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The Therapy response in Parkinson ’ s disease

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

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The Therapy response in Parkinson ’ s disease

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  1. 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........

  2. 800 patients • Early onset (<40) v Late onset (>70) • Rate of progression, cognitive deterioration • TD v PIGD • Rate of progression, cognitive, motor, functional impairment

  3. rd

  4. TD = PIGD wrt Cognition • Bradykinesia/ working memory impairment (DA) • Axial signs/ episodic memory/ visuospatial impairment (ACh)

  5. Mild Motor comps Non DA probs All domains Young Youngest Older Older

  6. LOPD linked to earlier Postural instability Younger age at onset associated with Dystonia, Dyskinesia (independent of parkin status).

  7. 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

  8. 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)

  9. Pathophysiology of Dyskinesia development(Prevailing knowledge) • Synaptic Plasticity • - DARPP-32 pathway • Dopamine as a false transmitter • Severity of DA deficit • 5-HT • Dopamine receptor super-sensitivity • DA receptor internalisation • arrestins

  10. 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

  11. Proband- dyskinesia evaluationPatients diagnosed for less than 3 years • What we are not doing. • High dose L-dopa challenge combined with Dyskinesia rating scale

  12. Proband- dyskinesia evaluationPD onset < 50 years • MDS UPDRS at baseline • Likely retrospective date of dyskinesia • Duration and severity of dyskinesia • Adjustment for known confounders

  13. Possible Genetic influences on Dyskinesia development to be investigated

  14. 2. Levodopa responsiveness If a patient has insufficient response of non-tremor symptoms, concern is that they do not have PD • Confounders • Comorbidity e.g. Vascular disease • Anticholinergic use • Propranolol, Botox • UK Brain bank criteria are inclusion criteria for Proband- lack of L-dopa response excludes patients from recruitment

  15. Proband- Levodopa responsiveness Patients diagnosed for less than 3 years. L-dopa challenge • All aspects of MDS UPDRS part 3 will be judged • Adjustment for confounders • 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

  16. 2. Levodopa responsiveness (of PD tremor) • MDS UPDRS • Off & On meds

  17. 2. Levodopa responsiveness of PD tremor • Resting tremor • Postural tremor (re-emergent tremor) • Tripartite tremor

  18. 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.

  19. 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

  20. 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

  21. 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

  22. Therapy impact on cognition.....

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