Microsleep disturbances are associated with noradrenergic dysfunction in Parkinson’s disease

Abstract

Study Objectives Parkinson’s disease (PD) commonly involves degeneration of sleep-wake regulating brainstem nuclei; likewise, sleep-wake disturbances are highly prevalent in PD patients. As polysomnography macroparameters typically show only minor changes in PD, we investigated sleep microstructure, particularly cyclic alternating pattern (CAP), and its relation to alterations of the noradrenergic system in these patients. Methods We analysed 27 PD patients and 13 healthy control (HC) subjects who underwent over-night polysomnography and 11C-MeNER positron emission tomography for evaluation of noradrenaline transporter density. Sleep macroparameters as well as CAP metrics were evaluated according to the consensus statement from 2001. Statistical analysis comprised group comparisons and correlation analysis of CAP metrics with clinical characteristics of PD patients as well as noradrenaline transporter density. Results PD patients and HC subjects were comparable in demographic characteristics (age, sex, body mass index) and polysomnography macroparameters. CAP rate as well as A index differed significantly between groups, with PD patients having a lower CAP rate (46.7 ± 6.6% versus 38.0 ± 11.6%, p = 0.015) and lower A index (49.0 ± 8.7/hour versus 40.1 ± 15.4/hour, p = 0.042). In PD patients, both CAP metrics correlated significantly with diminished noradrenaline transporter density in arousal prompting brainstem nuclei (locus coeruleus, raphe nuclei) as well as arousal propagating brain structures like thalamus and bitemporal cortex. Conclusions Sleep microstructure is more severely altered than sleep macrostructure in PD patients and is associated with widespread dysfunction of the noradrenergic arousal system.

Noradrenergic circuit control of non-REM sleep substates

“…Furthermore, the human noradrenergic system remains active during NREMS 22 , during which it is critical for memory consolidation 41 , expression of plasticity-related genes 42 and perhaps for dreams 43 . As sleep spindles serve as EEG hallmarks to distinguish light and deep sleep states in human 6 , monitoring the LC in human sleep could also shed light on these and other 9, 44 unique aspects of primate sleep. Finally, there is strong evidence that LC and sleep disruptions could be linked in post-traumatic stress disorders 45 , in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease 44, 46 and in insomnia 47 .…”

“…As sleep spindles serve as EEG hallmarks to distinguish light and deep sleep states in human 6 , monitoring the LC in human sleep could also shed light on these and other 9, 44 unique aspects of primate sleep. Finally, there is strong evidence that LC and sleep disruptions could be linked in post-traumatic stress disorders 45 , in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease 44, 46 and in insomnia 47 . Our findings highlight a need to further develop tools to monitor LC activity in human sleep as a possible neural target for the origin of these sleep disruptions.…”

“…This insight requires a renewal of current models of sleep-wake control in which reciprocal and exclusive antagonism is so far prevalent 58 . We are now able to concretize questions into the origins of a large variety of primary and secondary sleep disorders, in which hyperarousals, autonomic arousals and movement-related arousals prominently feature 9, 44, 47, 51 .…”

“…These events occur preferentially at phases of transitions between sleep stages and lead to higher arousability every 20 -40 s. 44 Intriguingly, the integrity of cyclic alternating patterns has been recently linked to the preservation of noradrenergic terminal density in LC and forebrain. 45 Periodic leg movements that are widespread arousal events in the human sleep are yet another type of sleep-related arousal event on infraslow time scales. 46 Currently available insights thus indicate that noradrenergic signaling is likely important for NREMS across species and in particular in humans, playing critical roles for NREMS substates and the control of arousability, including its alterations in neurodegenerative disorders.…”

The connections of Locus Coeruleus with hypothalamus: potential involvement in Alzheimer’s disease

“…Indeed, LC can be studied by MRI profiting of T1-weighted neuromelanin-sensitive sequences (Galgani et al 2020 ; Liu et al 2017 ), and this approach has already been applied to assess LC involvement in healthy elderly subjects (Liu et al 2020 ), as well as in patients affected by several neurological disorders, including AD, PD, REM-behavior disorder, Multiple system Atrophy, chronic traumatic encephalopathy essential tremor (e.g., García-Lorenzo et al 2013 ; Matsuura et al 2013 ; Isaias et al 2016 ; Betts et al 2019 ). Positron Emission Tomography tracers specific for NA terminal transporters are also under development, such as 11 C-MeNER, which has been tested already in PD patients (Sommerauer et al 2018 ; Doppler et al 2021 ). Those imaging techniques may be used in the near future to directly evaluate LC-NA system integrity in specific target regions, including the hypothalamus (Brumberg et al 2019 ; Andersen et al 2020 ).…”