早期帕金森病診斷及治療新進(jìn)展-中山大學(xué)第一醫(yī)院神經(jīng)內(nèi)科+徐評(píng)議

徐評(píng)議中山大學(xué)附屬第一醫(yī)院神經(jīng)內(nèi)科早期帕金森病診斷及治療新進(jìn)展共同特點(diǎn):老年,進(jìn)行性發(fā)展,特定腦區(qū)和特定癥狀中樞神經(jīng)退行性病帕金森病、老年性癡呆、多系統(tǒng)萎縮等

不同腦區(qū)退行性變特定遞質(zhì)代謝障礙中老年，隱匿，癡呆、震顫麻痹、運(yùn)動(dòng)障礙和病理性肌萎縮等共同特征-不同區(qū)間神經(jīng)元胞體或胞核內(nèi)出現(xiàn)不同成份的異常蛋白沉積，神經(jīng)元變性凋亡中樞神經(jīng)退行性病InPD,theintracellularinclusionbodiescalledLewe’sbodyinmidbrainisaGoldenstandardforconfirmeddiagnosisofPD;whileamyloidplaquesandphosphoredtautanguesarepathologicalhallmarkerforAlzheimer’sdisease.Lewe’sbodydiseaseiswildlyspreadincortex,andmidbrain;inMSA,theneuronallossismainlypresentinnigro,striatum,pon,cellebrum,andspinalcordandvagusnuclei.中樞神經(jīng)退行性病的病理機(jī)制Over70proteinshavebeenidentifiedinLewybodies

-Crystallin;

-Synuclein

Calcium-calmodulin-dependentproteinkinaseIICalbindinD28K;Chondroitinsulfate;ChromograninAClusterin/apolipoproteinCochaperoneCterminusofHsp-70-interactingproteinComplementproteins(C3d,C4d,C7,andC9);Cyclin-dependentkinase5Cytochromec;DJ-1;Dorfin;14-3-3proteinGelsolin-relatedamyloidproteinFinnishtypeHeat-shockproteins27,40,70,60,90,and110P;hosphorylated

IkBa;LipidsMAP-2;MAP-5/MAP-1b;MitochondriaMulticatalytic

proteinase;MxAproteinNEDD8;Neurofilaments;NFkBOmi/HtrA2P35nck5a;p62/sequestosomePael-R;ROC1;SphingomyelinCu/Znsuperoxidedismutase;MnsuperoxidedismutaseSynapticvesicle-specificprotein;Synphilin-1;Synaptophysin;TauTorsinA;Tubulin;TyrosinehydroxylaseUbiquitin;UbiquitinC-terminalhydroxylase

Shults,

PNAS2006;103:1661Savittetal,JCI,2006;116:1744帕金森病的臨床病程早期標(biāo)記的發(fā)現(xiàn)期TolosaEetal,LancetNeurology2006中樞神經(jīng)變性病的不同臨床特征吞咽困難發(fā)音困難凝視麻痹失用步態(tài)不穩(wěn)跌倒強(qiáng)直運(yùn)動(dòng)遲緩震顫癡呆植物神經(jīng)功能障礙帕金森背景發(fā)病情況:我國(guó)帕金森病(PD)＞200萬(wàn)↑.ZhangZ,etal.

Lancet.2005無(wú)癥狀前10～20年，黑質(zhì)多巴胺(DA)神經(jīng)元大量變性病理發(fā)展：發(fā)病機(jī)制:基因/環(huán)境/老化可能與大多數(shù)PD相關(guān)替代療法5～年后逐漸失效,難以控制的不良反應(yīng);且DA神經(jīng)元持續(xù)變性,需發(fā)展新的治療方法，干預(yù)疾病發(fā)展治療現(xiàn)狀:發(fā)病機(jī)制不清:環(huán)境因素、遺傳易感、老年背景結(jié)果分析:Initialclinicaldiagnosiswithin5yrsofdiseaseonsetwascorrectin65%ofcases

Afterameandurationof12yrs,thefinaldiagnosisofPDbytheclinicianwasconfirmedatautopsyin76%ofcasesWiththeuseofstandardclinicalcriticalcriteriasuchastheUKParkinson’sDiseaseBrainBankCriteria,accuracyofaclinicaldiagnosisofthediseasecanbeimproved10%.(Jankovicetal,ArchNeurol2000;57:369;Hughesetal,JNeurolNeurosurg1992,55:181;Rajputetal,CanJNeurol

Sci1991;18:275-278)病理性標(biāo)志LossofnigralcellsPresenceofLewybodiesDepositionofreactivemicrogliaandotherinflammatorycellsShults,PNAS2006;103:1661存在問題:病理診斷標(biāo)準(zhǔn)LBD并非PD特有的特征，見于許多其他疾?。浑S年齡增加LBD也增多<80%之PD有LBD，但都有多巴胺能神經(jīng)元減少遺傳性帕金森征中， 有臨床特征類似PD，但是病理檢查無(wú)LBD(PARK2);

或有LBD的病理特征，但是臨床表現(xiàn)不典型(PARK4)難以排除能導(dǎo)致其他帕金森征的病理證據(jù)方面： 不同的神經(jīng)變性病之病理表現(xiàn)有交叉，如PD和AD鑒別PDD和DLBD存在的問題：

PD的病理從腦干發(fā)展至全腦，最后皮層彌漫性受累；DLBD的第三階段是LBD分布在腦干、邊緣系統(tǒng)和皮層Predispositiontoneuronaldeath

α-syn介導(dǎo)的細(xì)胞應(yīng)激與GSK3β信號(hào)傳導(dǎo)6-OHDA介導(dǎo)GSK3β細(xì)胞凋亡信號(hào)級(jí)聯(lián)反應(yīng)（LiY,XuP,etal.BrainRes.2010,inpress）帕金森病的鐵離子誘導(dǎo)氧化應(yīng)激JNK通路假說

[Kuan,etal.2005]

目前PD研究的問題85%PD患者基因并無(wú)其它變異單從DNA序列尋找本病的分子機(jī)制，可能片面DNA序列的表觀遺傳學(xué)變化衰老及環(huán)境毒素的暴露直接或間接改變基因DNA的甲基化狀態(tài)，從而影響個(gè)體對(duì)疾病的易感性

衰老及環(huán)境因素可直接或間接地改變DNA甲基化狀態(tài)而影響個(gè)體對(duì)疾病的易感性。Parkin和UCHL-1的表達(dá)受其啟動(dòng)子區(qū)DNA甲基化水平的影響（Agirre,2006;Okochi-Takada,2006）PD黑質(zhì)致密部的TNF-α基因的甲基化程度減低導(dǎo)致TNF-α表達(dá)升高（Pieperetal.,2008）。帕金森的表觀遺傳學(xué)-新進(jìn)展目前PD存在問題:PDisnotONLYjustamovementdisorderAutonomicDysfunction,upto64%Constipation,upto55%Rapideyemovementsleepdisorder,upto48%CognitiveImpairmentandDementia,upto58%Depression,upto50%Sensoryabnormalitiesincludingparesthesias,akathisia,oral,legandgenitalpain,upto35%Litvanetal,2007;Jankovic,2007;Ravinaetal,2007;Reijndersetal,2007;Halliday,2008

PDisnotONLYanigro-striatalDAdeficiencydisorderWhenPDpatientshaveclinicalsymptomsSerotoninergicneuronsinraphenuclei,lossabout20%Cholinergicneuronsincortex,lossabout15%GABAergicneuronsinbasalganglia,lossabout10%帕金森病病理并非始于黑質(zhì)致密部NEUROLOGY2007;68:948–952Braak病理分級(jí)運(yùn)動(dòng)前期1：(延髓:IX,X背核,前嗅核,嗅球/中