Activated Wake Systems in Narcolepsy Type 1
Annals of Neurology, vol. 94, pp. 762–771
Abstract
OBJECTIVE: Narcolepsy type 1 (NT1) is assumed to be caused solely by a lack of hypocretin (orexin) neurotransmission. Recently, however, we found an 88% reduction in corticotropin-releasing hormone (CRH)-positive neurons in the paraventricular nucleus (PVN). We assessed the remaining CRH neurons in NT1 to determine whether they co-express vasopressin (AVP) to reflect upregulation. We also systematically assessed other wake-systems, since current NT1 treatments target histamine, dopamine, and norepinephrine pathways. METHODS: In postmortem tissue of people with NT1 and matched controls, we immunohistochemically stained and quantified neuronal populations expressing: CRH and AVP in the PVN, and CRH in the Barrington nucleus; the key neuronal histamine-synthesizing enzyme, histidine decarboxylase (HDC) in the hypothalamic tuberomammillary nucleus (TMN); the rate-limited-synthesizing enzyme, tyrosine hydroxylase (TH), for dopamine in the mid-brain and for norepinephrine in the locus coeruleus (LC). RESULTS: In NT1, there was: a 234% increase in the percentage of CRH cells co-expressing AVP, while there was an unchanged integrated optical density of CRH staining in the Barrington nucleus; a 36% increased number of histamine neurons expressing HDC, while the number of typical human TMN neuronal profiles was unchanged; a tendency toward an increased density of TH-positive neurons in the substantia nigra compacta; while the density of TH-positive LC neurons was unchanged. INTERPRETATION: Our findings suggest an upregulation of activity by histamine neurons and remaining CRH neurons in NT1. This may explain earlier reports of normal basal plasma cortisol levels but lower levels after dexamethasone suppression. Alternatively, CRH neurons co-expressing AVP neurons are less vulnerable. ANN NEUROL 2023;94:762-771.
Authors 12
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Ling Shan corresponding Aachen Department of Neurology, Leiden Sleep Wake Centre SEIN Heemstede The Netherlands Sleep Wake Centre SEIN
Leiden University · Netherlands Institute for Neuroscience · Royal Netherlands Academy of Arts and Sciences · Leiden University Medical Center · Stichting Epilepsie Instellingen Nederland
Affiliation as printed
Department Neuropsychiatric Disorders Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences Amsterdam The Netherlands
Leiden University Medical Centre, Department of Neurology, Leiden, The Netherlands, and Sleep Wake Centre SEIN Heemstede The Netherlands
Department Neuropsychiatric Disorders, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands
Leiden University Medical Centre, Department of Neurology, Leiden, The Netherlands, and Sleep Wake Centre SEIN, Heemstede, The Netherlands
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Netherlands Institute for Neuroscience · Royal Netherlands Academy of Arts and Sciences
Affiliation as printed
Department Neuropsychiatric Disorders Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences Amsterdam The Netherlands
Department Neuropsychiatric Disorders, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands
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Netherlands Institute for Neuroscience · Royal Netherlands Academy of Arts and Sciences
Affiliation as printed
Department Neuropsychiatric Disorders Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences Amsterdam The Netherlands
Department Neuropsychiatric Disorders, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands
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Netherlands Institute for Neuroscience · Royal Netherlands Academy of Arts and Sciences
Affiliation as printed
Department Neuropsychiatric Disorders Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences Amsterdam The Netherlands
Department Neuropsychiatric Disorders, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands
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Netherlands Institute for Neuroscience · Royal Netherlands Academy of Arts and Sciences
Affiliation as printed
Department Neuropsychiatric Disorders Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences Amsterdam The Netherlands
Department Neuropsychiatric Disorders, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands
-
Netherlands Institute for Neuroscience · Royal Netherlands Academy of Arts and Sciences
Affiliation as printed
Department Neuropsychiatric Disorders Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences Amsterdam The Netherlands
Department Neuropsychiatric Disorders, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands
-
Netherlands Institute for Neuroscience · Royal Netherlands Academy of Arts and Sciences
Affiliation as printed
Department Neuropsychiatric Disorders Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences Amsterdam The Netherlands
Department Neuropsychiatric Disorders, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands
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Amsterdam Neuroscience · Amsterdam University Medical Centers · University of Amsterdam
Affiliation as printed
Department of (Neuro) Pathology, Amsterdam University Medical Center University of Amsterdam, Amsterdam Neuroscience Amsterdam The Netherlands
Department of (Neuro) Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands
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Jingru Zhou Aachen Department of Neurology, Leiden Sleep Wake Centre SEIN Heemstede The Netherlands Sleep Wake Centre SEIN
Leiden University · Leiden University Medical Center · Stichting Epilepsie Instellingen Nederland
Affiliation as printed
Leiden University Medical Centre, Department of Neurology, Leiden, The Netherlands, and Sleep Wake Centre SEIN Heemstede The Netherlands
Leiden University Medical Centre, Department of Neurology, Leiden, The Netherlands, and Sleep Wake Centre SEIN, Heemstede, The Netherlands
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Gert Jan Lammers Aachen Department of Neurology, Leiden Sleep Wake Centre SEIN Heemstede The Netherlands Sleep Wake Centre SEIN
Leiden University · Leiden University Medical Center · Stichting Epilepsie Instellingen Nederland
Affiliation as printed
Leiden University Medical Centre, Department of Neurology, Leiden, The Netherlands, and Sleep Wake Centre SEIN Heemstede The Netherlands
Leiden University Medical Centre, Department of Neurology, Leiden, The Netherlands, and Sleep Wake Centre SEIN, Heemstede, The Netherlands
-
Netherlands Institute for Neuroscience · Royal Netherlands Academy of Arts and Sciences
Affiliation as printed
Department Neuropsychiatric Disorders Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences Amsterdam The Netherlands
Department Neuropsychiatric Disorders, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, the Netherlands
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Rolf Fronczek Aachen Department of Neurology, Leiden Sleep Wake Centre SEIN Heemstede The Netherlands Sleep Wake Centre SEIN
Leiden University · Leiden University Medical Center · Stichting Epilepsie Instellingen Nederland
Affiliation as printed
Leiden University Medical Centre, Department of Neurology, Leiden, The Netherlands, and Sleep Wake Centre SEIN Heemstede The Netherlands
Leiden University Medical Centre, Department of Neurology, Leiden, The Netherlands, and Sleep Wake Centre SEIN, Heemstede, The Netherlands
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