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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
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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
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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
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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
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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
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Mechanism of Dopamine and Hypocretin
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Parkinson’s Disease: Extrapyramidal System
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Synthesis of Dopamine and Norepinephrine
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Narcolepsy
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Hypothalamus and Hypocretin
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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 substantia nigra also present MHC-1 proteins, targeted by T-cells in Parkinson’s Disease
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Demographics and Relationship between Narcolepsy and Parkinson’s Disease
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Normal level of dopamine ↓ level of dopamine Age of onset usually between 35-45 Age of onset mostly between 50-60 150,000 patients in America 3 million patients worldwide 1 million patients in US 20 million patients worldwide ↑ in Japanese people (1/600) And ↓ Israel and US ↑ rate of occurrence in whites ↓ African-Americans and Asians ↓ level of hypocretin Slightly higher rate of incidence in men - Daytime sleep attacks - Nocturnal insomnia - REM sleep disorder - Hallucinations - Depression
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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
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Drug Therapy for Narcolepsy and Parkinson’s Disease
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Narcolepsy: Symptoms & Treatments Excessive Daytime Sleepiness and Sleep Attacks Amphetamines Methylphenidate Modafinil Sodium oxybate Cataplexy Sodium oxybate Antidressants
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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
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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
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Narcolepsy: Symptoms & Treatments Excessive Daytime Sleepiness and Sleep Attacks Cataplexy Sodium oxybate Antidressants – CNS depressant – Can treat both EDS and cataplexy – Contraindicated for sedative hypnotic agents and alcohol
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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
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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.
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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
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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
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References Asai, H., Hirano, M., Furiya, Y., Udaka, F., Morikawa, M., Kanbayashi, T., Shimizu, T., and Ueno, S. (2009). Clin Neurol Neurosurg, 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.10.5610.1586/ern.10.5 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.105810.1002/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.x10.1046/j.0022- 202x.2001.00011.x
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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 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. Mov Disord, 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.htmwww.sciencedaily.com/releases/2007/05/070504122134.htm
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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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