Cerebrospinal-fluid Orexin-A levels in different neurocognitive disorders: a comparison study

In the present study, we investigated the differences in cerebrospinal fluid (CSF) orexin-A levels among patients with different neurocognitive disorders, such as mild or moderate to severe Alzheimer's disease (AD; mAD, msAD, respectively), behavioral variants of frontotemporal dementia (bv-FTD), non-fluent primary aphasia (NFPA), and idiopathic normal pressure hydrocephalus (iNPH). A total of 214 participants were evaluated (mAD, 45; msAD, 31; bv-FTD, 12; NFPA, 22; iNPH, 13; non-demented elderly controls, 91). The highest CSF orexin-A levels were found in iNPH patients (263.31 ± 56.89 pg/mL). Patients affected by NFPA (210.86 ± 61.99 pg/mL), iNPH, and msAD (173.04 ± 19.76 pg/mL) showed higher CSF orexin-A concentrations than controls (145.18 ± 27.01pg/mL) (p < 0.001). Bv-FTD (190.12 ± 100.84 pg/mL) and mAD (130.76 ± 21.70 pg/mL) patients showed no significant differences in CSF orexin-A levels compared with controls. mAD patients showed also lower CSF orexin-A concentrations than all other patient groups.In conclusion, orexin-A presents different CSF levels among neurocognitive disorders. The mechanisms underlying this difference vary and may include sleep-wake cycle impairment, behavioral disturbances, and CSF dynamics. The development of drugs that antagonize the orexin system could open a new frontier of research linking orexin neurotransmission to neurocognitive disorders.