Progressive dopamine and hypocretin deficiencies in Parkinson’s disease: is there an impact on sleep and wakefulness?

Abstract

Summary Sleep–wake disturbances are frequent in patients with Parkinson’s disease, but prospective controlled electrophysiological studies of sleep in those patients are surprisingly sparse, and the pathophysiology of sleep–wake disturbances in Parkinson’s disease remains largely elusive. In particular, the impact of impaired dopaminergic and hypocretin (orexin) signalling on sleep and wakefulness in Parkinson’s disease is still unknown. We performed a prospective, controlled electrophysiological study in patients with early and advanced Parkinson’s disease, e.g. in subjects with presumably different levels of dopamine and hypocretin cell loss. We compared sleep laboratory tests and cerebrospinal fluid levels with hypocretin‐deficient patients with narcolepsy with cataplexy, and with matched controls. Nocturnal sleep efficiency was most decreased in advanced Parkinson patients, and still lower in early Parkinson patients than in narcolepsy subjects. Excessive daytime sleepiness was most severe in narcolepsy patients. In Parkinson patients, objective sleepiness correlated with decrease of cerebrospinal fluid hypocretin levels, and repeated hypocretin measurements in two Parkinson patients revealed a decrease of levels over years. This suggests that dopamine and hypocretin deficiency differentially affect sleep and wakefulness in Parkinson’s disease. Poorer sleep quality is linked to dopamine deficiency and other disease‐related factors. Despite hypocretin cell loss in Parkinson’s disease being only partial, disturbed hypocretin signalling is likely to contribute to excessive daytime sleepiness in Parkinson patients.

Sleep stability and transitions in patients with idiopathic REM sleep behavior disorder and patients with Parkinson’s disease

“…This delineates the role of the hypocretin system in wake-sleep regulation and in NREM-REM regulation. Cerebrospinal hypocretin levels are often normal or subnormal but there are fewer hypocretinergic neurons in hypothalamus in PD (Wienecke et al, 2012). Surprisingly, one study found high a level of hypocretin-1 (orexin-A) (Bridoux et al, 2013), but the small number of patients limited further conclusions.…”

Intranasal gene delivery for treating Parkinson’s disease: overcoming the blood–brain barrier

“…First, sleep disturbances, such as excessive daytime sleepiness, nocturnal insomnia, and REM sleep behavior disorder (RBD), are common non-motor symptoms of PD, which are thought to arise from the progressive loss of oxerin-producing neurons in the hypothalamus [95][96][97]. Intranasal orexin may be able to normalize the sleep disturbances in PD.…”

Sleep-wake disturbances in the premotor and early stage of Parkinson's disease

“…Second, the loss of dopaminergic transmission in Parkinson's disease not only affects the nigro-striatal projection but also dopaminergic circuits between basal ganglia and brainstem structures (particularly the pedunculopontine and laterodorsal tegmental nucleus), where important neurons of the arousal pathway and for the modulation of sleep stages are located [1,101,108]. Finally, mesocortical dopamine neurons innervate limbic areas (thalamus and hypothalamus) [1,101], where important regulators of sleep-wake cycle are located: a) the master circadian clock in the suprachiasmatic nuclei of the hypothalamus, which mainly involves coordinated expression and activation of various clock genes [109][110][111][112][113][114] and regulation of melatonin production [115], and b) orexin/hypocretin-containing neurons, important excitatory neuromodulators of sleep homeostasis [116], which interestingly seem to be progressively reduced over the course of Parkinson's disease [117].…”