曹明 陳彪

·專題綜述·

吸煙與帕金森病嗅覺障礙

曹明 陳彪

帕金森病是臨床常見的神經(jīng)變性病，根據(jù)臨床癥狀可以分為運(yùn)動癥狀和非運(yùn)動癥狀，嗅覺障礙作為帕金森病最常見的非運(yùn)動癥狀越來越受到重視。既往研究顯示，尼古丁可能降低帕金森病發(fā)病風(fēng)險(xiǎn)，而有吸煙史的帕金森病患者嗅覺障礙輕微，因此吸煙可能通過嗅覺系統(tǒng)對帕金森病產(chǎn)生保護(hù)作用。吸煙對帕金森病患者嗅覺功能的影響可能有助于我們更全面地了解帕金森病發(fā)病過程。

吸煙；帕金森??；嗅覺障礙；綜述

This study was supported by the National High Technology Research and Development Program of China(863 Program,No.2012AA02A514).

帕金森?。≒D）是一種漸進(jìn)性神經(jīng)變性病，主要病理改變?yōu)榛咨窠?jīng)節(jié)黑質(zhì)多巴胺能神經(jīng)元缺失。帕金森病臨床癥狀分為運(yùn)動癥狀和非運(yùn)動癥狀（NMS），前者表現(xiàn)為靜止性震顫，肌強(qiáng)直，少動和姿勢步態(tài)異常；后者包括嗅覺減退，自主神經(jīng)功能紊亂，睡眠障礙，認(rèn)知功能障礙等［1］。在上述非運(yùn)動癥狀中，嗅覺減退可以出現(xiàn)在帕金森病臨床前期，有研究顯示，在發(fā)展為帕金森病的前4年即可出現(xiàn)顯著的嗅覺減退［2］，故嗅覺障礙可能是帕金森病臨床早期診斷的標(biāo)記。此為早期預(yù)測帕金森病的可能性提供依據(jù)。Braak研究團(tuán)隊(duì)曾經(jīng)提出帕金森病病理發(fā)展過程最先由鼻黏膜和胃腸系統(tǒng)開始，即神經(jīng)毒素可能通過上述兩個(gè)系統(tǒng)由外環(huán)境直接進(jìn)入內(nèi)環(huán)境，引起嗅覺障礙和以便秘為主的胃腸功能障礙［3?4］。因此，研究帕金森病非運(yùn)動癥狀發(fā)生、發(fā)展機(jī)制有助于了解基因與環(huán)境如何共同作用引起帕金森病的過程［5］，這也是目前越來越多的研究關(guān)注環(huán)境因素相關(guān)帕金森病非運(yùn)動癥狀的原因。與帕金森病相關(guān)的環(huán)境和生活習(xí)慣因素眾多，有多項(xiàng)研究顯示，吸煙可以降低帕金森病發(fā)病風(fēng)險(xiǎn)［6?7］，但目前對帕金森病嗅覺障礙與吸煙保護(hù)作用之間的關(guān)系研究甚少。

一、嗅覺障礙與帕金森病

帕金森病嗅覺障礙于20世紀(jì)70年代由Ansari和Johnson［8］通過對22例帕金森病患者進(jìn)行研究后首次提出，此后Doty等［9］采用美國賓夕法尼亞大學(xué)嗅覺識別測驗(yàn)（UPSIT）進(jìn)一步證實(shí)約75%的帕金森病患者存在嗅覺察覺力損害，而90%的帕金森病患者存在嗅覺識別力損害。并且，帕金森病患者的這種嗅覺障礙與疾病進(jìn)展和嚴(yán)重程度無關(guān)聯(lián)性，也不隨抗帕金森病藥物的使用而改善［10］。多數(shù)研究通過對帕金森病亞型（靜止性震顫為主型，肌強(qiáng)直為主型及其他型）分析顯示，帕金森病各亞型之間嗅覺障礙并無顯著差異［11?12］。Hawkes等［3］和Duda［13］發(fā)現(xiàn)，α?突觸核蛋白（α?Syn）相關(guān)病理改變最早出現(xiàn)于嗅球處，由此提出假說即帕金森病嗅覺障礙是這種病理過程逐漸向腦內(nèi)進(jìn)展的過程［3］。當(dāng)然，有研究顯示，這種嗅覺減退可能是由于嗅球處出現(xiàn)病理性損傷，嗅球內(nèi)神經(jīng)元減少，嗅球旁多巴胺能神經(jīng)元代償性增多導(dǎo)致多巴胺能神經(jīng)遞質(zhì)增多，而這種神經(jīng)遞質(zhì)阻礙嗅覺神經(jīng)沖動傳遞，從而引起嗅覺減退［13?14］。盡管嗅覺障礙的發(fā)生機(jī)制尚未闡明，目前研究普遍認(rèn)為，嗅覺減退是發(fā)生在帕金森病運(yùn)動癥狀前的非運(yùn)動癥狀，且國際運(yùn)動障礙學(xué)會（MDS）從2015年開始將嗅覺減退納入帕金森病支持診斷標(biāo)準(zhǔn)，突出嗅覺減退對帕金森病診斷的重要性［15］。

二、吸煙與帕金森病

據(jù)統(tǒng)計(jì)，有超過60項(xiàng)流行病學(xué)調(diào)查研究均提示吸煙可以降低帕金森病發(fā)病風(fēng)險(xiǎn)［16?17］。其中一項(xiàng)納入300×103例受試者的流行病學(xué)調(diào)查研究顯示，在具有相同吸煙強(qiáng)度的人群中，煙齡與帕金森病發(fā)病風(fēng)險(xiǎn)呈負(fù)相關(guān)，且煙齡越久、帕金森病發(fā)病風(fēng)險(xiǎn)降低越明顯，但在相同煙齡人群中，日吸煙量與帕金森病發(fā)病風(fēng)險(xiǎn)無關(guān)聯(lián)性［18］。不可否認(rèn)，吸煙給人體帶來很多負(fù)面影響，增加心腦血管病和肺部惡性腫瘤等的發(fā)病風(fēng)險(xiǎn)，但是由于上述諸多流行病學(xué)研究提示吸煙可能具有神經(jīng)保護(hù)作用，這為隨后的相關(guān)機(jī)制研究提供研究背景。現(xiàn)有研究主要認(rèn)為尼古丁可能是神經(jīng)保護(hù)和降低帕金森病發(fā)病風(fēng)險(xiǎn)的重要因素［19］。Morens等［20］曾試圖解釋尼古丁對帕金森病的保護(hù)機(jī)制，即尼古丁可以刺激多巴胺能神經(jīng)遞質(zhì)釋放，通過一氧化碳阻止自由基損傷黑質(zhì)神經(jīng)元，同時(shí)抑制單胺氧化酶B（MAO?B）或通過競爭性抑制神經(jīng)毒素以保護(hù)神經(jīng)元。在動物模型中也可以觀察到尼古丁減緩黑質(zhì)紋狀體的損害進(jìn)展［21］，但在針對帕金森病患者的臨床實(shí)驗(yàn)中，尼古丁皮貼或口香糖均無法緩解帕金森病癥狀，因此尼古丁也許并不能單獨(dú)發(fā)揮神經(jīng)保護(hù)作用［21?23］。縱向研究顯示，吸煙的帕金森病患者與非吸煙的帕金森病患者在運(yùn)動癥狀進(jìn)展與病死率方面無顯著差異［24?27］，提示對于明確診斷的帕金森病患者，吸煙并不能起保護(hù)作用，但是有研究顯示，吸煙人群帕金森病發(fā)病年齡高于非吸煙人群［28］。因此認(rèn)為，尼古丁對帕金森病患者的影響可能在發(fā)病前即已存在，并且是緩慢影響過程，這也可能是明確診斷為帕金森病的患者再次使用尼古丁制劑治療效果不明顯的原因［29］。

三、吸煙對帕金森病患者嗅覺的影響

盡管針對帕金森病患者嗅覺障礙的相關(guān)研究已進(jìn)行近40年，但關(guān)于吸煙對帕金森病患者嗅覺影響的研究卻較少。帕金森病患者UPSIT評分較低。但近期一項(xiàng)研究顯示，有吸煙史的帕金森病患者UPSIT評分優(yōu)于非吸煙的帕金森病患者，而在正常對照組中卻未觀察到類似現(xiàn)象，研究者猜測吸煙可能對帕金森病患者的嗅覺功能具有保護(hù)作用［29］。另一項(xiàng)研究也發(fā)現(xiàn)吸煙人群中帕金森病患者與正常對照者UPSIT評分無顯著差異，而帕金森病患者中吸煙人群UPSIT評分顯著優(yōu)于非吸煙和既往吸煙者［30］。這一結(jié)果并不受吸煙習(xí)慣如是否戒煙、戒煙時(shí)間長短、吸煙量和帕金森病藥物治療的影響。大多數(shù)研究顯示，吸煙可引起正常人群嗅覺障礙［31?32］，Moccia等［33］的橫斷面研究顯示，正常人群中吸煙者UPSIT評分顯著低于非吸煙者，但是這一現(xiàn)象并未出現(xiàn)在帕金森病患者中，因此他們認(rèn)為，帕金森病患者嗅覺障礙可能受帕金森病與吸煙的共同影響。另有針對毒氣引起嗅覺障礙的研究顯示，非吸煙者出現(xiàn)嗅覺障礙的風(fēng)險(xiǎn)相對增加，盡管其發(fā)生機(jī)制尚不清楚，但吸煙可能對嗅覺功能存在某種保護(hù)作用［34?35］?；贐raak等［36］對帕金森病病理進(jìn)展過程的解釋，吸煙降低帕金森病發(fā)病風(fēng)險(xiǎn)可能是由于吸煙損害嗅黏膜，導(dǎo)致外環(huán)境毒素較少通過嗅覺系統(tǒng)進(jìn)入中樞。有研究顯示，尼古丁成分可影響膽堿能系統(tǒng)，而膽堿能系統(tǒng)能夠輔助嗅覺的氣味察覺功能［37?39］。其他研究則提出尼古丁可以增加嗅球處血流量從而減少自由基對嗅球的損害［40］。Rothermel等［41］認(rèn)為，尼古丁可以上調(diào)或直接刺激基底前腦突觸前尼古丁受體，而此區(qū)域與嗅覺有關(guān)，推測尼古丁可以使受損嗅皮質(zhì)功能增強(qiáng)。在阿爾茨海默病（AD）動物模型研究中發(fā)現(xiàn)，尼古丁可以減少嗅束淀粉樣變性［42］。將膽堿能受體阻斷劑注入小鼠嗅球，嗅覺辨別功能增強(qiáng)，而阻斷嗅球處尼古丁受體時(shí)，嗅覺功能減退［10］。但Bryant等［43］認(rèn)為，尼古丁并未直接通過尼古丁?膽堿能受體作用于嗅覺系統(tǒng)，而是通過cAMP介導(dǎo)的嗅覺感受器通路激活嗅覺神經(jīng)元。因此，對于尼古丁如何影響嗅覺功能的作用機(jī)制尚待進(jìn)一步研究。流行病學(xué)研究顯示，戒煙困難的人群相對于戒煙容易的人群，帕金森病發(fā)病風(fēng)險(xiǎn)降低約31%［44］。研究者認(rèn)為這種吸煙行為的改變可能是并列于其他非運(yùn)動癥狀如嗅覺減退、便秘、睡眠障礙等［45］的另一種帕金森病臨床前期非運(yùn)動癥狀。但是吸煙行為中仍有許多不確定因素，如吸煙強(qiáng)度不能僅考慮數(shù)包或數(shù)只香煙而忽略每種香煙的尼古丁含量，開始吸煙年齡、煙齡、戒煙年齡和戒斷時(shí)間，研究對象是否攜帶帕金森病風(fēng)險(xiǎn)基因，吸煙人群所占研究隊(duì)列中的比例等因素，均有可能影響研究結(jié)果。因此，尚不能確定吸煙對帕金森病的嗅覺功能具有保護(hù)作用。

四、結(jié)語

上述研究闡述吸煙與帕金森病嗅覺障礙的關(guān)系。嗅覺障礙作為帕金森病較為明確的臨床前期癥狀，受多種外環(huán)境因素的影響，而吸煙作為流行病學(xué)研究發(fā)現(xiàn)的可能降低帕金森病發(fā)病風(fēng)險(xiǎn)的因素之一，很可能通過嗅覺系統(tǒng)降低帕金森病發(fā)病風(fēng)險(xiǎn)。因此在帕金森病患者中，吸煙與嗅覺系統(tǒng)的相互作用也越來越受到關(guān)注。通過吸煙與嗅覺和帕金森病的相關(guān)研究，可以更全面地了解帕金森病發(fā)病過程，嗅覺障礙發(fā)生機(jī)制以及如何利用香煙中的成分對帕金森病臨床前期進(jìn)行保護(hù)性干預(yù)。

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Relationship between smoking and olfactory dysfunction in Parkinson's disease

CAO Ming,CHAN Piu
Department of Neurology,Xuanwu Hospital,Capital Medical University,Beijing 100053,China Corresponding author:CHAN Piu(Email:pbchan90@gmail.com)

Parkinson's disease(PD)is a common neurodegenerative disease.It is characterized by a combination of motor symptoms and non?motor symptoms(NMS)based on clinical symptoms.More and more attention has been drawn to olfactory dysfunction as an early NMS in PD.It is believed that nicotine in cigarettes may lower the risk of getting PD and people with smoking history may have lower risk of olfactory dysfunction.So smoking may have protective effect on PD.The effect of smoking on olfactory function in PD patients may lead us to have a better understanding of the pathogenesis of PD.

Smoking;Parkinson disease;Olfaction disorders;Review

2016?10?30）

10.3969/j.issn.1672?6731.2017.02.004

國家高技術(shù)研究發(fā)展計(jì)劃（863計(jì)劃）項(xiàng)目（項(xiàng)目編號：2012AA02A514）

100053北京，首都醫(yī)科大學(xué)宣武醫(yī)院神經(jīng)內(nèi)科

陳彪（Email：pbchan90@gmail.com）