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1、Parkinsons Disease Background,Best described as “shaking palsy” by James Parkinson in 1817 “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 sens
2、es and intellects being uninjured.”,Olanow CW et al. Neurology. 2001;56 (suppl 5):S1-S88. National Parkinson Foundation Web site. www.parkinson.org. 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 tow
3、ards its last stage, the trunk is almost permanently bowed”,Neurodegenerative diseases Prevalence in US,Fast Facts about PD,Annual incidence: 60,000 new cases/yr Increase with age (3% population 65 years old) Slightly more common in men Mean age at onset: 60 years old 85% of patients are over 65 yea
4、rs old,Risk of Parkinsons Disease,Increased risk Age High Body Mass Index Male gender Family history Depression Environment factors rural living well-water drinking welding head injury,Decreased risk Caffeine intake Smoking cigarettes Anti-oxidants in diet,Motor Symptoms,Tremor at rest Bradykinesia
5、Rigidity Postural instability Decreased arm swing when walking Micrographia Hypophonia Masked face Slow, shuffling gait Stooped posture,Olanow CW, Watts RL, Koller WC Neurology. 2001;56 (suppl 5):S1-S88. Waters CH. Diagnosis and Management of Parkinsons Disease. 3rd ed. 2002. National Parkinson Foun
6、dation. http:/www.parkinson.org.,“the hand failing to answer with exactness to the dictates of the will.”,Manifestations of PD,Additional Features Cognitive, mood, and behavioral dysfunction Olfactory disturbance Sleep disturbance Constipation Seborrheic dermatitis Pain Autonomic disturbances,Nutt J
7、G, Wooten GF. N Engl J Med. 2005;353:1021-1027. Parkinsons Disease Foundation Web site. www.pdf.org.,Diagnosing PD,United Kingdom Brain Bank Criteria Stage I Hoehn and Yahr (H&Y)- unilateral Stage II H&Y bilateral Stage III H&Y bilateral with loss of balance/falls Stage IV H&Y all above and signific
8、ant disability Stage V H&Y- bedbound,Parkinsons Disease Pathology,Lewy body,CNS Motor Organization,Pyramidal system Weakness,Extrapyramidal system Modulator of pyramidal system Symptoms involuntary movement slow, interrupted movement posture/tone,Parkinsons Disease,N caudatus,Putamen,Thalamus,Tempor
9、al cortex,Parietal cortex,Prefrontal premotoric cortex,Striatum:,Substantia nigra,Damier P et al. Brain. 1999;122:1437-1448.,Dopamine deficiency in PD PET scan,Presymptomatic phase,Onset,Sleep Olfactory* Mood Autonomic system,Diagnosis,Early nonmotor symptoms,Specific symptoms,Motor,Treatment Based
10、on Replacing Dopamine,Dopaminergic neuron loss in PD,% Remaining Dopaminergic 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 neuroprotectiv
11、e 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;63:167-1
12、73.,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,Chaperones prevent toxic alpha-synuclein from forming Develop antibodies that keep alpha-synuc
13、lein from forming aggregates Find small molecules that can prevent misfolding,Oxidative stress MPTP Pesticides Herbicides Bacterial toxins,Mechanisms of Neurodegeneration,ENVIRONMENTAL FACTORS,GENETIC FACTORS,Mitochondria Complex I ROS,PARK1 (-synuclein) PARK2 (Parkin) PARK5 (UCH-L1) PARK6 (PINK1) P
14、ARK7 (DJ-1) PARK8 (LRRK2, dardarin) Other genes,NIGRAL CELL DEATH,Toxic injury Apoptosis,Inflammation Excitotoxicity,a-Synuclein Related proteins?,Altered protein conformation,Ubiquitin system Proteasome dysfunction?,Protein aggregates (Lewy bodies: good or bad?),BenMoyal-Segal L, Soreq H. J Neuroch
15、em. 2006;97:1740-1755. Dawson TM, Dawson VL. J Clin Invest. 2003;111:145-151. Mouradian MM. Neurology. 2002;58:179-185.,Neurons & synapses,Dopamine receptors,DA,L-DOPA,3-OMD,DA,Dopamine agonists,COMT inhibitors,Carbidopa,MAO-Binhibitors,DOPAC,DA,3-MT,DA,DA,AADC,DA,COMTinhibitor*,L-DOPA,Blood-brain b
16、arrier,Periphery,Brain,Neuron,Sites of Action of PD Drugs,*Only tolcapone inhibits COMT in brain.,L-DOPA = levodopa 3-OMD = 3-O-methyldopa DA = dopamine,AADC = aromatic acid decarboxylase DOPAC = dihydroxyphenylacetic acid 3-MT = 3-methoxytyramine,PD: Treatment,Amantadine Anticholinergics Carbidopa/Levodopa (SINEMET) Immediate release (IR), controlled release (CR), combined with entacapone (COMTAN) STALEVO Dopamine agonists Pramipexole (MIRAPEX) Immediate, CR release Ropinirole (REQUIP) Immediate release, CR release MAO-B Inhibitors Rasagiline (AZILECT) Selegiline (ELDEPRYL, ZELAPAR),
