范　曉(綜述)　劉偉才(審校)

(同濟大學口腔醫(yī)學院修復教研室,上海牙組織修復與再建工程技術研究中心　上海　200072)

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口腔健康不良對認知障礙影響的研究進展

范曉(綜述)劉偉才△(審校)

(同濟大學口腔醫(yī)學院修復教研室,上海牙組織修復與再建工程技術研究中心上海200072)

認知障礙與口腔健康不良常同時發(fā)生。許多學者提出認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行日?？谇恍l(wèi)生護理造成的。然而,越來越多的研究從不同方面證實口腔健康與認知障礙具有雙向關系,即口腔問題可能不僅僅是認知損害的結果,也是認知損害的原因。其機制可能涉及感染、咀嚼功能、營養(yǎng)不良以及社會經(jīng)濟狀況。也有認為口腔健康不良與認知下降有共同的危險因素,例如心血管疾病以及社會經(jīng)濟狀況。本文就現(xiàn)階段口腔問題與認知障礙相關的流行病學證據(jù)及可能機制進行綜述。

牙缺失;牙周炎;咀嚼;營養(yǎng);社會經(jīng)濟狀況;海馬;認知

牙齒是口腔健康的重要組成部分,對美觀、發(fā)音具有重要意義。此外,良好的咀嚼功能有助于營養(yǎng)的吸收,對身體健康有重要影響。認知涉及到心理過程,包括注意力、記憶力、生成并理解語言、解決問題及做決定等方面。人的一生中,認知功能都在發(fā)生變化,認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)記憶和語言功能障礙;血管性癡呆除上述癥狀外還會出現(xiàn)情緒性格的變化[1]。癡呆癥的患者由于認知功能下降,會忽視或者不能夠進行日?？谇恍l(wèi)生的護理,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,越來越多研究從不同方面證實口腔健康與認知功能具有雙向關系——即口腔問題可能不僅僅是認知障礙的結果,也是認知損害的危險因素。

口腔健康對認知的影響在針對老年人的隨訪調(diào)查中發(fā)現(xiàn),較高的牙齦指數(shù)、牙齦炎與認知障礙相關[4]。缺牙數(shù)以及引起牙缺失的牙周炎、齲病可能預示著認知功能下降[5]。Luo等[6]則首次報道中國老年人缺牙數(shù)在16顆以上與癡呆癥呈正相關。在對逾一萬名2型糖尿病患者進行的前瞻性隨訪研究發(fā)現(xiàn),牙齒少或無牙頜者記憶或執(zhí)行的認知表現(xiàn)不佳[7]。隨時間進展,余留牙越少則認知損害越重[8]。

中年人不能進行日常口腔護理可能是認知改變的早期征象。Naorungroj等[3]對美國4個州的中年人進行了6年的隨訪,發(fā)現(xiàn)認知功能下降與缺牙數(shù)的增加相關。此外,也與低刷牙頻率、菌斑堆積、無牙頜相關,但與牙周病無關。他們另一個研究[9]發(fā)現(xiàn),中老年無牙頜者記憶和語言測試結果相較于有牙頜者更差。全牙列的缺失與認知功能密切相關,但無牙頜、余留牙數(shù)或牙周病并不能預示著認知功能下降。兩個實驗在無牙頜患者認知下降的速度上得出了相反的結論,作者總結認為可能由于參與人群的不同導致。

在日本老年人中,缺牙但未恢復、未定期檢查牙齒個體癡呆癥的發(fā)病風險較高[10]。Elsig等[11]與Lexomboon等[12]認為咀嚼能力對認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)認知障礙。

口腔健康對認知影響的機制

牙周炎牙周炎是常見口腔疾病,由細菌感染引起。牙周炎致病菌會引起系統(tǒng)性感染,其血清抗體被看做是AD和輕度認知損害保護性的危險標志物,AD患者血清常見牙周致病菌內(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照組。據(jù)美國健康與營養(yǎng)調(diào)查(National Health And Nutrition Examination Survey,NHANES Ⅲ)對60歲以上老年人的統(tǒng)計結果,牙齦卟啉單細胞菌的血清標志物含量越高,則認知表現(xiàn)越差[15]。此外,慢性牙周炎會引起身體釋放促炎因子,后者可能隨體循環(huán)到達腦部,加重感染過程以及血管病變。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,中樞或周圍組織的炎性反應在發(fā)病過程中發(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,多顆牙缺失與急性缺血性腦卒中造成的血管性認知障礙相關[18]。腦卒中多與動脈粥樣硬化相關。牙周炎患者C反應蛋白 (C reactive protein,CRP)增加含量高,頸動脈內(nèi)膜中層厚度增加,更容易發(fā)生動脈粥樣硬化[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)生動脈粥樣硬化[20]。因此,也有人認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知下降的共同危險因素[21-22]。究竟三者為何關系有待進一步研究確認。

咀嚼咀嚼增加覺醒水平、警覺性以及對運動控制的效果,這些效應可能改善認知能力[23]。Morgan等[24]研究了口香糖對Bakan型警戒任務的影響,這種任務需要不斷更新短期命令記憶。相較于對照組,口香糖組的主觀警覺性降幅小,且校正反應時間的降幅在任務后期也明顯短于對照組,這些發(fā)現(xiàn)與Tucha 等[25]一致。Allen等[26]從心率、腦電圖等方面證實咀嚼對警覺的易化作用。也有研究發(fā)現(xiàn)口香糖對短期記憶[27]、警覺性[28]有負性影響,推測參與者因咀嚼口香糖而分心[29]。

Onyper等[30]在學生中進行了咀嚼對認知功能影響的試驗,發(fā)現(xiàn)試驗前5 min咀嚼可以提高測試環(huán)節(jié)的前15～20 min認知任務表現(xiàn)。因此,咀嚼的益處是有時限的并且與其引起的覺醒相關。Smith等[31]發(fā)現(xiàn)咀嚼可提高皮質(zhì)醇濃度,認為其激活了神經(jīng)系統(tǒng),提高警覺性表現(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明顯差異[32],由于皮質(zhì)醇一日內(nèi)不同時間點的分泌量并不恒定,試驗時間可能對結果產(chǎn)生影響。有研究表明,在警覺性任務時,假咀嚼組的生理及主觀測量睡意更加類似于無口香糖組,表明僅僅運動不足以解釋口香糖的覺醒作用,推測試驗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)咀嚼進行記憶任務時右側額中回的顯著激活;咀嚼后的記憶任務中右側前運動區(qū)、楔前葉、丘腦、海馬以及頂下葉明顯激活。他們另一項試驗[23]發(fā)現(xiàn)運動前區(qū)在咀嚼時完成警覺和執(zhí)行任務更為激活,表明此過程中咀嚼可能影響運動控制,因此處理速度加快。咀嚼可能通過丘腦影響網(wǎng)狀激活系統(tǒng),提高覺醒水平,這些效果提高了認知表現(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]。

營養(yǎng)情況許多因素會影響個體對營養(yǎng)的攝取。當個體由于牙松動或缺失未修復而導致咀嚼功能下降時,會影響食物的攝取以及營養(yǎng)狀況。Tsakos等[39]通過對英國老年人的大樣本研究發(fā)現(xiàn)無牙頜患者較對照組隨訪10年后身體和認知功能明顯下降。由于他們均無牙頜,故排除牙周炎的原因,推測可能的影響因素是營養(yǎng)?？趦?nèi)缺牙數(shù)較多時,個體會改變飲食結構,對于較難咀嚼的食物,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族攝取低與認知下降相關[42]。在佩戴義齒后,個體咀嚼能力往往會有提升,因而營養(yǎng)狀態(tài)也得以改善[43]。

社會經(jīng)濟狀況Matthews等[44]的研究發(fā)現(xiàn)牙缺失與認知功能下降是相關的,但在根據(jù)社會經(jīng)濟地位和年齡調(diào)節(jié)后,相關性反倒不是很明顯。收入、教育程度可能直接是口腔健康影響認知表現(xiàn)的原因,或者是口腔健康與認知表現(xiàn)的共同影響因素。對已有牙缺失的受試者測量CRP濃度后發(fā)現(xiàn),牙缺失引起的感染并不會影響認知表現(xiàn)。據(jù)NHANESⅢ研究顯示,差的口腔健康與差的認知表現(xiàn)有顯著相關性,其原因可能是早期教育以及社會經(jīng)濟地位[45]。對法國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,癡呆的風險反而更低[46]。可能是由于低教育程度者拔除大量牙齒,牙周更為健康。

由于此類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。提醒我們在今后的試驗中社會人口學因素也必須納入評估。

口腔健康對海馬結構的影響海馬是更高級別神經(jīng)活動的關鍵區(qū)域,控制情緒、行為、學習、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明顯上調(diào),而β-淀粉樣前體蛋白會導致β-淀粉樣多肽在組織內(nèi)沉積[47]。牙缺失的小鼠模型過度表達淀粉樣蛋白前體,其與海馬CA1及CA3亞區(qū)錐體束細胞含量下降相關[48]。余留牙數(shù)量與情節(jié)記憶和詞匯記憶呈正相關,而這些記憶是由海馬決定的認知功能[49]。長期磨牙缺失的小鼠恢復磨牙后,發(fā)現(xiàn)其迷宮錯誤率雖然高于對照組,但明顯低于無磨牙組,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)元對于學習記憶至關重要,其結構、數(shù)量、再生與認知功能密切相關[51]。當磨牙缺失后,小鼠DG神經(jīng)的分布、結構、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)元干細胞數(shù)量,且較咀嚼正常食物的小鼠Moris水迷宮試驗表現(xiàn)更好[53]。

結語牙周炎會引發(fā)身體免疫反應,因牙周炎而導致牙缺失且不及時修復時,咀嚼能力下降,營養(yǎng)的攝取會受到影響,這些都可能造成認知功能的損害?？谇唤】凳呛苤匾恼J知調(diào)節(jié)因素。因此,應對人群進行口腔健康宣教,提高其口腔健康意識,認識到保持口腔衛(wèi)生并及時恢復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的干預方式,能夠幫助改善認知功能。

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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)

上海市自然科學基金 (13ZR1444900)

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