1. Treatment of Parkinson’s Disease Dementia (PDD) Shanil Ebrahim

2. Outline Rivastigmine for Parkinson’s Disease Dementia  Background  Neurobiology  Different studies  Methodology  Results  Side effects  Evaluation  Conclusion

3. Background 40-70 % of patients with Parkinson’s Disease develop dementia 40-70 % of patients with Parkinson’s Disease develop dementia atleast 2 years after Parkinson’s diagnosis atleast 2 years after Parkinson’s diagnosis If before or within 2 years  diffuse Lewy-body disease (DLB) If before or within 2 years  diffuse Lewy-body disease (DLB) Both considered subtypes of more inclusive diagnosis of dementia with lewy bodies Both considered subtypes of more inclusive diagnosis of dementia with lewy bodies Risk Factor  Mainly aging – usually over 65 Risk Factor  Mainly aging – usually over 65 Increasing cholinergic function is beneficial Increasing cholinergic function is beneficial Rivastigmine for Parkinson’s Disease Dementia

4. Neurobiology The presence of Lewy bodies The presence of Lewy bodies  Intracytoplasmic neuronal inclusion containing alpha- synuclein  Intracytoplasmic neuronal inclusion containing alpha- synuclein Found in neocortical and paralimbic regions Found in neocortical and paralimbic regions Lewy body counts increased neocortex & limbic areas Lewy body counts increased neocortex & limbic areas (10 fold) Majority of patients with PDD have pathological finding characteristic of alzheimer’s disease Majority of patients with PDD have pathological finding characteristic of alzheimer’s disease *** In parkinson’s without dementia  lewy bodies are generally restricted to subcortical structures such as substantia nigra

5. Rivastigmine for Parkinson’s Disease Dementia Neurobiology Deficits in multiple neurotransmitters: - Serotonergic & noradrenergic lead to cognitive symptoms - Dopaminergic and particularly cholinergic lead to dementia *Dopaminergic agents – little improvement, also frequently worsen hallucinations and cognitive symptoms. PDD is associated with the cholinergic cell loss in the nucleus basalis of Meynert ** Increasing Cholinergic activity may alleviate cognitive dysfunction

6. Since, cholinesterase breaks down acetylcholine, a cholinesterase inhibitor will suppress the action of the enzyme   increases acetylcholine Since, cholinesterase breaks down acetylcholine, a cholinesterase inhibitor will suppress the action of the enzyme   increases acetylcholine Cholinesterase inhibitor  Rivastigmine Cholinesterase inhibitor  Rivastigmine. First Developed by Novartis Pharmaceuticals First Developed by Novartis Pharmaceuticals Initially used for the treatment of mild to moderate Alzheimer's Initially used for the treatment of mild to moderate Alzheimer's In 2006, it became the first product approved by the US FDA for the treatment of mild to moderate PDD In 2006, it became the first product approved by the US FDA for the treatment of mild to moderate PDD Rivastigmine Background Rivastigmine for Parkinson’s Disease Dementia

7. Study 1 - Giladi et al (2003) Rivastigmine for Parkinson’s Disease Dementia Conducted study on effects of rivastigmine on cognitive functions and other clinical features Conducted study on effects of rivastigmine on cognitive functions and other clinical features 28 consenting patients with PD and Dementia (17M/11F), (mean age – 75 +/- 4.6 yrs), (symptoms duration – 7.0 +/- 5.3 yrs) 28 consenting patients with PD and Dementia (17M/11F), (mean age – 75 +/- 4.6 yrs), (symptoms duration – 7.0 +/- 5.3 yrs) Had atleast 2 years of PD symptoms with a clear response to levodopa for more than 1 year Had atleast 2 years of PD symptoms with a clear response to levodopa for more than 1 year Excluded patients with: Excluded patients with:  Cognitive changes in first year  Psychotic features prior to or during first year after levodopa being introduced  Other Psychiatric disorders

8. Rivastigmine for Parkinson’s Disease Dementia Study 1 - Giladi et al (2003) ASSESSMENT  Unified Parkinsons’ Disease Rating scale (UPDRS)  Alzheimer’s Disease Assessment Scale (ADAS cog) DOSAGE Week 1-4  1.5mg twice daily Week 1-4  1.5mg twice daily Week 5-8  3mg twice daily Week 5-8  3mg twice daily Week 8-12  4.5mg twice daily Week 8-12  4.5mg twice daily Week 13-26  6mg twice daily (maximum dose) Week 13-26  6mg twice daily (maximum dose) Week 26  Dose tapered down over 2 weeks Week 26  Dose tapered down over 2 weeks Week 34  Final assessment Week 34  Final assessment

9. Rivastigmine for Parkinson’s Disease Dementia Study 1 - Giladi et al (2003) RESULTS  Tolerated rivastigmine well - (mean dose at week 12  7.3 +/- 3.3 mg/day)  Significant improvement at weeks 12 and 26 (P < 0.0001)  Improvement disappeared at end of washout period (week 34)  Significant improvement in total UPDRS score from baseline (from 67.5 +/- 12 to 64.3 +/- 13.8)  Significant improvement in total ADAScog score - remembering, recognition and concentration

10. Rivastigmine for Parkinson’s Disease Dementia Study 1 - Giladi et al (2003) LIMITATIONS  Adverse Side effects – Increased salivations and tremor  17 experienced side effects, 11 decreased their dose  8 Patients discontinued due to:  motor worsening, palpitations, confusional state, acute psychosis, heart attack and one found dead  Deterioration after 26 weeks was only picked up by mental part of UPDRS  low sensitivity  Limited sample size  Alternative explanations – placebo effect & training effect

11. Rivastigmine for Parkinson’s Disease Dementia Study 1 - Giladi et al (2003) EVALUATION Provided significant effects Provided significant effects Did improve cognitive decline Did improve cognitive decline Positive behavioural changes Positive behavioural changes Did not really cause any major motor disturbances Did not really cause any major motor disturbancesSUGGESTIONS  Use better measurement  Requires long term study  Requires larger sample size  Requires double blind

12. Rivastigmine for Parkinson’s Disease Dementia Study 2 – Emre et al (2004) Conducted double blind, randomized, placebo- controlled study on effects of rivastigmine on PDD. Conducted double blind, randomized, placebo- controlled study on effects of rivastigmine on PDD. Total of 541 patients – 410 completed the study. Total of 541 patients – 410 completed the study. 2:1 ratio of rivastigmine group to placebo group 2:1 ratio of rivastigmine group to placebo group Onset – At least 2 years after diagnosis of PD Onset – At least 2 years after diagnosis of PD 24 week treatment started off with 1.5 mg of rivastigmine or placebo daily. – Increased by 3 mg per day every 4 weeks until highest well-tolerated dose. Until 16 week dose escalation period. 24 week treatment started off with 1.5 mg of rivastigmine or placebo daily. – Increased by 3 mg per day every 4 weeks until highest well-tolerated dose. Until 16 week dose escalation period. The highest well tolerated dose was maintained for each patient. The highest well tolerated dose was maintained for each patient.

13. RESULTS  Mean dose  8.6 mg per day  Moderate but significant improvements in global rating of dementia, cognition, and behavioural symptoms (ADAScog and ADCS-CGIC)  More patients in treatment group improved and more patients in placebo group worsened Rivastigmine for Parkinson’s Disease Dementia Study 2 – Emre et al (2004)

14. DISCONTINUATION Adverse events, withdrew consent, lost to follow up, protocol violation, died, unsatisfactory therapeutic results and abnormal test results Adverse events, withdrew consent, lost to follow up, protocol violation, died, unsatisfactory therapeutic results and abnormal test results ADVERSE EVENTS Primary reason for discontinuation Primary reason for discontinuation Nausea, tremor, anorexia, dizziness, constipation, confusion Nausea, tremor, anorexia, dizziness, constipation, confusion Tremor was more frequent in the rivastigmine- treated patients but rarely resulted in withdrawal. Tremor was more frequent in the rivastigmine- treated patients but rarely resulted in withdrawal. Rivastigmine for Parkinson’s Disease Dementia Study 2 – Emre et al (2004)

15. EVALUATION Did have placebo, randomized, double blind study Did have placebo, randomized, double blind study Did have large size Did have large size Provided significant effects Provided significant effects Did improve cognitive decline Did improve cognitive decline Positive behavioural changes Positive behavioural changesSUGGESTIONS  Use better measurement as there is a problem with low sensitivity.  Requires long term study Rivastigmine for Parkinson’s Disease Dementia Study 2 – Emre et al (2004)

16. Quantitative EEG - Fogelson et al (2003) Rivastigmine for Parkinson’s Disease Dementia  19 Patients, suffering from PD atleast one year before dementia.  In PDD, there is a slowing of background activity  Rivastigmine increases higher frequency activity in the qEEG and decrease in slow-wave activity with concomitant improvement in cognitive state  Increase in alpha activity (greater in left hemisphere) and increase in beta activity  Decrease in delta and theta ** could be in an indication of arousal rather than improvement in cognitive state *** Problems with placebo effects, training and not blinded.

17. Efficacy Rivastigmine for Parkinson’s Disease Dementia  Efficacy must be looked at in 3 domains: 1)Cognition 2)Neuropsychiatric symptoms 3)Parkinsonian symptoms  Cognition - rivastigmine produced a moderate effect on cognitive symptoms  Neuropsychiatric – Did improve but not clear if improvement is clinically significant  Parkinsonian – Rivastigmine does worsen parkinsonian symptoms but the tests may not detect deterioration (may be considered not significant)

18. Rivastigmine for Parkinson’s Disease Dementia Conclusion & Suggestions  Rivastigmine may only have a mild to moderate effect on PDD  Tolerability is an issue (high dropout rates)  Worsening of parkinsonian symptoms  However, not much choices as of now since there are not many options for PDD  May have underestimated improvements due to the lack of sensitivity in measurements  Rivastigimine and cholinesterase inhibitors should be closely monitored for response and adverse events and physicians should evaluate each patient individually before initiating treatment