The Therapy response in Parkinson ’ s disease
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Transcript of The Therapy response in Parkinson ’ s disease
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The Therapy response in Parkinson’s disease
• How this will be assessed in the Proband study• How this will tie in to prevailing knowledge in early PD• How this will answer the hypotheses of the Proband study
• Hypothesis 3: Dopaminergic therapy response. A range of therapy response in PD relates to phenotypic profile (e.g. The presence of tremor; postural instability gait disorder; cognitive impairment) and genotypic profiling (eg COMT enzyme activity and dopamine receptor polymorphisms).
• Heterogeneity........
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• 800 patients• Early onset (<40) v Late onset (>70)
– Rate of progression, cognitive deterioration
• TD v PIGD– Rate of progression, cognitive, motor, functional
impairment
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rd
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• TD = PIGDwrt Cognition
• Bradykinesia/ working memory impairment (DA)• Axial signs/ episodic memory/ visuospatial
impairment (ACh)
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Mild Motor comps Non DA probs All domainsYoung Youngest Older Older
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• LOPD linked to earlier Postural instability
Younger age at onset associated with Dystonia, Dyskinesia (independent of parkin status).
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Therapy response in Parkinson’s disease
• Pragmatic approach
• 1. The development of dyskinesia = the rate of dopaminergic degeneration
• 2. Levodopa responsiveness (specifically including response of tremor)
• 3. PIGD development = the rate of non-dopaminergic degeneration
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1. Development of dyskinesia(Prevailing knowledge)
• Age at onset– Parkin etc
• Duration of disease
• Dose & pattern of DA replacement– & NMDA, ACh, 5HT, NA
• Comorbidity
• (DBS)
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Pathophysiology of Dyskinesia development(Prevailing knowledge)
• Dopamine as a false transmitter
– Severity of DA deficit
– 5-HT
• Dopamine receptor super-sensitivity
– DA receptor internalisation
– arrestins
• Synaptic Plasticity
- DARPP-32 pathway
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L-Dopa
DA
CEREBRAL CORTEX
Striatal Medium SpinyNeuron
BG output
D1rAC
cAMP
PKA
DARPP-32
PP
GRK
D1rP
Arrestin
D1r
P Arrestin
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Proband- dyskinesia evaluationPatients diagnosed for less than 3 years
• MDS UPDRS
• Performed every 18 months
• Will likely identify date of dyskinesia onset prospectively
• Time interval data
• Adjusted for known confounders
– Will also have daytime duration and functional severity of LID
• Adjusted for known confounders
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Proband- dyskinesia evaluationPatients diagnosed for less than 3 years
• What we are not doing.
• High dose L-dopa challenge combined with Dyskinesia rating scale
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Proband- dyskinesia evaluationPD onset < 50 years
• MDS UPDRS at baseline
• Likely retrospective date of dyskinesia
• Duration and severity of dyskinesia
• Adjustment for known confounders
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Possible Genetic influences on Dyskinesia development to be investigated
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• UK Brain bank criteria are inclusion criteria for Proband- lack of L-dopa response excludes patients from recruitment
• Confounders– Comorbidity e.g.
Vascular disease– Anticholinergic use– Propranolol, Botox
2. Levodopa responsiveness
If a patient has insufficient response of non-tremor symptoms, concern is that they do not have PD
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• Only patients on L-dopa
• 6-12 months after L-dopa initiation
• Patient’s regular dose to be used- pragmatic
• Standardised v tailored timing of evaluation
• All aspects of MDS UPDRS part 3 will be judged
• Adjustment for confounders
Proband- Levodopa responsiveness Patients diagnosed for less than 3 years. L-dopa challenge
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• MDS UPDRS• Off & On meds
2. Levodopa responsiveness (of PD tremor)
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• Resting tremor• Postural tremor (re-
emergent tremor)• Tripartite tremor
2. Levodopa responsiveness of PD tremor
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Genetic influences on L-dopa responsiveness to be tested
• CHONG DJ, SUCHOWERSKY O, SZUMLANSKI C, WEINSHILBOUM RM, BRANT R, CAMPBELL NR: The relationship between COMT genotype and the clinical effectiveness of tolcapone, a COMT inhibitor, in patients with Parkinson's disease. Clin Neuropharmacol. (2000) 23(3):143-148.
• LEE MS, KIM HS, CHO EK, LIM JH, RINNE JO: COMT genotype and effectiveness of entacapone in patients with fluctuating Parkinson's disease. Neurology. (2002) 58(4):564-567.
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3. Rate of progression (PIGD development)Assessment at time 2- assessment at time 1
• Progression in dopamine responsive symptoms
• Progression in dopa unresponsive symptoms
• MDS UPDRS• H&Y
• Confounders• Age• Comorbidity• LED
– Long duration symptomatic effects• Disease modifying drugs
– Long duration symptomatic effects– Preservation of healthy behaviours– Nicotine, Caffeine– Neuroprotection
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PROBAND- OPTION 1Change in motor score- MDS UPDRS part 3
• Longitudinal evaluation using MDS UPDRS
• “On medication” scores only reflect non-dopa responsive disease severity
• “Off medication” score will only be assessed once during first 3 years of Proband
• ?. Repeat L-dopa challenge in PROBAND Extension and use this as long term goal
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PROBAND OPTION 2. Time to major milestone
– Falls– Freezing
• Time to-– LID– first freeze– Balance impairment– Dementia
– adjustment for confounders e.g. age, comorbidity, medication dose
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Therapy impact on cognition.....