Document Detail

Hypocretin (orexin) cell loss in Parkinson's disease.
MedLine Citation:
PMID:  17491094     Owner:  NLM     Status:  MEDLINE    
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.
Thomas C Thannickal; Yuan-Yang Lai; Jerome M Siegel
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2007-05-09
Journal Detail:
Title:  Brain : a journal of neurology     Volume:  130     ISSN:  1460-2156     ISO Abbreviation:  Brain     Publication Date:  2007 Jun 
Date Detail:
Created Date:  2007-05-25     Completed Date:  2007-06-27     Revised Date:  2008-03-06    
Medline Journal Info:
Nlm Unique ID:  0372537     Medline TA:  Brain     Country:  England    
Other Details:
Languages:  eng     Pagination:  1586-95     Citation Subset:  AIM; IM    
Department of Psychiatry, University of California at Los Angeles, Los Angeles, CA 90095, USA.
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MeSH Terms
Aged, 80 and over
Cell Count
Disease Progression
Glial Fibrillary Acidic Protein / analysis
Hypothalamic Hormones / analysis
Hypothalamus / chemistry,  pathology
Immunoenzyme Techniques
Intracellular Signaling Peptides and Proteins / analysis*,  deficiency
Melanins / analysis
Middle Aged
Neurons / chemistry
Neuropeptides / analysis*,  deficiency
Parkinson Disease / metabolism*,  pathology
Pituitary Hormones / analysis
Severity of Illness Index
Substantia Nigra / chemistry
alpha-Synuclein / analysis
Grant Support
Reg. No./Substance:
0/Glial Fibrillary Acidic Protein; 0/Hypothalamic Hormones; 0/Intracellular Signaling Peptides and Proteins; 0/Melanins; 0/Neuropeptides; 0/Pituitary Hormones; 0/alpha-Synuclein; 0/orexins; 67382-96-1/melanin-concentrating hormone
Comment In:
Brain. 2008 Mar;131(Pt 3):e91   [PMID:  17898005 ]
Brain. 2008 Jan;131(Pt 1):e87   [PMID:  17898004 ]

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