1、Parkinsons DiseaseLaboratory of Neurogenetics,National Institute on AgingClinical Characteristics Impaired olfaction Absent convergence Masked facies Monotonal and Hypophonetic speech Micrographia Difficulty initiating movements Shuffling gait Freezing and“On”“Off”symptoms FEATURES OF PARKINSONS DIS
2、EASE DOPAMINERGIC resting tremor rigidity Bradykinesia masklike facies reduced blinking Small handwriting Hypophonia Gait disorder Postural instability NONDOPAMINERGIC Loss of sense of smell Constipation Choking,drooling Autonomic(sexual,urinary,BP)dysfunction Sleep disturbance mood disorders depres
3、sion psychosis dementiaRothstein TL,Olanow CW.Neglected side of PD.American Scientist 2008Epidemiology of PD in USAPrevalence 0.3%general population1%of population over age 6050000 new cases annually130 patients per 100,0001.5 million cases in USAMenWomen 1.2:1.0Young onset PD affects 5-10%of patien
4、tsEtiology of PD Specific causative factor unknown Genetic and environmental factors probably involved Rare families with autosomal dominant and autosomal recessiveinheritance patterns have been described Major epidemiologic study suggests:Genetic factors play larger role in patients with Young Onse
5、tPD Environmental insults play larger role in patients with PDonset after age 50 Excessive protein accumulation due to genetic or environmentalinsults may underlie all cases of PDOlanow CW et al.Neurology 2001(Suppl.5)S1-2.Possible Etiologies of PD Genes Autosomal dominant inheritance is rare andinc
6、ludes:a-synuclein Ubiquitin carboxy-terminal hydrolase L1(UCH-L1)Autosomal recessive juvenile parkinsonism(AR-JP)has been associatedwith mutations in the parkin gene Parkin gene mutations may account for PD in upto 50%of familial patients with AR-JP Genes plus environment?Barbosa et al.Psychiatr Cli
7、n North Am.1997;20:769-90.Papadimitriou et al.Neurology.1999;52:651-4.McNaught et al.Nat Rev Neurosci.2001;2:589-94.Munoz.J Neurol Neurosurg Psychiatry.2002;73:582-4.Pankratz et al.NeuroRx.2004;1:235-42.CONTINUEDTime(years)HyposmiaConstipationBladder disorderSleep disorderDepressionNeocortex(seconda
8、ry&primary)Neocortex associationMesocortexRigidityAkinesiaBilateral diseasePoor balanceUnilateral tremorFallsDependencyCognitive declineChair/bed boundDementia1Substantia nigraLocus ceruleusDorsal IX/X nucleusOlfactory bulb1.Hawkes et al.61st American Academy of Neurology Meeting;April 28,2009;Seatt
9、le,WA.P02.066.2.Braak et al.J Neurol.2002;249(suppl 3):III/1-5.The Braak 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
10、with idiopathic Parkinsons disease(preclinical and clinical stages),249(suppl 3),2002,page III/4,by Braak HPresymptomatic PhaseSymptomatic PhaseThe Basal Gangliaa collection of nuclei deep in the white matter of the cerebral cortex.They include:CaudatePutamenglobus pallidussubstantia nigrasubthalami
11、c nucleus(the caudate nucleus and the putamen taken together are known as the striatum)MAIN CONNECTIONS MOTOR CIRCUITObeso et al.Neurology 62(Suppl.1)2004Biochemical Basis Depletion of striatal dopamine Asymptomatic at 50%loss Early symptoms at 70%loss At death 90%lossFactors to consider as having a
12、 role in Parkinsons disease Substantia nigra is a highly oxidative environment Substantia nigra contains high levels of oxidatively damaged proteins in PD Surviving neurons often contain intracytoplasmic inclusions(Lewy Bodies)Lewy bodies may represent defective aggrosomes and their accumulation may
13、 protect the cell from further damageParkinsons diseaseNormalParkinsonsThe pars compacta region of the substantia nigra in the normal brain appears dark because dopamine-producing neurons are highly pigmented;as neurons die from Parkinsons disease,the color fades.Parkinsons diseaseAt the left,normal
14、 numbers of neurons in the subtantia nigra are pigmented.At the right,there is loss of neurons and loss of pigmentation with Parkinsons disease.Diminished Striatal-CITParkinson Study Group.JAMA.2002;287:1653-1661.Baseline22 Months34 Months46 Months-CITUptakeHighLowStriatal-CIT uptake is typically re
15、duced by 50%at the time of diagnosis and continues to declineAbnormal Proteins Degraded by the Ubiquitin-Proteasome Pathway Misfolded proteins(due to mutation or synthetic error)Denatured proteins Oxidatively damaged proteins Incomplete proteins Proteins that fail to fold correctly in the ER Protein
16、s that fail to bind to co-factors Misdirected proteinsThe 20S Proteasome and its Activators The Ubiquitin-Proteasomal SystemENVIRONMENT&PDEnvironmental Toxins and PD Most PD cases are sporadic and are believed to be caused by exogenous environmental factors Several epidemiological reports have been
17、published on environmental factors associated with PD,but no exogenous factor has been consistently linked to PD2 Finding 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.MPTP-an experi
18、mental toxin Reproduces 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.PD Prevalence:Nebraska 329/100 KEnvironmental Risk Factors Non Geneti
19、c Causes of PD Environmental Factors&Secondary Parkinsonism Farming,rural living,well water,heavy metal exposure,low but chronic exposure to pesticides and herbicides Rotenone,paraquat,and maneb induce PD-like symptoms in animal models Smoking,caffeine,and NSAIDs lower risk Post-encephalitic PD -inf
20、luenza epidemic of 1918(Von Economos encephalitis)Epidemiological studies of drug induced Parkinsonism in the 1980s discovered MPTP contamination by synthetic opioid MPP+INTRACYTOPLASMIC INCLUSIONSLewy bodiesParkinsons diseaseRothstein T,Olanow CW.Neglected side of PD.American Scientist,2008.Braak H
21、.et al.Staging of Brain Pathology in PD,Neurobiol Aging,2003.GENETICS of PARKINSONSDiscoveries so far Using Parkin and alpha-synuclein mutations,cell and animal models created Several groups studying effects of these mutations to answer a number of questions Do these mutations effect the ability of
22、cells to resist toxins and stress(environment?)Do these mutations stop the cell from being able to destroy old or damaged proteins What are the pathways involved in these processes,can we block these pathways.CURE/TREATMENTAlpha-Synuclein Mutations in alpha-synuclein cause a rare form offamilial PD,
23、onset 40-50s Aug.1997 Gave a starting point for PD pathogenesisBaptista,Cookson,Miller(2004)Neuroscientist 10:63-72.Lewy bodies,Lewy neuritesNeuronal DamageMonomers(Natively unfolded)Oligomers(b-sheetsa-helixes)Fibrils(b-sheets)UbUbUbUbPores?cytoplasmmembraneProtection?a-helixMany structural faces o
24、f-synucleinParkin Mutations in Parkin cause early-onset recessive PD Gave clues about another step in the pathway to disease Aug.1999UblIBRUbCH7/8ParkinUbpeptidesRing1Ring2HSP70PaelRcyclinEsynphilin1cdcrel1tRNA synthaseCHIPhsel10?sp22Rpn10Non-substrate interactorsSubstratesE2UbUbUbUbUbcytoplasmmembr
25、aneCASKaa-synucleinOligomers/fibrilsBaptista,Cookson,Miller(2004)Neuroscientist 10:63-72.Parkin ProteinThe Ubiquitin-Proteasomal SystemUCH-L1a-synucleinPARKINIs Parkinsons disease a prion disorder?C.Warren Olanow and Stanley B.PrusinerProceedings National Academy of Science,August 2009aDepartments o
26、f Neurology and Neuroscience,Mount Sinai School of Medicine,New York,NY 10029;and bInstitute for Neurodegenerative Diseases and Department of Neurology,University of California,San Francisco,CA 94143 VASCULAR PARKINSONS Table 2.Neuroimaging Findings*Timeline of Parkinsons Disease TherapiesLevodopaMA
27、O-B inhibitorsSecond-generation MAO-B inhibitor(rasagiline)Dopamine agonists(ergot derived)COMT inhibitorsTolosa et al.Neurology.1998;50:S2-S10.Anti-cholinergics Non-ergot derived dopamine agonists(ropinirole,pramipexole)Significance of Motor complications Affect 80%of patients on LevoDopa Affect ap
28、proximately 100%of young-onset PD Major source of disability Commonest problem leading to Surgical Intervention Surgical Options Ablative procedures Thalamotomy/Subthalamotomy Pallidotomy Deep brain stimulation(DBS)Thalamus(vin nucleus)Globus pallidus(GPi)Subthalamic nucleus(STN)Fetal cell transplan
29、tation Autopsy studies support benefitsOlanow CW et al.Neurology.2001;56(suppl 5):S41-S44.EFFICACY OF DEEP BRAINSTIMULATION(DBS)DBS of GPi&STN seems to improveall aspects of PD motor symptomsIt can be performed bilaterallyThe precise mechanism of action isunknownProposed mechanism of DBS Neurons cou
30、ld 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 n
31、eurons or by properties of the network itself when driven by high rates.A Randomized Trial of DBS forParkinsons Disease:NEJM Aug 312006 156 patients randomized to Medical Rx vs.DBS DBS improved QOL scale 9.5 points DBS improved UPDRS 19.6 points DBS improved 24 to 36%in subscales formobility,ADL,emo
32、tional well being and bodilydiscomfort Serious complications 13%DBS vs 4%Best Medical RxActiva Therapy for the Treatment of PDAn implantable system that interacts with brain activity to improve some of the motor symptoms of Parkinsons diseaseReversibleReversibleAdjustableAdjustableBilateralBilateral
33、ComponentsLead&ExtensionLead&ExtensionNeurostimulator(Implantable Pulse Generator-IPG)Neurostimulator(Implantable Pulse Generator-IPG)Physician ProgrammerPhysician ProgrammerPatient Therapy Controller or MagnetPatient Therapy Controller or Magnet*The negative electrode exerts the therapeutic effectP
34、rocedure Computer calculated trajectory Microelectrode placementElectrophysiologyGary.mpgREFERENCES 1.Nutt J:Diagnosis and Early Management of Parkinsons Disease.New England Journal Medicine 353:Sept 8,2005.2.Rothstein TL,Olanow CW.The Neglected Side of Parkinsons Disease.American Scientist 96:pp 218-225,May-June,2008.3.Gasser T:Update on the Genetics of Parkinsons Disease.Movement Disorders 22:pp S343-350,2007.4.Lang AE,Lozano AM.Parkinsons disease.New England Journal Medicine:1044-1053,1130-1143,1998.
