Parkinson's disease

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Parkinson's disease

  1. 1. PARKINSON’S DISEASE Sankar Alagapan Nov 23 2009 From A Manual of Diseases of the Nervous System: William Gowers
  2. 2. OVERVIEW Introduction Disease Symptoms and Mechanisms Pathophysiolo Molecular Symptoms gy Mechanisms Treatment Strategies 2
  3. 3. INTRODUCTION• Neurodegenerative disease affecting movement, cognition and other autonomic activities• General age of onset of symptoms ~ 60 years• Currently around 1.5 million people in the United States with Parkinsons disease (1 in 272)• Medication costs for an individual person with PD average $2,500 a year, and therapeutic surgery can cost up to $100,000 dollars per patient. 3
  4. 4. HISTORY OF PARKINSON’S DISEASE• Kampavata - ancient Indian medical system of Ayurveda• Shaking Palsy – Galen (AD 175)• 1817: Description of Symptoms - James Parkinson• 1862: Coined the name- Jean-Martin Charcot• 1919: Degeneration of Substantia Nigra Tretjakov• 1968: First large scale results of treatment with L-Dopa Cotzias• 1979: MPTP induced Parkinsonism - Davis et al, Langston• 1997: PARK1 Gene Mutation was discovered - Polymeropoulus 4
  5. 5. SOME FAMOUS PARKINSONIAN PATIENTS 5
  6. 6. CLINICAL FEATURES• Motor Impairments – Tremor at rest – Rigidity – Akinesia (Bradykinesia) – Postural Deformity Jankovic 2008 – Speech and swallowing disturbances – Gait and Posture Disturbances 6
  7. 7. CLINICAL FEATURES• Non Motor Impairments – Autonomic Dysfunction • Orthostatic hypotension, sweating dysfunction, sphincter dysfunction and erectile dysfunction – Cognitive and Neurobehavioral Abnormalities • Dementia, Depression, Executive Dysfunction – Sleep Disorders • REM Behavior Disorder – Sensory Abnormalities • Olfactory dysfunction, Paresthesia, Akathisia 7
  8. 8. DIAGNOSIS• Neurologic Examination – Unified Parkinsons Disease Rating Scale (UPDRS)• Ioflupane – A radiological tracer for SPECT• FDOPA and PET 8
  9. 9. PATHOPHYSIOLOGY• Loss of dopaminergic neurons in Substantia Nigra pars compacta and Locus CoeruleusBabraham Institute Piers Emsom Dopamine and Parkinsons Disease Madame Curie Bioscience Database 9
  10. 10. NEURODEGENERATION IN SN• Striatum – 80% of Dopaminergic neurons – A9 group: Substantia Nigra pars compacta (SNpc) – A10: Ventral Tegmental Area (VTA)• Neuromelanin in Midbrain DA Neurons – SNpc: 84 – 98%, VTA: 50% – Neuroprotective role in the normal brain by preferentially sequestering pesticides, MPTP, Iron, etc.• Vesicular Monoamine Transporter (VMAT) – VMAT2 helps incorporating cytoplasmic dopamine in vesicles – VMAT2 expressed less in SNpc than in VTA 10
  11. 11. NEURODEGENERATION IN SN• Dopamine Transporter (DAT) – Neurotoxicity of MPTP by transporting MPP+ – Pattern of expression correlated with neuron loss – DAT knockout mice resistant to MPTP neurotoxicity• Calcium Binding Proteins – Calbindin D28K (CB), Calretinin (CR), and Parvalbumin(PV) – Administration of 6-hydroxydopamine (6-OHDA) and MPTP results in degeneration of the CB-negative TH-positive neurons in the SNpc, but not the TH- and CB - positive neurons in the dorsal tier of the SNpc• Mitochondrial DNA mutations 11
  12. 12. NEURODEGENERATION  SYMPTOMSInDirect Pathway Direct Pathway Globus Pallidus Internal Segment Suppression Theory Neocortex Hippocampus Thalamus Amygdala Gpi/SNr Striatum GPe STN SNpc/VTA 12
  13. 13. NEURODEGENERATION  SYMPTOMS• Basal Ganglia Selection Theory: – Basal ganglia are involved in the selection of motor programs – Bradykinesia due to failure to select or engage appropriate motor programs – Dyskinesia due to failure of basal ganglia to suppress inappropriate motor programs• Oscillator Theory 13
  14. 14. PATHOPHYSIOLOGY• Presence of Lewy Bodies – 1979 (Kosaka and Mehraein)• Lewy bodies stained strongly with antibodies of α – synuclein – 1997 (Spillantini et al) Spillantini et al 1997 14
  15. 15. α – SYNUCLEIN IN LEWY BODIES• α-synuclein monomers become oligomers (protofibrils), which coalesce into fibrils and then aggregate into Lewy body inclusions• Dysfunction of Ubiquitin Proteasome • Neurotoxic vs System Neuroprotective 15
  16. 16. OXIDATIVE STRESS Nigral cells seem to be under a heightened state of oxidative stress 16
  17. 17. OXIDATIVE STRESS Nigral cells seem to be under a heightened state of oxidative stress 17
  18. 18. α – SYNUCLEIN AND OXIDATIVE STRESS 18
  19. 19. EXCITOTOXICITY• SNc neurons receive extensive glutamate innervation from the cortex and the subthalamic nucleus• Dopamine lesions disinhibit the STN and increase the firing rate of its excitatory output neurons• NMDA antagonists protect against dopamine cell loss resulting from MPP+ infusion into the SNc of rats 19
  20. 20. CAUSATIVE FACTORS• Neurotoxins: – MPTP, Rotetone, 6-OHDA etc• Genetic Factors: – Mutations PARK1, PARK2, PARK5 etc.• Neuroinflammation 20
  21. 21. ANIMAL MODELS• Pharmacological Induced Models – Reserpine – Alpha-methyl-para-tyrosine• Toxin Induced Models – MPTP – Methamphetamine – Rotenone – 6 OHDA• Genetic Models – PARK1 – PARK2 – PARK5 21
  22. 22. PHARMACOLOGICAL INDUCED MODELS• Resperine – First used by Carlsson (1950) in rabbits – Showed DA depletion in caudate and putamen resulting in akinetic state – Led to use of Levodopa• Alpha Methyl Para Tyrosine – Depletes Catecholamine by inhibiting Tyrosine Hydroxylase• Transient Effects, No Biochemical/Pathological Changes 22
  23. 23. TOXIN INDUCED MODELS : MPTP• 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine• Neurotoxicity and associated Parkinsonism discovered in 1979 – Davis et al.• Drug abuse by 23 year old person lead to discovery• Used in animal models to induce Parkinsonian symptoms 23
  24. 24. MPTP MECHANISM OF ACTION Dauer et al 2003 24
  25. 25. α – SYNUCLEIN AND MPTP 25
  26. 26. OTHER TOXIN INDUCED MODELS• Rotenone: – Naturally occurring lipophillic compound – Specific inhibitor of Mitochondrial complex I – Degeneration of a subset of nigrostriatal dopaminergic neurons; the formation of cytoplasmic inclusions; and the development of parkinsonian motor behavior• 6 Hydroxydopamine (6 OHDA) – Accumulates in cytoplasm and produces ROS – Rapid degeneration of neurons when injected in SN – Progressive degeneration when injected in striatum 26
  27. 27. GENETIC MODELS • Generally mutations in the Ubiquitin Proteasome System • Major: Genes coding Alpha-Synuclein, Parkin, UCH-L1, PINK1, DJ-1Moore 2005 27
  28. 28. GENETIC MODELS• PARK1 (Italian and Greek families) – A30P and A53T substitution mutations in the gene encoding alpha-synuclein or triplicate of the gene – Proposed to cause misfolding or dysfunction of α- synuclein• PARK5 – Gene encoding UCHL1 (ubiquitin C terminal hydrolase L1) – Generates free Ubiquitin 28
  29. 29. GENETIC MODELS• PARK2 (Japanese Family) – Mutation in gene encoding protein Parkin, a E3 Ubiquitin Ligase – Ubiquitin is added to proteins by Ligase to target them to Proteasome – Absence of Lewy bodies in patients with homozygous deletion shows Parkin plays an important role in Lewy body formation – Enable investigation of the ubiquitin-mediated protein degradation pathways 29
  30. 30. GENETIC MODELS Moore 2005 30
  31. 31. MOLECULAR MECHANISMS 31
  32. 32. NEUROINFLAMMATION • Supported by Animal Apoptosis models – MPTP model ↑IL-1β and Cytokines ↓NGF in striatum TNFα, IL-1β, – 6-OHDA model showed IL-6, ↑TNFα in substantia nigra IL-2, BDNF and striatum IL-4, NGF TGFα, TGF β1, • Produced from activated TGF β2 Neurotrophins microglia – initially neuroprotective and becomes neurotoxic later 32
  33. 33. TREATMENT STRATEGIES• Drugs – L-Dopa and Dopamine Agonists – MAO Inhibitors and COMT Inhibitors• Gene therapy• Surgical Interventions – Stem cell therapy – Lesion surgeries and Deep Brain Stimulation• Physiotherapy 33
  34. 34. LEVODOPA Abbreviations: COMT - Catechol- O-methyltransferase 3-OMD - 3-O-methyldopa AAAD - Aromatic amino acid decarboxylase MAO - Monoamine oxidase DOPAC - 3,4-dioxyphenylacetic acid HVA - Homovanillic acid 34
  35. 35. LEVODOPA SIDE EFFECTS Loss of Dopamine Substantial release of Regulation DA in pulsatile fashion Motor Fluctuations Dyskinesia - Long Duration - Peak Dose Dyskinesia Response and Short - Biphasic Dyskinesia Duration Response - Square wave - On-Off Effect - Yo-Yoing 35
  36. 36. MAO INHIBITORS AND COMT INHIBITORS• Selegiline and Rasagiline• Neuroprotective nature, due to propargyl moiety, shown in vivo and in vitro MAO Inhibitors• Entacapone and Tolcapone• Used in conjunction with levodopa and an AAAD inhibitor COMT Inhibitors 36
  37. 37. GENE THERAPY • Genes to produce TH delivered virally (HSV) into Dopamine striatum Synthesis • Genetically delivered AAADC using an AAV • Multiple genes – VMAT and TH • Viral vectors have been used to deliver GDNF to the striatum and SNc Neurotrophins • In vivo lentiviral delivery of a modified neurturin construct produced neuroprotection of rat nigrostriatal projections. • Lentiviral delivery to increase expression of the normal Parkin gene in the substantia nigra of rats Parkin Gene • AAV carrier to deliver Hsp-70 to the substantia nigra of MPTP-treated mice 37
  38. 38. LESION SURGERIES• Early efforts focused on the sensory roots of spinal cord• Focus then shifted to motor cortex• Subcortical nuclei became areas of interest• Pallidotomy and Thalamotomy Clower 2002 38
  39. 39. LESION SURGERIES Clower 2002 39
  40. 40. LESION SURGERIES Clower 2002 40
  41. 41. DEEP BRAIN STIMULATION (DBS) Targets: Thalamus, GPi, STN Stimulation parameters: Frequency of 135 to 185 Hz, pulse width of 60 to 120 μs, and amplitude of 1 to 3V Wikipedia Wired.com 41
  42. 42. COMPLICATIONS ASSOCIATED WITH DBS • Hemorrhage, ischemic lesions, seizures, infections, and Surgical misplaced leads Procedures • Occurrence: ~ 5% • Electrode Failure, Lead breakage, cranial lead migration, DBS Infection, Erosion, IPG Malfunction Hardware • Occurrence: ~ 20% • Eyelid apraxia, dystonic posturing, dysarthria, dyskinesia, limb and facial muscle spasms, depression, Stimulation mood changes, visual disturbances, and pain • Suicide rate of 4.6% in patients with DBS. 42
  43. 43. STEM CELL THERAPY• Hormonally induce stem cell differentiation into nigrostriatal dopaminergic neurons or their precursors and then to transplant them into patients• Embryonic stem cell (ESC) Neural Progenitor cells (NP)• Human NPs grafted in striatum of Parkinsonian rats showed improvement of symptoms• Results have also shown that mouse ESC differentiate into DA neurons in vivo 43
  44. 44. PHYSIOTHERAPY• Supplementary Therapy• Help with movement, posture and balance• Relieve muscle and joint stiffness and discomfort• Exercises to maintain or improve muscle strength 44
  45. 45. PARKINSON’S DISEASE Molecular Mechanisms Cellular Level External Manifestations Manifestations Neurotoxins and Oxidative PATHOPHYSIOLOGY SYMPTOMS ?? External Agents Stress Loss of Dopaminergic Movement Disorders Genetic Factors cells in the Substantia Cognitive Decline Neuroinflammation Nigra Drugs, Stem Cell DBS, Gene therapy Therapy Physiotherapy TREATMENT STRATEGIES Complications and Side Effects 45

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