帕金森研究进展与机制parkinsonsdisease2010课件

Parkinsons Disease Background oBest described as “shaking palsy” by James Parkinson in 1817 o“Involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forwards, and to pass from a walking to a running pace: the senses and intellects being uninjured.” Olanow CW et al. Neurology. 2001;56 (suppl 5):S1-S88. National Parkinson Foundation Web site. . Marttila RJ, Rinne UK. Acta Neurol Scand. 1991;84(suppl 136):24-28. DeStefano AL et al. Am J Hum Genet. 2002;70:1089-1095. “As the disease proceeds towards its last stage, the trunk is almost permanently bowed” Neurodegenerative diseases Prevalence in US Fast Facts about PD oAnnual incidence: 60,000 new cases/yr oIncrease with age (3% population 65 years old) oSlightly more common in men oMean age at onset: 60 years old o85% of patients are over 65 years old Risk of Parkinsons Disease Increased risk oAge oHigh Body Mass Index oMale gender oFamily history oDepression oEnvironment factors nrural living nwell-water drinking nwelding nhead injury Decreased risk oCaffeine intake oSmoking cigarettes oAnti-oxidants in diet Motor Symptoms oTremor at rest oBradykinesia oRigidity oPostural instability oDecreased arm swing when walking oMicrographia oHypophonia oMasked face oSlow, shuffling gait oStooped posture Olanow CW, Watts RL, Koller WC . Neurology. Neurology. 2001;56 (2001;56 (supplsuppl 5):S1-S88. 5):S1-S88. Waters CH. Diagnosis and Management of Parkinsons Disease. 3rd ed. 2002. National Parkinson Foundation. National Parkinson Foundation. http:/. . “the hand failing to answer with exactness to the dictates of the will.” Manifestations of PD Additional Features oCognitive, mood, and behavioral dysfunction oOlfactory disturbance oSleep disturbance oConstipation oSeborrheic dermatitis oPain oAutonomic disturbances Nutt JG, Wooten GF. N Engl J Med. 2005;353:1021-1027. Parkinsons Disease Foundation Web site. . Diagnosing PD oUnited Kingdom Brain Bank Criteria oStage I Hoehn and Yahr (H122:1437-1448. Dopamine deficiency in PD PET scan Presymptomatic phase Onset Sleep Olfactory* Mood Autonomic system Diagnosis Early nonmotor symptomsSpecific symptoms Motor Treatment Based on Replacing Dopamine Dopaminergic neuron loss in PD % Remaining % Remaining Dopaminergic NeuronsDopaminergic Neurons Time (years) Nonmotor Adapted image reprinted from Neurotherapeutics, Vol. 6, Halperin I, Morelli M, Korczyn AD, Youdim MB, Mandel SA. Biomarkers for evaluation of clinical efficacy of multipotential neuroprotective drugs for Alzheimers and Parkinsons diseases, pages 128-140, Copyright 2009, with permission from Elsevier. *Olfactory dysfunction may predate clinical PD by at least 4 years. Halperin et al. Neurotherapeutics. 2009;6:128-140. Lang. Neurology. 2007;68:948-952. Ross et al. Ann Neurol. 2008;63:167-173. Olanow, C. W. et al. Neurology 2009;72:S1-S136 Braak Staging of PD Alpha-Synuclein Pathology in the Substantia Nigra and Neocortex Cerebral cortex Substantia nigra Alpha Synuclein Toxic Alpha-synuclein oChaperones prevent toxic alpha-synuclein from forming oDevelop antibodies that keep alpha- synuclein from forming aggregates oFind small molecules that can prevent misfolding Oxidative stressOxidative stress MPTPMPTP PesticidesPesticides HerbicidesHerbicides Bacterial toxinsBacterial toxins Mechanisms of Neurodegeneration ENVIRONMENTAL FACTORSGENETIC FACTORS Mitochondria Complex I ROS PARK1 (-synuclein) PARK2 (Parkin) PARK5 (UCH-L1) PARK6 (PINK1) PARK7 (DJ-1) PARK8 (LRRK2, dardarin) Other genes NIGRAL CELL DEATH Toxic injuryToxic injury ApoptosisApoptosis InflammationInflammation ExcitotoxicityExcitotoxicity a a-Synuclein-Synuclein Related proteins?Related proteins? Altered proteinAltered protein conformationconformation Ubiquitin systemUbiquitin system Proteasome dysfunction?Proteasome dysfunction? Protein aggregatesProtein aggregates (Lewy bodies: (Lewy bodies: good or bad?)good or bad?) BenMoyal-Segal L, Soreq H. J Neurochem. 2006;97:1740-1755. Dawson TM, Dawson VL. J Clin Invest. 2003;111:145-151. Mouradian MM. Neurology. 2002;58:179-185. Neurons L-dopa = levodopa. AZILECT Prescribing Information. 05/09. Olanow et al. Neurology. 2001;56(11 suppl 5):S1-S88. Jankovic. Neurology. 2002;58(4 suppl 1):S19-S32. Pros and Cons of Available FDA-Approved Monotherapy Levodopa: The Cornerstone of PD Therapy oLevodopa provides substantial antiparkinsonian symptom control, and significantly improves patient quality of life1 oLevodopa is the most efficacious antiparkinsonian medication in moderate and advanced disease oLevodopa provides relatively rapid symptomatic benefits2,3 oLevodopa is generally well tolerated with few initial side effects oLevodopa continues to provide antiparkinsonian benefits through the course of the illness oAll PD patients eventually require levodopa therapy 1. Louis ED, et al. Arch Neurol. 1997;54:260-264. 2. Olanow CW, et al. Neurology. 2001;56:S1-S86. 3. Agidy et al. Lancet. 2002;360:575. Early DiseaseAdvanced Disease Levodopa Plasma Level Neuronal Dopamine Level Levodopa Dosing Interval (h)Levodopa Dosing Interval (h) Schematic of Levodopa and Dopamine Levels as Disease Progresses Early Disease: Fluctuating Plasma Levodopa Levels Buffering by Striatal DA TerminalsBuffering by Striatal DA Terminals Relatively Constant Striatal Dopamine Levels Advanced Disease: Fluctuating Plasma Levodopa Levels Buffering by Striatal DA TerminalsBuffering by Striatal DA Terminals Striatal Dopamine Levels Mirror Levodopa Serum Levels in the Periphery Buffer CapacityBuffer Capacity Wearing Off oMost common motor fluctuation oOccurs toward end of dose o“wear down” oRegular and predictable oAdjust dose On-Off Response oSudden and unpredictable oDose failure nLate afternoon, probably related to poor gastric emptying or absorption oHardest feature oDose adjustments, add-ons Dyskinesia Off Freezing Continuous Delivery Theory oPulsatile stimulation causes levodopa-associated motor complications oStable plasma levels may prevent priming for motor fluctuations and dyskinesia oContinuous delivery systems in development Stocchi F, Olanow CW. Neurology. 2004;62:S56-S63. Olanow CW et al. Lancet Neurol. 2006;5:677-687. As the Disease Progresses, the Therapeutic Window Narrows* Symptoms and side effects occur as the levodopa therapeutic window diminishes* Smooth, extended response Diminished duration Shorter, unpredictable response Absent or infrequent dyskinesia Increased incidence “On” time with increased dyskinesia of dyskinesia Plasma Levodopa Concentrations Adapted from: Stocchi F, et al. Eur Neurol, 1996. Duodopa oDu Key Points: Early but No Impairment oEarly patients- no functional impairment nEasiest treatment category nADAGIO, TEMPO (rasagiline) and ELLDOPA trial indicate earlier treatment may be better oConsider rasagiline (Azilect), selegiline (Eldepryl,Zelapar) nRefer for potential neuroprotective trials oCoenzyme Q10, selegiline, rasagiline, creatine Key Points: Early with Impairment oEarly patient-functional impairment nBothersome tremor, stiffness, slowness, decrease in dexterity interfering with ADLs or job oAAN guidelines 2002 nMAO B inhibitors provide some benefit nDopamine agonists nLevodopa oIf the patient is chronologically or physiologically young (70) try a dopamine agonist as the first robust treatment oIf older, or cognitively impaired, use levodopa first Key Points: Middle Stage Patients oStarting to have wearing off of drug benefit prior to next dose oGoal is to enhance dopamine system in the brain, since these medications have different mechanisms of action=Polypharmacy is expected! oLayer on medications and adjust to best benefit Key Points: Later Mid-Stage Patient oExperiencing fluctuation in motor control to include significant wearing off with poor mobility and dyskinesias nHave patients keep diaries of motor control nAdd additional medications nConsider smaller, more frequent doses of medications to minimize “off” time and dyskinesia oOnset or worsening of many non-levodopa responsive symptoms, such as falling, worsening cognition, dysphagia, autonomic dysfunction Key Points: Advanced Parkinsons Disease oTreatment is made difficult by the worsening of motor complications, cognitive, psychiatric and autonomic disturbances oMedications may need to be streamlined (reduced or eliminated) because of confusion or psychosis Surgical Treatment for PD oPatient selection is KEY oPatients who are very sensitive to levodopa are the best candidates oPatients should have motor fluctuations including dyskinesias oPatients must be free of significant cognitive disease oUsually, consideration after 10 years of disease, but trend toward earlier use in several trials Deep Brain Surgery oMost commonly done is deep brain stimulation of the STN, bilateral oBest patient is fluctuating, still responsive to levodopa, good cognitive skills 0 1 2 3 DBS Lead Electrode Selection * The negative electrode exerts the therapeutic effect L