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Cited by 566Parkinson's Disease Mechanisms and TreatmentsSleep and Wakefulness ResearchNuclear Receptors and Signaling

Hypocretin (orexin) cell loss in Parkinson's disease

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Thannickal, T. C., Lai, Y.-Y., Siegel, J. M.·2007·Brain
DOI 10.1093/brain/awm097PMC PMC8762453
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Abstract

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.

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  • In controls, the total number of hypocretin neurons and their distribution across the lateral and posterior hypothalamus were similar to prior reports.

    “In controls, the total number of hypocretin neurons and their distribution across the lateral and posterior hypothalamus were similar to prior reports.7,8,14,15”

    From Loss of hypocretin (orexin) neurons with traumatic brain injury (2009) · cites this paper as [15]

    The Materials and methods and Quantitative analysis sections say the authors examined five normal brains and determined hypocretin-cell number and distribution. The passages available from our copy do not give a total control-neuron count or say that the count and lateral/posterior hypothalamic distribution were similar to prior reports (pages not provided). (LLM, conf=0.70)

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Cited by

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Authors
Thannickal, T. C., Lai, Y.-Y., & Siegel, J. M.
Affiliations
University of California, Los Angeles (US)
ORCID
Thannickal, T. C.
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2007-04-23
Volume
130
Issue
6
Pages
1586-1595
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awm097
PMC
PMC8762453
OpenAlex
W2168923588
Cited by
566
References
1
Citations by year
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FWCI
24.77
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Brain (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R01HL041370, R37HL041370, HL 41370)
  • National Institute of Mental Health (R01MH064109, MH 64109)
  • National Institute of Neurological Disorders and Stroke (NS 14610, R01NS014610, R01NS042566, NS42566, R37NS014610)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
Parkinson's disease, orexin, melanin-concentrating hormone, hypothalamus, substantia nigra, alpha-synuclein, glial fibrillary acidic protein, disease progression, Braak staging, REM sleep behavior disorder
MeSH terms
Orexins, Aged, Aged, 80 and over, Cell Count, Female, Glial Fibrillary Acidic Protein, Humans, Hypothalamic Hormones, Hypothalamus, Immunoenzyme Techniques, Male, Melanins, Middle Aged, Neurons, Neuropeptides, Parkinson Disease, Pituitary Hormones, Severity of Illness Index, Substantia Nigra, Disease Progression, Intracellular Signaling Peptides and Proteins, alpha-Synuclein

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