WP3: Sleep protocol, DNA risk score
Scientific background
Psychophysiology of sleep and disease risk
Prof. Dr Pierre Maquet heads the Department of Neurology at the University Hospital of Liège and specializes in the characterization of the early microstructural changes in neurological diseases that predict disease outcome (including in PD). In collaboration with Dr Gilles Vandewalle from the Sleep and Chronobiology Laboratory of the University of Liège, who also heads the GIGA-CRC Human Imaging Unit, they aim to determine the brain bases of the emerging detrimental bidirectional association between sleep alterations over the lifespan and the risk of developing complex brain diseases, including PD and to open up new intervention targets. They are using polygenic risk score (PRS) to provide biological bases to the associations between sleep electrophysiology and the (low) risk for developing diseases, decades prior to typical disease onset. Their recent unpublished work shows that the quality of Rapid Eye Movement (REM) sleep is associated with the PRS for PD in healthy young and older adults. Their current neuroimaging focus is on the LC and the hypothalamus which are essential centers for the regulation of sleep and wakefulness. They showed that LC function and structure are associated with variability in REM sleep quality in healthy younger and older individuals. They further reported region responses across the hypothalamus in the impact of light on wakefulness quality. Their short-term aim is to apply the tools developed by Weiskopf’s and Alkemade’s teams to 150 healthy adults (100 from Liège, 50 from Leipzig) of all ages to establish how subcortical structures may drive the sleep variability of the general population. This will provide the indispensable basis to the understanding of the brain alterations contributing complex diseases through sleep. They will assess how these features relate to the PRS for developing PD and to being de novo PD patients and isolate what underlies the REM sleep alterations found in patients suffering from REM sleep behavioral disorder (RBD), which almost inevitably leads to the onset of PD and is considered as a prodromal phase of PD.
Working plan and methodology
Sleep, genetic risk for PD & patients
We will extend the running IronSleep cohort by follow up MRI and EEG acquisitions measurements at 2y after the first acquisition for the 50 healthy individuals with known polygenic risk score, and 60 patients with increased risk of PD (30 patients with restless leg syndrome with moderately increased risk for PD, 30 prodromal PD patients suffering from RBD), and 15 de novo patients. We will seek confirmation of our initial findings focussed on the LC and extend our analysis beyond the LC. Following encouraging preliminary findings, we will integrate other key sleep and wake centers of the hypothalamus (using developments of WP2). Besides the analyses of functional responses, we will determine how the structural qMRI metrics of the LC, hypothalamus and SN (acquired using development in WP1) relate to the risk of developing PD and to being RBD or de novo PD patients. Our local structural 7T MRI data collection will be complemented by data from partner 1 (WP1 in HC) and partner 5
(WP5, in at risk and de novo patients). Part of our HC (N=20) and patient (N=20) data will be complemented by acquisition at 3T to help bridge 7T MRI data to lower field data of WP4 and thereby contribute to the clinical translation of HISTOPARK. Critically, given that sleep and wakefulness are shaped by a network of subcortical structures rather than by nuclei in isolation, our ultimate goal is to assess how the structural and functional connectivity between the hypothalamus and brainstem nuclei relates to PD risk and onset using models developed in WP6. Specifically, following recent report in animal models that the crosstalk between the LC and lateral hypothalamus (LH) may be critical for REM sleep regulation, we will test whether beyond the characteristics of both nuclei, the functional and structural connectivity between the LC and LH explains sleep variability. We will further determine whether a network including the LC, LH and SN provides a better explanation of the REM sleep alteration found in
relation to PD risk and onset. In addition, as asymmetries in sleep electrophysiology is observed in part of
prodromal RBD and PD patients, sometimes in relation to asymmetry in motor symptoms, we will assess whether the detection of asymmetry in sleep metrics is related to asymmetry in LC, LH and SN function and structure (asymmetry of subcortical degeneration and dysfunction has been reported in RBD and PD). We will also determine whether the same asymmetries can be detected in relation to the PRS to PD. This could provide support for (direct or indirect) causal link between alterations in subcortical structure and sleep alteration and be utilized for early stage diagnostic markers of PD. Following these primary analyses, we will explore whether nuclei of the anterior hypothalamus, i.e. the preoptic area, essential to sleep onset, and the suprachiasmatic nucleus, orchestrating the circadian organization of sleep, should integrate the network of areas significantly shaping REM and non-REM sleep and their links with PD risk and PD onset. All our analyses will include extension of our electrophysiology focus to microstructural elements of sleep, which we showed could be more sensitive in picking up early association between sleep and the neuropathology of neurodegenerative disease (Alzheimer’s disease). We will characterize sleep spindle and slow wave density and rhythmicity, the burst sleep spindle preceding REM sleep bout, REM sleep microarousal, as well as the periodic burst of rapid eye movement occurring during REM, in addition to measure of sleep macrostructure (i.e. based on sleep stages) and power densities of the EEG frequency bands. Critically, the inclusion of longitudinal measurements at 24 months will allow prediction
of the individual trajectories associated with the increased risk for PD and PD onset using tools developed in WP6.
We will recruit a postdoctoral researcher for 3y (following tax-free Belgian scheme) specifically dedicated
to WP3 (with support of other local team members).
Team – University of Liège
Professor Dr Pierre Maquet
