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

• 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

impairment

rd

• TD = PIGDwrt Cognition

• Bradykinesia/ working memory impairment (DA)• Axial signs/ episodic memory/ visuospatial

impairment (ACh)

Mild Motor comps Non DA probs All domainsYoung Youngest Older Older

• LOPD linked to earlier Postural instability

Younger age at onset associated with Dystonia, Dyskinesia (independent of parkin status).

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

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)

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

L-Dopa

DA

CEREBRAL CORTEX

Striatal Medium SpinyNeuron

BG output

D1rAC

cAMP

PKA

DARPP-32

PP

GRK

D1rP

Arrestin

D1r

P Arrestin

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

Proband- dyskinesia evaluationPatients diagnosed for less than 3 years

• What we are not doing.

• High dose L-dopa challenge combined with Dyskinesia rating scale

Proband- dyskinesia evaluationPD onset < 50 years

• MDS UPDRS at baseline

• Likely retrospective date of dyskinesia

• Duration and severity of dyskinesia

• Adjustment for known confounders

Possible Genetic influences on Dyskinesia development to be investigated

• 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

• 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

Therapy impact on cognition.....