Abstract
Narcolepsy is a chronic sleep disorder caused by a loss of hypocretin (hcrt) neurons in the hypothalamus. Cerebrospinal fluid (CSF) hcrt-1 measurement has been well established as a gold standard of narcolepsy diagnosis, although some portions of narcoleptic patients show normal hcrt-1 levels. We aimed to examine peptide degradation of hcrt-1 and its abnormality in the CSF of patients by using high performance liquid chromatography (HPLC) followed by radioimmunoassay (RIA). CSF was collected from healthy controls, narcoleptic patients of type 1 with hcrt-1 deficiency, type 1 with normal hcrt-1 level, and type 2 with normal hcrt-1 level. We found that the majority of hcrt-1 immunoreactivity in extracted CSF was derived from unauthentic hcrt-1 peaks, which are predicted to be inactive metabolites, and the intact hcrt-1 peptide was less than 10% of the gross amount, suggesting that the regular RIA for CSF hcrt-1 measures largely reflect the unauthentic hcrt-1-related metabolites rather than the intact one. As expected, all hcrt-1-related peaks were abolished in type 1 with hcrt-1 deficiency. Importantly, we also found that the sum of the authentic hcrt-1 peptide (peaks 3 and 4) significantly decreased in non-deficient type 1 and tended to decrease in type 2 narcoleptic patients although the levels with the regular RIA in non-extracted CSF was equivalent to healthy controls. Immunoreactivity with unauthentic hcrt-1 metabolites may masks the possible decline in authentic hcrt-1 level caused by the partial loss of hcrt neurons. Our findings may provide new insights into the degradation of the hcrt-1 peptide and the pathophysiology of narcolepsy.
Highlights
Narcolepsy is a chronic sleep disorder caused by a loss of hypocretin neurons in the hypothalamus
Since reduced number of hcrt cells are observed in narcolepsy with cataplexy patients and a mutation in hcrt-related genes is extremely rare in human cases[2,3], Cerebrospinal fluid (CSF) hcrt-1 measurement has been well established as a gold standard of diagnosis of narcolepsy by the ICSD-24,5
All narcoleptics had been diagnosed based on the clinical symptoms and CSF hcrt-1 level according to ICSD-2 and were regrouped in this study according to ICSD-3 as follows: type 1, narcolepsy-cataplexy with hcrt-1 deficiency (n = 6); non-deficient type 1, narcolepsy-cataplexy with normal levels of hcrt-1 (n = 12); non-deficient type 2, narcolepsy without cataplexy with normal levels of hcrt-1 (n = 5)
Summary
Narcolepsy is a chronic sleep disorder caused by a loss of hypocretin (hcrt) neurons in the hypothalamus. Cerebrospinal fluid (CSF) hcrt-1 measurement has been well established as a gold standard of narcolepsy diagnosis, some portions of narcoleptic patients show normal hcrt-1 levels. We found that the sum of the authentic hcrt-1 peptide (peaks 3 and 4) significantly decreased in non-deficient type 1 and tended to decrease in type 2 narcoleptic patients the levels with the regular RIA in non-extracted CSF was equivalent to healthy controls. Mechanisms underlying normal hcrt-1 level in narcolepsy are largely unknown and studies focusing on hcrt-1 non-deficient type 1 patients are very limited. A postmortem study reported that a narcolepsy without cataplexy patient showed a partial loss of hcrt cells in the posterior hypothalamus, accompanied by prominent gliosis, but not in the anterior hypothalamus[23]. Evidence linking a focal loss and an absence of cataplexy remains unclear
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