神經(jīng)病學(xué)課件-運(yùn)動障礙疾病

1、Movement disorders diseaseMovement disorders disease神經(jīng)病學(xué)課件-運(yùn)動障礙疾病神經(jīng)病學(xué)課件-運(yùn)動障礙疾病DefinitionMovement disorder disease is induced by basal ganglia damage with different kind causes, such as : toxin, degeneration, infalmanntary, infarction , genetics, ect.It comprise a spectrum of abnormalities that range

2、 from the hypokinetic disorders (of which Parkinsons disease is the best-known example) at one extreme to the hyperkinetic disorders (exemplified by Huntingtons disease and hemiballismus) at the other.DefinitionMovement disorder di神經(jīng)病學(xué)課件-運(yùn)動障礙疾病Major Diseases of the Basal GangliaParkinsons diseaseHun

3、tingtons diseaseDystoniaRestless Leg SyndromePsychiatric diseases (OCD)Major Diseases of the Basal GaThe most common type is :Parkinsons diseaseHuntingtons diseaseWilson diseaseMultiple system atrophy: SND,OPCA,SDSDystoniaRestless leg syndromeThe most common type is :ParkiTremor definitionTremor: Vi

4、deo. PD.avia rhythmic oscillatory movementbest characterized byits relationship to voluntary motor activityTremor definitionTremor: VideTremor classificationIntension: cerebellar rest : PD(4-6 Hz).PDbrother 012.mpgaction: Essential and cerebellar postural: metabolism(8-12 Hz)Tremor classificationCho

5、rea and TicChorea: denotes rapid irregular muscle jerks that occur involuntarily and unpredictably in different parts of the body(Video:)HD- chorea.MPGTic: Sudden,repetitive,stereotyped,purposeless brief actions,gestures,soundsand words that emerge from a background of normal motor activity.Chorea a

6、nd TicChorea: denotes Spasticity and MyoclonusSpasticity: continue clonic contraction, upper motor neuron( hereditary spastic paraplegia,HSP)Myoclonus: a single sudden jerk or a short series occurring in slow : CJD(Creutzfeldt-Jakob disease(Prion disease), AIDS dementia complexSpasticity and Myoclon

7、usSpastiAthetosis and DystoniaAthetosis : in contrast to chorei form movementsthese are slowerwriting,resembling the actions like a worm or snakeAthetosis and DystoniaAthetosiDystoniaDystoniasustained muscle contractionsoften causing twisting movements or abnormal posturesDystoniaDystoniaParkinsons

8、diseasGeneral considerationPathogenesisPreventionClinical findingsDifferent diagnosistreatmentParkinsons diseasGeneral consThe stone of parkinsons diseaseJame parkinsons foundingBiochemistry foundingMPTPMutaion of GeneThe stone of parkinsons diseaHistory of Parkinsons disease (PD)First described in

9、1817 by an English physician, James Parkinson, in “An Essay on the Shaking Palsy.”The famous French neurologist, Charcot, further described the syndrome in the late 1800s.History of Parkinsons diseaseParkinson DiseaseMotor system disorder in the brain.Results from the loss of Dopamine.First describe

10、d by James Parkinson in 1817.Symptoms (Primary)Tremor of one or more than one limb.Rigidity .Bradykinesia.Postural instability.Parkinson DiseaseNolte, Fig 8-33Dopamine PathwaysNolte, Fig 8-33Dopamine PathwaEpidemiology of PDThe most common movement disorder affecting 1-2 % of the general population

11、over the age of 65 years.The second most common neurodegenerative disorder after Alzheimers disease (AD).Epidemiology of PDParkinsons disease1.5 men/women ratioMain risk factor : ageYoung onset: before 50 y.o.Rare familiar forms: genetic cluesParkinsons disease1.5 men/womIncidence of PDWorld Health

12、Organization estimates for incidence and prevalence follow:wemen: 4.9/100,000 men: 5.8/100,000 0-19 years: 0.0/100,000 20-64 years: 3.9/100,000 65 years and over: 49.3/100,000Incidence of PDWorld Health OrPrevalence of PDwemen: 6/100,000 men: 8/100,000 0-19 years: 0/100,000 20-64 years: 6/100,000 65

13、 years and over: 70/100,000Theres about 170,000 PD patient in China.Prevalence of PDwemen: 6/100,0May be less prevalent in China and other Asian countries, and in African-Americans.Prevalence rates in men are slightly higher than in women; reason unknown, though a role for estrogen has been debated.

14、神經(jīng)病學(xué)課件-運(yùn)動障礙疾病Common causesPrimary (75%):Idiopathic Parkinsons diseaseSecondary (25%):Vascular disease Infectious and postinfectious Postencephalitic NeurosyphilisAIDSToxins:Manganese ,Cyanide ,Methanol ,Carbon monoxide ,MPTP,PesticidesMedications:Neuroleptics , Dopamine-depleting agents,Calcium-chan

15、nel blockers ,Valproic acid ,Fluoxetinecauses:Common causescauses:Rare causes Hypoparathyroidism with basal ganglia calcification , Hypothyroidism and hyperthyroidism Miscellaneous:Repeat trauma (notably from boxing) Structural lesions: Tumors ,Infarctions ,HydrocephalusRare causesDauer W, Przedbors

16、ki S. Parkinsons disease: mechanisms and models. Neuron. 2003 39:889-909.Dauer W, Przedborski S. ParkiThe role of basal ganglia disinhibition in the generation of saccadic eye movementsThe role of basal ganglia disiDiagnosis of PD Anamnesis and clinical examination No disease-specific biological mar

17、ker available Positron Emission Tomography (PET) or Single-photon Emission Computed Tomography (SPECT) with dopaminergic radioligands Exclusion of several causes of secondary ParkinsonismDiagnosis of PD The patient is evaluated by interview and clinical assessment in the following categories:Mentati

18、on, behavior, and mood Activities of daily living Motor Complications of therapy Hoehn-Yahr Stage Schwab and England Activities of Daily Living ScaleThe Unified Parkinsons Disease Rating Scale (UPDRS)The patient is evaluated by in Neuropathology of PDEosinophilic, round intracytoplasmic inclusions c

19、alled lewy bodies and Lewy neurites.First described in 1912 by a German neuropathologist - Friedrich Lewy.Inclusions particularly numerous in the substantia nigra pars compacta. Neuropathology of PD神經(jīng)病學(xué)課件-運(yùn)動障礙疾病Neuropathology of PD: Lewy bodiesNot limited to substantia nigra only; also found in the

20、motor nucleus of the vagus nerve, the hypothalamus, the nucleus basalis of Meynert the cerebral cortex, the olfactory bulb and the autonomic nervous system.Confined largely to neurons; glial cells only rarely affected.Neuropathology of PD: Lewy bodLewy bodiesLewy bodiesFunctional neuroanatomy of PDS

21、ubstantia nigra: The major origin of the dopaminergic innervation of the striatum.Part of extrapyramidal system which processes information coming from the cortex to the striatum, returning it back to the cortex through the thalamus.One major function of the striatum is the regulation of posture and

22、 muscle tone.Functional neuroanatomy of PDSchapira AH, Olanow CW. Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions. JAMA. 2004 Jan 21;291(3):358-64. Schapira AH, Olanow CW. NeuroGenes involved in familial PDPARK 1-8Park1: alpha-synuclein dominant: mutationPark2: Parkin, mai

23、nly recessive; Park3 (Chr 2p13 dominant) 1998Park4: alpha-synuclein dominant: gene duplicationPark5: UCHL1, possibly dominant) Park6: PINK1, recessivePark7 (Chr 1p33-p34; recessive)Park8: LRKK2-dardarinMore genes?Genes involved in familial PDPCase-control study of pesticides in Taiwan*+ Odds ratio,

24、adjusted for age, gender, smoking*Liou HH, et al. Neurology 1997;48:1583-8Case-control study of pesticidParkinsons diseaseParkinsons diseaseMain signs for PDMotor signsNon-motor signsMain signs for PDMotor signsMotor signsTremorAkinesiaRigiditylose of postural reflexesReduced arm swingMotor signsMot

25、or signsMasked facesStrooped Posture / Shuffling GaitLow Speech Volume (Hypomimia)Micrographia(Small Handwriting)Postural Instabilty(Ususally Late)Motor signsMasked facesMicrographia(micrographia1.MPG)Micrographia(micrographia1.MPGMicrographia（continue and not)Micrographia（continue and not)Macrograp

26、hiaMacrographiaNon-motor signsOrthostatic HypotensionHyposomiaUrinary IncontinenceSleep Behaviour DisorderDementia (Late)- In 40-80% at some stage of PDNon-motor signsOrthostatic HyNon-motor signsdepressionconstipation PainDementiaSlowed ThinkungAnxiety / Pain attacksNon-motor signsdepressionClassif

27、ication of motor complicationDyskinesiaDYSKINEIA1.MPGPeak dyskinesiaBiphasic dyskinesiadystoniaMotor-fluctuationWearing off phenominaOn-off phynomena0n-delayClassification of motor compliTwo type-Dyskinesia-VideoMotor dyskineia(confortable)peak dyskinesia2.MPGPD-Motor and non-motor.avi(unconfortable

28、)Two type-Dyskinesia-VideoMotorMotor fluctuationCompletely off: Severe PD-OFF 031.aviON time decreasedOFF time increase: 翁采琴 129.aviOn delayMotor fluctuationCompletely ofNARROWING THERAPEUTIC WINDOW WITH TIMEL-DOPAyearstherapeuticwindowdyskinesiabradykinesiaSurgeryNARROWING THERAPEUTIC WINDOW WThe C

29、hallenge of PD TreatmentEarly treatment:Hypotentionnause,vomitingHallucinationPrecaution:individual dosage,little by littleThe Challenge of PD TreatmentEThe challenge of PD treatment:Late stage Dyskinesias Motor fluctuationDepressionInsomiaPainDementiaConstipationThe challenge of PD treatment:Treatm

30、entParkinsons disease is a chronic disorder that requires broad-based management including patient and family education, support group servicesgeneral wellness maintenance physiotherapy, exercise, and nutrition. Medications or surgery can just provide relief from the symptoms.TreatmentParkinsons dis

31、ease iI. increase dopamine synthesis capacityII. direct activate post-synaptic receptorsIII. inhibit dopamine metabolismIV. alter the interaction/balance with other neurotransmitters V. dopamine releasersVI. L-DOPA peripheral metabolism inhibitors What is the desired goal of pharmacological therapie

32、s for Parkinsons disease?- Produce more output from the striatal dopamine neuronsWhat is the desired goal of phDRUG THERAPYReview Main Line Agents: L-DOPA plus carbidopa (Sinemet) dopamine receptor agonists (ropinirole, pramipexole ) MAO B Inhibitors (rasagiline , selegiline)Lower Efficacy/Second Li

33、ne or Adjuvant Agents:anticholinergics (benztropine, trihexyphenidol) DA reuptake Inhibitor (amantadine) COMT Inhibitor (entacapone)DRUG THERAPYReview Main The dopamine-agonists bromocriptine, pergolide, pramipexole, ropinirole , cabergoline, apomorphine, and lisuride, are moderately effective. Dopa

34、mine agonists initially act by stimulating some of the dopamine receptors. Dopamine agonists can be useful for patients experiencing on-off fluctuations and dyskinesias as a result of high doses of L-dopa. Other treatments :Dopamine AgonistsThe dopamine-agonists bromocri1st generation agonists (ergo

35、t derivatives*)bromocriptine (D2 agonist)pergolide (D2/D3 agonist)1st generation agonists2nd generation agonists: (non-ergot)ropinirole (D2/D3 agonist)pramipexole (D2 agonist)rotigotine (D3/D2/D1 agonist)神經(jīng)病學(xué)課件-運(yùn)動障礙疾病Other Dopamine Agonistsshort-acting non-ergoline agonistapomorphine( D1 and D2 rece

36、ptors )Other Dopamine AgonistsOther Dopamine Agonistsshort-acting non-ergoline agonistapomorphine( D1 and D2 receptors )Other Dopamine AgonistsSelegiline and rasagiline reduce the symptoms by inhibiting monoamine oxidase-B (MAO-B), which inhibits the breakdown of dopamine secreted by the dopaminergi

37、c neurons.Other treatments : MAO-B InhibitorsSelegiline and rasagiline reduMAO-B inhibitor: SelegilineRasagilineCOMT inhibitor:entacaponeMAO-B inhibitor: Amantadine block DA reuptake,glutamate receptors A2A antiagonist: clinical trialAmantadine DBS plantationDBS plantationOperation stimulate side：Gp

38、i 、STN現(xiàn)在的手術(shù)靶點： 蒼白球腹內(nèi)側(cè)核（Gpi) 丘腦（Vim) 丘腦底核（STN）Operation stimulate side：Gpi 、Historical Aspects1872: Meigs and Mason Academy of Medicine adult-onsetprogression tendency to insanity and suicideinheritance pattern. Hereditary Chorea.George Huntington “I have drawn your attention to this form of chorea g

39、entlemen, not that I considered it of any great practical importance to you, but merely as a medical curiosity, and as such it may have some interest.”Historical AspectsGeorge HuntHuntington Disease: Historical Aspects “ Over fifty years ago, in riding with my father on his professional rounds, I sa

40、w my first cases of that disorder, which was the way in which the natives always referred to the dreaded disease.we suddenly came upon two women, mother and daughter, both tall, thin, almost cadaverous, both bowing, twisting, grimacingmy medical education had its inception. From this point on my int

41、erest in the disease has never wholly ceased.”First described by George Huntington in 1872 in families in East Hampton, Long IslandHuntington Disease: Historical Huntington ChoreaHuntington disease,HD： is transmitted as autosomal dominant trait With complete penetrance.Both sexes are equally affecte

42、d. VIEDO- HDfamily1.avi1 HD2.MPG Huntington ChoreaHuntingtGenetics characteristics：Gusella etal (cell,1993) identified the gene_IT15,IT15 with exon 67: Genetics characteristics：IT15 gene code:PloyQ(Huntingtin, Htt）:IT15 gene code:PloyQ(HuntingtiCoronal planeDorso-ventral directionSagittal planeCaudo

43、-rostral directionOrdered and topographic distributionCoronal planeDorso-ventral dirHD in Venezuela1972-CentennialRamon Avila-GironEl Mal de San Vito165 families studied in 4 townsOf the 1352 people, 28 had HD203 people in those families had died with HDA sailor (A.D.) involved in dividivi trade wit

44、h Germany probably introduced HD in this region between 1860 and 1870HD in Venezuela1972-CentennialJuvenile-onset HDDystonia and parkinsonism predominateSeizuresTypically paternal inheritance due to anticipation; expansion of CAG repeatFaster progression (duration 5-15 years)Juvenile-onset HDDystoni

45、a and Venezuela Collaborative Huntingtons Disease Project1979- First American expedition to Maracaibo led by Dr. Nancy Wexler1981- First of annual trips to the region1983- Discovery of the HD gene marker on chromosome 4 1993- Identification of IT-15Venezuela Collaborative HuntinPsychiatricDepression

46、AnxietyOCDPsychosisMotorEye movementsChoreaDystoniaGait and balanceDysarthria and dysphagiaParkinsonismCognitiveFrontal-ExecutiveAttentionPlanningMemoryVisuospatialPsychiatricMotorCognitive神經(jīng)病學(xué)課件-運(yùn)動障礙疾病MRIMRICTCTPreclinical Studies:Models of HDMouseTransgenic (R 6/2 best studied)Knock-in D. melanoga

47、sterC. elegans YeastCell CulturePreclinical Studies:Models of Effective Targets for Therapy Based on Mouse Preclinical StudiesExcitotoxicityMitochondrialdysfunctionAggregatetoxicityTranscriptional dysregulationProteasomal andlysosomaldysfunction Caspase-mediated cell deathRemacemide,RiluzoleCoQ10, Creatine, BN 82451 Ethyl-EPA, lipoic acid HDAC Inhibitors: SAHA, sodium butyrateTransglutaminaseInhibitors: CystaminePolyQ a