PARKINSON’S DISEASE
Sankar Alagapan
Nov 23 2009
From A Manual of Diseases of the Nervous System: William Gowers
OVERVIEW
2
Molecular Mechanisms
PathophysiologySymptoms
Treatment Strategies
Disease Symptoms and Mechanisms
Introduction
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 UnitedStates with Parkinson's disease (1 in 272)
• Medication costs for an individual person with PDaverage $2,500 a year, and therapeutic surgerycan cost up to $100,000 dollars per patient.
3
HISTORY OF PARKINSON’S DISEASE
4
• Kampavata - ancient Indian medical system ofAyurveda
• Shaking Palsy – Galen (AD 175)
• 1817: Description of Symptoms - JamesParkinson
• 1862: Coined the name- Jean-Martin Charcot
• 1919: Degeneration of Substantia NigraTretjakov
• 1968: First large scale results of treatment withL-Dopa Cotzias
• 1979: MPTP induced Parkinsonism - Davis et al,Langston
• 1997: PARK1 Gene Mutation was discovered -Polymeropoulus
SOME FAMOUS PARKINSONIAN PATIENTS
5
CLINICAL FEATURES
• Motor Impairments– Tremor at rest
– Rigidity
– Akinesia (Bradykinesia)
– Postural Deformity
– Speech and swallowing disturbances
– Gait and Posture Disturbances
6
Jankovic 2008
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
DIAGNOSIS
• Neurologic Examination– Unified Parkinson's Disease Rating Scale (UPDRS)
• Ioflupane – A radiological tracer for SPECT
• FDOPA and PET
8
PATHOPHYSIOLOGY
• Loss of dopaminergic neurons in Substantia Nigra pars compacta and Locus Coeruleus
9
Babraham Institute Piers Emsom Dopamine and Parkinson's DiseaseMadame Curie Bioscience Database
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
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
NEURODEGENERATION SYMPTOMS
12
Neocortex
Thalamus
Gpi/SNr
Hippocampus
Amygdala
Striatum
GPe
SNpc/VTA
Direct PathwayInDirect Pathway Globus Pallidus Internal Segment Suppression Theory
STN
NEURODEGENERATION SYMPTOMS
• Basal Ganglia Selection Theory:– Basal ganglia are involved in the selection of
motor programs
– Bradykinesia due to failure to select or engageappropriate motor programs
– Dyskinesia due to failure of basal ganglia tosuppress inappropriate motor programs
• Oscillator Theory
13
PATHOPHYSIOLOGY
• Presence of Lewy Bodies– 1979 (Kosaka and
Mehraein)
• Lewy bodies stained strongly with antibodies of α – synuclein– 1997 (Spillantini et al)
14
Spillantini et al 1997
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 ProteasomeSystem
• Neurotoxic vs Neuroprotective
15
OXIDATIVE STRESS
16
Nigral cells seem to be under a heightened state of oxidative stress
OXIDATIVE STRESS
17
Nigral cells seem to be under a heightened state of oxidative stress
α – SYNUCLEIN AND OXIDATIVE STRESS
18
EXCITOTOXICITY
• SNc neurons receive extensive glutamateinnervation from the cortex and thesubthalamic nucleus
• Dopamine lesions disinhibit the STN andincrease the firing rate of its excitatory outputneurons
• NMDA antagonists protect against dopaminecell loss resulting from MPP+ infusion into theSNc of rats
19
CAUSATIVE FACTORS
• Neurotoxins:– MPTP, Rotetone, 6-OHDA etc
• Genetic Factors:– Mutations PARK1, PARK2, PARK5 etc.
• Neuroinflammation
20
ANIMAL MODELS
• Pharmacological Induced Models– Reserpine– Alpha-methyl-para-tyrosine
• Toxin Induced Models– MPTP– Methamphetamine– Rotenone– 6 OHDA
• Genetic Models– PARK1– PARK2– PARK5
21
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
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 Parkinsoniansymptoms
23
MPTP MECHANISM OF ACTION
24Dauer et al 2003
α – SYNUCLEIN AND MPTP
25
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 cytoplasmicinclusions; and the development of parkinsonianmotor 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
GENETIC MODELS
• Generally mutations in the Ubiquitin Proteasome System
• Major: Genes coding Alpha-Synuclein, Parkin, UCH-L1, PINK1, DJ-1
27Moore 2005
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
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
GENETIC MODELS
30Moore 2005
MOLECULAR MECHANISMS
31
NEUROINFLAMMATION
• Supported by Animal models– MPTP model ↑IL-1β and
↓NGF in striatum
– 6-OHDA model showed ↑TNFα in substantia nigra and striatum
• Produced from activated microglia– initially neuroprotective and
becomes neurotoxic later
32
Apoptosis
TNFα, IL-1β, IL-6, IL-2,IL-4,
TGFα, TGF β1, TGF β2
BDNFNGF
Cytokines
Neurotrophins
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
LEVODOPA
34
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
Loss of Dopamine Regulation
Substantial release of DA in pulsatile fashion
Motor Fluctuations
- Long Duration Response and Short Duration Response
- On-Off Effect
Dyskinesia
- Peak Dose Dyskinesia
- Biphasic Dyskinesia
- Square wave
- Yo-Yoing
LEVODOPA SIDE EFFECTS
35
COMT Inhibitors
MAO Inhibitors
MAO INHIBITORS AND COMT INHIBITORS
• Selegiline and Rasagiline
• Neuroprotective nature, due to propargyl moiety, shown in vivo and in vitro
• Entacapone and Tolcapone
• Used in conjunction with levodopa and an AAAD inhibitor
36
GENE THERAPY
• Genes to produce TH delivered virally (HSV) into striatum
• Genetically delivered AAADC using an AAV• Multiple genes – VMAT and TH
Dopamine Synthesis
• Viral vectors have been used to deliver GDNF to the striatum and SNc
• In vivo lentiviral delivery of a modified neurturin construct produced neuroprotection of rat nigrostriatal projections.
Neurotrophins
• Lentiviral delivery to increase expression of the normal Parkin gene in the substantia nigra of rats
• AAV carrier to deliver Hsp-70 to the substantia nigra of MPTP-treated mice
Parkin Gene
37
LESION SURGERIES
• Early efforts focused onthe sensory roots ofspinal cord
• Focus then shifted tomotor cortex
• Subcortical nucleibecame areas ofinterest
• Pallidotomy andThalamotomy
38Clower 2002
LESION SURGERIES
39Clower 2002
LESION SURGERIES
40Clower 2002
DEEP BRAIN STIMULATION (DBS)
41
Wikipedia Wired.com
Targets: Thalamus, GPi, STNStimulation parameters: Frequency of 135 to 185 Hz, pulse width of 60 to 120 μs, and amplitude of 1 to 3V
COMPLICATIONS ASSOCIATED WITH DBS
• Hemorrhage, ischemic lesions, seizures, infections, and misplaced leads
• Occurrence: ~ 5%
Surgical Procedures
• Electrode Failure, Lead breakage, cranial lead migration, Infection, Erosion, IPG Malfunction
• Occurrence: ~ 20%
DBS Hardware
• Eyelid apraxia, dystonic posturing, dysarthria, dyskinesia, limb and facial muscle spasms, depression, mood changes, visual disturbances, and pain
• Suicide rate of 4.6% in patients with DBS.
Stimulation
42
STEM CELL THERAPY
• Hormonally induce stem cell differentiation intonigrostriatal dopaminergic neurons or theirprecursors and then to transplant them intopatients
• Embryonic stem cell (ESC) Neural Progenitorcells (NP)
• Human NPs grafted in striatum of Parkinsonianrats showed improvement of symptoms
• Results have also shown that mouse ESCdifferentiate into DA neurons in vivo
43
PHYSIOTHERAPY
• Supplementary Therapy
• Help with movement, posture and balance
• Relieve muscle and joint stiffness and discomfort
• Exercises to maintain or improve muscle strength
44
Neurotoxins and External AgentsGenetic FactorsNeuroinflammation
Molecular Mechanisms
PATHOPHYSIOLOGYLoss of Dopaminergic cells in the Substantia Nigra
SYMPTOMSMovement DisordersCognitive Decline
Cellular Level Manifestations
External Manifestations
Drugs, Gene therapy
Stem Cell Therapy
DBS, Physiotherapy
TREATMENT STRATEGIES
Complications and Side Effects
Oxidative Stress
??
PARKINSON’S DISEASE
45