帕金森病(英文版)課件

1、Parkinsons DiseaseLaboratory of Neurogenetics, National Institute on AgingParkinsons DiseaseLaboratory Clinical CharacteristicsImpaired olfactionAbsent convergenceMasked faciesMonotonal and Hypophonetic speechMicrographiaDifficulty initiating movementsShuffling gaitFreezing and “On” “Off” symptomsCl

2、inical CharacteristicsImpai FEATURES OF PARKINSONS DISEASEDOPAMINERGICresting tremorrigidityBradykinesiamasklike faciesreduced blinkingSmall handwritingHypophoniaGait disorderPostural instabilityNONDOPAMINERGICLoss of sense of smellConstipationChoking, droolingAutonomic (sexual, urinary, BP) dysfunc

3、tionSleep disturbancemood disorders depressionpsychosisdementiaRothstein TL, Olanow CW. Neglected side of PD. American Scientist 2008 FEATURES OF PARKINS帕金森病(英文版)Epidemiology of PD in USAPrevalence 0.3% general population1% of population over age 6050000 new cases annually130 patients per 100,0001.5

4、 million cases in USAMenWomen 1.2:1.0Young onset PD affects 5-10% of patientsEpidemiology of PD in USAPreva帕金森病(英文版)帕金森病(英文版)Time (years)HyposmiaConstipationBladder disorderSleep disorderDepressionNeocortex(secondary & primary)Neocortex associationMesocortexRigidityAkinesiaBilateral diseasePoor bala

5、nceUnilateral tremorFallsDependencyCognitive declineChair/bed boundDementia1Substantia nigraLocus ceruleusDorsal IX / X nucleusOlfactory bulb1. Hawkes et al. 61st American Academy of Neurology Meeting; April 28, 2009; Seattle, WA. P02.066.2. Braak et al. J Neurol. 2002;249(suppl 3):III/1-5.The Braak

6、 Hypothesis: An Evolving Concept of Disease Progression and TimingAdaptation of figure reprinted with kind permission from Springer Science+Business Media: J Neurol, Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinsons disease (preclinical and clinical stages),

7、 249(suppl 3), 2002, page III/4, by Braak HPresymptomatic PhaseSymptomatic PhaseTime (years)HyposmiaSleep disoThe Basal Gangliaa collection of nuclei deep in the white matter of the cerebral cortex.They include: CaudatePutamenglobus pallidussubstantia nigrasubthalamic nucleus(the caudate nucleus and

8、 the putamen taken together are known as the striatum)The Basal Ganglia帕金森病(英文版)MAIN CONNECTIONS MOTOR CIRCUITObeso et al. Neurology 62 (Suppl. 1) 2004MAIN CONNECTIONS MOTOR CIRCUITBiochemical BasisDepletion of striatal dopamineAsymptomatic at 50% lossEarly symptoms at 70% lossAt death 90% lossBioch

9、emical BasisDepletion ofFactors to consider as having a role in Parkinsons diseaseSubstantia nigra is a highly oxidative environmentSubstantia nigra contains high levels of oxidatively damaged proteins in PDSurviving neurons often contain intracytoplasmic inclusions (Lewy Bodies)Lewy bodies may repr

10、esent defective aggrosomes and their accumulation may protect the cell from further damageFactors to consider as havingParkinsons diseaseParkinsons diseaseNormalParkinsonsThe pars compacta region of the substantia nigra in the normal brain appears dark because dopamine-producing neurons are highly p

11、igmented; as neurons die from Parkinsons disease, the color fades.Parkinsons diseaseNormalParkinsonsThe pars compAt the left, normal numbers of neurons in the subtantia nigra are pigmented. At the right, there is loss of neurons and loss of pigmentation with Parkinsons disease.At the left, normal nu

12、mbers of帕金森病(英文版)Diminished Striatal -CITParkinson Study Group. JAMA. 2002;287:1653-1661. Baseline22 Months34 Months46 Months-CITUptakeHighLowStriatal -CIT uptake is typically reduced by 50% at the time of diagnosis and continues to declineDiminished Striatal -CITParkiThe Ubiquitin-Proteasomal Syste

13、m is the primary system for the degradation and clearance of abnormal and unwanted proteins in normal nerve cells The Ubiquitin-Proteasome SystemThe Ubiquitin-Proteasomal SystAbnormal Proteins Degraded by the Ubiquitin-Proteasome PathwayMisfolded proteins (due to mutation or synthetic error)Denature

14、d proteinsOxidatively damaged proteinsIncomplete proteinsProteins that fail to fold correctly in the ERProteins that fail to bind to co-factorsMisdirected proteinsAbnormal Proteins Degraded by The 20S Proteasome and its Activators The 20S Proteasome and its 帕金森病(英文版)帕金森病(英文版)The Ubiquitin-Proteasoma

15、l SystemThe Ubiquitin-Proteasomal Syst帕金森病(英文版)ENVIRONMENT & PDENVIRONMENT & PDEnvironmental Toxins and PDMost PD cases are sporadic and are believed to be caused by exogenous environmental factors Several epidemiological reports have been published on environmental factors associated with PD, but n

16、o exogenous factor has been consistently linked to PD2Finding true causally-linked associations in PD has been challengingBackground 1. Henchcliffe C & Beal MF. Nat Clin Prac Neurol. 2008;4:600-609; 2. Rajput A. Neurology 2001;56:4-5.Environmental Toxins and PDMos MPTP- an experimental toxin Reprodu

17、ces all major features of PDMPTP In Astrocytes MAO-BMPP+ Dopminergic Neuron Mitochondria Inhibits NADH-CoQ (Complex 1) Fall in ATP production ApoptosisByproduct of illicit Heroin and Meperidine (Demerol) synthesis MPTP- an experimental toxin.PD Prevalence: Nebraska 329/100 KPD Prevalence: Nebraska 3

18、29/10帕金森病(英文版)Environmental Risk Factors Non Genetic Causes of PDEnvironmental Factors & Secondary ParkinsonismFarming, rural living, well water, heavy metal exposure, low but chronic exposure to pesticides and herbicidesRotenone, paraquat, and maneb induce PD-like symptoms in animal modelsSmoking,

19、caffeine, and NSAIDs lower riskPost-encephalitic PD - influenza epidemic of 1918 (Von Economos encephalitis)Epidemiological studies of drug induced Parkinsonism in the 1980s discovered MPTP contamination by synthetic opioid MPP+Environmental Risk Factors NoINTRACYTOPLASMIC INCLUSIONSLewy bodiesParki

20、nsons diseaseINTRACYTOPLASMIC INCLUSIONSLew帕金森病(英文版)Rothstein T, Olanow CW. Neglected side of PD. American Scientist, 2008.Braak H. et al. Staging of Brain Pathology in PD, Neurobiol Aging, 2003.Rothstein T, Olanow CW. NeglecGENETICS of PARKINSONSGENETICS of PARKINSONSDiscoveries so farUsing Parkin

21、and alpha-synuclein mutations, cell and animal models createdSeveral groups studying effects of these mutations to answer a number of questionsDo these mutations effect the ability of cells to resist toxins and stress (environment?)Do these mutations stop the cell from being able to destroy old or d

22、amaged proteinsWhat are the pathways involved in these processes, can we block these pathways.CURE/TREATMENTDiscoveries so farUsing Parki帕金森病(英文版)Baptista, Cookson, Miller (2004) Neuroscientist 10: 63-72. Lewy bodies,Lewy neuritesNeuronal DamageMonomers(Natively unfolded)Oligomers(b-sheetsa-helixes)

23、Fibrils(b-sheets)UbUbUbUbPores?cytoplasmmembraneProtection?a-helixMany structural faces of -synucleinBaptista, Cookson, Miller ParkinMutations in Parkin cause early-onset recessive PDGave clues about another step in the pathway to disease Aug. 1999ParkinMutations in Parkin causUblIBRUbCH7/8ParkinUbp

24、eptidesRing1Ring2HSP70PaelRcyclinEsynphilin1cdcrel1tRNA synthaseCHIPhsel10?sp22Rpn10Non-substrate interactorsSubstratesE2UbUbUbUbUbcytoplasmmembraneCASKa-synucleinOligomers/fibrilsBaptista, Cookson, Miller (2004) Neuroscientist 10: 63-72. Parkin ProteinUblIBRUbCH7/8ParkinUbpeptidesR帕金森病(英文版)Is Parki

25、nsons disease a prion disorder?C. Warren Olanow and Stanley B. PrusinerProceedings National Academy of Science, August 2009aDepartments of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, NY 10029; and bInstitute for Neurodegenerative Diseases and Department of Neurology, Univer

26、sity of California, San Francisco, CA 94143 Is Parkinsons disease a prionVASCULAR PARKINSONSVASCULAR PARKINSONS帕金森病(英文版)Timeline of Parkinsons Disease Therapies1967Levodopa1981MAO-B inhibitorsSecond-generation MAO-B inhibitor (rasagiline)Early 2000s1970sDopamine agonists(ergot derived)1997COMT inhib

27、itorsTolosa et al. Neurology. 1998;50:S2-S10.1800sAnti-cholinergics Non-ergot derived dopamine agonists(ropinirole, pramipexole)1994Timeline of Parkinsons Diseas帕金森病(英文版)Significance of Motor complicationsAffect 80% of patients on LevoDopaAffect approximately 100% of young-onset PDMajor source of di

28、sabilityCommonest problem leading to Surgical Intervention Significance of Motor complSurgical OptionsAblative proceduresThalamotomy/SubthalamotomyPallidotomyDeep brain stimulation (DBS)Thalamus (vin nucleus)Globus pallidus (GPi)Subthalamic nucleus (STN)Fetal cell transplantationAutopsy studies supp

29、ort benefitsOlanow CW et al. Neurology. 2001;56(suppl 5):S41-S44.Surgical OptionsAblative proceEFFICACY OF DEEP BRAINSTIMULATION (DBS)DBS of GPi & STN seems to improveall aspects of PD motor symptomsIt can be performed bilaterallyThe precise mechanism of action isunknownEFFICACY OF DEEP BRAINSTIMULA

30、TProposed mechanism of DBSNeurons could be held in depolarized state and could not produce action potentials (depolarization block)The neural network could be disrupted by the additional nerve impulses generated by stimulation (neural jamming)Stimulation may produce net inhibition in the network by preferential activation of inhibitory neurons or by properties of the network itself when driven by high rates.Proposed mechanism of DBSNeuro帕金森病(英文版)Activa Therapy for the Treatment of PDAn implantable system that interacts with brain ac