1 Current Concepts and Perspectives in Parkinson’s Disease Anthony H.V. Schapira, DSc, MD, FRCP, FMedSci Professor of Neurology University Department of.

1

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


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


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


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


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 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


Time (h)

Early PDEarly PD

Levodopa

Cli

nic

al E

ffec

tC

lin

ical

Eff

ect

2 4 6

Response Threshold

Time (h)

4


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


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


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


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



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



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


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)


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


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


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


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


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


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


* 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


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


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)


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


132


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


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


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


* 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


* 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


* 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

Produced by:LMS Group75 rue Guy Môquet92240 MalakoffFrance

Phone: +33 1 42 53 03 03Fax: +33 1 42 53 03 02E-mail: [email protected]

www.lms-group.com

1 Current Concepts and Perspectives in Parkinson’s Disease Anthony H.V. Schapira, DSc, MD, FRCP, FMedSci Professor of Neurology University Department of.

Documents

parkinsons disease anthony

parkinsons disease samii

wilsons disease

disease progresses

scores disease burden

epidemiology slide

parkinsons diseasedrug

definition slide