Localized loss of hypocretin (orexin) cells in narcolepsy without cataplexy.
OBJECTIVE
Narcolepsy with cataplexy is characterized by a loss of approximately 90% of hypocretin (Hcrt) neurons. However, more than a quarter of narcoleptics do not have cataplexy and have normal levels of hypocretin in their cerebrospinal fluid, raising the possibility that their disease is caused by unrelated abnormalities. In this study we examined hypocretin pathology in narcolepsy without cataplexy.


METHODS
We examined postmortem brain samples, including the hypothalamus of 5 narcolepsy with cataplexy patients; one narcolepsy without cataplexy patient whose complete hypothalamus was available (patient 1); one narcolepsy without cataplexy patient with anterior hypothalamus available (patient 2); and 6 normal brains. The hypothalamic tissue was immunostained for Hcrt-1, melanin-concentrating hormone (MCH), and glial fibrillary acidic protein (GFAP).


RESULTS
Neither of the narcolepsy without cataplexy patients had a loss of Hcrt axons in the anterior hypothalamus. The narcolepsy without cataplexy patient whose entire brain was available for study had an overall loss of 33% of hypocretin cells compared to normals, with maximal cell loss in the posterior hypothalamus. We found elevated levels of gliosis with GFAP staining, with levels increased in the posterior hypothalamic nucleus by (295%), paraventricular (211%), periventricular (123%), arcuate (126%), and lateral (72%) hypothalamic nuclei, but not in the anterior, dorsomedial, or dorsal hypothalamus. There was no reduction in the number of MCH neurons in either patient.


CONCLUSIONS
Narcolepsy without cataplexy can be caused by a partial loss of hypocretin cells.
Thannickal
Thomas C
TC
Veterans Administration Greater Los Angeles Healthcare System, Neurobiology Research, North Hills, CA 91343, USA.
Nienhuis
Robert
R
Siegel
Jerome M
JM
D000368:Aged; D000369:Aged, 80 and over; D001931:Brain Mapping; D002385:Cataplexy / Q000473:pathology*; D002452:Cell Count; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007028:Hypothalamic Hormones; D007031:Hypothalamus / Q000473:pathology*; D007124:Immunoenzyme Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008543:Melanins; D008875:Middle Aged; D009290:Narcolepsy / Q000473:pathology*; D009474:Neurons / Q000473:pathology; D009479:Neuropeptides / Q000378:metabolism*; D000068797:Orexins; D010907:Pituitary Hormones
D005904:Glial Fibrillary Acidic Protein; D007028:Hypothalamic Hormones; D047908:Intracellular Signaling Peptides and Proteins; D008543:Melanins; D009479:Neuropeptides; D000068797:Orexins; D010907:Pituitary Hormones; C019463:melanin-concentrating hormone