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Current Concepts and Perspectives in Parkinson’s Disease
Current Concepts and Perspectives in Parkinson’s Disease
Anthony H.V. Schapira, DSc, MD, FRCP, FMedSciAnthony H.V. Schapira, DSc, MD, FRCP, FMedSciProfessor of NeurologyProfessor of Neurology
University Department of Clinical NeurosciencesUniversity Department of Clinical NeurosciencesRoyal Free and University College Medical School, and Institute of NeurologyRoyal Free and University College Medical School, and Institute of Neurology
University College LondonUniversity College LondonLondon, UKLondon, UK
Matthias R. Lemke, MDMatthias R. Lemke, MDProfessor of PsychiatryProfessor of Psychiatry
Centre of Psychiatry and NeurologyCentre of Psychiatry and NeurologyRhine Clinic BonnRhine Clinic BonnBonn, Germany Bonn, Germany
2
Contents
• Section I – Epidemiology, Pathophysiology and Diagnosis of Parkinson’s Disease
– Introduction and Historical Perspectives– Definition– Epidemiology– Pathophysiology and Genetics– Diagnosis and Symptoms– Differential Diagnosis– Clinical Evaluation – Scales and Scores– Disease Burden
• Section II – Treatment of Parkinson’s Disease
– General Principles– Drug Therapy in Parkinson’s Disease– Surgery– Management of Non-Motor Symptoms– Disease Modification (Neuroprotection)– Physical Therapy– Future Treatments
• Section III – Depression in Parkinson’s Disease
– Overview– Epidemiology and Pathophysiology– Burden– Diagnosis and Evaluation– Treatment
3
Section I
Epidemiology, Pathophysiology and Diagnosis of Parkinson’s
Disease
Section I
Epidemiology, Pathophysiology and Diagnosis of Parkinson’s
Disease
4
Section I – Summary
• Introduction and Historical Perspectives
• Definition
• Epidemiology
• Pathophysiology and Genetics
• Diagnosis and Symptoms
• Differential Diagnosis
• Clinical Evaluation – Scales and Scores
• Disease Burden
5
Introduction and Historical Perspectives
Introduction and Historical Perspectives
6
Parkinson’s Disease – Introduction
• Parkinson’s disease: a progressive neurodegenerative disease
– Early clinical features:
• Typical motor symptoms result from the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain
• Other dopaminergic structures (e.g. the limbic system) may be affected, resulting in early symptoms such as depression
– As the disease progresses, additional brain areas degenerate, resulting in non-dopaminergic, non-motor features
• Introduction of levodopa treatment has resulted in significant improvements in both quality of life (QoL) and life expectancy
• Current challenges:
– Prevention of motor complications
– Treatment of non-motor features
– Slowing of disease progression
Schapira AHV, Olanow WC. In: Principles of Treatment in Parkinson’s Disease; 2005.
7
• 1500s: Leonardo da Vinci identifies a “paralytic” condition involving trembling limbs.
• 1700s: John Hunter, a British surgeon, describes patients with ‘severe tremor on awakening who do not complain from tiredness in the muscles.’
• 1817: James Parkinson publishes the Essay on the Shaking Palsy, the first and definitive clinical description of paralysis agitans, the condition that subsequently comes to bear his name.
First Description of the “Shaking Palsy” as a Clinical Syndrome by James Parkinson in 1817
Parkinson J. An Essay on the Shaking Palsy; 1817.
8
Parkinson’s Disease – Historical Perspective
• James Parkinson, 1817– Shaking Palsy
Detailed analyses of the clinical effects
• Jean-Martin Charcot, 1867– Clinical classification and differential diagnosis
– Proposes the eponymous label “Parkinson’s disease”
– First effective treatment: belladonna alkaloids
• Friedrich Heinrich Lewy, 1912– Intracytoplasmic inclusions: the hallmark of Parkinson's disease
• Constantin Trétiakoff, 1919 – Cell degeneration in the substantia nigra
• Herbert Ehringer and Oleh Hornykiewicz, 1960– Dopamine deficiency in the striatum
Parkinson J. An Essay on the Shaking Palsy; 1817.Lewy FH. In: Handbuch der Neurologie; 1912:920-33. Trétiakoff C. PhD Thesis, University of Paris; 1919.Ehringer H, Hornykiewicz O. Klin Wochenschr 1960;38:1236-9.
9
DefinitionDefinition
10
Parkinson’s Disease – Definition
• Parkinson’s disease:– A clinical and neuropathological entity characterised by:
• Bradykinesia
• Rigidity
• Tremor
– Onset usually asymmetric and responsive to dopaminergic treatment
– No historical or examination clues to indicate secondary parkinsonism (e.g. Wilson’s disease, multiple system atrophy)
– The brunt of the early pathology falls on the dopaminergic nigrostriatal pathway
• Parkinsonism:– Any bradykinetic-rigid syndrome that is not Parkinson’s disease
Samii A, et al. Lancet 2004;363:1783-94.Nutt JG, Wooten GF. N Engl J Med 2005;353:1021-7.
11
EpidemiologyEpidemiology
12de Lau LM, Breteler MM. Lancet Neurol 2006;5:525-35. © 2006, with permission from Elsevier.
Epidemiology of Parkinson’s Disease – Prevalence
Population-based prevalence studies of Parkinson’s disease
Idiopathic Parkinson’s disease is a common age-related condition
0
5
10
15
20
25
30
35
40
45
50
30 40 50 60 70 80 90 100
Rotterdam, the NetherlandsCentral SpainCopiah County, USAFranceSicilyAragon, SpainEuropeChinaTaiwan, China
Pre
vale
nce
(%)
Age (years)
13
Epidemiology of Parkinson’s Disease – Incidence
• Idiopathic Parkinson’s disease is uncommon before the age of 50
• There is a sharp increase in incidence after the age of 60
0
200
300
400
500
600
700
30 40 50 60 70 80 90 100
100
SpainRotterdam, the NetherlandsHawaii, USAManhattan, USATaiwan, ChinaLondon, UKRochester, USAItalyChina
Inci
denc
e R
ate
(c
ases
per
100
,000
per
son
-ye
ars)
Prospective population-based incidence studies of Parkinson’s disease
Age (years)
de Lau LM, Breteler MM. Lancet Neurol 2006;5:525-35.© 2006, with permission from Elsevier.
14
Mortality in Parkinson’s Disease
Studies of mortality hazard ratios in patients with Parkinson’s disease
Morens (1996) Honolulu (USA) Cohort study Population 92 Incident 29.0 2.50*Louis (1997) New York (USA) Case-control Hospital 180 Prevalent 3.0 2.70 (1.7-4.4)Hely (1999) Sydney (Australia) Case series Hospital 130 Prevalent 10.0 1.58 (1.21-2.02)**Berger (2000) Europe (5 countries) 5 cohort studies Population 252 Prevalent Variable 2.30 (1.80-3.00)Morgante (2000) Sicily (Italy) Case-control Population 59 Prevalent 8.0 2.30 (1.60-3.39)Guttman (2001) Ontario (Canada) Case-control Register 15,304 Prevalent 6.0 2.50 (2.40-2.60)Elbaz (2003) Olmsted (USA) Case-control Register 196 Incident 7.2 1.60 (1.20-2.14)Fall (2003) Ostergotland (Sweden) Case-control Population 170 Prevalent 9.4 2.40 (1.9-3.0)Herlofson (2004) Rogaland (Norway) Case series Population 245 Prevalent 8.7 1.52 (1.29-1.79)*Hughes (2004) Leeds (UK) Case-control Hospital 90 Prevalent 11.0 1.64 (1.21-2.23)de Lau (2005) Rotterdam (Netherlands) Cohort study Population 166 Both 6.9 1.83 (1.47-2.26)
Location (country) Type of study Source of study Cases Type of cases Follow-up (years) HR (95% CI)
* In people aged 70-89 years (95% CI not provided); ** standardised mortality ratio; HR, mortality hazard ratio.
de Lau LM, Breteler MM. Lancet Neurol 2006;5:525-35.
15
Pathophysiology and GeneticsPathophysiology and Genetics
16
Pathology of Parkinson’s Disease – Macroscopy
A: Rostral (R), intermediate (I) and caudal (C) transverse planes of the mesencephalon on a sagittal MRI of the brainstem.B: MRI of the intermediate transverse plane. Arrows show the emergence of the third cranial nerve fibres.
Normal Parkinson’s disease
Normal substantia nigra Depigmentation of substantia nigra
Damier P, Brain 1999;122:1421-36.
Images courtesy of JJ Hauw, Department of Neuropathology, Hôpital de la Pitié-Salpêtrière, Paris, France.
17
• Loss of pigmented dopaminergic neurons
Normal substantia nigra
Normal
Degeneration of nigral cells
Parkinson’s disease
Pathology of Parkinson’s Disease – Microscopy
• Histopathological hallmark: Lewy bodies
Gibb WR, Lees AJ. Neuropathol Appl Neurobiol 1989;15:27-44.
Images courtesy of JJ Hauw, Department of NeuropathologyHôpital de la Pitié-Salpêtrière, Paris, France.
Images courtesy of É tienne Hirsch, MD, INSERM U679, Hôpital de la Pitié-Salpêtrière, Paris, France.
18
Control Parkinson’s disease
SNpc SNpc
SNpl SNplrn rn
A8A8
cpcp
PGS CGS
Abbreviations: SNpc, substantia nigra pars compacta; SNpl, substantia nigra pars lateralis; A8, dopamingergic group A8; rn, red nucleus; PGS, periaqueductal gray substance; cp, cerebellus peduncule; CGS, central gray substance
Staining for tyrosine hydroxylase on a section of human post-mortem mesencephalon
Neuronal Cell Death and Motor Symptoms
Hirsch E, et al. Nature 1988;334:345-8.
19
Multicentric Neurodegeneration
Lang AE, Obeso JA. Lancet Neurol 2004;3:309-16. © 2004, with permission from Elsevier.
STN subthalamic nucleus
GPi globus pallidus interna
Gpe globus pallidus externa
SNpc substantia nigra pars compacta
VTA ventral tegmental area
Dopamine
Parkinson’s disease brain
SerotoninNoradrenaline
GPi
GPe
Putamen
STN
Amygdala
Thalamus
Substantia innominata
Caudate
SNpc
VTA
Locus coeruleusRaphe nuclei
Pedunculopontine nucleus
20
Basal Ganglia Circuit
Cortex
GPe
STN
GPi
SNpr
PPN
VL
Putamen
SNpc
Cortex
GPe
STN
GPi
SNpr
PPN
VL
Putamen
SNpc
Cortex
GPe
STN
GPi
SNpr
PPN
VL
Putamen
SNpc
(a) (b) (c)Normal Parkinsonism Levodopa dyskinesia
DA DA
Excitatory Neuronal Firing Inhibitory Neuronal FiringOlanow CW. Annu Rev Med 2004;55:41-60.Copyright © 2004 by Annual Reviews. All rights reserved
21
Cell Death in Parkinson’s Disease
ApoptoticDA neuron
HealthyDA neuron
Cell deathprogram
Free radicalsIronNitric oxideExcitotoxicityComplex I deficiencyProteasomal inhibition
Glial factorsInflammation
Activationsignal
Genetics Environment
?
DamagedDA neuron
Abbreviation: DA, dopamine
Courtesy of Andreas Hartmann, MD, INSERM U679, Hôpital de la Pitié-Salpêtrière, Paris, France
22
Potential Neuroprotective Approaches
Abbreviations: AMPA, -amino-3-hydroxy-5-methyl-4-isoxazolepropionate; DAT, dopamine transporter; GAPDH, glyceraldehyde-3-phosphate dehydrogenase;iNOS, inducible nitric oxide synthase; MAO-B, monoamine oxidase B; MLK, mixed lineage kinase; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NMDA, N-methyl-D-aspartate; nNOS, neuronal nitric oxide synthase; PARP, poly (ADP-ribose) polymerase; ROS, reactive oxygen species; PPAR, peroxisome proliferator-activated receptors-gamma
Reprinted by permission from Macmillan Publishers Ltd: Dawson TM, Dawson VL. Nat Neurosci 2002;(5 Suppl):1058-61, © 2002.
Pathways involved in MPTP toxicity and potential neuroprotective drugs or strategies
NMDAreceptor
Ca2+ Na+/Ca2+
NMDA antagonists AMPA
AMPAreceptor
MAO-B inhibitors DAT inhibitorsMPTP
MPP+
DA transporter
MAO-B
H
Complex IROS, ONOO-
ROS scavengersEnergy mimeticsCoenzyme Q10
Metal chelators
nNOS inhibitorsPARP inhibitors
IronHeavy metals?
Necrotic Death PathwaysnNOS activationDNA damagePARP activation
Apoptotic Death PathwaysGeneration of the apoptosomeCaspase activationp53 activationER stress
Cell death
Inhibitors of -syntoxicity
Caspase inhibitorsInhibitors of ER stress responsep53 inhibitorsMLK inhibitorsGAPDH translocation inhibitors
MinocyclineiNOS inhibitorsPPAR inhibitors
Microglialactivation
ROS
–syn
Altered -synConformationoligomer/fibrils
Cell death
23
Genetic Factors in Parkinson’s Disease
GeneLocus
(Chromosomal position)
Age of onset
Inheritance Clinical phenotype
-synuclein PARK1 (4q21-q23) Young AD Similar to IPD, rapid progression
Parkin PARK2 (6q25.2-q27) Young ARSymptomatic improvement following sleep, mild dystonia, good response to levodopa, slow progression
UCHL1 PARK5 (4p14)Similar to
IPDAD Similar to IPD
PINK1 PARK6 (1p35-p36) Young AR Benign course, levodopa-responsive
DJ1 PARK7 (1p36) Young AR Levodopa-responsive
LRRK2 PARK8 (12q12)Similar to
IPDAD
Similar to IPD (LRRK2 mutations are the commonest cause of either familial or ‘sporadic’ PD)
PARK9, 10, and 11
(1p36, 1p32, and 2q36-q37, respectively )
AR (PARK9)
PARK9: spasticity, dementia and supranuclear palsy
PARK10: similar to IPD
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; IPD, idiopathic Parkinson’s disease; LRRK2, leucine-rich repeat kinase 2; PARK2, parkin-encoding gene; PINK1, PTEN induced putative kinase 1; UCHL1, ubiquitin carboxyl-terminal esterase L1; UPS, ubiquitin-proteasome system.
Farrer MJ. Nat Rev Genet 2006;7:306-18. de Lau LM, Breteler MM. Lancet Neurol 2006;5:525-35.
24
Diagnosis and SymptomsDiagnosis and Symptoms
25
Diagnostic Criteria
Clinical diagnostic criteria for idiopathic Parkinson’s disease
Clinically possible
One of:
• Asymmetric resting tremor
• Asymmetric rigidity
• Asymmetric bradykinesia
Clinically probable
Any two of:
• Asymmetric resting tremor
• Asymmetric rigidity
• Asymmetric bradykinesia
Clinically definite
Criteria for clinically probable, plus
• Definitive response to antiparkinson drugs
Exclusion criteria
• Exposure to drugs that can cause parkinsonism, such as neuroleptics, some anti-emetic drugs, tetrabenazine, reserpine, flunarizine and cinnarizine
• Cerebellar signs
• Corticospinal tract signs
• Eye-movement abnormalities other than slight limitation of upward gaze
• Severe dysautonomia
• Early moderate to severe gait disturbance or dementia
• History of encephalitis, recurrent head injury (such as seen in boxers)
• Evidence of severe subcortical white-matter disease, hydrocephalus or other structural lesions on MRI that may account for parkinsonism
Samii A, et al. Lancet 2004;363:1783-94.Calne DB, et al. Ann Neurol 1992;32(Suppl):S125-7. Ward CD, Gibb WR. Adv Neurol 1990;53:245-9.
26Adapted from Chaudhuri KR, et al. Lancet Neurol 2006;5:235-45.
Non-Motor Symptoms of Parkinson’s Disease (1)
Neuropsychiatric symptomsDepression, apathy, anxietyAnhedoniaAttention deficitHallucinations, illusions, delusionsDementiaObsessional behaviour (can be drug-induced) and
repetitive behaviourConfusionDelirium (could be drug-induced)Panic attacks
Sleep disordersRestless legs and periodic limb movementsRapid eye movement (REM) sleep behaviour disorder
and REM loss of atoniaNon-REM sleep-related movement disordersExcessive daytime somnolenceVivid dreamingInsomniaSleep-disordered breathing
Autonomic symptomsBladder disturbances
UrgencyNocturiaFrequency
SweatingOrthostatic hypotensionFalls related to orthostatic hypotensionCoat-hanger painSexual dysfunctionHypersexuality (likely to be drug-induced)Erectile impotenceDry eyes
27
Non-Motor Symptoms of Parkinson’s Disease (2)
Gastrointestinal symptoms(overlap with autonomic symptoms)Drooling AgeusiaDysphagia and chokingReflux, vomitingNauseaConstipationUnsatisfactory voiding of bowelFaecal incontinence
Sensory SymptomsPainParaesthesiaOlfactory disturbance
Other symptomsFatigueDiplopiaBlurred visionSeborrhoeaWeight lossWeight gain (possibly drug-induced)
Adapted from Chaudhuri KR, et al. Lancet Neurol 2006;5:235-45.
28
Neuroimaging in Parkinson’s Disease
• Diagnosis of Parkinson’s disease (PD) is mainly clinical
• MRI can be helpful in detecting other causes of parkinsonism such as vascular parkinsonism
• Neuroimaging of the nigrostriatal dopaminergic pathway:
Single photon emission computed tomography (SPECT) with [123I]-2β-carbomethoxy-3β-(4-iodophenyl)tropane (β-CIT) and positron emission tomography (PET) with 6-[18F]fluoro-L-dopa (F-DOPA)
• Mostly used in therapeutic trials measuring disease progression
• SPECT may be helpful to distinguish PD from essential tremor (ET)
Tolosa E, et al. Lancet Neurol 2006;5:75-86.Samii A, et al. Lancet 2004;363:1783-94.
29
Differential DiagnosisDifferential Diagnosis
30
Classification – Differential Diagnosis of Parkinsonism
• Idiopathic– Parkinson’s disease: approximately
75% of cases
• Symptomatic– Drug-induced: up to 20% of cases
• Dopamine blockers: major neuroleptics, metoclopramide
– Hydrocephalus
– Metabolic (hepatocerebral) degeneration, parathyroid disorders
– Structural lesions of the brain: tumour, infarct or haemorrhage
– Toxins (carbon monoxide, MPTP)
– Infections
• Hereditary disorders– Frontotemporal dementias
– Dystonias
– Huntington’s disease
– Wilson’s disease
– Inherited ataxias
• Parkinson-plus syndromes– Dementia with Lewy bodies
– Multiple system atrophy (olivopontocerebellar atrophy, Shy-Drager syndrome, striatonigral degeneration)
– Progressive supranuclear palsy
– Corticobasal degenerationColcher A, Simuni T. Med Clin North Am 1999;83:327-47. Hughes AJ, et al. J Neurol Neurosurg Psychiatry 1992;55:181-4.Hughes AJ, et al. Brain 2002;125:861-70.Bower JH, et al. Neurology 1999;52:1214-20.
31
Parkinson’s Disease and Essential Tremor
• Differential criteria– Essential tremor (ET):
• Tremor with no other sign of parkinsonism
• Presence of a head or voice tremor
• Strong and usually autosomal dominant family history
• Improvement with alcohol
– Parkinson’s disease (PD):• Resting tremor
• Clear asymmetry
• Presence of bradykinesia or rigidity
• Leg tremor
• Improvement with dopaminergic treatment
• Both PD and ET have a kinetic and rest component
• Kinetic tremor can interfere with rapid alternating movements
• Cogwheel rigidity is rare in ET
Deuschl G, et al. Mov Disord 1998;13(Suppl 3):2-23.Chaudhuri KR, et al. J Neurol Neurosurg Psychiatry 2005;76:115-7.
32
Clinical Evaluation – Scales and Scores
Clinical Evaluation – Scales and Scores
33
Parkinson’s Disease Scales and Scores –Hoehn and Yahr Staging of Parkinson’s Disease
Stage One1. Signs and symptoms on one side only2. Symptoms mild3. Symptoms inconvenient but not disabling4. Usually presents with tremor of one limb5. Friends have noticed changes in posture, locomotion and facial expression
Stage Two1. Symptoms are bilateral2. Minimal disability3. Posture and gait affected
Stage Three 1. Significant slowing of body movements 2. Early impairment of equilibrium on walking or standing 3. Generalised dysfunction that is moderately severe
Stage Four 1. Severe symptoms 2. Can still walk to a limited extent 3. Rigidity and bradykinesia 4. No longer able to live alone 5. Tremor may be less than earlier
stages
Stage Five 1. Cachectic stage 2. Invalidism complete 3. Cannot stand or walk 4. Requires constant nursing care
Hoehn MM, Yahr MD. Neurology 1967;17:427-42.
34
• 100% – Completely independent. Able to do all chores without slowness, difficulty or impairment.
• 90% – Completely independent. Able to do all chores with some slowness, difficulty or impairment. May take twice as long.
• 80% – Independent in most chores. Takes twice as long. Conscious of difficulty and slowing.
• 70% – Not completely independent. More difficulty with chores. Three to four times as long on chores for some. May take large part of day for chores.
• 60% – Some dependency. Can do most chores, but very slowly and with much effort. Errors. Some chores impossible.
• 50% – More dependent. Help with 1/2 of chores. Difficulty with everything.
• 40% – Very dependent. Can assist with all chores, but do few alone.
• 30% – With effort, now and then does a few chores alone or begins alone. Much help needed.
• 20% – Nothing alone. Can do some slight chores with some help. Severe invalidity.
• 10% – Totally dependent, helpless.
• 0% – Vegetative functions such as swallowing, bladder and bowel function are not functioning. Bedridden.
Gillingham FJ, Donaldson MC, eds. Third Symposium of Parkinson’s Disease.Edinburgh, Scotland: E&S Livingstone; 1969:152-7.
Parkinson’s Disease Scales and Scores –Schwab and England Activities of Daily Living
35
I. Mentation, Behaviour, Mood
• Non-motor symptoms with one question on intellect, one on thought disorders, one on depression, and one on motivation
II. Activities of Daily Living (ADL)
• 13 questions, almost all about motor symptoms
• Two questions on salivation (autonomic function) and sensory complaints
III. Motor Examination
• Motor symptoms
IV. Treatment Complications
• Yes/no questions on anorexia, nausea, vomiting and sleep
A total of 199 points are possible, with 199 representing total disability and 0 meaning no disability
Movement Disorder Society Task Force on Rating Scales for Parkinson’s Disease. Mov Disord 2003;18:738-50.
Parkinson’s Disease Scales and Scores –Unified Parkinson’s Disease Rating Scale (UPDRS)
36
Disease BurdenDisease Burden
37
Burden of Parkinson’s Disease
• Reduced quality of life1
• Higher susceptibility to depression and cognitive impairment2
• Increased risk for comorbidities such as pneumonia2
• Increased medical expenses (physician visits and emergency care)2
• Caregiver burden and risk of early nursing home placement2,3
1. Dodel RC, et al. Pharmacoeconomics 2001;19:1013-38.2. Parashos SA, et al. Mayo Clin Proc 2002;77:918-25.3. Carter JH, et al. Mov Disord 1998;13:20-8.
38
Section I – Conclusion
• Parkinson’s disease affects about 1% of adults over the age of 60.
• Clinical features:– Motor symptoms define the disorder: bradykinesia, rigidity and rest tremor.
– Non-motor symptoms: autonomic dysfunction, cognitive and other psychiatric changes, sensory symptoms and sleep disturbances.
Therapeutic challenge
• The diagnosis of Parkinson’s disease is clinical but can be supported in certain circumstances with SPECT imaging.
• Parkinson’s disease is a complex, multifactorial disease. – Several genetic causes have been characterised and appear to result in
downstream effects that include abnormal free radical metabolism, defective mitochondrial function, and dysfunction of the ubiquitin proteasomal system.
– The determination of mechanisms of dopamine neurons has major consequences on the development of drugs slowing cell degeneration and improving symptomatology.
39
Section II
Treatment of Parkinson’s Disease
Section II
Treatment of Parkinson’s Disease
40
Section II – Summary
• General Principles
• Drug Therapy in Parkinson’s Disease
• Surgery
• Management of Non-Motor Symptoms
• Disease Modification (Neuroprotection)
• Physical Therapy
• Future Treatments
41
General PrinciplesGeneral Principles
42
• Accurate and early diagnosis: an opportunity for coherent long-term treatment strategy
– Diagnostic accuracy as high as 98.5% based on clinical criteria alone
– Single photon emission computed tomography (SPECT) useful to differentiate PD from essential tremor
• Purpose of treatment:
– Symptomatic treatment of motor features
– Prevention of motor complications
– Symptomatic control of motor complications
– Symptomatic treatment of non-motor features
– Prevention of disease progression: disease modification (neuroprotection)
General Principles for the Treatment of Parkinson’s Disease
Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinson’s Disease; 2005.Hughes AJ, et al. Brain 2002;125:861-70.
Evidence on Efficacy of Treatment Interventions
Category evaluated LevodopaCOMT
inhibitorsMAO-B
inhibitorsAnticholinergics& amantadine
Dopamine agonists(details on slide 70)
Monotherapy in early PD
√ NA √ ±√ (pramipexole, ropinirole, pergolide)
Combination with levodopa in advanced PD
NA √(MF) ? ±√ (pramipexole, bromocriptine, cabergoline, pergolide)
Treatment of motor complications
- √(MF) ?√ (D; amantadine)
- (MF)√ (pramipexole, ropinirole, pergolide)
Prevention of motor complications
- ?- (D)
? (MF)?
√ (pramipexole, ropinirole, cabergoline)
Imaging indicates slowed loss of dopamine neurons
-(?) ? ? ?√ (pramipexole, ropinirole)
√ efficacious (maximum strength of evidence)± probably efficacious - not efficacious? insufficient data0 no studies
D dsykinesiasMF motor fluctuationsCOMT catechol-O-methyltransferaseMAO-B monoamine oxidase BDAs dopamine agonists
Rascol O, et al. Lancet 2002;359:1589-98.Goetz CG, et al. Mov Disord 2005;20:523-39.Fahn S, et al. N Engl J Med 2004;351:2498-508.
Horstink M, et al. Eur J Neurol 2006;13:1170-85.Horstink M, et al. Eur J Neurol 2006;13:1186-202. 43
44
Drug Therapy in Parkinson’s DiseaseDrug Therapy in Parkinson’s Disease
45
Drug Therapy in Parkinson’s Disease – Summary
• Therapeutic Approaches and Strategies
• Levodopa
– Efficacy
– Management of motor complications
• Dopamine Agonists
– Clinical pharmacology
– Efficacy
– Tolerability
• Other Drug Therapies for Parkinson’s Disease
– MAO-B* inhibitors
– Anticholinergics
– Amantadine
* Monoamine oxidase B
46
Drug Therapy in Parkinson’s DiseaseDrug Therapy in Parkinson’s Disease
Therapeutic Approaches and Strategies
47
Drug Therapy in Parkinson’s Disease – Initiation
• Traditionally
– When symptoms interfere with social, domestic or professional life
• Patient judgment
• Physician advice to prevent:
– Unnecessary prolongation of disability
– Impaired quality of life
• Alternative approach
– Consider advantages of early treatment
• Symptomatic relief of motor symptoms
• Improvement of quality of life
• Avoidance of irreversible motor programme loss
• Potential disease modification (neuroprotection) with some agents
– Delay levodopa therapy and use alternatives to avoid or delay motor complications
Nutt JG, Wooten GF. N Engl J Med 2005;353:1021-7.Schapira AH, Obeso J. Ann Neurol 2006;59:559-62.
48
Drug Therapy – Symptomatic Treatment of Motor Symptoms
• Dopaminergic agents– Levodopa
• Levodopa + carbidopa• Levodopa + benserazide• COMT inhibitors* (entacapone,
tolcapone) – Dopamine agonists
• Non-ergot† – Pramipexole– Ropinirole– Rotigotine– Piribedil
• Ergot– Bromocriptine– Pergolide– Cabergoline – Dihydroergocryptine– Lisuride
– Selective MAO-B‡ inhibitors• Selegiline• Rasagiline
• Non-dopaminergic agents– Anticholinergic agents:
• Trihexyphenidyl
• Benztropine
– NMDA§ antagonists
• Amantadine
* catechol-O-methyltransferase inhibitors; always used in conjunction with levodopa
† apomorphine is available for subcutaneous injections and may be useful in patients with levodopa-related motor fluctuations
‡ monoamine oxidase type-B§ N-methyl-D-aspartate
Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinson’s Disease; 2005.
49
Algorithm for the Management of Early Parkinson’s Disease
1. Dopamine agonists are not recommended in patients with cognitive disturbance.
2. Gradual dose escalation is important for patient compliance and maintaining motor control.
3. Dopamine agonist dosage should be gradually increased over time in order to maintain motor control.
4. Levodopa introduction is necessary in the majority of patients to maintain and optimise motor control.
Adapted from Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinson’s Disease; 2005:127. © 2005, with permission from Elsevier.
Diagnosis
Decision to treat
YES
Evaluate degree of disability
Moderate motor disabilityNo cognitive disability
Begin dopamine agonist
Treat to maximum response ortolerance of dopamine agonist
Consider MAO-B inhibitor
Disability requiringadditional therapy
NO
Review
Mild motor disability
Begin dopamine agonistor MAO-B inhibitor *
Additional symptomaticbenefit required
Begin dopamine agonistif not already started
Titrate to maximum responseor tolerance of dopamine agonist
Disability requiringadditional therapy
Begin levodopa
1, 2
3
1
2
3
4
* Monoamine oxidase B
50Adapted by permission from Macmillan Publishers Ltd: Youdim MB, et al. Nat Rev Neurosci 2006;7:295-309 © 2006.
The Basis for Symptomatic Drug Therapy of Motor Symptoms in Parkinson’s Disease
Abbreviations: DDC, dopa decarboxylase; TH, tyrosine hydroxylase; L-DOPA, levodopa; MAO-A, monoamine oxidase A; MAO-B, monoamine oxidase B; COMT, catechol-O-methyltransferase; D, dopamine receptors; 3-OMD, 3-O-methyldopa
Dopaminetransporter
Postsynaptic terminal
in the striatum
Synaptic vesicle
DopamineL-DOPATyrosine
MAO-A
THDDC
Presynaptic terminalfrom the substantia nigra
D
D
D
D
D
Blood-brain barrier
L-DOPATyrosine
3-OMD
Dopamine
Entacapone
BenzerazideCarbidopa
DDC
COMT
Moclobemide
SelegilineRasagiline
LazabemideSafinamide
MAO-A
MAO-B
MAO-A
MAO-B
COMT
COMT
Glial cell
Astrocyte
51
Main Mechanisms of Action of Therapeutic Interventions in Parkinson’s Disease
Action
DrugsPromote dopamine
synthesisActivate specific
receptors
Prolong dopamine availability
Prolong levodopa
bioavailability
Dopaminergic Levodopa DAs MAO-B inhibitors COMT inhibitors
Antiglutamatergic Amantadine*
Anticholinergic† TrihexyphenidylBenztropine
Surgery
LesionThalamotomyPallidotomy
Subthalamic nucleotomy
DBSThalamusPallidum
Subthalamic nucleus
Transplantation‡
Foetal mesencephalic
cells
Rehabilitation procedures
Physical therapyOccupational therapy
Speech therapy
Abbreviations: DAs, dopamine agonists; MAO-B, monoamine oxidase B; COMT, catechol-O-methyltransferase; DBS, deep brain stimulation
* mechanism of action not fully known, the antiglutamatergic action being only part of the drug's effect
† only drugs commonly used are listed‡ experimental
Rascol O, et al. Lancet 2002;359:1589-98.Goetz CG, et al. Mov Disord 2005;20:523-39.
52
Drug Therapy in Parkinson’s DiseaseDrug Therapy in Parkinson’s Disease
Levodopa
53
Levodopa in the Management of Parkinson’s Disease (1)
• First of the dopaminergic drugs
– Used since late 1960s1
• Highly effective drug
– Relatively rapid relief2 of bradykinesia, rigidity and associated pain
– Reduces tremor in many patients
Levodopa improves quality of life3 and life expectancy4 in patients with PD
1. Tolosa E, et al. Neurology 1998;50(Suppl 6):S2-10.2. Stacy M. Pharmacotherapy 2000;20(Suppl):8S-16S.3. Rajput AH. Parkinsonism Relat Disord 2001;8:95-100.4. Karlsen KH, et al. J Neurol Neurosurg Psychiatry 2000;69:584-9.
54
Levodopa in the Management of Parkinson’s Disease (2)
1. Jankovic J. Neurology 2002;58(Suppl 1):S19-32. 2. Deleu D. Clin Pharmacokinet 2002;41:261-309.3. Olanow CW, Stocchi F. Eur J Neurol 2000;7(Suppl 1):3-8.
• Must be metabolised to dopamine to be effective1
• Addition of dopa decarboxylase inhibitors (DDIs) (benserazide, carbidopa) is required to limit additional peripheral side effects1
• Absorption delayed or diminished by large neutral amino acids or agents that slow transit time, antacids and anticholinergics1,2
• Short half-life causes pulsatile stimulation of dopamine receptors3
55
1. Olanow CW, Stocchi F. Eur J Neurol 2000;7(Suppl 1):3-8.2. Fahn S. Adv Neurol 1996;69:477-86.3. Poewe WH, Wenning GK. Neurology 1996;47(Suppl 3):S146-52.4. Parkinson Study Group. Ann Neurol 1996;39:37-45.5. Kostic V, et al. Neurology 1991;41:202-5.
Levodopa in the Management of Parkinson’s Disease (3)
• Levodopa induces motor complications
– Up to 80% of PD patients suffer from motor fluctuations and dyskinesias after approximately 5 to 10 years of treatment with levodopa1
– 50 to 75% of patients develop motor fluctuations 3 to 6 years after initiating therapy2-4
– 70% of young-onset PD patients develop motor complications after 3 years5
56
Causes of Treatment-Related Motor Complications in Parkinson’s Disease
• Pulsatile stimulation of dopamine receptors with short half-life drugs
• Progressive dopaminergic neuronal degeneration
Obeso JA, et al. Neurology 2000;55(Suppl 4):S13-20.
57
Dyskinesia Threshold
Response Threshold
• Shorter duration motor response
• Increased incidence of dyskinesias
• Short durationmotor response
• “On” time consistently associated with dyskinesias
• Long duration motor response
• Low incidence of dyskinesias
Advanced PDAdvanced PD
Time (h)
Cli
nic
al E
ffec
t
Levodopa 2 4 6
Response to Levodopa and Progression of Parkinson’s Disease
Obeso JA, et al. Trends Neurosci 2000;23(Suppl):S2-7.
Response Threshold
Dyskinesia Threshold
Time (h)
Early PDEarly PD
Levodopa
Cli
nic
al E
ffec
tC
lin
ical
Eff
ect
2 4 6
Response Threshold
Time (h)
4
Dyskinesia Threshold
2
Moderate PDModerate PD
Cli
nic
al E
ffec
t
Levodopa 6
58
Management of Motor Fluctuations
• Increase the frequency of dose administration (e.g. change from t.i.d. levodopa to q.i.d. levodopa, with the last dose during the day rather than at bedtime)
– Useful in short but not long term
• Maintain levodopa and– Add a dopamine agonist
– Add a COMT inhibitor
– Add a MAO-B inhibitor • Levodopa dose may need modification depending on patient response
• Surgery
• Continuous infusion of carbidopa-levodopa for rescue therapy
Abbreviations: COMT, catechol-O-methyltransferase; MAO-B, monoamine oxidase B; t.i.d., ter in die; q.i.d., quater in die
Treatment options
Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinson’s Disease; 2005.Rascol O, et al. Lancet 2002;359:1589-98.Goetz CG, et al. Mov Disord 2005;20:523-39.
59
Management of Dyskinesias
Treatment options for the management of peak-dose dyskinesias
• Administer fractionated levodopa doses (with or without increased total daily doses) in order to avoid peak plasma levodopa concentrations
– Useful in short but not long term
• Or, reduce levodopa dose and
• Increase dopamine agonist dose
• Add a dopamine agonist if not already used
• Surgery
Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinson’s Disease; 2005.
60
Drug Therapy in Parkinson’s DiseaseDrug Therapy in Parkinson’s Disease
Dopamine Agonists
61
Dopamine Agonists in the Treatment of Parkinson’s Disease
• First-line therapy in early PD in younger patients
– Rare motor complications
• Delay the use of levodopa and related motor complications
– Good side-effect tolerance
• Avoid ergot dopamine agonists: rare but serious fibrotic reactions1,2
• Agonist monotherapy can provide control of motor symptoms for several years in some patients2
• Adjunctive treatment in more advanced PD4
• Putative neuroprotection with some agents, particularly pramipexole3 and ropinirole4
1. Pritchett AM, et al. Mayo Clin Proc 2002;77:1280-6. 2. Horstink M, et al. Eur J Neurol 2006;13:1170-85. 3. Parkinson Study Group. JAMA 2002;287:1653-61. 4. Whone AL, et al. Ann Neurol 2003;54:93-101.
62
Chemical Structures of Dopamine Agonists
Bromocriptine -Dihydroergocryptine Cabergoline Lisuride
Pergolide
OH
O
HN
CH3
Br
O H
HO
HN
O H
H
H
H
HN
O
H
H
H
HN
HN
H
H
H
H
Non-ergot dopamine agonists
OH
N
CH3
S
RotigotinePramipexoleRopinirole
S
NH2
N
H3CH2CH2CHN
H
CH2CH2N(CH2CH2CH3)2
O
HN
CH2CH2CH3N
HN
CH2SCH3
NCH3
CON(CH2CH3)2
NCONHCH2CH3
CH2CHCH2
N
CH2CH2CH2N(CH3)2
CH3
N
OH
CH2CH(CH3)2
(CH3)2CH
NH N
O N
CH2CH(CH3)2
NO
N
NH
N
(CH3)2HC
63
Dopamine Receptor Nomenclature
D1 family
receptorsubtypes
D1 D5
D2 family
receptorsubtypes
D2 D3 D4
Localisation D1, D2 striatum and substantial nigraD3, D4 limbic brain areasD5 hippocampus, hypothalamus, parafascicular nucleus of the thalamus
Missale C, et al. Physiol Rev 1998;78:189-225.Poewe W. In: Principles of Treatment in Parkinson’s Disease; 2005.
64
Dopaminergic Pathways
Putamen
Substantia nigra
Ventral tegmental areaAmygdala
Nucleus accumbens
Caudate nucleus
mesolimbic pathway
nigrostriatal pathway
D3 receptor
D2 receptor
Missale C, et al. Physiol Rev 1998;78:189-225.Shafer RA, et al. Psychopharmacology (Berl) 1998;135:1-16.
65
Dopamine Agonists – Pharmacological Advantages
• Direct dopamine-receptor stimulation
• No need for conversion to dopamine
• No interference with food for absorption
• Longer half-life compared with levodopa (pramipexole, ropinirole, rotigotine, pergolide, cabergoline)
• Putative neuroprotective action (pramipexole, ropinirole)
Poewe W. In: Principles of Treatment in Parkinson’s Disease; 2005.
Pharmacological profile of dopamine agonistsAdvantages over levodopa
66
Clinical Pharmacology of Dopamine Agonists
DrugDopamine receptor
interactionInteraction with other
receptorsHalf-life (h)
NA 5-HTP
Non-ergot
Pramipexole D2 ± - 10
Ropinirole D2 - - 6
Rotigotine D2 > D1 + + 5-7 (td)
Apomorphine D2/D1 - - 0.5 (sc)
Ergot
Bromocriptine D2 + + 3-6
Pergolide D2 > D1 + + 15
Cabergoline D2 + + 65All mentioned D2-family agonists have D3/D2 subtype affinity ratio > 1 except for bromocriptine.Abbreviations: NA, noradrenaline; 5-HT, 5-hydroxytryptophan; td, transdermal; sc, subcutaneous
Poewe W. In: Principles of Treatment in Parkinson’s Disease; 2005.Kyniyoshi S and Jankovic J. In: Parkinson’s Disease; 2005.Jenner P. Neurology 2005;65(2 Suppl 1):S3-5.
67
Dopamine Agonists in the Treatment of Parkinson’s Disease – Mean Daily Dosage
DrugMonotherapy
(mg)Adjunct to levodopa
(mg)
Non-ergot
Pramipexole 0.375-4.5 0.375-4.5
Ropinirole 6-18 6-12
Rotigotine 4-8 -
Apomorphine - 1.5-6 (sc* bolus)
Ergot
Bromocriptine 25-45 15-25
Pergolide 1.5-5.0 0.75-5
Cabergoline 2-6 2-4
* subcutaneous
Poewe W. In: Principles of Treatment in Parkinson’s Disease; 2005.
68
Clinical Importance of D2 Selectivity
• All dopamine agonists stimulate D2 receptors
– stimulation of D2 receptors is thought to mediate improvement of cardinal motor symptoms1
• Stimulation of D1 receptors results in dyskinesias in experimental animal models2
1. Guttman M, Jaskolka J. Parkinsonism Relat Disord 2001;7:231-4.2. Fici GJ, et al. Life Sci 1997; 60:1597-603.
69
Clinical Implications of D3 Preference
• D3 receptors in the mesolimbic dopamine system may be involved in cognition, mood and behaviour1,2
• Preferential stimulation of D3 receptors (D3 preference) may explain the antidepressive and anti-anhedonic properties of dopamine agonists such as pramipexole3,4
1. Guttman M, Jaskolka J. Parkinsonism Relat Disord 2001;7:231-4.2. Missale C, et al. Physiol Rev 1998;78:189-225.3. Piercey FM. Clin Neuropharmacol 1998;21:141-51.4. Willner P. Int Clin Psychopharm 1997;12(Suppl 3):S7-14.
70
Evidence on Efficacy of Dopamine Agonists in Patients With Parkinson’s Disease
Evaluation of published studies according to evidence-based medicine criteria
√ efficacious (maximum strength of evidence)± probably efficacious ? insufficient data0 no studies
Rascol O, et al. Lancet 2002;359:1589-98.Goetz CG, et al. Mov Disord 2005;2:523-39Horstink M, et al. Eur J Neurol 2006;13:1170-85.Horstink M, et al. Eur J Neurol 2006;13:1186-202.
Category evaluated Bromocriptine Cabergoline Lisuride Pergolide Pramipexole Ropinirole
Monotherapy in early PD ± ? ± √ √ √
Combination withL-Dopa in advanced PD √ √ ± √ √ ?
Treatment of motor fluctuations ± ± ? √ √ √
Prevention of motor complications and dyskinesias
± √ ? ? √ √
Imaging indicates slowed loss of dopamine neurons
0 0 0 0 √ √
71
Adverse events (%)
Nausea Somnolence Hallucinations
CALM-PD1Pramipexole 36.4 32.4 9.3
Levodopa 36.7 17.3 3.3
RQP 0562Ropinirole 48.6 27.4 17
Levodopa 49.4 19.1 6
CBS 093Cabergoline 37.4 26.5* 4.3
Levodopa 32.2 28.4* 4.8
* includes sleep problems and insomnia
1. Parkinson Study Group. JAMA 2000;284:1931-8. 2. Rascol O, et al. N Engl J Med 2000;342:1484-91.3. Rinne UK, et al. Drugs 1998;55 (Suppl 1):23-30.
Tolerability of Dopamine Agonists in Early Parkinson’s Disease – Main Adverse Events
There are no head-to-head studies comparing the various agents: these data do not allow for direct comparisons of dopamine agonists.
72
80
60
40
20
0
Va
lvu
lar
Re
gurg
itatio
n (
%)
31*31*
43*43*
10101414
Pergolide Cabergoline PramipexoleRopinirole
Controls
Peralta et al.1
* P < 0.05 vs. controls
Yamamoto et al.2
** P < 0.001 vs. controls
2929
69**69**
25251818
1. Peralta C, et al. Mov Disord 2006;21:1109-13.2. Yamamoto M, et al. Neurology 2006;67:1225-9.
Drug-Induced Valvular Heart Disease –Ergot versus Non-Ergot Dopamine Agonists
73
Drug Therapy in Parkinson’s DiseaseDrug Therapy in Parkinson’s Disease
Other Drug Therapies for Parkinson’s Disease
74
Other Drug Therapies for Parkinson’s Disease
• Other dopaminergic agents
– MAO-B* inhibitors
• Compounds interacting with receptors other than dopaminergic receptors may be useful in some patients
– Anticholinergics
– Amantadine
* monoamine oxidase B
Cersosimo MG, Koller WC. In: Principles of Treatment in Parkinson’s Disease; 2005.
75
Other Dopaminergic Agents – MAO-B* Inhibitors (1)
• Selegiline and rasagiline
– Selective MAO-B inhibitors; however, selectivity is lost at high doses
• Risk of tyramine-induced hypertension (the “cheese effect”) at high doses
– Symptomatic effect in Parkinson’s disease
– Neuroprotective effect in the laboratory
• Mechanisms of action
– Irreversible inhibition of MAO-B, which catalyses the oxidative deamination of neuroactive amines
Prolongation of dopamine availability
– Possible enhancement of catecholaminergic neurons by other mechanisms
– Effect on mitochondrial membrane, anti-apoptotic effect and reduction of oxidative stress with potential neuroprotective properties
* monoamine oxidase B
Cersosimo MG, et al. In: Principles of Treatment in Parkinson’s Disease; 2005.Horstink M, et al. Eur J Neurol 2006;13:1170-85.
76
• Selegiline– Mild antiparkinsonian effect in de novo Parkinson’s disease
– No evidence that MAO-B inhibition delays the development of motor fluctuations other than through the delay in introducing levodopa and an ability to use a lower dose
• Rasagiline– 10–15 times more potent than selegiline
• Antiparkinsonian effect comparable to selegiline: not as great as the dopamine agonists
– Less effective than dopamine agonists in reducing off-periods in patients optimised on levodopa
Other Dopaminergic Agents – MAO-B* Inhibitors (2)
* monoamine oxidase B
Cersosimo MG, et al. In: Principles of Treatment in Parkinson’s Disease; 2005.Parkinson Study Group. Arch Neurol 2004;61:561-6.
77
• Conclusion
– Mild to moderate symptomatic motor control in early Parkinson’s disease (PD)
– Not particularly effective for treating motor fluctuations
– Relatively safe drugs
Other Dopaminergic Agents – MAO-B* Inhibitors (3)
* monoamine oxidase B
Horstink M, et al. Eur J Neurol 2006;13:1170-85. Cersosimo MG, et al. In: Principles of Treatment in Parkinson’s Disease; 2005.Arch Neurol 2004;61:561-6.
78
Non-Dopaminergic Antiparkinsonian Drugs – Anticholinergics
• Mechanism of action:
– State of relative cholinergic sensitivity due to dopamine depletion
• Cholinergic drugs exacerbate and anticholinergic agents (e.g. trihexyphenidyl, benztropine) improve parkinsonian symptoms
• Typically used in younger patients with Parkinson’s disease in whom tremor is the major symptom
• However:
– Little data on potency and tolerance
– Common side effects that limit their usefulness
• Cognitive side effects: memory impairment, acute confusion, hallucinations, sedation, dysphoria
• Dyskinesias
• Peripheral antimuscarinic side effects: dry mouth, constipation, accommodation impairment, nausea, urinary retention, impaired sweating, tachycardia
• Contraindicated in patients with prostate hypertrophy, closed-angle glaucoma, tachycardia, gastrointestinal obstruction, megacolon
Cersosimo MG, et al. In: Principles of Treatment in Parkinson’s Disease; 2005.Samii A, et al. Lancet 2004;363:1783-94. Horstink M, et al. Eur J Neurol 2006;13:1170-85.
79
• Mechanism of action
– Although the exact mechanism of action is not established, amantadine seems to have dopaminergic, anticholinergic and antiglutamatergic activities
• Mild and transitory improvement of parkinsonian symptoms
– More effective in the control of bradykinesia and rigidity than tremor
– Generally considered unsuitable for monotherapy in Parkinson's disease
– Mostly used as an adjunct
• Potential cognitive side effects also limit its use
Non-Dopaminergic Antiparkinsonian Drugs – Amantadine
Cersosimo MG, et al. In: Principles of Treatment in Parkinson’s Disease; 2005.Samii A, et al. Lancet 2004;363:1783-94.Horstink M, et al. Eur J Neurol 2006;13:170-85.
80
SurgerySurgery
81
Surgical Treatment for Parkinson’s Disease
• Early 20th century
– First interventions directed at motor cortex and corticospinal tract
• Some success, particularly with regard to tremor
• Success complicated by motor paresis
– Ventrointermediate thalamotomy in the 1950s and 1960s
• Antitremor effects
• Currently
– Levodopa-induced motor complications
– Severe tremor
– Procedure-dependent results
Goetz CG, et al. Mov Disord 2005;20:523-39.
82
Surgical Procedures for Parkinson’s Disease
Ablative procedure Deep brain stimulation Restorative procedure
ThalamotomyUnilateral pallidotomySubthalamotomy
VIM nucleus of thalamus
GPi STN
Cell-based therapiesHuman foetal nigral cellsPorcine foetal nigral cellsRetinal pigmented epithelial cellsStem cellsTrophic factorsGene therapies
Abbreviations: VIM, ventrointermediate; GPi, globus pallidus pars interna; STN, subthalamic nucleus
In practice:• Potential benefit for advanced disease not controlled with medical therapy• Ablative procedures have been largely abandoned• Effects not superior to optimised medical therapy• Non-dopaminergic features not affected
Goetz CG, et al. Mov Disord 2005;20:523-39.Pahwa R, et al. Neurology 2006;66:983-95.
83
Management of Non-Motor Symptoms
Management of Non-Motor Symptoms
84
Non-Motor Features of Parkinson’s Disease
Cognitive and other psychiatric symptoms
Sleep disorders Autonomic dysfunctions(including gastrointestinal symptoms)
DepressionCognitive declineDelirium, hallucinations,
psychosis*DementiaObsessional behaviour*ConfusionPanic attacks
InsomniaDaytime sleepiness and excessive
daytime sleepinessParasomniasAbnormal simple and complex
nocturnal movementsRLS and PLMS
RBD and REM loss atoniaNon-REM sleep-related movement
disordersVivid dreamingSleep-disordered breathing
Bladder dysfunctionUrgencyNocturiaFrequency
SweatingOrthostatic hypotensionSexual dysfunction
Hypersexuality*Erectile impotence
ConstipationSialorrhoeaWeight lossWeight gain*Dry eyes
Other symptoms
Pain, paresthesia, diplopia, olfactory disturbances and fatigue
Abbreviations: REM, rapid eye movement; RBD, REM sleep behaviour disorder;RLS, restless legs syndrome; PLMS, periodic leg movements of sleep
* possibly drug-induced
Chaudhuri KR, et al. Lancet Neurol 2006;5:235-45.Tetrud JW. In: Parkinson’s Disease; 2005.
85
Management of Non-Motor Symptoms in Parkinson’s Disease – Diagnosis and Evaluation
• Non-motor symptoms are frequently overlooked
– Depression, anxiety, fatigue and sleep not discussed with more than 50% of patients1
• Despite a probable frequency of depression of 40–50% in PD patients2
– Difficult diagnosis in some cases
• Role of neurologists in identifying and differentiating symptoms
• Non-motor scales
– Improve the identification of non-motor symptoms
– Evaluate therapeutic interventions
1. Shulman LM, et al. Parkinsonism Relat Disord 2002;8:193-7.2. Cummings JL. Am J Psychiatry 1992;149:443-54.
86
Non-Motor Symptoms in Parkinson’s Disease – Assessment Tools
Non-motor feature Scale
Neuropsychiatric symptomsMini Mental Test; Hospital Anxiety and Depression ScaleHamilton Depression Rating Scale; Beck Depression Inventory
Autonomic symptoms SCOPA-Aut
SleepParkinson's Disease Sleep Scale; SCOPA-Sleep; Epworth Sleepiness Scale
Fatigue Fatigue Severity Scale; PF-16
Health-related quality of lifePDQ 39; PDQ 8; PDQUALIF; PD Quality of Life Questionnaire; SCOPA-PS (psychological aspect); EQ-5D
Comprehensive assessmentThe Parkinson's disease NMS scale (in development); the Parkinson's disease NMS questionnaire (NMSQuest); Revised UPDRS (not validated); wearing-off patient questionnaire
Abbreviations: NMSQuest, non-motor symptom questionnaire for Parkinson's disease; UPDRS, unified Parkinson's disease rating scale; SCOPA, scales for outcomes in Parkinson's disease; PDQUALIF, Parkinson's disease quality of life scale; PDQ, Parkinson's disease questionnaire
Chaudhuri KR, et al. Lancet Neurol 2006;5:235-45.
87
Treatment of Non-Motor Symptoms in Parkinson’s Disease – Neuropsychiatric Disorders
Treatment approach
Anxiety, panic attacks• Treat wearing-off• SSRIs• Benzodiazepines
Depression• Tricyclic antidepressants• SSRIs• Pramipexole
Hallucinations and psychosis
• Discontinue: sedatives, hypnotics, narcotic analgesics, anticholinergics, amantadine, MAO-B inhibitors
• Taper or discontinue dopamine agonists if possible• Clozapine or quetiapine if needed
Abbreviations: SSRI, selective serotonin reuptake inhibitors; MAO-B, monamine oxidase B
Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7.Sawabini KA, et al. In: Principles of Treatment in Parkinson's Disease; 2005. Lieberman A. Acta Neurol Scand 2006;113:1-8.Miyasaki JM, et al. Neurology 2006;66:996-1002.
88
Treatment of Non-Motor Symptoms in Parkinson’s Disease – Autonomic Dysfunction
Treatment option
Bladder urgency• Oxybutinin• Tolterodine• Amitriptyline (if concomitant depression)
Erectile dysfunction• Sildenafil• Apomorphine
Sialorrhoea• Simple measures: chewing gum, sucking sweets• Anticholinergic drugs (glycopyrrolate)• Botulinum toxin for refractory cases
Constipation• Consider dopamine agonists• Adequate fluid intake, exercise• Aperients: psyllium fibre, lactulose, polyethylene glycol
Orthostatic hypotension• Adjust dopamine agonist dose if needed• Fludrocortisone• Midodrine
Stocchi F. In: Principles of Treatment in Parkinson’s Disease; 2005.Raffaele R, et al. Eur Urol 2002;41:382-6.O'Sullivan JD. J Neurol Neurosurg Psychiatry 2002;72:681.Tetrud JW. In: Parkinson’s Disease; 2005. Goldstein DS. Lancet Neurol 2003;2:669-76.
89
Treatment of Non-Motor Symptoms in Parkinson’s Disease – Sleep Disturbances
Treatment option
Insomnia • Non-pharmacological: sleep hygiene• Pharmacological: benzodiazepines, zopiclone, zolpidem
RBD • Benzodiazepine (clonazepam)
RLS• Dopamine agonists• Levodopa• Opiates
EDS
• Caffeine• Modafinil• Reduce dopaminergic drug dose• Switch from one dopamine agonist to another
Abbreviations: RBD, rapid eye movement (REM) sleep behaviour disorder; RLS, restless legs syndrome; EDS, excessive daytime sleepiness
Adler CH, Thorpy MJ. Neurology 2005;64(12 Suppl 3):S12-20. Stocchi F. In: Principles of Treatment in Parkinson’s Disease; 2005.Barone P, et al. Neurology 2004;63(8 Suppl 3):S35-8.Phillips B. Neurology 2004;62(5 Suppl 2):S9-16.
90
Disease Modification (Neuroprotection)Disease Modification (Neuroprotection)
91
Disease Modification in Parkinson’s Disease – Summary
• Rationale for Neuroprotection
• Evaluating Neuroprotection
• Approaches in Neuroprotection
• Clinical trials
– Antioxidants and monoamine oxidase type-B inhibitors
– Anti-excitotoxic agents
– Bioenergetic agents
– Coenzyme Q10
• Dopamine Agonists
– Rationale for the use of dopamine agonists as potential neuroprotective agents
– Possible mechanisms for neuroprotection
– Experimental basis
– Neuroimaging
– Clinical trials
• Perspectives in Neuroprotection
92
Disease Modification (Neuroprotection)Disease Modification (Neuroprotection)
Rationale
93
Limit Neuropsychiatric andNon-Dopaminergic
Symptoms
Slow Disease Progression
Restorative Therapies• Cells, genes,
trophic factors
Reduce Motor Complications
• Early dopamine agonist therapy
• Continuous dopamine stimulation
• Deep brain stimulation
• Antidyskinesia drugs, amantadine, dopamine transport inhibitors, glutamatergic drugs, and GABA*
• Dementia
• Depression
• Postural instability
• Freezing
• Autonomic failure
Block Neurodegenerative Process• Improved mitochondrial function
• Oxidative stress• Protein aggregation• Apoptosis, necrosis
Reduce Motor Symptoms(see algorithm on slide 49)
Treatment of Parkinson’s Disease
Schapira AH, Olanow CW. JAMA 2004;291:358-64. Olanow CW, Jankovic J. Mov Disord 2005;20(S11):S3-10.
* Gamma-aminobutyric acid
94
Neuroprotection – Definitions
• Neuroprotection (disease modification)
– Prevent further neuronal cell death in order to slow or halt disease progression
– Does not necessarily affect the underlying pathophysiological biochemical mechanisms
• Neurorescue
– Salvage of dying neurons by reversal of established metabolic abnormalities
• Neurorestoration (is not neuroprotection)
– Increasing the number of dopaminergic neurons
• Cell implantation
• Nerve growth factors
Schapira AH. BMJ 1999;318:311-4.
95
Disease Modification (Neuroprotection)Disease Modification (Neuroprotection)
Evaluation
96
Neuroprotection – Evaluation
• Decreased loss of neurons in the dopaminergic and other neurotransmitter systems
– Impossible to assess directly in life
• Surrogate markers:
– Clinical rating scales (e.g. UPDRS*)
– Time to clinical endpoints (e.g. time to levodopa therapy requirement)
– Neuroimaging (-CIT SPECT,† fluorodopa PET‡)
* Unified Parkinson's Disease Rating Scale † single photon emission computed tomography‡ positron emission tomography
Clarke CE. Lancet Neurol 2004;3:466-74.
97
Issues in the Evaluation of Neuroprotective Effects of Drugs in Parkinson’s Disease
Outcome measure Issue Suggested solution
Clinical measure*
Differentiation of symptomatic from neuroprotective effects
• Prolonged washout of drug
• Delayed-start studies
Neuroimaging†
• SWEDD‡
• Discrimination with progressive supranuclear palsy or multiple system atrophy
• Appropriate sample size calculations taking into account misdiagnosis
• Lack of correlation between clinical outcomes and neuroprotection
• Larger or longer studies
• Modification of radionuclide tracer pharmacokinetics by the putative neuroprotective agent
• Repeat imaging to assess any differential effect of the drug
All • Small magnitude of neuroprotective effect • Appropriate sample size
All• Lack of meaning to patients • Inclusion of quality-of-life parameters
and mortality evaluation
* clinical rating scales, time to endpoint, mortality; † β-CIT single photon emission computed tomography (SPECT) or fluorodopa positron emission tomography (PET); ‡ scans without evidence of dopaminergic deficit
Clarke CE. Mov Disord 2004;19:491-8.Clarke CE. Lancet Neurol 2004;3:466-74.
98
Disease Modification (Neuroprotection)Disease Modification (Neuroprotection)
Approaches
99
Neurorescue and Neuroprotection in Parkinson’s Disease
• Neurorescue (yellow line)
Restore damaged neurons that are at risk of death (area between curves) to normal function
Age-related loss will probably be attenuated with ongoing treatment
• Neuroprotection (green line)
Prevents further neuronal loss other than by attenuated age- related loss
Putative time course for loss of dopamine neurons from substantia
nigra and clinical expression
Threshold for clinical symptoms
0%
100%
Pe
rce
nta
ge
of
Su
bst
an
tia N
igra
N
eu
ron
s R
em
ain
ing
40 80
Years
Diagnosis
Schapira AH. BMJ 1999;318:311-4. © 1999 BMJ Publishing Group Ltd.
100
Neuroprotection in Parkinson’s Disease –Clues and Targets
Aetiological and pathogenetic factors in Parkinson’s disease and possible neuroprotective approaches
Abbreviations: COX-2, cyclo-oxygenase-2;GDNF, glial-derived neurotrophic factor
Genetic factors
Environmental factors
Gene-environment interaction
Oxidative stress
Mitochondrial dysfunction
Excitotoxicity
Inflammation
Protein handling dysfunctionwith Levy body formation
Neuronal dysfunction
Apoptosis
AETIOLOGY
PATHOGENESISAntioxidants (e.g. vitamin E, vitamin C, iron chelators)Monoamine oxidase B inhibitors(e.g. selegiline, rasagiline)Bioenergetic agents(e.g. coenzyme Q10)Antiglutamatergic agents(e.g. N-methyl-D-aspartate[NMDA] receptor antagonists)
Calcium channel blockers
Anti-inflammatory agents(e.g. COX-2 inhibitors)
Proteosomal enhancers
Heat shock proteins
Trophic factors(e.g. GDNF, nurturin)
Anti-apoptotic agents(e.g. dopamine agonists, caspase inhibitors, propargylamines)
Schapira AH, Olanow CW. JAMA 2004;291:358-64.
© 2004 American Medical Association. All rights reserved.
101
Disease Modification (Neuroprotection)Disease Modification (Neuroprotection)
Clinical Trials
102
Neuroprotection Trials – Antioxidants and Monoamine Oxidase Type-B Inhibitors (1)
• Rationale1 – Role of oxidative stress in the pathogenesis of neuronal cell death– Increased levels of iron (promote oxidative stress) in SN*– Decreased levels of glutathione (the major brain antioxidant)– Evidence of oxidative damage to carbohydrates, lipids, proteins and DNA in
SNpc†
– Oxidative metabolism of levodopa and/or dopamine
• Candidate drugs1,2
-tocopherol (vitamin E)• The most potent lipid-soluble antioxidant in plasma
– Selegiline • Inhibits the MAO-B‡ oxidation of MPTP§ (responsible for MPTP toxicity)• Possibly inhibits the oxidation of other toxins that contribute to neuronal degeneration• Might block the MAO-B-dependent oxidative metabolism of levodopa/dopamine
– Rasagline• Another potent MAO-B inhibitor• Has also shown protective effects in laboratory models2
* substantia nigra; † substantia nigra pars compacta; ‡ monoamine oxidase type-B; §1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
1. Stocchi F, Olanow CW. Ann Neurol 2003;53(Suppl 3):S87-97.2. Olanow CW. Neurology 2006;66(10 Suppl 4):S69-79.
103
Neuroprotection Trials – Antioxidants and Monoamine Oxidase Type-B Inhibitors (2)
• DATATOP* study -tocopherol: no effect on the time-to-levodopa requirement
– Selegiline: delayed need for levodopa
• SELEDO† study– Selegiline: less requirement for increased levodopa doses
• SINDEPAR‡
– Selegiline: less deterioration in UPDRS§ score
• TEMPO**– Rasagiline: more deterioration in UPDRS score if delayed start
Stocchi F, Olanow CW. Ann Neurol 2003;53(Suppl 3):S87-97.Parkinson Study Group. Arch Neurol 2004; 61:561-6.
• Limitations– Selegiline has symptomatic effects in Parkinson’s disease
• Prevents any conclusion as to neuroprotective effect
– Same limitation is valid for other MAO-B inhibitors (lazabemide, rasagiline)
* Deprenyl and Tocopherol Antioxidant Therapy of PD; † Selegiline-L-dopa; ‡ Sinemet-Deprenyl-Parlodel; § Unified Parkinson's Disease Rating Scale; ** rasagiline mesylate (TVP-1012) in Early Monotherapy for Parkinson's disease Outpatients
104
Neuroprotection Trials – Anti-excitotoxic Agents (1)
• Rationale– Neuronal activity in the STN* is increased in PD
– STN uses the excitatory neurotransmitter glutamate and projects to the GPi†, pedunculopontine nucleus and SNpc‡
• Potential excitotoxic damage of these targets
– NMDA§ receptor antagonists may protect dopamine neurons from glutamate-mediated toxicity
– A retrospective study suggests decreased rate of PD progression after administration of amantadine (an NMDA receptor antagonist)
* subthalamic nucleus; † globus pallidus interna; ‡ substantia nigra pars compacta§ N-methyl-D-aspartate
Rodriguez MC, et al. Ann Neurol 1998;44(3 Suppl 1):S175-88.Stocchi F, Olanow CW. Ann Neurol 2003;53(Suppl 3):S87-97.
105
Neuroprotection Trials – Anti-excitotoxic Agents (2)
• Remacemide hydrochloride (low-affinity NMDA channel blocker)
– No symptomatic effect in Parkinson’s disease
– No neuroprotective benefit in Huntington’s disease
– No formal study of neuroprotection in Parkinson’s disease
• Riluzole (sodium channel blocker)
– No neuroprotective effect confirmed in Parkinson’s disease patients
Stocchi F, Olanow CW. Ann Neurol 2003;53(Suppl 3):S87-97. Suchowersky O, et al. Neurology 2006;66:976-82.
106
Neuroprotection Trials – Bioenergetic Agents
• Rationale– Reduction in the activity of mitochondrial respiratory complex I in the SNpc* in
Parkinson’s disease
– Selective complex I inhibitors such as MPTP† and rotenone induce parkinsonism
– Inhibition of complex I results in increased free radical generation
– Free radicals, in turn, can damage the respiratory chain, reducing complex I and IV activities in particular
– Creatine and coenzyme Q10 protect dopamine neurons in MPTP-treated rodents
• Candidate drugs: bioenergetic agents– Mitochondrial enhancers
– Counteract oxidative stress
* substantia nigra pars compacta; † 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Stocchi F, Olanow CW. Ann Neurol 2003;53(Suppl 3):S87-97. Schapira AH. Mitochondrial disease. Lancet 2006;368:70-82.
107
Neuroprotective Trials – Coenzyme Q10
• Coenzyme Q10 both enhances respiratory chain function and scavenges free radicals
• Pilot phase II study in early patients with de novo Parkinson’s disease
– 1200 mg/day, but not lower doses, produce significant improvement in UPDRS* scores compared with placebo at 16 months
– Limitations
• Short-term improvement in ADL† scores consistent with a symptomatic effect
• Therefore, neuroprotective beneficial effect of coenzyme Q10 needs confirmation
Shults CW, et al. Arch Neurol 2002;59:1541-50.
* Unified Parkinson's Disease Rating Scale; † activities of daily living (part II of UPDRS)
108
Disease Modification (Neuroprotection)Disease Modification (Neuroprotection)
Dopamine Agonists
109
Rationale for Use of Dopamine Agonists as Neuroprotective Agents in Parkinson’s Disease
• Already in use for symptomatic relief– Appropriate initial symptomatic treatment in most PD patients
• Limitations of levodopa therapy in Parkinson’s disease– Possible contribution to cell damage
• The ELLDOPA study does not resolve the issue of whether or not levodopa is toxic in Parkinson’s disease
– Long-term use associated with motor complications
• Laboratory evidence suggests neuroprotective benefits
• Neuroimaging studies support putative neuroprotection with pramipexole and ropinirole
Olanow CW, et al. Mov Disord 2005;20(Suppl 11):S3-10.Schapira AHV, et al. Ann Neurol 2003;53(Suppl 3):S149-157.
110
Levodopa and Neurodegeneration
• Powerful symptomatic effect
• Concerns that levodopa may hasten neurodegeneration
– Oxidative metabolism
• Potential to generate cytotoxic free radicals
– Evidence of levodopa toxicity to cultured dopamine neurons
– No convincing evidence that levodopa is toxic in in vivo models or in patients with Parkinson’s disease
Agid Y. Lancet 2002;360:575.
111
• Early Parkinson’s disease
• Randomised, double blind, placebo-controlled
• N = 361
• Carbidopa/levodopa: 37.5/150 mg, 75/300 mg, 150/600 mg
• 40 weeks followed by a 2-week withdrawal
• Primary outcome: UPDRS* between baseline and 42 weeks
• Neuroimaging study in 142 patients
– Baseline and week 40
– Striatal DAT† density assessed by 123I--CIT‡ SPECT§
Levodopa and Neurodegeneration – The ELLDOPA Study (1)
* Unified Parkinson's Disease Rating Scale; † dopamine transporter; ‡ 2β-carbomethoxy-3β-(4-iodophenyl)tropane; § single photon emission computed tomography
Fahn S, et al. N Engl J Med 2004;351:2498-508.
112
Levodopa and Neurodegeneration – The ELLDOPA Study (2)
Fahn S, et al. N Engl J Med 2004;351:2498-508.Parkinson Study Group. JAMA 2002;287:1653-61.
* Unified Parkinson’s Disease Rating Scale† 2β-carbomethoxy-3β-(4-iodophenyl)tropane
% Change in striatal 123I-β-CIT† uptakeCALM-CIT vs. ELLDOPA CIT
-8
-6
-4
-2
0
2
4
6
8
10
12
-2 2 6 10 14 18 22 26 30 34 38 42 46
Week
Ch
ang
e in
To
tal
UP
DR
S f
rom
Bas
elin
e
Placebo 150mg 300mg 600mg
ELLDOPA – UPDRS* Changes
-30
-20
-10
0
10
0 10 20 30 40 50
(39)
(36)
(35)
(33)
(32)
(39) Elldopa 600
Elldopa 300
Elldopa 150
Elldopa Placebo
Calm-Levodopa
Calm-PramipexoleELLDOPAat 9 months
Scan Time (months)
Copyright © 2004 Massachusetts Medical Society.
113
• Patients on levodopa had significantly better UPDRS* scores compared with those who received placebo
– Less deterioration in patients on levodopa even after the two-week washout period
• Possible persistent benefit of levodopa, suggesting that levodopa is protective; or
• Insufficient washout period to exclude persistent symptomatic effect
• Significantly greater rate of decline in the imaging biomarker uptake in patients on levodopa
– Consistent with a possible levodopa toxic effect
• Conclusion
– Conflicting results: do not permit a clear determination of whether or not levodopa is toxic
Levodopa and Neurodegeneration – The ELLDOPA Study (3)
* Unified Parkinson's Disease Rating Scale
Fahn S, et al. N Engl J Med 2004;351:2498-508.
114
Dopamine Agonists – Possible Mechanisms for Neuroprotection in Parkinson’s Disease (1)
• Levodopa-sparing
– Delay in levodopa use
– Reduced levodopa dose requirement
Potential reduction of oxidative radicals derived from levodopa metabolism
• Antioxidant effects
– Direct free radical scavenging effect at higher concentrations than those achieved in routine treatment
• Autoreceptor effect
– Antioxidant effect through activation of presynaptic receptors
Schapira AH, Olanow CW. Ann Neurol 2003;53(Suppl 3):S149-57.
115
• Amelioration of subthalamic nucleus-mediated excitotoxicity
• Anti-apoptotic effects
– Possible direct or receptor-mediated effect on mitochondrially based pro-apoptotic intracellular signals
– Pramipexole
• Decreases apoptotic cell death in SHSY-5Y neuronal-derived dopaminergic cells exposed to toxins
• Induces increased expression of anti-apoptotic proteins BcL-xL and BcL-2
• Induces up-regulation of several genes associated with neuroprotective effects
Dopamine Agonists – Possible Mechanisms for Neuroprotection in Parkinson’s Disease (2)
Schapira AH, Olanow CW. Ann Neurol 2003;53(Suppl 3):S149-57.
116Blum D, et al. Prog Neurobiol 2001;65:135-72.Tatton WG, et al. Ann Neurol 2003;53(Suppl 3):S61-72.
Abbreviations: BDNF, brain-derived neurotrophic factor; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPP+, 1-methyl-4-phenylpyridinium; TNF-, tumour necrosis factor-; NMDA, N-methyl-D-aspartate.
Cellular Dysfunctions in Parkinson’s Disease and Targets for Dopamine Agonists in Neuroprotection
Caspaseactivation
Apoptosis(nuclear changes
& cell death)
Free radicals
Cytochrome c
Mitochondrial damageMPTP/MPP+
TNF- receptorExcitotoxicity
Glutamate receptor(NMDA)
Ca2+
BcL-2, BcL-xLinhibit release of
cytochrome c
Trophic factors (e.g. BDNF) inhibit apoptosis
Proteinaggregation
117
Dopamine Agonists – Inhibition of Multiple Pathways of Cellular Dysfunction
Caspaseactivation
Apoptosis(nuclear changes
& cell death)
Free radicals
Cytochrome c
Mitochondrial damageMPTP/MPP+
TNF- receptorExcitotoxicity
Glutamate receptor(NMDA)
Ca2+
Pramipexole increases Bcl-2, Bcl-xl
Pramipexole may induce up-regulation of a trophic factor
Proteinaggregation
= Inhibition
Gu M, et al. J Neurochem 2004;91:1075-81.Blum D, et al. Prog Neurobiol 2001;65:135-72.Tatton WG, et al. Ann Neurol 2003; 53(Suppl 3):S61-
72.
Abbreviations: NMDA, N-methyl-D-aspartate; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPP+, 1-methyl-4-phenylpyridinium; TNF-, tumour necrosis factor-
118
Mitochondrial-Mediated Apoptotic Cell Death in SHSY-5Y Cells
MPP+ Rotenone
Free radicals
Cytochrome c release*
Caspase activation*
Apoptotic cell death*
Pore opening*
ATPproduction
* blocked by pramipexole
Gu M, et al. J Neurochem 2004;91:1075-81. Copyright © 2004, Blackwell Publishing Ltd.
119
Pramipexole Protects Against MPTP Toxicityin Primates
Abbreviations: MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; TH-ir, tyrosine hydroxylase-immunoreactive
TH-ir cell counts at the level of the 3rd cranial nerve
Group A, animal controlsGroup B, MPTP onlyGroup C, pramipexole prior to MPTPGroup D, pramipexole coincident with MPTP Group E, pramipexole after MPTP* P < 0.05; NS, non significant
TH-ir neuronal counts in the rostrocaudal plane
0
50
100
150
200
250
300
Group A Group B Group C Group D Group E
Treatment Group
NS
NS*
Mea
n T
H+
ve C
ell C
ou
nts
at
3rd N
erve
0
50
100
150
200
250
300
Mea
n C
ou
nts
of
TH
+ve
Neu
ron
s
0 500 1000 1500 2000 2500 3000
Rostrocaudal Distance (m)
Iravani MM, et al. J Neurochem 2006;96:1315-21. Copyright © 2006, Blackwell Publishing Ltd.
120
Neuroprotection Trials – Evaluation of Dopamine Agonist Efficacy
• Limitations of clinical measures
– Confounded by symptomatic benefits
• Biological markers
– Accurate assessment of dopaminergic nigrostriatal system
– Possible confound of drug effects on imaging
Suchowersky O, et al. Neurology 2006;66:976-82.Ahlskog JE. Neurology 2003;60:381-9.
121
Dopamine Nuclear Imaging
• Radioligands that label nigrostriatal neurons– 123I--CIT*
• Labels the dopamine transporter (DAT) protein, selectively expressed on dopaminergic neurons
• Uses SPECT† technology
– 18F-dopa‡
• Is transported into dopaminergic neurons and concentrated within synaptic vesicles as 18F-dopamine
• Uses PET§ technology
• Objective estimation of the extent of neuronal loss in patients with Parkinson’s disease
* 2β-carbomethoxy-3β-(4-iodophenyl)tropane † single photon emission computed tomography ‡ 18F-6-fluorodopa§ positron emission technology
Lee CS, et al. Ann Neurol 2000;47:493-503.Ahlskog JE. Neurology 2003;60:381-9.
122
Dopamine Nuclear Imaging: Where Do Ligands Bind?
Marek K, et al. Science 2000 21;289:409-11.
* 123I-iodobenzamide
PostsynapticPresynaptic
D2 receptors(IBZM*, raclopride)
DOPA Dopamine Dopaminereceptors
Dopamine transporters(β-CIT, others)
Neuronal dopamine metabolism (F-dopa)
© 2000 American Association for the Advancement of Science.
123
* positron emission tomography † 2β-carbomethoxy-3β-(4-iodophenyl)tropane ‡ single photon emission computed tomography
Neuroimaging in Parkinson’s Disease
Schapira AH, Olanow CW. JAMA 2004;291:358-64.
Early-Stage PDControl Late-Stage PD
Fluorodopa PET*
Control Late-Stage PDEarly-Stage PD Mid-Stage PD
123I--CIT† SPECT‡
Early-Stage PD Late-Stage PD
Late-Stage PDEarly-Stage PD Mid-Stage PD
© 2004 American Medical Association. All rights reserved.
124
Neuroprotection Trials with Dopamine Agonists – CALM-PD and REAL-PET Studies
• Patients with early Parkinson’s disease
• CALM-PD– Pramipexole versus levodopa
– 123I--CIT* SPECT† to follow the rate of loss of dopaminergic nigrostriatal cell density
• REAL-PET– Ropinirole versus levodopa
– 18F-dopa‡ PET§ to follow the rate of loss of dopaminergic nigrostriatal cell density
* 2β-carbomethoxy-3β-(4-iodophenyl)tropane† single photon emission computed tomography‡ 18F-6-fluorodopa§ positron emission tomography
Parkinson Study Group. JAMA 2002;287:1653-61.Whone AL, et al. Ann Neurol 2003;54:93-101.
125
Neuroprotection Trials with Dopamine Agonists – CALM-PD Study
• Early, symptomatic patients with Parkinson’s disease
• Multicentre, double-blind, randomised
– Initial treatment with pramipexole (n = 42) or carbidopa/levodopa (n = 40)
• Four-year follow-up
• In vivo imaging of the dopamine transporter with 123I--CIT* SPECT†
– Progression of dopaminergic degeneration
* 2β-carbomethoxy-3β-(4-iodophenyl)tropane† single photon emission computed tomography
Parkinson Study Group. JAMA 2002;287:1653-61.
126
CALM-PD – Striatal 123I--CIT* Uptake (SPECT†)
* 2β-carbomethoxy-3β-(4-iodophenyl)tropane† single photon emission computed tomography
Parkinson Study Group. JAMA 2002;287:1653-61.
(%)
Mea
n C
han
ge fr
om B
asel
ine
-30
-20
-10
0
10
Scan Interval (months)
0 10 20 30 40 50
pramipexole
levodopa
(39)
(36)
(35)
(33)
(39)
(n=82)
(32)
© 2002 American Medical Association. All rights reserved.
127
Neuroprotection Trials with Dopamine Agonists – REAL-PET Study
• Early, symptomatic patients with Parkinson’s disease
• Multicentre, double-blind, randomised
– Initial treatment with ropinirole (n = 68) or carbidopa/levodopa (n = 59)
• Two-year follow-up
• In vivo imaging of dopamine terminals with 18F-dopa* PET†
– Progression of dopaminergic degeneration
* 18F-6-fluorodopa† positron emission tomography
Whone AL, et al. Ann Neurol 2003;54:93-101.
128
*
* P < 0.0001
Whone AL, et al. Ann Neurol 2003;54:93-101.
REAL-PET – Putamen 18F-dopa‡ Uptake (PET†)
-14
-23-25
-20
-15
-10
-5
0
% change in putamen F-dopa Ki % change in putamen F-dopa Ki ((nn))
% C
hang
e fr
om B
asel
ine
in 1
8F
-dop
a U
ptak
e
Ropinirole (63) L-dopa (58)
Copyright © 2003 American Neurological Association.
‡ 18F-6-fluorodopa† positron emission tomography
129
Percentage Change in Putamen 123I--CIT* and18F-dopa† Uptake by Treatment
* 2β-carbomethoxy-3β-(4-iodophenyl)tropane† 18F-6-fluorodopa
Parkinson Study Group. JAMA 2002;287:1653-61.Whone AL, et al. Ann Neurol 2003;54:93-101.
% C
han
ge fr
om B
ase
line
-30
-20
-10
0
10
Scan Interval (months)
0 10 20 30 40 50
Pramipexole
CALM-PD CIT
Levodopa
RopiniroleREAL-PET
Levodopa
130
• Early Parkinson’s disease– Initial treatment with pramipexole or ropinirole
Significant delay in the rate of decline of a surrogate marker of nigrostriatal function
• Possible interpretations– Real reduction in the rate of cell loss in the substantia nigra
• Consistent with laboratory findings• No corresponding clinical benefits over levodopa with either drug
– Longer follow-up is needed
– Levodopa toxicity• Controversial
– Pharmacological difference in the ability of dopamine agonists or levodopa to regulate the dopamine transporter or fluorodopa metabolism
• Insufficient information to confirm
Neuroprotection Trials with Dopamine Agonists – Conclusions from Neuroimaging Studies
Olanow CW. Trends Neurosci 1993;16:439-44.Agid Y, et al. Lancet 2002;360:575.Schapira AH, Olanow CW. JAMA 2004;291:358-64.
131
• Combination of in vitro, in vivo and clinical trials: – Supports but does not prove disease-modifying effect of
pramipexole and ropinirole in Parkinson’s disease
– Compelling evidence to stimulate further research
• In practice:– The decision to introduce putative neuroprotective therapy
for Parkinson’s disease:• A matter of judgment and personal approach on the part of
the patient and the physician
– The challenge of defining reliable methods for detecting disease progression
Neuroprotection Trials with Dopamine Agonists – Conclusions
Schapira AH, Olanow CW. JAMA 2004;291:358-64.
132
Disease Modification (Neuroprotection)Disease Modification (Neuroprotection)
Perspectives
133
Perspectives in Neuroprotection
• Presymptomatic detection of Parkinson’s disease
– Value of Parkinson’s disease biomarkers
• Prove neuroprotective benefits of current and future agents
– Appropriate trial designs
• Initiate treatment before clinical symptoms occur
• Identify and remove/modify possible environmental contribution to Parkinson’s disease aetiology
Schapira AH. BMJ 1999;318:311-4.Clarke CE. Mov Disord 2004;19:491-8.Kieburtz K. Ann Neurol 2003;53(Suppl 3):S100-7.
134
• Clinical
– Olfaction (UPSIT*)
– Sleep - RBD†
– Gut
– Cardiac
– Skin
– Motor analysis
– Speech
– Cognition
– Depression
– Personality changes
• Imaging – Phenotomics
– SPECT‡/PET§-DAT**
– PET F-Dopa
– MRI-spectroscopy
– Functional MRI
– Nigral transcranial ultrasound
• Genetics
– Synuclein, LRRK2
– Parkin DJ1, PINK1
• Laboratory
– Proteomics
– Transcriptomics
– Metabolomics
Perspectives in Neuroprotection – Parkinson’s Disease Biomarkers
* University of Pennsylvania Smell Identification Test; † rapid eye movement (REM) sleep behaviour disorder;‡ single photon emission computed tomography; § positron emission tomography; ** dopamine transporter
Michell AW, et al. Brain 2004;127:1693-705.Ponsen MM, et al. Ann Neurol 2004;56:173-81.
Stiasny-Kolster K, et al. Brain 2005;128:126-37.Sommer U, et al. Mov Disord 2004;19:1196-202.
135
Physical TherapyPhysical Therapy
136
Role of Physical Therapy in Parkinson’s Disease
• Hypometria, bradykinesia, rigidity and disturbed postural control compromise patient mobility and quality of life1
– Bedtime mobility
– Transfers
– Gait
– Balance loss, falling
• Need for an individualised programme
– Exercise
– Posture awareness
– Pain control
– Patient/family education for safety, stress reduction, movement enhancement and comprehension strategies
• Only 3–29% of patients regularly consult a paramedical therapist (physical, occupational, speech)2
1. De Goede CJ, et al. Arch Phys Med Rehabil 2001;82:509-15.2. Deane KH, et al. Mov Disord 2002;17:984-91.
137
Physical Therapy in Early Parkinson’s Disease
• Enhances patient mobility by encouraging an active lifestyle
• Provides information on treatment options beyond medication
• Exercise may enhance dopaminergic pathways in PD
Technique Goal
Multidimensional exercise routine
• Address deficit in balance, mobility and risk of falls• Promote spinal flexibility to delay and reduce significant
limitations• Strengthen core muscles of stability
Fitness• Maintain activity tolerance and cardiovascular fitness
Caution: some fitness equipment may be inappropriate, e.g. treadmill
Posture training • Improve posture control and prevent falls
Worksite evaluation*• Identify areas of difficulty• Optimise work conditions, task performance and safety
Relaxation techniques • Reduce stress and exacerbation of PD-related symptoms
* Approximately 30% of patients with PD remain professionally active.Wichmann R. In: Parkinson’s Disease; 2005.Lugassy M, Garcies JM. In: Principles of Treatment in Parkinson’s Disease; 2005.
138
Physical Therapy in Moderate Parkinson’s Disease
Progression of the disease • Decreased mobility skills
• Increased gait disturbances; possible festination and/or freezing
• Significant balance problems in many patients and episodes of falling
• Possible motor fluctuationsTechnique Goal
Compensatory mobility strategies • Maximise functional independence
Attention strategies and sensory cueing
• Improve magnitude in motor tasks by substitution of deficient motor cues provided by basal ganglia with external cues
Gait training • Overcome motor fluctuations and freezing
Gait-assistive devices • Maximise safety when ambulating
Early physical therapy in the event of fracture or other illness
• Initiate timely mobilisation to reduce the risk of complications
Adjustment of daily exercise • Perform adapted and safe routine exercises
Wichmann R. In: Parkinson’s Disease; 2005.Lugassy M, Garcies JM. In: Principles of Treatment in Parkinson’s Disease; 2005.
139
Physical Therapy in Advanced Parkinson’s Disease
• Optimise functional independence by compensation strategies for worsening motor impairment
• Emphasis on discipline in order to avoid risky activities such as walking and swallowing
• Detect depression
Technique Goal
Continued instruction• Teach the fundamental difference between
automatic and consciously controlled movements• Emphasise the need to switch to conscious
movements for almost all daily motor activities
Behavioural strategies • Substitute deficient motor cues provided by basal
ganglia with external cues
Wheelchair and body mechanics • Engage in safe ambulation and transfers
Instruction in proper positioning• Prevent risk of aspiration while eating• Avoid habits that worsen flexed posture
(excessive pillows)
Appropriate daily exercise programme • Maximise flexibility and improve patient comfort
Pain control (heat, cold, massage, etc.) • Control excessive rigidity and agitation
Wichmann R. In: Parkinson’s Disease; 2005.Lugassy M, Garcies JM. In: Principles of Treatment in Parkinson’s Disease; 2005.
140
Future TreatmentsFuture Treatments
141
Rationale for New Therapeutic Approaches
• Success of dopaminergic treatment in controlling motor symptoms
– Research focus on dopamine systems
• Limitation
– Pathophysiology
• Involvement of non-dopaminergic systems
– Clinical
• Loss of drug efficacy with disease progression
• Lack of control over most non-motor symptoms
Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinson’s Disease; 2005.Jenner P. In: Principles of Treatment in Parkinson’s Disease; 2005.
142
Novel Therapeutic Approaches for Parkinson’s Disease
Target/Approach Goal
Dopaminergic system
Dopamine agonists • Refined interaction with dopamine agonist receptors
Dopamine reuptake blockers• Highly potent specific blockers with antiparkinsonian effect and
reduced induction of involuntary movements
Continuous dopaminergic stimulation
• Long-acting agonists for a more physiological replacement therapy
Non-dopaminergic systems
Other monoamine transmitters• Interaction with noradrenergic and serotoninergic receptors for the
control of motor symptoms and reduced motor complications
Cholinergic and GABAergic systems• Avoidance of dyskinesias• Potential for the control of cognitive deficits
Glutamatergic systems• Selective agonists to suppress dyskinesia and improve the
response to dopaminergic treatment
Opioid receptors • Control of levodopa-induced dyskinesias
Cannabinoid receptors • Control of motor symptoms
Adenosine receptors • Antagonists for symptomatic antiparkinsonian effect
Schapira, et al. Nature Rev Drug Discov 2006;5:845-54.
143
Section III – Depression in Parkinson’s Disease
Section III – Depression in Parkinson’s Disease
144
• Overview
• Epidemiology and Pathophysiology
• Burden
• Diagnosis and Evaluation
• Treatment
Depression in Parkinson’s Disease – Summary
145
OverviewOverview
146
Neuropsychiatric Non-Motor Symptoms of Parkinson’s Disease
• Anxiety
• Anhedonia
• Apathy
• Depression
– The strongest predictor of quality of life in Parkinson’s disease
• Dementia
Global Parkinson’s Disease Survey Steering Committee. Mov Disord 2002;17:60-7.Schrag A, et al. J Neurol Neurosurg Psychiatry 2000;69:308-12.
147
Patterns of Depression in Parkinson’s Disease
• Off-period related
– Typically associated with motor symptoms (akinesia, rigidity, dystonia)
– Often associated with other non-motor symptoms, e.g. pain, anxiety, panic (delusions, hallucinations)
– Related to medication timing
– Treatment:
• Adjustment of antiparkinsonian medication
• Additional treatment interventions when needed
• Not off-period related– In the majority of patients with
depression and Parkinson’s disease
– No clear relationship with motor symptoms or medication timing
– May precede motor symptoms
– No clear relationship with PD severity and stage
– Need for treatment approaches specific to the depressive symptoms
Sawabini KA, et al. In: Principles of Treatment in Parkinson’s Disease; 2005. Lieberman A. Acta Neurol Scand 2006;113:1-8.
148
Epidemiology and Pathophysiology
Epidemiology and Pathophysiology
149
Depression in Parkinson’s Disease – Epidemiology
• Frequency of depression in Parkinson’s disease: probably 40–50%– Compared to a 16% prevalence of depression in the general population (USA)
– Depression is the most common psychiatric complication in PD patients
– Exact epidemiological data are lacking
– Frequency varies between 4 and 70% depending on: • Criteria used
• Population studied
– Frequency higher in studies from research centres than from community-based studies
– Severity of depression in PD patients• 50% moderate to severe
• 50% mild
– Bimodal distribution: increased rates at the onset and a later peak in advanced disease
• Severity of depression correlates with reduced quality of life
Cummings JL. Am J Psychiatry 1992;149:443-54. Lieberman A. Acta Neurol Scand 2006;113:1-8. Schrag A, et al. J Neurol Neurosurg Psychiatry 2000;69:308-12.
150
Depression in Parkinson’s Disease Is Under-Recognised
• Association between Parkinson’s disease and depression is well known1,2
– Depression in PD is insufficiently treated
– Pathophysiology not well understood
• Prospective study on PD patients (n = 101)3
– Standardised testing: depression in 44% of patients
– Treating neurologist
• Depression identified in 21% of patients
• Diagnostic accuracy of 35%
– During routine office visits, neurologists fail to identify depression more than half of the time
– Need for improving diagnostic accuracy and timely therapeutic interventions
1. Livingston G, et al. J Affect Disord 1997;46:255-62.
2. Schrag A, et al. J Neurol Neurosurg Psychiatry 2000;69:308-12.
3. Shulman LM, et al. Parkinsonism Relat Disord 2002;8:193-7.
151
Causes of Depression in Parkinson’s Disease
• Reactive (chronic disease)
• Coincidental (high prevalence in age group)
• Parkinson’s disease-related causes
– Disturbance of monoaminergic pathways
– Dopaminergic, serotonergic and noradrenergic systems
Lieberman A. Acta Neurol Scand 2006;113:1-8.
152
Depression in Parkinson’s Disease –Dopaminergic Neurotransmitter Systems
• Dopaminergic mesolimbic and mesocortical pathways
– Project from ventral mesencephalon to limbic and cortical structures that regulate cognition, emotions and reward-seeking behaviour
• Implicated in apathy, anhedonia and depression in Parkinson’s disease
• D3 dopamine receptors are preferentially localised in the limbic system
Lieberman A. Acta Neurol Scand 2006;113:1-8.
153
Depression in Parkinson’s Disease – Neurotransmitters Other Than Dopamine
• Extensive cell loss in the nucleus coeruleus, the major source of brain noradrenaline1
• Alterations of the raphe nucleus, the major source of brain serotonin2
– Other studies do not support the role of the serotonergic system in depressed patients with Parkinson’s disease3
– Serotonergic hypothesis for depression in PD remains controversial
1. Taylor AE, Saint-Cyr JA, J Neuropsychiatry Clin Neurosci 1990;2:92-8.
2. Yamamoto M. J Neurol 2001;248(S3):III5-11.
3. Leentjens AF, et al. Neuropsychopharmacology 2006;31:1009-15.
154
Depression in Parkinson’s Disease –Amygdala Dopaminergic System
• Absence of robust amygdala response to emotions in patient with Parkinson’s disease
• Dopamine repletion partially restores this response
Difference in BOLD* fMRI† response of the amygdala in normal subjects and PD patients in drug-off (12h after the last dose of dopaminergic treatment) and in drug-on (1–2h after the first daily dose) states; z = Talairach coordinate
* blood oxygen-level dependent; † functional magnetic resonance imaging
Normal controls PD Drug-off PD Drug-on
z = -14 z = -12 z = -12 T value
Tessitore A, et al. J Neurosci 2002;22:9099-103. Copyright © 2002 Society for Neuroscience.
155
Depression in Parkinson’s Disease – Loss of Dopamine and Noradrenaline Innervation in the Limbic System
• Depressed Parkinson’s disease patients had lower [11C]RTI-32* binding than non-depressed Parkinson’s disease cases in:
– Locus coeruleus
– Several regions of the limbic system, including:
• Anterior cingulate cortex
• Thalamus
• Amygdala
• Ventral striatum.
* 11C-methyl (1R-2-exo-3-exo)-8- methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octane-2-carboxylate (RTI-32)
Remy P, et al. Brain 2005;128:1314-22.
Locus coeruleus
Medial thalamus Medial ventral thalamus
Right amygdala
Copyright © 2005 by the Guarantors of Brain.
156
BurdenBurden
157Global Parkinson’s Disease Survey Steering Committee. Mov Disord 2002;17:60-7.
Factors Predicting Poor Quality of Life in Parkinson’s Disease
Depression
Disease stage and medication
Satisfaction with explanation given at diagnosis
Current level of optimism
Not explained
158
Determinants of Quality of Life in Parkinson’s Disease
Reference Study population Factors associated with poor QoL
Kuopio et al. (2000a) Population-based Depression, disease severity (freezing, nocturnal akinesia, early morning akinesia, dystonia)
Larsen et al. (2000) Population-based Depression, insomnia, disability, disease severity
Schrag et al. (2000a) Population-based Depression, disability, postural instability, cognitive impairment (akinetic-rigid)
Damiano et al. (2000) Clinic-based Dyskinesias, comorbidity
Hobson et al. (1999) Clinic-based Disease severity, depression, cognitive impairment
Rubenstein et al. (1998) Clinic-based Disease severity, off-periods, dyskinesias, dystonia, sleep disturbances
Lyons et al. (1998) Parkinson’s disease registry
Postural instability, gait abnormalities, bradykinesia, disease duration
GPDSC* (2002) Clinic-based Depression, disease severity and medication, satisfaction with explanation at diagnosis, current optimism
Zach et al. (2004) Clinic-based Depression, disease duration
Chapuis et al. (2005) Clinic-based Levodopa doses, disease severity, dyskinesias
* Global Parkinson’s Disease Steering Committee studyCopyright © 2002 Movement Disorder Society.
159
Complex Relationship between Depression and Parkinson’s Disease Symptoms
0
10
20
30
40
50
60
70
80
I II III IV V
Celesia GG, Wanamaker WM. Dis Nerv Syst 1972;33:577-83.
Starkstein SE, et al. J Nerv Ment Dis 1990;178:27-31
Hoehn & Yahr
Dep
ress
ion
%
160
Correlates of Depression in Parkinson’s Disease
• No/poor relationship between :
– Age
– Age of onset
– Gender
– Disease duration
– Disease severity
• Close relationship between:
– Quality of life
Schrag A, et al. J Neurol Neurosurg Psychiatry 2000;69:308-12. Lieberman A. Acta Neurol Scand 2006;113:1-8.
161
Treatment of Depression in Parkinson’s Disease
• Approximately 25% of patients with Parkinson’s disease diagnosed with depression receive treatment1,2
• Efficacy of antidepressants3
– Large placebo effect, which may result in similar effect of antidepressants and placebo
– Older patients appear to respond better
– Minor depression and dysthymia less likely to respond
1. Richard IH, Kurlan R. Neurology 1997;49:1168-70.2. Weintraub D, et al. J Geriatr Psychiatry Neurol 2003;16:178-83.3. Weintraub D, et al. Mov Disord 2005;20:1161-9.
162
Depression May Precede Motor Symptoms in Parkinson’s Disease
• Diagnosis of depression is more common in patients with PD before the onset of the disease
• Patients with depression have a two- to threefold risk of developing PD
• Depression is not only a reaction to having PD
• Depression is either an early symptom in PD or a risk factor for developing PD
Ishihara L, Brayne C. Acta Neurol Scand 2006;113:211-20. Lieberman A. Acta Neurol Scand 2006;113:1-8.
163
Impact and Treatment of Depression in Patients with Parkinson’s Disease
• Depression is the strongest predictor of poor quality of life in PD
• Depression may be more disabling than motor symptoms
• Treatment of depression is often insufficient in PD
– Should become an important target in the management of the disease
Schrag A, et al. Neurol Neurosurg Psychiatry 2000;69:308-12.
164
Diagnosis and EvaluationDiagnosis and Evaluation
165
Diagnosis of Depression – DSM-IV Criteria
1. Depressed mood
2. Decreased interest (apathy) or pleasure in activities (anhedonia)
3. Significant weight loss
4. Insomnia or excessive sleep
5. Psychomotor retardation or agitation
6. Loss of energy (anergia)
7. Feelings of inappropriate guilt
8. Recurrent thoughts of death
Major depression is diagnosed if five or more of the following symptoms are present:
Statistical Manual of Mental Disorders, 4th ed. 1994.
166
Difficulties in Diagnosing Depressionin Parkinson’s Disease
• Overlap of Parkinson’s disease with DSM-IV criteria:– Psychomotor retardation (including hypomimia, hypophonia, slowed
movement, fatigability and stooped posture)
– Apathy
– Insomnia
– Anergia
– Weight loss
– Loss of libido
• DSM-IV criteria exclude concomitant disease
• Minor depression is more frequent than major depression
• Relative absence of traditional symptoms of depression: – Feelings of guilt
– Shame
– Sorrow
Lieberman A. Acta Neurol Scand 2006;113:1-8.
167
Diagnosis of Depression in Parkinson’s Disease
• Feelings of emptiness and hopelessness
• Reduced reactivity to emotional stimuli
• Loss of the ability to enjoy and feel pleasure (anhedonia)
Diagnosis of depression in PD is based on subjectively experienced depressive symptoms:
Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7.
168
Depression Scales in Parkinson’s Disease
• Observer-rated
– Hamilton Depression Rating Scale1
– Montgomery-Asberg Depression Rating Scale1
• Patient-rated
– Beck Depression Inventory2,3
1. Leentjens AF, et al. Int J Geriatr Psychiatry 2000;15:644-9 2. Leentjens AF, et al. Mov Disord 2000;15:1221-4. 3. Levin BE, et al. J Neurol Neurosurg Psychiatry 1988;51:1401-4.
169
TreatmentTreatment
170
Depression in Parkinson’s Disease –Treatment Options
• Off-period related depression– Adjustment of dopaminergic treatment
• Primary depression– Pharmacological treatment
• Dopamine agonists (e.g. pramipexole)
• Tricyclic or tetracylic antidepressants
• Selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and noradrenaline reuptake inhibitors (SSNRIs)
• Selective noradrenaline reuptake inhibitors (SNRIs)
• Other antidepressants– Selective MAO-A* inhibitors
– Bupropion
– Non-pharmacological treatment• Cognitive behavioural therapy, counselling, coping strategies, sleep deprivation
• In therapy-resistant forms– Transcranial magnetic stimulation (TMS)
– Electroconvulsive therapy (ECT)
Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7.Miyasaki JM, et al. Neurology 2006;66:996-1002.
* Monoamine oxidase type-A
171
Treatment of Off-Period Related Depression in Parkinson’s Disease
• Anxiety and depression are increased during off-periods and can even precede akinetic states1
• Off-period related depression occurs particularly in patients with suboptimal medication:2
– Switch to immediate-release levodopa
– Shorten dosing intervals of levodopa or add a dopamine agonist
– If wearing off:
• Add a dopamine agonist or a catechol-O-methyltransferase (COMT) inhibitor; or
• Amantadine
• In recently diagnosed patients with Parkinson’s disease who are depressed:
– Start treatment with dopamine agonists (e.g. pramipexole)1, 3
• Delay the onset of dyskinesia and motor fluctuations
• Antidepressant effects of dopamine agonists (pramipexole)1
1. Lemke MR, et al. J Neurol 2004;25(Suppl 6):VI/24-7.2. Sawabini KA, et al. In: Principles of Treatment in Parkinson’s Disease; 2005. 3. Lieberman A. Acta Neurol Scand 2006;113:1-8.
172
Treatment of Depression in Parkinson’s Disease – Dopamine Agonists
• First-generation ergot-derived agonists (bromocriptine, pergolide)
– Non-blinded studies in depressed patients without Parkinson’s disease suggested an antidepressant effect
– Subsequent double-blind studies did not give confirmation, or resulted in minimal or modest improvement
• Second-generation non-ergot agonists (pramipexole, ropinirole)
– Pramipexole has been shown to have some antidepressant effects
– Stimulation of D3 receptors and preference for D3 versus D2 receptors seem to have antidepressant effect
– Anxiolytic effects of dopamine agonists in laboratory-based studies
– Antidepressant effects of dopamine agonists
• Not yet thoroughly studied
• Most available data relate to pramipexole
Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7.Lieberman A. Acta Neurol Scand 2006;113:1-8.
173
Reference Agent Design Effects
Willner et al. 1994 Pramipexole Experimental Anti-anhedonic
Maj et al. 1997 Pramipexole Experimental Antidepressive
Corrigan et al. 2000 Pramipexole Double-blind, placebo-controlled, n = 174
Antidepressive better than placebo, comparable with fluoxetine in depression
Perugi et al. 2001 Pramipexole, Ropinirole
Open, prospective, n = 18 Antidepressive in refractory bipolar II depression, combination
Rektorova et al. 2003 PramipexolePergolide
Open, randomised, controlled, n = 41
Antidepressive in Parkinson‘s Disease
Reichmann et al. 2003 Pramipexole Open, prospective, n = 657 Improvement of motor signs and depression in Parkinson’s disease
Goldberg et al. 2004 Pramipexole Double-blind, randomised, placebo-controlled, n = 22
Antidepressive, refractory bipolar depression, add-on to mood stabilisers
Zarate et al. 2004 Pramipexole Double-blind, randomised, placebo-controlled, n = 21
Antidepressive, refractory bipolar depression, add-on to mood stabilisers
Lemke et al. 2005 Pramipexole Open, prospective, n = 657 Antidepressive and anti-anhedonic in Parkinson‘s disease
Barone et al. 2006 Pramipexole vs. Sertraline
Parallel-group, randomised, n = 67
Remission: pramipexole 60.6% vs. sertraline 27.3%
Studies on Dopamine Agonists in the Treatment of Depression
174
0
10
20
30
40
50
60
70
80
Pramipexole 1.19 mg/d
Placebo
P < 0.05
% Responders(≥ 50% reduction in HAM-D† scores after 6 weeks) Double-blind,
placebo-controlled, randomised study(n = 22)
* carbamazepine, lithium, divalproex, lamotrigine, gabapentin
† 17-item Hamilton Depression Rating Scale
Pramipexole as Add-on Therapy to Existing Mood Pramipexole as Add-on Therapy to Existing Mood Stabilisers* in Treatment-Resistant Bipolar DepressionStabilisers* in Treatment-Resistant Bipolar Depression (1)(1)
Goldberg JF, et al. Am J Psychiatry 2004;161:564-6.
175Goldberg JF, et al. Am J Psychiatry 2004;161:564-6.
Pramipexole as Add-on Therapy to Existing Mood Pramipexole as Add-on Therapy to Existing Mood Stabilisers* in Treatment-Resistant Bipolar Depression Stabilisers* in Treatment-Resistant Bipolar Depression (2)(2)
* carbamazepine, lithium, divalproex, lamotrigine, gabapentin
† Clinical Global Impression (CGI) –Severity of Illness score
Pramipexole 1.19 mg/d
Placebo
CGI-SI†
score
0
1
2
3
4
5
Baseline 6 weeks
P = 0.02Double-blind, placebo-controlled, randomised study(n = 22)
176
Pramipexole versus Pergolide in the Treatment of Pramipexole versus Pergolide in the Treatment of Depression in Patients with Parkinson’s DiseaseDepression in Patients with Parkinson’s Disease
Rektorova I, et al. Eur J Neurol 2003;10:399-406.
Open, multicentre, randomised study (n = 41)
0
3
6
9
12
15
18
21
24
Baseline After 8 months
Pramipexole (1.9 mg /day)
Pergolide (3.0 mg /day)MADRS*
NS
P < 0.05
* Montgomery-Asberg Depression Rating Scale
Copyright © 2003, Blackwell Publishing Ltd.
177Lemke MR, et al. J Neuropsych Clin Neurosci 2005;17:214-20.
* loss of pleasure† T1 = baseline‡ T2 = at the end of a maintenance period of 9 weeks on average
§ SHAPS-D: Snaith-Hamilton Pleasure Scale (German version)
Course of Anhedonia* during Treatment with Course of Anhedonia* during Treatment with Pramipexole in Parkinson’s DiseasePramipexole in Parkinson’s Disease
Anhedonia (Frequency):T1† : n = 286 (45.7%) T2‡ : n = 160 (25.5%)
(2 = 94.45, df = 1, P < 0.001)
Anhedonia:SHAPS-D§ (0–14)
3
6
T1 T2
SH
AP
S-D
(P < 0.001)
© 2005 American Psychiatric Press, Inc. Blackwell Publishing Ltd.
178
Course of Depression during Treatment with Course of Depression during Treatment with Pramipexole in Parkinson’s DiseasePramipexole in Parkinson’s Disease
Lemke MR, et al. J Neuropsych Clin Neurosci 2005;17:214-20.
* T1 = baseline† T2 = at the end of a maintenance period of 9 weeks on average‡ SPES = Short Parkinson’s Evaluation Scale
0
50
100
150
200
250
300
350
400
Mild Moderate Severe None
Depression (SPES‡)
Pat
ien
ts (
n)
T1*
T2†
**
**
**
****P < 0.01
© 2005 American Psychiatric Press, Inc. Blackwell Publishing Ltd.
179
Pramipexole Pramipexole vs.vs. Sertraline in the Treatment of Sertraline in the Treatment of Parkinson’s Disease Parkinson’s Disease (1)(1)
HAM-D* scores decreased in both groups throughout 12 weeks of treatment
* 17-item Hamilton Depression Rating Scale
15
5
10
20
0
25
30
Mea
n H
AM
-D s
core
Baseline Endpoint
*** P < 0.001 versus baseline
Pramipexole
Sertraline
***
***
Barone P, et al. J Neurol 2006;253:601-7. Copyright © 2006 Springer.
180
Pramipexole group:
• More remission/recovery†
• Improvement on the Unified Parkinson’s Disease Rating Scale (UPDRS) motor subscore
• None (0%) vs. 7 (14.7%) in the sertraline group withdrew for adverse events
† as defined by HAM-D score 8
Conclusions:
• Pramipexole (1.5–4.5 mg/day) has comparable efficacy with sertraline (SSRI) (50 mg/day) on depressive symptoms
• Dopamine agonists may be an alternative to antidepressants in Parkinson’s disease
Pro
po
rtio
n o
f P
atie
nts
wh
o R
eco
vere
d (
%)
60.6
27.330
10
20
40
0
50
60
Pramipexole Sertraline
P = 0.006
100
90
80
70
Barone P, et al. J Neurol 2006;253:601-7.
Pramipexole Pramipexole vs.vs. Sertraline in the Treatment of Sertraline in the Treatment of Parkinson’s Disease Parkinson’s Disease (2)(2)
181
Antidepressive Effects of Dopamine Agonists
Reduction of off-periods
Dopamine agonist
Antidepressive effect
Mesolimbic D3 receptors
+ potential neuroprotective effects?
?
Lieberman A. Acta Neurol Scand 2006;113:1-8. Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7.
182
Treatment of Depression in Parkinson’s Disease – Tricyclic Antidepressants
• Five randomised, controlled, double-blind studies in Parkinson’s disease1,2
– Probably effective: amitriptyline, nortriptyline, imipramine and desipramine
– Anticholinergic effects may also improve motor symptoms
• Worsen cognitive functions
• May be even more effective than SSRIs*3
– Higher rates of side effects and withdrawals
1. Lemke MR, et al. J Neurol. 2004;251(Suppl 6):VI/24-7.2. Miyasaki JM, et al. Neurology 2006;66:996-1002.3. Serrano-Duenas M. Rev Neurol 2002;35:1010-4.
* selective serotonin reuptake inhibitors
183
• Anticholinergic effects
– Alternation of cognitive functions
• Sedation
• Confusion, delirium
– Orthostatic hypotension
Poorly tolerated in cognitively impaired elderly patients
– Cardiotoxicity
• Possible serotonin syndrome if associated with the MAO-B* inhibitors
Tricyclic Antidepressants in Parkinson’s Disease – Side Effects
Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7.Lieberman A. Acta Neurol Scand 2006;113:1-8.
* monoamine oxidase type-B
184
Selective Serotonin and Noradrenaline Reuptake Inhibitors (SSRIs and SNRIs) in the Treatment of Depression in Parkinson’s Disease
• Similar efficacy with tricyclic antidepressants but different safety profile
– Better tolerability in elderly patients
• Possibility of worsening of motor symptoms with SSRIs (fluoxetine, paroxetine and fluvoxamine)
– Considered a rare phenomenon
Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7.
185
• Sedation
• Insomnia
• Dry mouth
• Nausea
• Sexual dysfunction
• Weight gain or weight loss
• Increased risk of serotonin syndrome if concomitant treatment with MAO-B* inhibitors
Selective Serotonin and Noradrenaline Reuptake Inhibitors (SSRIs and SNRIs) – Side Effects
Lieberman A. Acta Neurol Scand 2006;113:1-8.
* monoamine oxidase type-B
186
Non-Pharmacological Treatment of Depression in Parkinson’s Disease
• Psychotherapy– No controlled trials
– Subjective experience of deficits determine quality of life (QoL) and subjective well-being
• Psychotherapy may be integrated into treatment programmes– Interpersonal psychotherapy
– Cognitive therapy
– Training of social functions
– Relaxation therapies
• Sleep deprivation• Transcranial magnetic stimulation (TMS)
– Treatment-resistant depressed patients with Parkinson’s disease Insufficient evidence
• Electroconvulsive therapy (ECT)– Treatment-resistant depressed PD patients
Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7. Miyasaki JM, et al. Neurology 2006;66:996-1002.
187
Treatment of Anxiety Associated with Depression in Parkinson’s Disease
• SSRIs* and SNRIs†
– If moderate depression and moderate anxiety
– Not all have been approved for anxiety
• Benzodiazepines– May be required because of the frequent association of anxiety with
depression in Parkinson’s disease
– Cause multiple side effects• Impair cognition
• Impair motor functions
• Cause falls
May be particularly detrimental in elderly PD patients
– Potential addiction
– Consider short-term use
Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7.Lieberman A. Acta Neurol Scand 2006;113:1-8.
* selective serotonin reuptake inhibitors† selective noradrenaline reuptake inhibitors
188
Psychotropic Agents to Avoid in Parkinson’s Disease
• Lithium
• Sodium Valproatecan increase parkinsonism and tremor
can increase extrapyramidal symptoms
can increase parkinsonism
• Amoxapine
• Neuroleptic medication
Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7. Miyasaki JM, et al. Neurology 2006;66:996-1002.
189
Abbreviations: SSRI, selective serotonin reuptake inhibitors; SNRI, selective noradrenaline reuptake inhibitor; TCA, tricyclic antidepressants; TMS, transcranial magnetic stimulation; ECT, electroconvulsive therapy; MAO-B, monoamine oxidase BLemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7.Sawabini KA, et al. In: Principles of Treatment in Parkinson’s Disease; 2005. Lieberman A. Acta Neurol Scand 2006;113:1-8.Schapira A. In: Neurology and Clinical Neuroscience; 2006.
Depression in Parkinson’s disease
Primary "Off-period" dysphoria
Optimise existing antiparkinsoniantherapy
Improvement?
Patient underlevodopa
Educational programme/Psychotherapy
Start treatment withsecond-generation dopamine agonists
De novo Parkinson’s disease
Educational programme/Psychotherapy
Start treatment withsecond-generation dopamine agonists
Improvement?
YesNo
Start SSRI, SNRI,or moclobemide
Change to TCAif no improvement
Combine TCAswith SSRIs or SNRI
TMS or ECTif resistant to medication
Yes
Continue and review
COMT inhibitor
No
Apomorphine support
Dopamine agonist
MAO-B inhibitor
Duodenal levodopa
Surgery
Optimise PD symptoms with additional/alternative drugs
if not already used
Levodopa
Continue and review
190
Depression in Parkinson’s Disease – Conclusion (1)
• Depression is frequent in patients with PD and a major independent factor of poor quality of life
• Depression is difficult to recognise and measure in PD patients and its treatment is often insufficient
• Depression may precede the diagnosis of PD
• Dopaminergic, noradrenergic and, probably, serotonergic mechanisms are involved
191
• Adjustment of antiparkinsonian treatment and patient education may be sufficient in patients with off-period related depression
• Main pharmacological treatment options in not off-period related depression:
– Second-generation dopamine agonists • Most available data support potential antidepressant properties of pramipexole
• Possible first-line therapy in many depressed patients with Parkinson’s disease Offer a combined treatment approach to depression and motor symptoms and avoid
polypharmacy
– Tricyclics and newer selective antidepressants• Probably effective; however, should not be considered as first-line therapy
• Consultation with a psychiatrist– Is mandatory for PD patients with severe depression or when depression is the
leading symptom
– Is mandatory for PD patients with depression resistant to pharmacological treatment
– Recommended in PD patients with minor depression
Depression in Parkinson’s Disease – Conclusion (2)
192
Supported by an educational grant from Boehringer Ingelheim International GmbH
Scientific coordination: Armine Najand, MD
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