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Relationship Between Parkinson’s Disease and Narcolepsy

Relationship Between Parkinson’s Disease and Narcolepsy. Eunjung Lee Jacinthe Chong Wenjia Dai Zipeng Shang. PHM142 Fall 2014 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson. Outline. What is Parkinson’s Disease and Narcolepsy? Symptoms and Relationship

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Relationship Between Parkinson’s Disease and Narcolepsy

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  1. Relationship Between Parkinson’s Disease and Narcolepsy Eunjung Lee Jacinthe Chong Wenjia Dai Zipeng Shang PHM142 Fall 2014 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

  2. Outline • What is Parkinson’s Disease and Narcolepsy? • Symptoms and Relationship • Mechanisms of Dopamine and Hypocretin • PD Extrapyramidal System • Hypocretin synthesis and action • Demographics and Relationship • Treatment • Narcolepsy and PD drugs

  3. What is Narcolepsy? • Chronic neurological disease characterized by: • Excessive Daytime Sleepiness (EDS) • Cataplexy (muscle weakness) • Abnormal REM sleep • Linked to the peptide hypocretin (orexin) deficiency in the cerebrospinal fluid

  4. What is Parkinson’s Disease? • Progressive neurodegenerative disease • Most commonly known for motor symptoms • Bradykinesia, rigidity, resting tremor • Also accompanied with non-motor symptoms • Sleep disorders • Mood disorders and cognitive deficits • Can have sleep attacks that resemble narcoleptic sleep attacks

  5. How are they linked? • Share symptoms of sleep disorders • Degeneration of cells that produce hypocretin in PD • Lower hypocretin levels in narcolepsy • Many patients with advanced PD also display most symptoms of narcolepsy

  6. Mechanism of Dopamine and Hypocretin

  7. Parkinson’s Disease: Extrapyramidal System

  8. Synthesis of Dopamine and Norepinephrine

  9. Narcolepsy

  10. Hypothalamus and Hypocretin

  11. Autoimmunity • Suspected autoimmune response killing hypocretin-secreting neurons • Polymorphisms in HLA gene encoding for HLA proteins and MHC proteins • Antigens presented on cell surface of neurons • For narcolepsy, variant in TCRA gene as well, encoding for receptor on T-cells • Increased likelihood of T-cells producing autoimmune response • Dopaminergic neurons in substantianigra also present MHC-1 proteins, targeted by T-cells in Parkinson’s Disease

  12. Demographics and Relationship between Narcolepsy and Parkinson’s Disease

  13. Normal level of dopamine ↓ level of dopamine Age of onset mostly between 50-60 Age of onset usually between 35-45 ↓ level of hypocretin 1 million patients in US 20 million patients worldwide 150,000 patients in America 3 million patients worldwide • - Daytime sleep attacks • Nocturnal insomnia • REM sleep disorder • Hallucinations • Depression Slightly higher rate of incidence in men ↑ rate of occurrence inwhites ↓ African-Americans and Asians ↑ in Japanese people (1/600) And ↓ Israel and US

  14. Does one cause the other? • Daytime sleepiness in 76% of PD patients • 75% of patients with REM sleep behavior disorder developed Parkinsonian conditions • However no direct evidence for narcolepsy causing Parkinson’s Disease

  15. Drug Therapy for Narcolepsy and Parkinson’s Disease

  16. Narcolepsy: Symptoms & Treatments Cataplexy • Sodium oxybate • Antidressants Excessive Daytime Sleepiness and Sleep Attacks • Amphetamines • Methylphenidate • Modafinil • Sodium oxybate

  17. Narcolepsy: Symptoms & Treatments Excessive Daytime Sleepiness and Sleep Attacks • Amphetamines • Methylphenidate • Modafinil • Sodium oxybate • Central nervous system stimulants • Early treatment for EDS and sleep attacks • Patients can develop tolerance • Not commonly prescribed since modafinil came onto the market

  18. Narcolepsy: Symptoms & Treatments Excessive Daytime Sleepiness and Sleep Attacks • Amphetamines • Methylphenidate • Modafinil • Sodium oxybate • Central nervous system stimulants • Most commonly prescribed for EDS in narcolepsy • Side effects: headache and nausea

  19. Narcolepsy: Symptoms & Treatments Cataplexy • Sodium oxybate • Antidressants Excessive Daytime Sleepiness and Sleep Attacks • CNS depressant • Can treat both EDS and cataplexy • Contraindicated for sedative hypnotic agents and alcohol

  20. Treatment of Motor Symptoms of Parkinson’s Disease • Levodopa • Converted into dopamine in presynaptic dopaminergic neurons • Effects enhanced with DOPA decarboxylase inhibitors such as carbidopa • Most effective therapy, but associated with motor complications • Dopamine agonists • Modest efficacy in early stages of PD • E.g. pramipexole, ropininirole, pergolide (removed from market) • Anticholinergics • Not recommended due to side effects

  21. Side effects of PD drugs • Sleep attacks associated with dopaminergic drugs. • Stimulating D3 receptors increases incidence of sleep attacks • Due to reduction of hypocretin levels in the CSF. • Replacing pramipexole with pergolide resolved sleep attacks and increased hypocretin levels in the CSF.

  22. Narcolepsy Drugs for the Treatment of Sleep Disorders in PD? • Modafinil • 3 studies, conflicting results • Insufficient evidence for efficacy in treatment of EDS in PD patients. • Sodium oxybate • One study showed promising results. • Insufficient evidence

  23. Possible Future Therapies? • Hypocretin • BBB is impermeable • Hypocretin agonists • None reported yet • Hypocretin systems have been used to treat sleep disorders • Hypocretin receptor antagonist for treatment of insomnia

  24. References • Asai, H., Hirano, M., Furiya, Y., Udaka, F., Morikawa, M., Kanbayashi, T., Shimizu, T., and Ueno, S. (2009). ClinNeurolNeurosurg, 111(4), 341-344. doi: 10.1016/j.clineuro.2008.11.007. • Billiard, M. (2008). Narcolepsy: current treatment options and future approaches. Neuropsychiatr Dis Treat, 4(3), 557-566. • Cebrián C, Zucca FA, Mauri P, Steinbeck JA, Studer L, Scherzer CR, Kanter E, Budhu S, Mandelbaum J, Vonsattel JP, Zecca L, Loike JD, Sulzer D (2014) MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration. Nat Comms 5:3633. DOI: 10.1038/ncomms4633 http://dx.doi.org/10.1038/ncomms4633 • e-CPS [Internet]. Ottawa (ON): Canadian Pharmacists Association; c2014 [cited 2014 Oct 9]. Available from: http://www.e-cps.ca. Also available in paper copy from the publisher. • Gray Jean, editor. e-Therapeutics+ [Internet]. Ottawa (ON): Canadian Pharmacists Association; c2014 [cited 2014 Oct 9]. Available from: http://www.e-therapeutics.ca.myaccess.library.utoronto.ca Also available in paper copy from the publisher. • Haq, I.Z.; Naidu, Y.; Reddy, P. & Chaudhuri, K.R. (2010). Narcolepsy in Parkinson’s disease. Expert Review of Neurotherapeutics, 10(6), 879-884. doi: 10.1586/ern.10.56 • Hungs, M. & Mignot, E. (2001). Hypocretin/orexin, sleep and narcolepsy. BioEssays : news and reviews in molecular, cellular and developmental biology, 23(5), 379-408. doi: 10.1002/bies.1058 • Jankovic, J., & Aguilar L.G. (2008). Current approaches to the treatment of Parkinson’s disease. Neuropsychiatr Dis Treat, 4(4): 743-757. • Kobayashi, K. (2001). Role of catecholamine signaling in brain and nervous system functions: new insights from mouse molecular genetic study. Journal of Investigative Dermatology Symposium Proceedings, 6(1), 115-121. doi: 10.1046/j.0022-202x.2001.00011.x

  25. Kornum, B. R., Faraco, J., & Mignot, E. (2011). Narcolepsy with hypocretin/orexin deficiency, infections and autoimmunity of the brain. Current Opinion in Neurobiology, 21(6), 897-903. • Mieda, M., and Sakurai, T. (2013). Orexin (hypocretin) receptor agonists and antagonists for treatment of sleep disorders. CNS Drugs, 27(2), 83-90. doi: 10.1007/s40263-012-0036-8. • National Sleep Foundation. (2014). Parkinson's Disease and Sleep. Retrieved October 18, 2014 from http://sleepfoundation.org/sleep-topics/parkinsons-disease-and-sleep • Nishino, S. (2007). Clinical And Neurobiological Aspects Of Narcolepsy.Sleep Medicine, 8(4), 373-399. • Ondo, W.G., Perkins, T., Swick, T., Hull, K.L., Jimenez, J.E., Garris, T.S., and Pardi, D. (2008). Sodium oxybate for excessive daytime sleepiness in parkinson disease. Arch Neurol, 65(10), 1337-1340. doi: 10.1001/archneur.65.10.1337. • Seppi, K., Weintraub, D., Coelho, M., Perez-Lloret, S., Fox, S. H., Katzenschlager, R., Hametner, E.-M., Poewe, W., Rascol, O., Goetz, C. G. and Sampaio, C. (2011). The Movement Disorder Society Evidence-Based Medicine Review Update: Treatments for the non-motor symptoms of Parkinson's disease. MovDisord, 26: S42–S80. doi: 10.1002/mds.23884 • Swick, T. J. (2012). Parkinson's Disease and Sleep/Wake Disturbances. Parkinson's Disease, 2012, 1-14. • UCLA. (2007, May 4). Link Between Parkinson's And Narcolepsy Discovered. ScienceDaily. Retrieved October 20, 2014 from www.sciencedaily.com/releases/2007/05/070504122134.htm

  26. Summary Overview: • Parkinson’s Disease: progressive neurodegenerative disease well known for motor symptoms but also include non-motor symptoms like sleep disorders • Narcolepsy: chronic neurological disease characterized by excessive daytime sleepiness, cataplexy, and abnormal REM sleep behavior Relationship: • Both diseases have a decrease in hypocretin levels (or neurons secreting hypocretin) – believed to be responsible for sleep symptoms in both diseases • Polymorphisms in HLA gene lead to antigen presenting neurons in the brain, becoming a target for T-cells to attack and destroy neurons that regulate the sleep-wake cycle • No evidence to show one causing the other but share common sleep disorder symptoms that can potentially be treated with same classes of drugs Function of Hypocretin: • To integrate information from different systems in the body (i.e. the circadian cycle) in order to determine or promote wakefulness • Stimulates catecholaminergic(dopamine, norepinephrine and epinephrine) pathways in the brain stabilizing wakefulness or sleep Drugs: • Modafinil and Sodium oxybate are used to treat narcolepsy while Levodopa and dopamine agonists are used to treat PD • Hypocretin agonists are a possible future therapy for narcolepsy and sleep disorder symptoms in PD

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