口腔健康不良对认知障碍影响的研究进展

范　晓(综述)　刘伟才(审校)

(同济大学口腔医学院修复教研室,上海牙组织修复与再建工程技术研究中心　上海　200072)



口腔健康不良对认知障碍影响的研究进展

范晓(综述)刘伟才△(审校)

(同济大学口腔医学院修复教研室,上海牙组织修复与再建工程技术研究中心上海200072)

认知障碍与口腔健康不良常同时发生。许多学者提出认知障碍引起口腔健康不良,例如增高龋病发病率、加速牙周病进展以及增加牙缺失数,这可能是由于患者忽视或者不能够进行日常口腔卫生护理造成的。然而,越来越多的研究从不同方面证实口腔健康与认知障碍具有双向关系,即口腔问题可能不仅仅是认知损害的结果,也是认知损害的原因。其机制可能涉及感染、咀嚼功能、营养不良以及社会经济状况。也有认为口腔健康不良与认知下降有共同的危险因素,例如心血管疾病以及社会经济状况。本文就现阶段口腔问题与认知障碍相关的流行病学证据及可能机制进行综述。

牙缺失;牙周炎;咀嚼;营养;社会经济状况;海马;认知

牙齿是口腔健康的重要组成部分,对美观、发音具有重要意义。此外,良好的咀嚼功能有助于营养的吸收,对身体健康有重要影响。认知涉及到心理过程,包括注意力、记忆力、生成并理解语言、解决问题及做决定等方面。人的一生中,认知功能都在发生变化,认知功能下降是痴呆症的早期征象之一。其中,阿尔茨海默病 (Alzheimer disease,AD)发病率最高,患者常出现记忆和语言功能障碍;血管性痴呆除上述症状外还会出现情绪性格的变化[1]。痴呆症的患者由于认知功能下降,会忽视或者不能够进行日常口腔卫生的护理,更有可能发生龋病、牙周炎、口腔卫生不佳的情况[2-3]。近年来,越来越多研究从不同方面证实口腔健康与认知功能具有双向关系——即口腔问题可能不仅仅是认知障碍的结果,也是认知损害的危险因素。

口腔健康对认知的影响在针对老年人的随访调查中发现,较高的牙龈指数、牙龈炎与认知障碍相关[4]。缺牙数以及引起牙缺失的牙周炎、龋病可能预示着认知功能下降[5]。Luo等[6]则首次报道中国老年人缺牙数在16颗以上与痴呆症呈正相关。在对逾一万名2型糖尿病患者进行的前瞻性随访研究发现,牙齿少或无牙颌者记忆或执行的认知表现不佳[7]。随时间进展,余留牙越少则认知损害越重[8]。

中年人不能进行日常口腔护理可能是认知改变的早期征象。Naorungroj等[3]对美国4个州的中年人进行了6年的随访,发现认知功能下降与缺牙数的增加相关。此外,也与低刷牙频率、菌斑堆积、无牙颌相关,但与牙周病无关。他们另一个研究[9]发现,中老年无牙颌者记忆和语言测试结果相较于有牙颌者更差。全牙列的缺失与认知功能密切相关,但无牙颌、余留牙数或牙周病并不能预示着认知功能下降。两个实验在无牙颌患者认知下降的速度上得出了相反的结论,作者总结认为可能由于参与人群的不同导致。

在日本老年人中,缺牙但未恢复、未定期检查牙齿个体痴呆症的发病风险较高[10]。Elsig等[11]与Lexomboon等[12]认为咀嚼能力对认知的影响相较于余留天然牙数量要大,使用义齿的人未出现认知障碍。

口腔健康对认知影响的机制

牙周炎牙周炎是常见口腔疾病,由细菌感染引起。牙周炎致病菌会引起系统性感染,其血清抗体被看做是AD和轻度认知损害保护性的危险标志物,AD患者血清常见牙周致病菌内氏放线菌[13]、中间普氏菌和具核梭杆菌[14]的抗体含量明显高于对照组。据美国健康与营养调查(National Health And Nutrition Examination Survey,NHANES Ⅲ)对60岁以上老年人的统计结果,牙龈卟啉单细胞菌的血清标志物含量越高,则认知表现越差[15]。此外,慢性牙周炎会引起身体释放促炎因子,后者可能随体循环到达脑部,加重感染过程以及血管病变。在AD和健康老年人中,血清TNF-α以及IL-6的含量有所差异[16-17]。AD是一种神经系统退行性疾病,中枢或周围组织的炎性反应在发病过程中发挥了重要作用。因此,有提出慢性牙周炎是AD的病因之一。也有研究证实,多颗牙缺失与急性缺血性脑卒中造成的血管性认知障碍相关[18]。脑卒中多与动脉粥样硬化相关。牙周炎患者C反应蛋白 (C reactive protein,CRP)增加含量高,颈动脉内膜中层厚度增加,更容易发生动脉粥样硬化[19]。此外,也有研究发现齿垢密螺旋体水平较高的患者高密度脂蛋白含量较低,因此更容易发生动脉粥样硬化[20]。因此,也有人认为慢性牙周炎是脑卒中的病因之一。

此外,也有人提出或许心脑血管疾病是牙周炎与认知下降的共同危险因素[21-22]。究竟三者为何关系有待进一步研究确认。

咀嚼咀嚼增加觉醒水平、警觉性以及对运动控制的效果,这些效应可能改善认知能力[23]。Morgan等[24]研究了口香糖对Bakan型警戒任务的影响,这种任务需要不断更新短期命令记忆。相较于对照组,口香糖组的主观警觉性降幅小,且校正反应时间的降幅在任务后期也明显短于对照组,这些发现与Tucha 等[25]一致。Allen等[26]从心率、脑电图等方面证实咀嚼对警觉的易化作用。也有研究发现口香糖对短期记忆[27]、警觉性[28]有负性影响,推测参与者因咀嚼口香糖而分心[29]。

Onyper等[30]在学生中进行了咀嚼对认知功能影响的试验,发现试验前5 min咀嚼可以提高测试环节的前15～20 min认知任务表现。因此,咀嚼的益处是有时限的并且与其引起的觉醒相关。Smith等[31]发现咀嚼可提高皮质醇浓度,认为其激活了神经系统,提高警觉性表现。但也有研究人员发现受试者皮质醇含量在咀嚼口香糖前后并无明显差异[32],由于皮质醇一日内不同时间点的分泌量并不恒定,试验时间可能对结果产生影响。有研究表明,在警觉性任务时,假咀嚼组的生理及主观测量睡意更加类似于无口香糖组,表明仅仅运动不足以解释口香糖的觉醒作用,推测试验采用的薄荷味口香糖可能也起到一定作用[33]。Davidson等[34]研究发现含咖啡因的口香糖有助于记忆。

咀嚼不仅会提高部分脑区血氧含量[35],还可以增加脑血流量[36],改善相关中枢神经系统及交感神经活性。Hirano等[37]发现咀嚼进行记忆任务时右侧额中回的显著激活;咀嚼后的记忆任务中右侧前运动区、楔前叶、丘脑、海马以及顶下叶明显激活。他们另一项试验[23]发现运动前区在咀嚼时完成警觉和执行任务更为激活,表明此过程中咀嚼可能影响运动控制,因此处理速度加快。咀嚼可能通过丘脑影响网状激活系统,提高觉醒水平,这些效果提高了认知表现。而戴用合适的可摘局部义齿可提高咀嚼功能,提高人脑的激活程度[38]。

营养情况许多因素会影响个体对营养的摄取。当个体由于牙松动或缺失未修复而导致咀嚼功能下降时,会影响食物的摄取以及营养状况。Tsakos等[39]通过对英国老年人的大样本研究发现无牙颌患者较对照组随访10年后身体和认知功能明显下降。由于他们均无牙颌,故排除牙周炎的原因,推测可能的影响因素是营养。口内缺牙数较多时,个体会改变饮食结构,对于较难咀嚼的食物,如水果、蔬菜、海鲜等摄取不足,由于其富含多种体内所需维生素、矿物质以及蛋白质,个体常出现微量元素和维生素含量明显偏低的情况[40]。而微量元素的缺乏是痴呆症的重要影响因素[41]。曾有研究发现维生素B族摄取低与认知下降相关[42]。在佩戴义齿后,个体咀嚼能力往往会有提升,因而营养状态也得以改善[43]。

社会经济状况Matthews等[44]的研究发现牙缺失与认知功能下降是相关的,但在根据社会经济地位和年龄调节后,相关性反倒不是很明显。收入、教育程度可能直接是口腔健康影响认知表现的原因,或者是口腔健康与认知表现的共同影响因素。对已有牙缺失的受试者测量CRP浓度后发现,牙缺失引起的感染并不会影响认知表现。据NHANESⅢ研究显示,差的口腔健康与差的认知表现有显著相关性,其原因可能是早期教育以及社会经济地位[45]。对法国老年人的纵向研究显示受教育水平偏低者有大量牙齿缺失时,痴呆的风险反而更低[46]。可能是由于低教育程度者拔除大量牙齿,牙周更为健康。

由于此类研究主要靠自述病史,很难获得精确的数据,因此可能有偏差。提醒我们在今后的试验中社会人口学因素也必须纳入评估。

口腔健康对海马结构的影响海马是更高级别神经活动的关键区域,控制情绪、行为、学习、记忆功能。AD典型病理变化是老年斑,由β-淀粉样多肽沉积形成,早期即累及海马。牙周炎患者的炎性牙周组织IL-1β以及β-淀粉样前体蛋白的表达明显上调,而β-淀粉样前体蛋白会导致β-淀粉样多肽在组织内沉积[47]。牙缺失的小鼠模型过度表达淀粉样蛋白前体,其与海马CA1及CA3亚区锥体束细胞含量下降相关[48]。余留牙数量与情节记忆和词汇记忆呈正相关,而这些记忆是由海马决定的认知功能[49]。长期磨牙缺失的小鼠恢复磨牙后,发现其迷宫错误率虽然高于对照组,但明显低于无磨牙组,且其海马CA1、CA3、DG亚区神经元密度与迷宫表现一致[50]。海马齿状回 (DG)的神经元对于学习记忆至关重要,其结构、数量、再生与认知功能密切相关[51]。当磨牙缺失后,小鼠DG神经的分布、结构、神经发生的能力都有所降低[52]。咀嚼硬性食物可以提高小鼠DG神经元干细胞数量,且较咀嚼正常食物的小鼠Moris水迷宫试验表现更好[53]。

结语牙周炎会引发身体免疫反应,因牙周炎而导致牙缺失且不及时修复时,咀嚼能力下降,营养的摄取会受到影响,这些都可能造成认知功能的损害。口腔健康是很重要的认知调节因素。因此,应对人群进行口腔健康宣教,提高其口腔健康意识,认识到保持口腔卫生并及时恢复缺失牙都能够降低痴呆症的发生率。此外,咀嚼口香糖可能是一种廉价的干预方式,能够帮助改善认知功能。

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E-mail:weicai_liu@tongji.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;编辑:王蔚)

上海市自然科学基金 (13ZR1444900)

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