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Relationship Between Parkinson’s Disease and
Narcolepsy Eunjung LeeJacinthe Chong
Wenjia DaiZipeng Shang
PHM142 Fall 2014Coordinator: Dr. Jeffrey HendersonInstructor: Dr. David Hampson
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
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
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
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
Parkinson’s Disease:
Extrapyramidal System
Synthesis of Dopamine and Norepinephrine
Narcolepsy
Hypothalamus and Hypocretin
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
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 America3 million patients worldwide
1 million patients in US20 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
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
Narcolepsy: Symptoms & Treatments
Excessive Daytime Sleepiness and Sleep Attacks
Amphetamines
Methylphenidate
Modafinil
Sodium oxybate
Cataplexy• Sodium oxybate• Antidressants
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
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
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
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
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.
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
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
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.10.56
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
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. 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.htm
SummaryOverview:
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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