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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

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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