Brain Advance Access originally published online on May 9, 2007
Brain 2007 130(6):1586-1595; doi:10.1093/brain/awm097
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Hypocretin (orexin) cell loss in Parkinson's disease*
1Department of Psychiatry, University of California at Los Angeles, Los Angeles, CA 90095, 2Neurobiology Research (151A3), Veterans Administration Greater Los Angeles Healthcare System, North Hills, CA 91343 and 3Brain Research Institute, University of California at Los Angeles, Los Angeles, CA 90095, USA
Corresponding to: Jerome M. Siegel, PhD, UCLA/VAGLAHS – Sepulveda, Neurobiology Research (151A3), 16111 Plummer Street, North Hills, CA 91343, USA E-mail: jsiegel{at}ucla.edu
It has recently been reported that Parkinson's disease (PD) is preceded and accompanied by daytime sleep attacks, nocturnal insomnia, REM sleep behaviour disorder, hallucinations and depression, symptoms which are frequently as troublesome as the motor symptoms of PD. All these symptoms are present in narcolepsy, which is linked to a selective loss of hypocretin (Hcrt) neurons. In this study, the Hcrt system was examined to determine if Hcrt cells are damaged in PD. The hypothalamus of 11 PD (mean age 79 ± 4) and 5 normal (mean age 77 ± 3) brains was examined. Sections were immunostained for Hcrt-1, melanin concentrating hormone (MCH) and alpha synuclein and glial fibrillary acidic protein (GFAP). The substantia nigra of 10 PD brains and 7 normal brains were used for a study of neuromelanin pigmented cell loss. The severity of PD was assessed using the Hoehn and Yahr scale and the level of neuropathology was assessed using the Braak staging criteria. Cell number, distribution and size were determined with stereologic techniques on a one in eight series.
We found an increasing loss of hypocretin cells with disease progression. Similarly, there was an increased loss of MCH cells with disease severity. Hcrt and MCH cells were lost throughout the anterior to posterior extent of their hypothalamic distributions. The percentage loss of Hcrt cells was minimal in stage I (23%) and was maximal in stage V (62%). Similarly, the percentage loss of MCH cells was lowest in stage I (12%) and was highest in stage V (74%). There was a significant increase (P = 0.0006, t = 4.25, df = 15) in the size of neuromelanin containing cells in PD patients, but no difference in the size of surviving Hcrt (P = 0.18, t = 1.39, df = 14) and MCH (P = 0.28, t = 1.39, df = 14) cells relative to controls.
In summary, we found that PD is characterized by a massive loss of Hcrt neurons. Thus, the loss of Hcrt cells may be a cause of the narcolepsy-like symptoms of PD and may be ameliorated by treatments aimed at reversing the Hcrt deficit. We also saw a substantial loss of hypothalamic MCH neurons. The losses of Hcrt and MCH neurons are significantly correlated with the clinical stage of PD, not disease duration, whereas the loss of neuromelanin cells is significantly correlated only with disease duration. The significant correlations that we found between the loss of Hcrt and MCH neurons and the clinical stage of PD, in contrast to the lack of a relationship of similar strength between loss of neuromelanin containing cells and the clinical symptoms of PD, suggests a previously unappreciated relationship between hypothalamic dysfunction and the time course of the overall clinical picture of PD.
Key Words: Parkinson; narcolepsy; sleep; hypocretin; orexin; melanin concentrating hormone
Abbreviations: GFAP, glial fibrillary acidic protein; Hcrt, hypocretin; MCH, melanin concentrating hormone; PD, Parkinson's disease
.
Received December 14, 2006. Revised March 21, 2007. Accepted March 30, 2007.
*An abstract of this work was submitted to the Society for Neuroscience annual meeting on May 15, 2006 and presented at the Society for Neuroscience meeting in Atlanta on October 15, 2006.
These authors contributed equally to this work.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Knudsen, S. Gammeltoft, and P. J. Jennum Rapid eye movement sleep behaviour disorder in patients with narcolepsy is associated with hypocretin-1 deficiency Brain, February 3, 2010; (2010): awp320v1 - awp320. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Compta, J. Santamaria, L. Ratti, E. Tolosa, A. Iranzo, E. Munoz, F. Valldeoriola, R. Casamitjana, J. Rios, and M. J. Marti Cerebrospinal hypocretin, daytime sleepiness and sleep architecture in Parkinson's disease dementia Brain, December 1, 2009; 132(12): 3308 - 3317. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Honda, T. Arai, M. Fukazawa, Y. Honda, K. Tsuchiya, A. Salehi, H. Akiyama, and E. Mignot Absence of ubiquitinated inclusions in hypocretin neurons of patients with narcolepsy Neurology, August 18, 2009; 73(7): 511 - 517. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. E. Benarroch, A. M. Schmeichel, B. N. Dugger, P. Sandroni, J. E. Parisi, and P. A. Low Dopamine cell loss in the periaqueductal gray in multiple system atrophy and Lewy body dementia Neurology, July 14, 2009; 73(2): 106 - 112. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. W. Olanow, M. B. Stern, and K. Sethi The scientific and clinical basis for the treatment of Parkinson disease (2009) Neurology, May 26, 2009; 72(21_Supplement_4): S1 - S136. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. K. Hassani, M. G. Lee, and B. E. Jones Melanin-concentrating hormone neurons discharge in a reciprocal manner to orexin neurons across the sleep-wake cycle PNAS, February 17, 2009; 106(7): 2418 - 2422. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J Jankovic Parkinson's disease: clinical features and diagnosis J. Neurol. Neurosurg. Psychiatry, April 1, 2008; 79(4): 368 - 376. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. R. Baumann, T. E. Scammell, and C. L. Bassetti Parkinson's disease, sleepiness and hypocretin/orexin Brain, March 1, 2008; 131(3): e91 - e91. [Full Text] [PDF]
|
|
|
|
|
|
T. C. Thannickal, Y.-Y. Lai, and J. M. Siegel Hypocretin (orexin) and melanin concentrating hormone loss and the symptoms of Parkinson's disease Brain, January 1, 2008; 131(1): e87 - e87. [Full Text] [PDF]
|
|
|
|
|
|
R. Fronczek, S. Overeem, S. Y.Y. Lee, Ingrid. M. Hegeman, J. van Pelt, S. G. van Duinen, G. J. Lammers, and D. F. Swaab Hypocretin (orexin) loss and sleep disturbances in Parkinson's Disease Brain, January 1, 2008; 131(1): e88 - e88. [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Deadwyler, L. Porrino, J. M. Siegel, and R. E. Hampson Systemic and Nasal Delivery of Orexin-A (Hypocretin-1) Reduces the Effects of Sleep Deprivation on Cognitive Performance in Nonhuman Primates J. Neurosci., December 26, 2007; 27(52): 14239 - 14247. [Abstract] [Full Text] [PDF]
|
|