注。本文就體育鍛煉對MCI患者認(rèn)知功能改善做一綜述，為MCI的治療與管理提供思路。體育訓(xùn)練可分為有氧訓(xùn)練與阻力訓(xùn)練，兩種訓(xùn)練方式均可以改善MCI患者的整體認(rèn)知功能，但不同運(yùn)動(dòng)對不同認(rèn)知領(lǐng)域的作用仍不明確。此外，體育訓(xùn)練聯(lián)合其他非藥物干預(yù)方式對MCI患者的認(rèn)知功能改善也展現(xiàn)出一定潛力。另一方面，運(yùn)動(dòng)改善認(rèn)知功能的機(jī)制與神經(jīng)發(fā)生、神經(jīng)元存活和突觸可塑性有關(guān)，這既可以在分子細(xì)胞水平解讀，也可以從器官等宏觀角度分析。最后，本文指出進(jìn)行同質(zhì)性研究、運(yùn)動(dòng)處方的探索與遠(yuǎn)程運(yùn)動(dòng)管理的實(shí)施作為MCI與運(yùn)動(dòng)相關(guān)研究的可能方向。

關(guān)鍵詞

輕度認(rèn)知功能障礙；阿爾茨海默?。惑w育鍛煉；非藥物干預(yù)；認(rèn)知

阿爾茨海默?。ˋlzheimer disease，AD）是導(dǎo)致癡呆的最常見原因，也是一個(gè)主要的公共健康問題[1]。AD引起的輕度認(rèn)知功能障礙（mild cognitive impairment，MCI）發(fā)生在疾病的早期，此階段存在明顯的認(rèn)知功能障礙跡像，但并不影響日?；顒?dòng)。盡管AD尚沒有治愈的方法，但越來越多的證據(jù)表明，體育活動(dòng)或許能夠降低從MCI到癡呆的轉(zhuǎn)換率[2]。

體育鍛煉旨在改善健康、提升生活質(zhì)量。運(yùn)動(dòng)訓(xùn)練可以分成兩種不同的類型：有氧訓(xùn)練和阻力訓(xùn)練[3]。有氧鍛煉可以提高有氧工作能力，進(jìn)而增強(qiáng)心肺功能，減少腦血管疾病、運(yùn)動(dòng)障礙和殘疾的發(fā)生[4]。它包括很多常見的運(yùn)動(dòng)形式，如健步走、慢跑、水中有氧運(yùn)動(dòng)、游泳、跳舞和騎自行車[5]。此外，當(dāng)運(yùn)動(dòng)強(qiáng)度達(dá)到有氧供能系統(tǒng)的要求時(shí)，太極拳、瑜伽等幾種特殊形式的運(yùn)動(dòng)也可歸為有氧運(yùn)動(dòng)。另一方面，阻力訓(xùn)練通常被應(yīng)用于從事運(yùn)動(dòng)相關(guān)工作的群體，或者其他想要誘導(dǎo)神經(jīng)肌肉適應(yīng)、以增加肌肉量和增強(qiáng)功能的個(gè)人[6]。這些運(yùn)動(dòng)在本質(zhì)上是無氧的，提供能量的燃料主要來自無氧糖酵解和三磷酸腺苷的分解。這種能量供應(yīng)非常迅速，促進(jìn)肌肉短時(shí)間內(nèi)產(chǎn)生強(qiáng)力收縮[7]。有氧代謝則隨著運(yùn)動(dòng)持續(xù)時(shí)間的延長和強(qiáng)度的降低而增強(qiáng)。

1運(yùn)動(dòng)鍛煉與聯(lián)合干預(yù)改善MCI患者的認(rèn)知功能

有氧鍛煉和阻力訓(xùn)練都能提高社區(qū)健康老年人的認(rèn)知能力，并改善MCI患者的整體認(rèn)知能力[2, 8-12 ]。然而，正向的結(jié)果與運(yùn)動(dòng)強(qiáng)度、持續(xù)時(shí)間和頻率高度相關(guān)。例如，短時(shí)間、高頻率的訓(xùn)練可能對認(rèn)知改善有更大的效果，因?yàn)槎虝r(shí)間的訓(xùn)練可能更不容易引起疲勞，這種情況與鍛煉的能力和動(dòng)機(jī)有關(guān)[13]。另一方面，由于研究的異質(zhì)性，運(yùn)動(dòng)對不同認(rèn)知領(lǐng)域的作用也存在差異[10, 14]。

TALAR等[14]在一項(xiàng)meta分析中得出結(jié)論，有氧運(yùn)動(dòng)對工作記憶和執(zhí)行功能方面的影響沒有統(tǒng)計(jì)學(xué)意義。與之對比，在一項(xiàng)臨床試驗(yàn)中，有氧鍛煉組和拉伸運(yùn)動(dòng)組的參與者進(jìn)行每周4天、每次45~60 min的高強(qiáng)度活動(dòng)，持續(xù)6個(gè)月。兩組在多任務(wù)處理、認(rèn)知靈活性、信息處理效率和選擇性注意等執(zhí)行控制過程中均取得較好的效果[11]。此外，有證據(jù)表明，有氧運(yùn)動(dòng)提高了即時(shí)回憶和延遲回憶能力，但對意向、執(zhí)行能力、語言流暢性或視覺空間功能等認(rèn)知領(lǐng)域沒有影響[10]。

類似的，阻力訓(xùn)練可以提高M(jìn)CI患者的執(zhí)行功能和聯(lián)想記憶能力[8-9 ]。有趣的是，ZHU等[15]發(fā)現(xiàn)進(jìn)行等距握力練習(xí)對認(rèn)知表現(xiàn)有長期的有益影響，但需要嚴(yán)謹(jǐn)?shù)姆椒ㄈピu估練習(xí)的可行性和有效性。瑜伽是一種典型的有氧運(yùn)動(dòng)，它主要關(guān)注大腦、身體和精神之間的相互作用。EYRE等[16]研究發(fā)現(xiàn)，昆達(dá)里尼瑜伽對記憶力改善的效果與認(rèn)知訓(xùn)練類似，并且對執(zhí)行功能和情緒癥狀具有額外的益處。此外，太極拳是中國傳統(tǒng)體育運(yùn)動(dòng)之一，有證據(jù)表明，它可以改善老年MCI患者的總體認(rèn)知表現(xiàn)、記憶、注意力、語言和執(zhí)行功能[17]。這些引起爭議的發(fā)現(xiàn)表明，體育鍛煉和認(rèn)知之間存在復(fù)雜的關(guān)系。鑒于有氧運(yùn)動(dòng)的類型和（或）設(shè)置各不相同，對認(rèn)知領(lǐng)域的確切影響需要未來更多科學(xué)的原始研究進(jìn)一步明確。

從理論上講，不同干預(yù)措施相結(jié)合可能會(huì)對MCI患者認(rèn)知功能提供更好的保護(hù)。事實(shí)上，有氧運(yùn)動(dòng)和認(rèn)知訓(xùn)練的結(jié)合已經(jīng)被證明可以減少視覺記憶和語言流暢性的衰退，并改善執(zhí)行功能[18]。一項(xiàng)meta分析還顯示，認(rèn)知-體育鍛煉聯(lián)合干預(yù)對MCI或癡呆老年人的整體認(rèn)知功能具有積極的小到中等效應(yīng)（SMD=0.32 [0.17; 0.47]，P<0.00），并且各研究之間無顯著異質(zhì)性[19]。然而，不合適的干預(yù)組合可能效果不佳。例如，接受全訓(xùn)練量阻力訓(xùn)練和認(rèn)知訓(xùn)練的患者在執(zhí)行和總體認(rèn)知方面的表現(xiàn)，明顯較接受單獨(dú)的漸進(jìn)式阻力訓(xùn)練的患者差[20]。這可能是由于聯(lián)合干預(yù)會(huì)產(chǎn)生過大的壓力，對精神和身體同時(shí)造成挑戰(zhàn)，患者因此可能更少參與家庭或社區(qū)活動(dòng)。另外，組合干預(yù)可能會(huì)導(dǎo)致副作用，抑制而非促進(jìn)神經(jīng)可塑性和認(rèn)知效益[20]。進(jìn)一步來說，運(yùn)動(dòng)處方的提供和開具應(yīng)該基于每例患者的具體情況，這將保證為每個(gè)人推薦合適強(qiáng)度的運(yùn)動(dòng)方式。

另一個(gè)有趣的研究方向是將體育鍛煉與經(jīng)顱直流電刺激（transcranial direct current stimulation，DCS）、經(jīng)顱磁刺激（transcranial magnetic stimulation，TMS）或其他非侵入性手段結(jié)合來改善認(rèn)知功能。盡管這一領(lǐng)域的相關(guān)文獻(xiàn)有限，但新的證據(jù)表明，在改善認(rèn)知相關(guān)的雙任務(wù)步行方面，陽極tDCS聯(lián)合太極訓(xùn)練效果優(yōu)于假刺激聯(lián)合太極訓(xùn)練[21]。

目前正在進(jìn)行的關(guān)于運(yùn)動(dòng)改善MCI患者認(rèn)知功能的臨床研究見表1。

表1正在進(jìn)行的關(guān)于運(yùn)動(dòng)對MCI患者認(rèn)知改善的臨床研究

注：NCT，國家臨床試驗(yàn)；MCI，輕度認(rèn)知功能障礙；aMCI，遺忘型輕度認(rèn)知功能障礙；mSIM，基于移動(dòng)的同步運(yùn)動(dòng)和記憶技能訓(xùn)練計(jì)劃；ACT，有氧練習(xí)聯(lián)合認(rèn)知訓(xùn)練。

2運(yùn)動(dòng)改善MCI患者認(rèn)知功能的機(jī)制

運(yùn)動(dòng)改善認(rèn)知的內(nèi)在機(jī)制尚未完全闡明。然而，運(yùn)動(dòng)誘導(dǎo)的大腦獲益很大程度上與神經(jīng)發(fā)生、神經(jīng)元存活和突觸可塑性有關(guān)。事實(shí)上，體育鍛煉可能促進(jìn)腦源性神經(jīng)營養(yǎng)因子（brain derived neurotrophic factor，BDNF）等神經(jīng)營養(yǎng)因子的產(chǎn)生、調(diào)節(jié)血清素和犬尿氨酸代謝、誘導(dǎo)肌腦交互作用中的肌細(xì)胞因子、增強(qiáng)抗炎反應(yīng)和線粒體介導(dǎo)的調(diào)節(jié)作用[22]。然而，一項(xiàng)meta分析的亞組分析證實(shí)，運(yùn)動(dòng)干預(yù)增加了MCI患者血清中BDNF水平，但趨勢不顯著（SMD=1.07；95%CI：-0.14~2.28；I2= 86%；P=0.080）。產(chǎn)生這種不確定結(jié)果的原因可能是統(tǒng)計(jì)效力低，也可能是認(rèn)知功能受損導(dǎo)致MCI患者按要求進(jìn)行運(yùn)動(dòng)干預(yù)的能力降低[23]，這也是與個(gè)人運(yùn)動(dòng)處方計(jì)劃相關(guān)的因素。另一個(gè)有趣的領(lǐng)域是線粒體和肌-腦軸的作用，BURTSCHER等[24]證實(shí)，在體育鍛煉后，骨骼肌中的線粒體會(huì)被激活，并分泌包括肌細(xì)胞因子、代謝產(chǎn)物和微小核糖核酸在內(nèi)的循環(huán)因子，直接或間接地改善大腦線粒體健康，并可能使認(rèn)知達(dá)到更好的狀態(tài)。此外，有氧系統(tǒng)在決定長時(shí)間高強(qiáng)度運(yùn)動(dòng)的表現(xiàn)方面起著重要作用[7]。過度活躍的有氧系統(tǒng)結(jié)合無氧糖酵解可能觸發(fā)蛋白質(zhì)的表達(dá)，這些蛋白將參與線粒體的產(chǎn)生和能量的生產(chǎn)，激活的有氧系統(tǒng)和糖酵解也會(huì)誘導(dǎo)氧化磷酸化相關(guān)蛋白的翻譯，并促進(jìn)骨骼肌中ATP的生成[24]。此外，劇烈運(yùn)動(dòng)會(huì)引起循環(huán)干細(xì)胞和祖細(xì)胞數(shù)量的增加，并同時(shí)啟動(dòng)內(nèi)源性神經(jīng)干細(xì)胞的動(dòng)員[25-26 ]。這些分子或細(xì)胞通路可以直接促進(jìn)海馬神經(jīng)元的活化和提高其可塑性，也可以通過增加腦血容量和毛細(xì)血管密度、改善全身情況等間接影響神經(jīng)元[22, 27]。有證據(jù)表明，認(rèn)知功能下降患者在接受體育訓(xùn)練后海馬體積增大[3]。

另一方面，β-淀粉樣蛋白（β-amyloid，Aβ）斑塊和細(xì)胞內(nèi)神經(jīng)纖維纏結(jié)的累積、tau蛋白的過度磷酸化是AD的主要特征，并被認(rèn)為是導(dǎo)致腦體積減小和腦功能下降的原因[28]。來自動(dòng)物研究的證據(jù)表明，運(yùn)動(dòng)可能有助于抑制Aβ產(chǎn)生和促進(jìn)大腦中Aβ清除[28]。同時(shí)，有證據(jù)表明，體育鍛煉水平可能會(huì)影響大腦、腦脊液和人體血液中的Aβ水平[29]。LIANG等[30]發(fā)現(xiàn)，達(dá)到美國心臟協(xié)會(huì)指導(dǎo)方針即7.5代謝當(dāng)量小時(shí)/周運(yùn)動(dòng)的個(gè)體（n=69），表現(xiàn)出明顯較低的匹茲堡化合物B（Pittsburgh compound B，PiB，它是硫黃素T的類似物，是淀粉樣蛋白成像最常用的示蹤劑）結(jié)合水平和較高的腦脊液Aβ42水平，提示一種更健康的淀粉樣蛋白譜。載脂蛋白E（apolipoprotein E，APOE）ε4等位基因是散發(fā)性AD最強(qiáng)的已知遺傳危險(xiǎn)因素[31]。它與Aβ聚集率升高、大腦Aβ清除減少、認(rèn)知能力下降和神經(jīng)易損性增加有關(guān)[28]。先前的研究表明，高水平體育活動(dòng)可能會(huì)降低APOE ε4載體帶來的Aβ沉積風(fēng)險(xiǎn)的增加[32]。此外，BROWN等[33]證實(shí)，在報(bào)告最高體力活動(dòng)水平且認(rèn)知功能正常的老年人中，正電子發(fā)射掃描量化的tau蛋白水平較低。然而，隨著關(guān)于Aβ和tau的檢測技術(shù)發(fā)展，我們希望有更多專門設(shè)計(jì)的、以運(yùn)動(dòng)為重點(diǎn)的隨機(jī)對照研究，并把運(yùn)用金標(biāo)準(zhǔn)測量的Aβ和tau作為結(jié)果。此外，探明運(yùn)動(dòng)的神經(jīng)保護(hù)機(jī)制也有助于藥物的開發(fā)（圖1）。

圖1運(yùn)動(dòng)改善MCI患者認(rèn)知功能的可能分子和細(xì)胞機(jī)制 注：Aβ，β淀粉樣蛋白。

不同形式的體育鍛煉可以通過作用于大腦不同區(qū)域來提高認(rèn)知能力。據(jù)報(bào)道，有氧運(yùn)動(dòng)與海馬的激活有關(guān)，而瑜伽則激活負(fù)責(zé)整合思想和情緒的額葉和島葉。此外，舉重通過對前額葉皮層作用來提高執(zhí)行功能。在一項(xiàng)縱向研究中，對接受6周運(yùn)動(dòng)訓(xùn)練的年輕成人進(jìn)行功能和結(jié)構(gòu)MRI研究，結(jié)果顯示額頂葉的網(wǎng)絡(luò)連通性增加，并與認(rèn)知功能的改善一致?；屹|(zhì)結(jié)構(gòu)改變也與前額葉和輔助運(yùn)動(dòng)區(qū)的功能連通性改變密切相關(guān)[34]。此外，阻力訓(xùn)練已經(jīng)被發(fā)現(xiàn)可以調(diào)節(jié)皮質(zhì)脊髓的適應(yīng)力和減少白質(zhì)病變體積[6]?？偟膩碚f，這些證據(jù)表明，一般性運(yùn)動(dòng)可能不能充分調(diào)動(dòng)運(yùn)動(dòng)在MCI中的治療潛力，包括內(nèi)定模態(tài)網(wǎng)絡(luò)、額頂網(wǎng)絡(luò)和額葉執(zhí)行網(wǎng)絡(luò)等腦網(wǎng)絡(luò)是認(rèn)知衰退干預(yù)的潛在靶點(diǎn)[35]。基于個(gè)體認(rèn)知域損傷的精確運(yùn)動(dòng)處方是可取的，這可能需要不同強(qiáng)度、持續(xù)時(shí)間和休息時(shí)間的鍛煉計(jì)劃，以最大限度地發(fā)揮運(yùn)動(dòng)對大腦健康的促進(jìn)作用。

3展望

遠(yuǎn)程鍛煉指導(dǎo)或遠(yuǎn)程監(jiān)督體育鍛煉處于對抗認(rèn)知衰退的新前線。MCI患者的短期運(yùn)動(dòng)干預(yù)通常在醫(yī)院的健康中心進(jìn)行，鑒于持續(xù)的運(yùn)動(dòng)可以提供長期保護(hù)作用，對MCI患者來說，長期的運(yùn)動(dòng)計(jì)劃是必要的。然而，長期堅(jiān)持有氧運(yùn)動(dòng)對MCI患者來說是一項(xiàng)挑戰(zhàn)，因?yàn)檫@需要收集生理數(shù)據(jù)，并測量運(yùn)動(dòng)強(qiáng)度。新的文獻(xiàn)表明，遠(yuǎn)程醫(yī)療是家庭認(rèn)知訓(xùn)練的理想手段。在家鍛煉可能是一個(gè)可行的選擇，因?yàn)樗奖銜r(shí)間安排，有良好的可接受性。在以家庭為基礎(chǔ)的環(huán)境中，遠(yuǎn)程鍛煉項(xiàng)目可以在家庭或附近社區(qū)的支持下，由專業(yè)教練提供遠(yuǎn)程監(jiān)督，從而提高患者的依從性和提高鍛煉的有效性。例如，Vivifrail項(xiàng)目是一個(gè)以家庭為基礎(chǔ)的鍛煉項(xiàng)目，其重點(diǎn)是根據(jù)老年人的功能能力制定個(gè)性化的多組分鍛煉處方，經(jīng)過12周的訓(xùn)練，試驗(yàn)組和對照組的認(rèn)知功能和握力具有顯著差異[36]。另一方面，較低的握力已被發(fā)現(xiàn)與較高的全因癡呆發(fā)病率和死亡率相關(guān)，獨(dú)立于重要的混雜因素[37]?？傊樟赡苁且环N很有希望的評估體育鍛煉效果的方法，也可能是認(rèn)知能力下降的預(yù)測指標(biāo)。綜上所述，未來的研究需要考慮不同運(yùn)動(dòng)強(qiáng)度和運(yùn)動(dòng)時(shí)長的影響、運(yùn)動(dòng)/休息恢復(fù)比以及更合適的測量方法。此外，與單純的步行、跑步或游泳相比，在運(yùn)動(dòng)中含有技巧元素的鍛煉方式可能會(huì)帶來更大的益處。

（參考文獻(xiàn)同英文版）

1Exercise and combined intervention can improve cognitive function in patients with MCI

Alzheimer disease (AD) is the most common cause of dementia and a major public health problem[1]. Mild cognitive impairment (MCI) due to AD is a prodromal stage of AD where there are notable signs of cognitive impairment. However, MCI does not interfere with activities of daily life. Although there is no cure for AD, accumulated evidence suggests that physical activity may reduce the conversion rates from MCI to dementia[2].

Exercise is a form of physical activity aimed to improve health and well-being. There are two distinct types of exercise training: aerobic training and resistance training[3]. Aerobic exercise can improve aerobic capacity, thereby enhancing cardiopulmonary capacity and reducing cerebrovascular disease, mobility limitations and disability[4]. Aerobic exercise includes many commonly practiced exercises such as brisk walking, jogging, water aerobics, swimming, dancing, or bicycle riding[5]. In addition, tai chi, yoga and several special forms of exercises can also be classified as aerobic exercise when the intensity of exercise meets the required demands of the aerobic exergy supply system. On the other hand, resistance exercise is usually performed by athletic populations and individuals who would like to induce neuromuscular adaptations to increase muscle size and performance[6]. These types of exercises are anaerobic in nature, and the fuel for energy provision comes predominantly from anaerobic glycolysis and the breakdown of adenosine triphosphate (ATP). The energy supply from these metabolic pathways is very rapid and facilitates strong powerful contractions over short time periods[7]. Aerobic metabolism increases as the duration of the activity becomes longer and decreases in intensity occur.

Both aerobic training and resistance training enhance cognitive performance in healthy, community-dwelling seniors and improve the overall cognitive performance of patients with MCI[2, 8-12 ]. However, the positive outcomes are highly associated with intensity, duration and frequency of exercise. For example, shorter duration training sessions and higher frequencies may have greater cognitive effects in that short sessions may induce less fatigue, the condition associated with the ability and motivation to exercise[13]. On the other hand, the action of exercise on the different domains of cognition remains diverse due to the heterogeneity of research[10, 14].

In a meta-analysis, TALAR et al. concluded that there were no statistically significant effects of aerobic exercise on working memory and executive function[14]. In contrast, in a clinical trial which participants in both the aerobic and stretching groups performed high-intensity activity routines 4 d/wk for 45 to 60 minutes per session for 6 months demonstrated favorable results. Both groups achieved a better executive control processes of multitasking, cognitive flexibility, information processing efficiency, and selective attention[11]. Moreover, there is evidence that aerobic exercise improves immediate recall ability as well as delayed recall ability but not cognitive domain of intention, executive ability, verbal fluency or visuospatial function[10].

Similarly, resistance training may promote executive function and associative memory in patients with MCI[8-9 ]. Interestingly, ZHU et al. discovered a trend that implementation of isometric handgrip exercise has a beneficial chronic effect on cognitive performance, while the rigorous methodological approach is needed to evaluate the feasibility and effectiveness of the exercise[15]. Yoga is a typical aerobic exercise with a focus on interactions among the brain, body and mind. Eyre’s study found that Kundalini yoga had similar improvements on memory during cognitive training, with additional beneficial effects on executive functioning and mood symptoms[16]. Additionally, Tai chi, as one of the traditional Chinese sports, showed evidence on improving cognitive performance, memory, attention, language and executive functions in older adults with MCI[17]. The controversial findings suggest that there are complex relationships between physical exercise and cognition. Given that the types and/or settings of aerobic exercise vary from one another, the precise effect on the cognition domains require more scientific original studies in the future.

Theoretically, the combination of different interventions may provide better protection on cognition in patients with MCI. Indeed, combinations of aerobic exercise and cognitive training, have been shown to reduce the decline of visual memory and verbal fluency and improve executive function[18]. A meta-analysis also demonstrated a positive small-to-medium effect of combined cognitive-physical exercise interventions on global cognitive function in older adults with MCI or dementia (SMD=0.32 [0.17;0.47], P<0.00)，without significant heterogeneity across the studies[19]. However, inadequate combinations may be less effective. For instance, patients receiving full doses of resistance training and cognitive training performed significantly poorer compared with isolated progressive resistance training on executive and global domains[20]. This may be due to the excessive stress of the combined intervention, which was both mentally and physically challenging. As a result, patients may be less engaged with home or community-based activities. Alternatively, combinations may induce side effects that inhibit rather than promote neural plasticity and cognitive benefits[20]. Further to this, the exercise training mode should be provided and prescribed to the patients on an individual basis. This will ensure that the modalities of exercise are prescribed at the correct intensities for individual subjects.

One interesting research direction would be to combine physical exercise with transcranial direct current stimulation (tDCS) or transcranial magnetic stimulation (TMS), non-invasive tools to enhance cognition. Although the relevant literature in this area is limited, emerging evidence suggests that concurrent anodal tDCS and Taichi training was superior to a sham stimulation with Taichi training in improving cognitive dual-task walking[21].

Ongoing clinical studies on exercise improving cognitive function in patients with MCI are shown in Table 1.

2The mechanisms of exercise improving cognitive function in MCI patients

The underlying mechanisms have not yet been fully elucidated. However, exercise-induced brain benefits are largely related to neurogenesis, neuronal survival, and synaptic plasticity. Indeed, physical exercise may promote the production of neurotrophins such as brain-derived neurotrophic factor (BDNF), modulate serotonin and kynurenine metabolism, induce myokines in muscle-brain crosstalk, increase anti-Inflammatory response and mitochondrial-mediated regulation[22].

However, subgroup analyses of a meta study confirmed that exercise interventions increased plasma BDNF levels for MCI with a non-significant trend (SMD= 1.07; 95% CI: -0.14~2.28; I2=86%; P=0.080). The indeterminate result might be potentially due to low statistical power, but also to the reduced ability of MCI patients to comply with the prescribed exercise interventions because of their cognitive impairment[23]. This is another factor related to individual exercise preion regimes.

Another interesting field is the role of the mitochondria and the muscle-brain axis. BURTSCHER et al. demonstrated that mitochondria in the skeletal muscle will be activated after physical exercise and secreting circulating factors including myokines, metabolites and microRNAs, which directly and indirectly improve brain mitochondria health, possibly resulting in a better cognitive state[24]. Moreover, the aerobic system plays a significant role in determining performance during high-intensity exercise over long exercise periods[7]. An overactive aerobic system in combination with anaerobic glycolysis may be a trigger to upregulate proteins involved in mitochondrial biogenesis and energy production, to induce the translation of oxidative phosphorylation-linked proteins, and to improve ATP generation in skeletal muscle[24].

Besides, acute exercise elicits an increase in circulating stem and progenitor cell numbers, while the mobilization of endogenous neural stem cells also begins[25-26 ]. Together, these molecular or cellular pathways may directly increase hippocampal neuronal activation and plasticity in turn, or indirectly affect neurons through increases in cerebral blood volume capillary densities, as well as improvement in whole body situation[22, 27]. Increased hippocampal volume has also been observed following physical training in people with cognition decline[3].

On the other hand, beta-amyloid (Aβ) plaques and intracellular accumulation of neurofibrillary tangles, hyperphosphorylated tau proteins, are the primary hallmarks of AD, and are proposed to contribute to a decline in brain volume and function[28]. Comprising evidence from animal studies suggests that exercise may contribute to both the inhibition of Aβ production and enhancement of Aβ clearance in the brain[28]. Meanwhile, there is evidence that physical exercise levels might affect Aβ levels in the brain, cerebrospinal fluid (CSF), and blood in human bodies[29]. LIANG et al. found that individuals (n=69) meeting the American Heart Association guidelines of 7.5 metabolic equivalent (MET) hours/week of exercise showed significantly lower PiB（The Pittsburgh compound B, which is the analogue of thioflavin T, is the most commonly used tracer for amyloid imaging）binding and higher levels of Aβ42in the CSF, indicating a healthier amyloid profile[30]. The Apolipoprotein E (APOE) ε4 allele is the strongest known genetic risk factor for sporadic onset AD[31]. It is associated with higher rates of Aβ aggregation, reduced clearance of Aβ from the brain, increased rate of cognitive decline and neuronal vulnerability[28]. Previous research suggested higher levels of physical activities may lead to mitigating the increased risk of Aβ deposition conferred by APOE ε4 carriage[32]. Besides, BROWN et al. demonstrated lower levels of PET-quantified tau in cognitively normal older adults reporting the highest levels of physical activity[33]. However, as the measurements of Aβ and tau are developing，studies applying gold-standard tau and Aβ measurements as outcome measures in specifically designed exercise-focused randomized controlled trials are expected. Furthermore, identification neuroprotective mechanism by exercise may also contribute to drug development (Figure 1).

Figure 1Possible molecular and cellular mechanisms of exercise improving cognitive function in MCI patients

Different forms of physical exercise may improve cognitive ability by targeting different areas of the brain. Aerobic exercise has been reported to be associated with the activation of the hippocampus, while Yoga activates the frontal lobe and insula, which are responsible for integrating thoughts and emotions. In addition, lifting weights boosts executive function through the action on the prefrontal cortex. Longitudinal functional and structural MRI study of young adults who accepted a 6-week motor training showed increased fronto-parietal network connectivity in accordance with cognitive performance improvements. The structural gray matter alterations were also tightly correlated with functional connectivity changes in prefrontal and supplementary-motor areas[34]. Moreover, resistance training has been found to modulate corticospinal adaptations and lower white matter lesion volume[6]. Collectively, this evidence suggests that generic exercise may not take full advantage of therapeutic potential of exercise in MCI. Several brain networks including Default Mode Network mainly, Fronto-Parietal Network and Fronto-Executive Network are potential targets for the interventions of cognitive decline[35]. Precision exercise preion based on individual cognitive domain impairment is desirable. This may require exercise regimes of different intensities, durations and rest recovery periods to maximize the full benefits of exercise on brain health.

3Expectations

Tele-exercise or remoted-supervised physical exercise is a new frontline in the battle against cognitive decline. Short-term exercise interventions in MCI people were usually conducted in hospitals health centers. Given that sustainable exercise can provide long-term protective effects, a long-term exercise program is necessary for MCI patients. However, long-term adherence to aerobic exercise is challenging for patients with MCI in that the physiological data needs to be collected and needs to be measured for the establishment of exercise intensity. Home-based Emerging literature has demonstrated that telemedicine is an ideal tool for home-based cognitive training. Home-based exercise may be a feasible option because of its convenient schedule and easy acceptability. In the home-based setting, tele-exercise programs can provide remote supervision by professional trainers while being supported by the family or near communities, thus improving patient adherence and increasing effectiveness of exercise. For instance, the Vivifrail programme was a home-based exercise programme focused on individualized multicomponent exercise preion according to the functional capacity of the older adults. After 12 weeks of training, significant differences were observed for cognitive function and handgrip strength[36]. On the other hand, lower handgrip strength has been found to be associated with a higher risk of all-cause dementia incidence and mortality, independent of important confounding factors[37]. Together, handgrip strength may be a promising measurement for the effect of physical exercise as well as a predictor for cognitive decline. In conclusion, future research needs to consider the effects of different intensities of exercise, the effects of different durations, work to rest recovery ratios and more suitable measurements. Further to this, exercise modalities that have an element of skill in the exercise being performed may provide greater benefits than simply walking, running or swimming.

Table 1Ongoing clinical studies of exercise on cognitive improvement in patients with MCI

1.LI J Q, TAN L, WANG H F, et al. Risk factors for predicting progression from mild cognitive impairment to Alzheimer's disease: a systematic review and meta-analysis of cohort studies[J]. J Neurol Neurosurg Psychiatry, 2016, 87(5): 476-484.

2.LAW C K, LAM F M, CHUNG R C, et al. Physical exercise attenuates cognitive decline and reduces behavioural problems in people with mild cognitive impairment and dementia: a systematic review[J]. J Physiother, 2020, 66(1): 9-18.

3.TEN BRINKE L F, BOLANDZADEH N, NAGAMATSU L S, et al. Aerobic exercise increases hippocampal volume in older women with probable mild cognitive impairment: a 6-month randomised controlled trial[J]. Br J Sports Med, 2015, 49(4): 248-254.

4.NEWMAN A B, KUPELIAN V, VISSER M, et al. Strength, but not muscle mass, is associated with mortality in the health, aging and body composition study cohort[J]. J Gerontol A Biol Sci Med Sci, 2006, 61(1): 72-77.

8.LIU-AMBROSE T, NAGAMATSU L S, GRAF P, et al. Resistance training and executive functions: a 12-month randomized controlled trial[J]. Arch Intern Med, 2010, 170(2): 170-178.

9.NAGAMATSU L S, HANDY T C, HSU C L, et al. Resistance training promotes cognitive and functional brain plasticity in seniors with probable mild cognitive impairment[J]. Arch Intern Med, 2012, 172(8): 666-668.

10.ZHENG G, XIA R, ZHOU W, et al. Aerobic exercise ameliorates cognitive function in older adults with mild cognitive impairment: a systematic review and meta-analysis of randomised controlled trials[J]. Br J Sports Med, 2016, 50(23): 1443-1450.

11.BAKER L D, FRANK L L, FOSTER-SCHUBERT K, et al. Effects of aerobic exercise on mild cognitive impairment: a controlled trial[J]. Arch Neurol, 2010, 67(1): 71-79.

16.EYRE HA, SIDDARTH P, ACEVEDO B, et al. A randomized controlled trial of Kundalini yoga in mild cognitive impairment[J]. Int Psychogeriatr, 2017, 29(4): 557-567.

17.ZHENG G, LIU F, LI S, et al. Tai Chi and the Protection of Cognitive Ability: A Systematic Review of Prospective Studies in Healthy Adults[J]. Am J Prev Med, 2015, 49(1): 89-97.

18.LISSEK V J, BEN ABDALLAH H, PRAETORIUS A, et al. go4cognition: Combined Physiological and Cognitive Intervention in Mild Cognitive Impairment[J]. J Alzheimers Dis, 2022, 89(2): 449-462.

19.KARSSEMEIJER E G A, AARONSON J A, BOSSERS W J, et al. Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[J]. Ageing Res Rev, 2017, 40: 75-83.

20.FIATARONE SINGH M A, GATES N, SAIGAL N, et al. The Study of Mental and Resistance Training (SMART) study-resistance training and/or cognitive training in mild cognitive impairment: a randomized, double-blind, double-sham controlled trial[J]. J Am Med Dir Assoc, 2014, 15(12): 873-880.

22.LIU Y, YAN T, CHU J M, et al. The beneficial effects of physical exercise in the brain and related pathophysiological mechanisms in neurodegenerative diseases[J]. Lab Invest, 2019, 99(7): 943- 957.

23.RUIZ-GONZALEZ D, HERNANDEZ-MARTINEZ A, VALENZUELA P L, et al. Effects of physical exercise on plasma brain-derived neurotrophic factor in neurodegenerative disorders: A systematic review and meta-analysis of randomized controlled trials[J]. Neurosci Biobehav Rev, 2021, 128: 394-405.

24.BURTSCHER J, MILLET G P, PLACE N, et al. The Muscle-Brain Axis and Neurodegenerative Diseases: The Key Role of Mitochondria in Exercise-Induced Neuroprotection[J]. Int J Mol Sci, 2021, 22(12): 6479.

25.SCHMID M, KROPFL J M, SPENGLER C M. Changes in Circulating Stem and Progenitor Cell Numbers Following Acute Exercise in Healthy Human Subjects: a Systematic Review and Meta-analysis[J]. Stem Cell Rev Rep, 2021, 17(4): 1091-1120.

27.TARUMI T, ZHANG R. Cerebral hemodynamics of the aging brain: risk of Alzheimer disease and benefit of aerobic exercise[J]. Front Physiol, 2014, 5: 6.

28.BROWN B M, PEIFFER J, RAINEY-SMITH S R. Exploring the relationship between physical activity, beta-amyloid and tau: A narrative review[J]. Ageing Res Rev, 2019, 50: 9-18.

29.BRINI S, SOHRABI H R, PEIFFER J J, et al. Physical Activity in Preventing Alzheimer's Disease and Cognitive Decline: A Narrative Review[J]. Sports Med, 2018, 48(1): 29-44.

30.LIANG K Y, MINTUN M A, FAGAN A M, et al. Exercise and Alzheimer's disease biomarkers in cognitively normal older adults[J]. Ann Neurol, 2010, 68(3): 311-318.

31.CORDER E H, SAUNDERS A M, STRITTMATTER W J, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families[J]. Science, 1993, 261(5123): 921-923.

32.BROWN B M, PEIFFER J J, TADDEI K, et al. Physical activity and amyloid-beta plasma and brain levels: results from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing[J]. Mol Psychiatry, 2013, 18(8): 875-881.

33.BROWN B M, RAINEY-SMITH S R, DORE V, et al. Self-Reported Physical Activity is Associated with Tau Burden Measured by Positron Emission Tomography[J]. J Alzheimers Dis, 2018, 63(4): 1299-1305.

34.TAUBERT M, LOHMANN G, MARGULIES D S, et al. Longterm effects of motor training on resting-state networks and underlying brain structure[J]. Neuroimage, 2011, 57(4): 1492-1498.

35.HUANG P, FANG R, LI B Y, et al. Exercise-Related Changes of Networks in Aging and Mild Cognitive Impairment Brain[J]. Front Aging Neurosci, 2016, 8: 47.

36.CASAS-HERRERO A, SAEZ D E, ASTEASU M L, et al. Effects of Vivifrail multicomponent intervention on functional capacity: a multicentre, randomized controlled trial[J]. J Cachexia Sarcope?nia Muscle, 2022, 13(2): 884-893.

37.Esteban-Cornejo I, Ho FK, Petermann-Rocha F, et al. Handgrip strength and all-cause dementia incidence and mortality: find?ings from the UK Biobank prospective cohort study[J]. J Cachexia Sarcopenia Muscle, 2022, 13(3): 1514-1525.

Physical exercise： a promising non-pharmacological intervention for patients with mild cognitive impairment

LI Yucheng Julien Baker

Department of Neurology， The First Affiliated Hospital， Sun Yatsen University

Hong Kong Baptist University

Abstract:Mild cognitive impairment (MCI) occurs in the early stage of Alzheimer disease (AD). Non-pharmacological interventions are one of the ways to improve the cognitive function of MCI patients. Among the non-pharmacological interventions, physical exercise is attracting more and more attention. This article reviews the effects of physical exercise on cognitive improvement in MCI patients, so as to provide ideas for the treatment and management of MCI. Physical training can be divided into aerobic training and resistance training. Both training methods can improve the overall cognitive function of MCI patients, but the effects of different exercises on different cognitive domains are still unclear. In addition, physical training combined with other non-pharmacological interventions also shows a certain potential for cognitive improvement in MCI patients. On the other hand, the mechanisms by which exercise improves cognition are related to neurogenesis, neuronal survival, and synaptic plasticity, which can be interpreted both at the molecular cellular level and from a macroscopic perspective such as organ. Finally, this paper provides conducting homogeneous research, exploration of exercise preion and implementation of remote exercise management as possible directions for MCI and exercise related research.

Keywords:Mild cognitive impairment；Alzheimer disease；Physical exercise；Non-pharmacological intervention；Cognition

聲明：本文作者享有本文著作權(quán)，《中國神經(jīng)精神疾病雜志》專有本文出版權(quán)和信息網(wǎng)絡(luò)傳播權(quán),轉(zhuǎn)載請注明作者與出處。部分圖轉(zhuǎn)自網(wǎng)絡(luò)。

初審：李立

審核：邢世會(huì)

審定發(fā)布：張為西返回搜狐，查看更多

責(zé)任編輯：