口腔健康不良對(duì)認(rèn)知障礙影響的研究進(jìn)展

范　曉(綜述)　劉偉才(審校)

(同濟(jì)大學(xué)口腔醫(yī)學(xué)院修復(fù)教研室,上海牙組織修復(fù)與再建工程技術(shù)研究中心　上海　200072)

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口腔健康不良對(duì)認(rèn)知障礙影響的研究進(jìn)展

范曉(綜述)劉偉才△(審校)

(同濟(jì)大學(xué)口腔醫(yī)學(xué)院修復(fù)教研室,上海牙組織修復(fù)與再建工程技術(shù)研究中心上海200072)

認(rèn)知障礙與口腔健康不良常同時(shí)發(fā)生。許多學(xué)者提出認(rèn)知障礙引起口腔健康不良,例如增高齲病發(fā)病率、加速牙周病進(jìn)展以及增加牙缺失數(shù),這可能是由于患者忽視或者不能夠進(jìn)行日常口腔衛(wèi)生護(hù)理造成的。然而,越來(lái)越多的研究從不同方面證實(shí)口腔健康與認(rèn)知障礙具有雙向關(guān)系,即口腔問(wèn)題可能不僅僅是認(rèn)知損害的結(jié)果,也是認(rèn)知損害的原因。其機(jī)制可能涉及感染、咀嚼功能、營(yíng)養(yǎng)不良以及社會(huì)經(jīng)濟(jì)狀況。也有認(rèn)為口腔健康不良與認(rèn)知下降有共同的危險(xiǎn)因素,例如心血管疾病以及社會(huì)經(jīng)濟(jì)狀況。本文就現(xiàn)階段口腔問(wèn)題與認(rèn)知障礙相關(guān)的流行病學(xué)證據(jù)及可能機(jī)制進(jìn)行綜述。

牙缺失;牙周炎;咀嚼;營(yíng)養(yǎng);社會(huì)經(jīng)濟(jì)狀況;海馬;認(rèn)知

牙齒是口腔健康的重要組成部分,對(duì)美觀、發(fā)音具有重要意義。此外,良好的咀嚼功能有助于營(yíng)養(yǎng)的吸收,對(duì)身體健康有重要影響。認(rèn)知涉及到心理過(guò)程,包括注意力、記憶力、生成并理解語(yǔ)言、解決問(wèn)題及做決定等方面。人的一生中,認(rèn)知功能都在發(fā)生變化,認(rèn)知功能下降是癡呆癥的早期征象之一。其中,阿爾茨海默病 (Alzheimer disease,AD)發(fā)病率最高,患者常出現(xiàn)記憶和語(yǔ)言功能障礙;血管性癡呆除上述癥狀外還會(huì)出現(xiàn)情緒性格的變化[1]。癡呆癥的患者由于認(rèn)知功能下降,會(huì)忽視或者不能夠進(jìn)行日常口腔衛(wèi)生的護(hù)理,更有可能發(fā)生齲病、牙周炎、口腔衛(wèi)生不佳的情況[2-3]。近年來(lái),越來(lái)越多研究從不同方面證實(shí)口腔健康與認(rèn)知功能具有雙向關(guān)系——即口腔問(wèn)題可能不僅僅是認(rèn)知障礙的結(jié)果,也是認(rèn)知損害的危險(xiǎn)因素。

口腔健康對(duì)認(rèn)知的影響在針對(duì)老年人的隨訪調(diào)查中發(fā)現(xiàn),較高的牙齦指數(shù)、牙齦炎與認(rèn)知障礙相關(guān)[4]。缺牙數(shù)以及引起牙缺失的牙周炎、齲病可能預(yù)示著認(rèn)知功能下降[5]。Luo等[6]則首次報(bào)道中國(guó)老年人缺牙數(shù)在16顆以上與癡呆癥呈正相關(guān)。在對(duì)逾一萬(wàn)名2型糖尿病患者進(jìn)行的前瞻性隨訪研究發(fā)現(xiàn),牙齒少或無(wú)牙頜者記憶或執(zhí)行的認(rèn)知表現(xiàn)不佳[7]。隨時(shí)間進(jìn)展,余留牙越少則認(rèn)知損害越重[8]。

中年人不能進(jìn)行日?？谇蛔o(hù)理可能是認(rèn)知改變的早期征象。Naorungroj等[3]對(duì)美國(guó)4個(gè)州的中年人進(jìn)行了6年的隨訪,發(fā)現(xiàn)認(rèn)知功能下降與缺牙數(shù)的增加相關(guān)。此外,也與低刷牙頻率、菌斑堆積、無(wú)牙頜相關(guān),但與牙周病無(wú)關(guān)。他們另一個(gè)研究[9]發(fā)現(xiàn),中老年無(wú)牙頜者記憶和語(yǔ)言測(cè)試結(jié)果相較于有牙頜者更差。全牙列的缺失與認(rèn)知功能密切相關(guān),但無(wú)牙頜、余留牙數(shù)或牙周病并不能預(yù)示著認(rèn)知功能下降。兩個(gè)實(shí)驗(yàn)在無(wú)牙頜患者認(rèn)知下降的速度上得出了相反的結(jié)論,作者總結(jié)認(rèn)為可能由于參與人群的不同導(dǎo)致。

在日本老年人中,缺牙但未恢復(fù)、未定期檢查牙齒個(gè)體癡呆癥的發(fā)病風(fēng)險(xiǎn)較高[10]。Elsig等[11]與Lexomboon等[12]認(rèn)為咀嚼能力對(duì)認(rèn)知的影響相較于余留天然牙數(shù)量要大,使用義齒的人未出現(xiàn)認(rèn)知障礙。

口腔健康對(duì)認(rèn)知影響的機(jī)制

牙周炎牙周炎是常見(jiàn)口腔疾病,由細(xì)菌感染引起。牙周炎致病菌會(huì)引起系統(tǒng)性感染,其血清抗體被看做是AD和輕度認(rèn)知損害保護(hù)性的危險(xiǎn)標(biāo)志物,AD患者血清常見(jiàn)牙周致病菌內(nèi)氏放線菌[13]、中間普氏菌和具核梭桿菌[14]的抗體含量明顯高于對(duì)照組。據(jù)美國(guó)健康與營(yíng)養(yǎng)調(diào)查(National Health And Nutrition Examination Survey,NHANES Ⅲ)對(duì)60歲以上老年人的統(tǒng)計(jì)結(jié)果,牙齦卟啉單細(xì)胞菌的血清標(biāo)志物含量越高,則認(rèn)知表現(xiàn)越差[15]。此外,慢性牙周炎會(huì)引起身體釋放促炎因子,后者可能隨體循環(huán)到達(dá)腦部,加重感染過(guò)程以及血管病變。在AD和健康老年人中,血清TNF-α以及IL-6的含量有所差異[16-17]。AD是一種神經(jīng)系統(tǒng)退行性疾病,中樞或周?chē)M織的炎性反應(yīng)在發(fā)病過(guò)程中發(fā)揮了重要作用。因此,有提出慢性牙周炎是AD的病因之一。也有研究證實(shí),多顆牙缺失與急性缺血性腦卒中造成的血管性認(rèn)知障礙相關(guān)[18]。腦卒中多與動(dòng)脈粥樣硬化相關(guān)。牙周炎患者C反應(yīng)蛋白 (C reactive protein,CRP)增加含量高,頸動(dòng)脈內(nèi)膜中層厚度增加,更容易發(fā)生動(dòng)脈粥樣硬化[19]。此外,也有研究發(fā)現(xiàn)齒垢密螺旋體水平較高的患者高密度脂蛋白含量較低,因此更容易發(fā)生動(dòng)脈粥樣硬化[20]。因此,也有人認(rèn)為慢性牙周炎是腦卒中的病因之一。

此外,也有人提出或許心腦血管疾病是牙周炎與認(rèn)知下降的共同危險(xiǎn)因素[21-22]。究竟三者為何關(guān)系有待進(jìn)一步研究確認(rèn)。

咀嚼咀嚼增加覺(jué)醒水平、警覺(jué)性以及對(duì)運(yùn)動(dòng)控制的效果,這些效應(yīng)可能改善認(rèn)知能力[23]。Morgan等[24]研究了口香糖對(duì)Bakan型警戒任務(wù)的影響,這種任務(wù)需要不斷更新短期命令記憶。相較于對(duì)照組,口香糖組的主觀警覺(jué)性降幅小,且校正反應(yīng)時(shí)間的降幅在任務(wù)后期也明顯短于對(duì)照組,這些發(fā)現(xiàn)與Tucha 等[25]一致。Allen等[26]從心率、腦電圖等方面證實(shí)咀嚼對(duì)警覺(jué)的易化作用。也有研究發(fā)現(xiàn)口香糖對(duì)短期記憶[27]、警覺(jué)性[28]有負(fù)性影響,推測(cè)參與者因咀嚼口香糖而分心[29]。

Onyper等[30]在學(xué)生中進(jìn)行了咀嚼對(duì)認(rèn)知功能影響的試驗(yàn),發(fā)現(xiàn)試驗(yàn)前5 min咀嚼可以提高測(cè)試環(huán)節(jié)的前15～20 min認(rèn)知任務(wù)表現(xiàn)。因此,咀嚼的益處是有時(shí)限的并且與其引起的覺(jué)醒相關(guān)。Smith等[31]發(fā)現(xiàn)咀嚼可提高皮質(zhì)醇濃度,認(rèn)為其激活了神經(jīng)系統(tǒng),提高警覺(jué)性表現(xiàn)。但也有研究人員發(fā)現(xiàn)受試者皮質(zhì)醇含量在咀嚼口香糖前后并無(wú)明顯差異[32],由于皮質(zhì)醇一日內(nèi)不同時(shí)間點(diǎn)的分泌量并不恒定,試驗(yàn)時(shí)間可能對(duì)結(jié)果產(chǎn)生影響。有研究表明,在警覺(jué)性任務(wù)時(shí),假咀嚼組的生理及主觀測(cè)量睡意更加類(lèi)似于無(wú)口香糖組,表明僅僅運(yùn)動(dòng)不足以解釋口香糖的覺(jué)醒作用,推測(cè)試驗(yàn)采用的薄荷味口香糖可能也起到一定作用[33]。Davidson等[34]研究發(fā)現(xiàn)含咖啡因的口香糖有助于記憶。

咀嚼不僅會(huì)提高部分腦區(qū)血氧含量[35],還可以增加腦血流量[36],改善相關(guān)中樞神經(jīng)系統(tǒng)及交感神經(jīng)活性。Hirano等[37]發(fā)現(xiàn)咀嚼進(jìn)行記憶任務(wù)時(shí)右側(cè)額中回的顯著激活;咀嚼后的記憶任務(wù)中右側(cè)前運(yùn)動(dòng)區(qū)、楔前葉、丘腦、海馬以及頂下葉明顯激活。他們另一項(xiàng)試驗(yàn)[23]發(fā)現(xiàn)運(yùn)動(dòng)前區(qū)在咀嚼時(shí)完成警覺(jué)和執(zhí)行任務(wù)更為激活,表明此過(guò)程中咀嚼可能影響運(yùn)動(dòng)控制,因此處理速度加快。咀嚼可能通過(guò)丘腦影響網(wǎng)狀激活系統(tǒng),提高覺(jué)醒水平,這些效果提高了認(rèn)知表現(xiàn)。而戴用合適的可摘局部義齒可提高咀嚼功能,提高人腦的激活程度[38]。

營(yíng)養(yǎng)情況許多因素會(huì)影響個(gè)體對(duì)營(yíng)養(yǎng)的攝取。當(dāng)個(gè)體由于牙松動(dòng)或缺失未修復(fù)而導(dǎo)致咀嚼功能下降時(shí),會(huì)影響食物的攝取以及營(yíng)養(yǎng)狀況。Tsakos等[39]通過(guò)對(duì)英國(guó)老年人的大樣本研究發(fā)現(xiàn)無(wú)牙頜患者較對(duì)照組隨訪10年后身體和認(rèn)知功能明顯下降。由于他們均無(wú)牙頜,故排除牙周炎的原因,推測(cè)可能的影響因素是營(yíng)養(yǎng)。口內(nèi)缺牙數(shù)較多時(shí),個(gè)體會(huì)改變飲食結(jié)構(gòu),對(duì)于較難咀嚼的食物,如水果、蔬菜、海鮮等攝取不足,由于其富含多種體內(nèi)所需維生素、礦物質(zhì)以及蛋白質(zhì),個(gè)體常出現(xiàn)微量元素和維生素含量明顯偏低的情況[40]。而微量元素的缺乏是癡呆癥的重要影響因素[41]。曾有研究發(fā)現(xiàn)維生素B族攝取低與認(rèn)知下降相關(guān)[42]。在佩戴義齒后,個(gè)體咀嚼能力往往會(huì)有提升,因而營(yíng)養(yǎng)狀態(tài)也得以改善[43]。

社會(huì)經(jīng)濟(jì)狀況Matthews等[44]的研究發(fā)現(xiàn)牙缺失與認(rèn)知功能下降是相關(guān)的,但在根據(jù)社會(huì)經(jīng)濟(jì)地位和年齡調(diào)節(jié)后,相關(guān)性反倒不是很明顯。收入、教育程度可能直接是口腔健康影響認(rèn)知表現(xiàn)的原因,或者是口腔健康與認(rèn)知表現(xiàn)的共同影響因素。對(duì)已有牙缺失的受試者測(cè)量CRP濃度后發(fā)現(xiàn),牙缺失引起的感染并不會(huì)影響認(rèn)知表現(xiàn)。據(jù)NHANESⅢ研究顯示,差的口腔健康與差的認(rèn)知表現(xiàn)有顯著相關(guān)性,其原因可能是早期教育以及社會(huì)經(jīng)濟(jì)地位[45]。對(duì)法國(guó)老年人的縱向研究顯示受教育水平偏低者有大量牙齒缺失時(shí),癡呆的風(fēng)險(xiǎn)反而更低[46]?？赡苁怯捎诘徒逃潭日甙纬罅垦例X,牙周更為健康。

由于此類(lèi)研究主要靠自述病史,很難獲得精確的數(shù)據(jù),因此可能有偏差。提醒我們?cè)诮窈蟮脑囼?yàn)中社會(huì)人口學(xué)因素也必須納入評(píng)估。

口腔健康對(duì)海馬結(jié)構(gòu)的影響海馬是更高級(jí)別神經(jīng)活動(dòng)的關(guān)鍵區(qū)域,控制情緒、行為、學(xué)習(xí)、記憶功能。AD典型病理變化是老年斑,由β-淀粉樣多肽沉積形成,早期即累及海馬。牙周炎患者的炎性牙周組織IL-1β以及β-淀粉樣前體蛋白的表達(dá)明顯上調(diào),而β-淀粉樣前體蛋白會(huì)導(dǎo)致β-淀粉樣多肽在組織內(nèi)沉積[47]。牙缺失的小鼠模型過(guò)度表達(dá)淀粉樣蛋白前體,其與海馬CA1及CA3亞區(qū)錐體束細(xì)胞含量下降相關(guān)[48]。余留牙數(shù)量與情節(jié)記憶和詞匯記憶呈正相關(guān),而這些記憶是由海馬決定的認(rèn)知功能[49]。長(zhǎng)期磨牙缺失的小鼠恢復(fù)磨牙后,發(fā)現(xiàn)其迷宮錯(cuò)誤率雖然高于對(duì)照組,但明顯低于無(wú)磨牙組,且其海馬CA1、CA3、DG亞區(qū)神經(jīng)元密度與迷宮表現(xiàn)一致[50]。海馬齒狀回 (DG)的神經(jīng)元對(duì)于學(xué)習(xí)記憶至關(guān)重要,其結(jié)構(gòu)、數(shù)量、再生與認(rèn)知功能密切相關(guān)[51]。當(dāng)磨牙缺失后,小鼠DG神經(jīng)的分布、結(jié)構(gòu)、神經(jīng)發(fā)生的能力都有所降低[52]。咀嚼硬性食物可以提高小鼠DG神經(jīng)元干細(xì)胞數(shù)量,且較咀嚼正常食物的小鼠Moris水迷宮試驗(yàn)表現(xiàn)更好[53]。

結(jié)語(yǔ)牙周炎會(huì)引發(fā)身體免疫反應(yīng),因牙周炎而導(dǎo)致牙缺失且不及時(shí)修復(fù)時(shí),咀嚼能力下降,營(yíng)養(yǎng)的攝取會(huì)受到影響,這些都可能造成認(rèn)知功能的損害?？谇唤】凳呛苤匾恼J(rèn)知調(diào)節(jié)因素。因此,應(yīng)對(duì)人群進(jìn)行口腔健康宣教,提高其口腔健康意識(shí),認(rèn)識(shí)到保持口腔衛(wèi)生并及時(shí)恢復(fù)缺失牙都能夠降低癡呆癥的發(fā)生率。此外,咀嚼口香糖可能是一種廉價(jià)的干預(yù)方式,能夠幫助改善認(rèn)知功能。

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E-mail:weicai_liu@#edu.cn

Recent developments in the effect of poor oral health on cognitive impairment

FAN Xiao, LIU Wei-cai△

(DepartmentofProsthodontics,HospitalofStomatology,TongjiUniversity,ShanghaiEngineeringResearchCenterofToothRestorationandRegeneration,Shanghai200072,China)

Cognitive impairment and poor oral health often occur together.Many investigators have suggested that cognitive impairment causes poor oral health,like increased incidence of caries,periodontal disease progression and more tooth loss,which is possibly due to a lack of interest in or forgetting about oral hygiene.However,growing evidence shows that periodontitis and tooth loss may be not only consequences of cognitive impairment,but also risk factors for cognitive impairment,hence investigators have raised the issue of bidirectional associations between poor oral health and impaired cognition.Four mechanisms may be the potential explainations,involving inflammation,mastication,malnutrition,and socio-economic status.An alternative interpretation derives from the observation that poor oral health and cognitive decline share common risk factors,such as cardiovascular diseases and socio-economic status.In this paper,we present epidemiologic evidence of links between poor oral health and cognitive impairment,and review plausible mechanisms linking these conditions.

tooth loss;periodontitis;mastication;nutrition;socio-economic status;hippocampus;cognition

R78,R749

Bdoi: 10.3969/j.issn.1672-8467.2016.04.019

2015-10-29;編輯:王蔚)

上海市自然科學(xué)基金 (13ZR1444900)

*This work was supported by the Natural Science Foundation of Shanghai (13ZR1444900).