Elevated Glial fibrillary acidic protein (GFAP) levels is an established indicator of astrogliosis. This process is characterized by rapid synthesis of GFAP and is demonstrated by an increase in protein content (Eng et al. 2000). GFAP levels in the CSF of narcoleptics (Feneberg et al. 2013) may represent hypothalamic gliosis and support the hypothesis of a neurodegenerative process (Thannickal et al. 2000). There was a significant increase in gliosis indicated by GFAP staining and a significant difference in the amount of gliosis across hypothalamic nuclei in narcoleptics (Fig. 4). Narcoleptics with cataplexy had increased GFAP staining throughout the hypothalamus, with a maximum percentage GFAP increase in the posterior hypothalamic nucleus. The number of Hcrt axons in the anterior hypothalamus was normal in narcolepsy without cataplexy (Thannickal et al. 2009). We speculate that high GFAP levels may be a differential biomarker in some sleep diseases such as secondary hypersomnia in Prader–Willi syndrome or neurologic disorders such as in certain cases of Guillain–Barré syndrome, both of which also may present with low CSF hcrt-1 levels (Mignot et al. 2002). In conclusion, GFAP may be useful as an additional disease biomarker in patients with narcolepsy.

It has been found that Hcrt concentration in the cerebral spinal fluid (CSF) of infants increased from birth until 2–4 postnatal months and then decreases throughout childhood and puberty (Feneberg et al. 2013). However, Aran et al. (2012) found no change in CSF Hcrt concentration between birth and 4 years of age. In older humans, the number of Hcrt neurons was unchanged between 50 and 90 of age (Kanbayashi et al. 2002; Fronczek et al. 2005). There was 24 % decrease in the number of Hcrt neurons in adults compared with infants and children (Fronczek et al. 2012). This may contribute to changes in sleep regulation during development and with aging. Animal studies have shown that decreased Hcrt expression is correlated with changes in sleep regulation with aging (Hunt et al. 2015; Brownell and Conti 2010).

Hcrt deficiency is directly involved in several neurological disorders. Dynorphin, glutamate and secretogranin II are found co-localized within Hcrt cells (Sawai et al. 2010; Chou et al. 2001; Bayer et al. 2002). There are several receptors and transporters that are expressed in Hcrt cells such as 5HT1-A, adenosine A1-R, GABA A alpha 3, GABA A epsilon, GABA B, group III metabotropic glutamate receptors, leptin R, Y4-R, vGlut1 and vGlut2 (Torrealba et al. 2003; Collin et al. 2002; Thakkar et al. 2002; Bäckberg et al. 2003, 2004; Moragues et al. 2003; Acuna-Goycolea et al. 2004; Håkansson et al. 1999; Rosin et al. 2003; Campbell et al. 2003). Acetylcholinesterase E, STAT-3, Narp and neuroglobin (Chou et al. 2004; Reti et al. 2002; Håkansson et al. 1999; Hundahl et al. 2008) are also found in Hcrt cells. Hcrt cell loss also causes the deficiency of these molecules. Their role in the symptoms of narcolepsy is not known.