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
S
Outline
S What is Parkinson’s Disease and Narcolepsy?
S Symptoms and Relationship
S Mechanisms of Dopamine and Hypocretin
S PD Extrapyramidal System
S Hypocretin synthesis and action
S Demographics and Relationship
S Treatment
S Narcolepsy and PD drugs
What is Narcolepsy?
S Chronic neurological disease characterized by:
S Excessive Daytime Sleepiness (EDS)
S Cataplexy (muscle weakness)
S Abnormal REM sleep
S Linked to the peptide hypocretin (orexin) deficiency in the
cerebrospinal fluid
What is Parkinson’s Disease?
S Progressive neurodegenerative disease
S Most commonly known for motor symptoms
S Bradykinesia, rigidity, resting tremor
S Also accompanied with non-motor symptoms
S Sleep disorders
S Mood disorders and cognitive deficits
S
Can have sleep attacks that resemble narcoleptic sleep attacks
How are they linked?
S Share symptoms of sleep disorders
S Degeneration of cells that produce hypocretin in PD
S Lower hypocretin levels in narcolepsy
S Many patients with advanced PD also display most
symptoms of narcolepsy
Mechanism of
Dopamine and
Hypocretin
S
Parkinson’s
Disease:
Extrapyramidal
System
Synthesis of Dopamine and
Norepinephrine
Narcolepsy
Hypothalamus and Hypocretin
Autoimmunity
S Suspected autoimmune response killing hypocretin-secreting neurons
S Polymorphisms in HLA gene encoding for HLA proteins and MHC
proteins
S
Antigens presented on cell surface of neurons
S For narcolepsy, variant in TCRA gene as well, encoding for receptor
on T-cells
S
Increased likelihood of T-cells producing autoimmune response
S Dopaminergic neurons in substantia nigra also present MHC-1
proteins, targeted by T-cells in Parkinson’s Disease
Demographics and Relationship
between
Narcolepsy and Parkinson’s
Disease
S
Normal level of
dopamine
↓ level of dopamine
Age of onset usually between
↓ level of
35-45
Age of onset mostly
between 50-60
hypocretin
150,000 patients in America
3 million patients worldwide
Slightly
- Daytime sleep attacks higher rate
of
Nocturnal
insomnia
↑ in Japanese people
incidence
- REM sleep disorder in men
(1/600)
And- ↓ Hallucinations
Israel and US
- Depression
1 million patients in US
20 million patients worldwide
↑ rate of occurrence
in whites
↓ African-Americans
and Asians
Does one cause the other?
S Daytime sleepiness in 76% of PD patients
S 75% of patients with REM sleep behavior disorder
developed Parkinsonian conditions
S However no direct evidence for narcolepsy causing
Parkinson’s Disease
Drug Therapy for
Narcolepsy and Parkinson’s
Disease
S
Narcolepsy: Symptoms &
Treatments
Excessive Daytime
Sleepiness and Sleep Attacks
S Amphetamines
S Methylphenidate
S Modafinil
S Sodium oxybate
Cataplexy
• Sodium oxybate
• Antidressants
Narcolepsy: Symptoms &
Treatments
Excessive Daytime
Sleepiness and Sleep Attacks
S Amphetamines
S Methylphenidate
S Modafinil
S 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
S Amphetamines
S Methylphenidate
S Modafinil
S 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
S
S
S
Levodopa
S
Converted into dopamine in presynaptic
dopaminergic neurons
S
Effects enhanced with DOPA decarboxylase
inhibitors such as carbidopa
S
Most effective therapy, but associated with motor
complications
Dopamine agonists
S
Modest efficacy in early stages of PD
S
E.g. pramipexole, ropininirole, pergolide (removed
from market)
Anticholinergics
S
Not recommended due to side effects
Side effects of PD drugs
S Sleep attacks associated with dopaminergic
drugs.
S Stimulating D3 receptors increases incidence
of sleep attacks
S Due to reduction of hypocretin levels in the
CSF.
S Replacing pramipexole with pergolide resolved
sleep attacks and increased hypocretin levels in
the CSF.
Narcolepsy Drugs for the Treatment
of Sleep Disorders in PD?
S Modafinil
S 3 studies, conflicting results
S Insufficient evidence for efficacy in treatment of EDS in PD
patients.
S Sodium oxybate
S One study showed promising results.
S Insufficient evidence
Possible Future Therapies?
S Hypocretin
S BBB is impermeable
S Hypocretin agonists
S None reported yet
S Hypocretin systems have been used to treat sleep disorders
S Hypocretin receptor antagonist for treatment of insomnia
References
S
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.
S
Billiard, M. (2008). Narcolepsy: current treatment options and future approaches. Neuropsychiatr Dis Treat, 4(3), 557-566.
S
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
S
e-CPS [Internet]. Ottawa (ON): Canadian Pharmacists Association; c2014 [cited 2014 Oct 9]. Available from: http://www.ecps.ca. Also available in paper copy from the publisher.
S
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.
S
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
S
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
S
Jankovic, J., & Aguilar L.G. (2008). Current approaches to the treatment of Parkinson’s disease. Neuropsychiatr Dis Treat, 4(4):
743-757.
S
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.0022202x.2001.00011.x
S
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.
S
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.
S
National Sleep Foundation. (2014). Parkinson's Disease and Sleep. Retrieved October 18, 2014 from
http://sleepfoundation.org/sleep-topics/parkinsons-disease-and-sleep
S
Nishino, S. (2007). Clinical And Neurobiological Aspects Of Narcolepsy.Sleep Medicine, 8(4), 373-399.
S
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.
S
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 EvidenceBased Medicine Review Update: Treatments for the non-motor symptoms of Parkinson's disease. Mov Disord,
26: S42–S80. doi: 10.1002/mds.23884
S
Swick, T. J. (2012). Parkinson's Disease and Sleep/Wake Disturbances. Parkinson's Disease, 2012, 1-14.
S
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
Summary
Overview:
S
Parkinson’s Disease: progressive neurodegenerative disease well known for motor symptoms but also include
non-motor symptoms like sleep disorders
S
Narcolepsy: chronic neurological disease characterized by excessive daytime sleepiness, cataplexy, and
abnormal REM sleep behavior
Relationship:
S
Both diseases have a decrease in hypocretin levels (or neurons secreting hypocretin) – believed to be
responsible for sleep symptoms in both diseases
S
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
S
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:
S
To integrate information from different systems in the body (i.e. the circadian cycle) in order to determine or
promote wakefulness
S
Stimulates catecholaminergic (dopamine, norepinephrine and epinephrine) pathways in the brain stabilizing
wakefulness or sleep
Drugs:
S
Modafinil and Sodium oxybate are used to treat narcolepsy while Levodopa and dopamine agonists are used
to treat PD
S
Hypocretin agonists are a possible future therapy for narcolepsy and sleep disorder symptoms in PD