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........
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 - PowerPoint PPT Presentation
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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........
• 800 patients• Early onset (<40) v Late onset (>70)
– Rate of progression, cognitive deterioration
• TD v PIGD– Rate of progression, cognitive, motor, functional
If a patient has insufficient response of non-tremor symptoms, concern is that they do not have PD
• 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
• MDS UPDRS• Off & On meds
2. Levodopa responsiveness (of PD tremor)
• Resting tremor• Postural tremor (re-
emergent tremor)• Tripartite tremor
2. Levodopa responsiveness of PD tremor
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.
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
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
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