Reduced Orexin-A Levels in Frontotemporal Dementia

Abstract

Sleep disturbances including excessive daytime sleepiness (EDS) are encountered in frontotemporal dementia (FTD). To investigate the relationship between the plasma orexin-A levels and sleep disturbance patterns, we measured the plasma orexin-A levels and performed sleep studies in patients with FTD. The orexin-A levels were measured in 10 consecutive patients with FTD and controls by enzyme-linked immunosorbent assay. Nocturnal polysomnography (PSG) and Multiple Sleep Latency Test (MSLT) were performed in 2 patients with FTD. The orexin-A levels were significantly lower in patients with FTD compared to controls. The PSG revealed increased rapid eye movement (REM) latency in patients, whether or not they reported EDS. Mean sleep latency in MSLT was less than 10 minutes in both the patients, being shorter in patient without EDS, but none of them had REM sleep onset. Some patients with FTD may develop narcolepsy-like involuntary sleep attacks, even without complaining of EDS. Involvement of hypothalamus and a subsequent alteration in the orexin levels might be one of the determining factors in this sleep disturbance.

CSF pro-orexin and amyloid-β38 expression in Alzheimer's disease and frontotemporal dementia

“…Sleep disturbance can also be observed in FTD albeit not as commonly ( McCarter et al., 2016 ). Consistent with this, we observed raised CSF pro-orexin in FTD compared with controls but to a lesser extent than AD ( Coban et al., 2013 ). It would be useful in future studies to correlate the presence of sleep symptoms with pro-orexin levels to see whether abnormalities in this protein can predict the presence of sleep disturbance.…”

Wake-active neurons across aging and neurodegeneration: a potential role for sleep disturbances in promoting disease

“…Thus, one possibility is that sleep loss exacerbates the age-related changes in orexinergic neurons through protein dyshomeostasis, eventually leading to the development of a cellular environment that is highly susceptible to neurodegeneration (Brown and Naidoo 2012 )(Roussel et al 2013 ). Consistent with this, AD, PD, and DLB patients have decreased orexin cell numbers compared with age-matched controls (Fronczek et al 2012 )(Thannickal et al 2007 )(Lessig et al 2010 ), and FTLD patients have decreased levels of orexin-A (Çoban et al 2013 ).…”

Sleep symptoms in syndromes of frontotemporal dementia and Alzheimer’s disease: A proof-of-principle behavioural study

“…We adapted items from relevant domains of the Cambridge Behavioural Inventory (Revised) [35] and Pittsburgh Sleep Quality Index [36] or created these de novo, in order to capture sleep symptoms predicted to be most relevant to both FTD and AD [[1], [2], [3], [4],[20], [21], [22], [23]]. The sleep symptom survey is presented in Table 3.…”

“…The disease process in FTD targets sleep circuitry in hypothalamus and basal forebrain [18,19] and patients with FTD have been reported to develop excessive somnolence as well as narcolepsy-like attacks, insomnia and other sleep-related symptoms [[20], [21], [22], [23]]. Sleep disturbance in FTD forms part of a much broader spectrum of homeostatic and related behavioural alterations, also affecting appetite and other biological drives [17,22,24].…”

“…Sleep disturbance in FTD forms part of a much broader spectrum of homeostatic and related behavioural alterations, also affecting appetite and other biological drives [17,22,24]. Whereas AD may be uniquely associated with elevated orexin levels [3], FTD is associated with reduced plasma and CSF orexin that correlates with excessive daytime somnolence [20,25]. These observations suggest that AD and FTD may have distinct sleep phenotypes, and sleep disturbance is potentially a quantifiable biomarker and therapeutic target in these dementias [1,2,26].…”