Sleep Disorders in Adults with Prader-Willi Syndrome: Review of the Literature and Clinical Recommendations Based on the Experience of the French Reference Centre

Prader–Willi syndrome (PWS) is a rare, genetic, multisymptomatic, neurodevelopmental disease commonly associated with sleep alterations, including sleep-disordered breathing and central disorders of hypersomnolence. Excessive daytime sleepiness represents the main manifestation that should be addressed by eliciting the detrimental effects on quality of life and neurocognitive function from the patients’ caregivers. Patients with PWS have impaired ventilatory control and altered pulmonary mechanics caused by hypotonia, respiratory muscle weakness, scoliosis and obesity. Consequently, respiratory abnormalities are frequent and, in most cases, severe, particularly during sleep. Adults with PWS frequently suffer from sleep apnoea syndrome, sleep hypoxemia and sleep hypoventilation. When excessive daytime sleepiness persists after adequate control of sleep-disordered breathing, a sleep study on ventilatory treatment, followed by an objective measurement of excessive daytime sleepiness, is recommended. These tests frequently identify central disorders of hypersomnolence, including narcolepsy, central hypersomnia or a borderline hypersomnolent phenotype. The use of wake-enhancing drugs (modafinil, pitolisant) is discussed in multidisciplinary expert centres for these kinds of cases to ensure the right balance between the benefits on quality of life and the risk of psychological and cardiovascular side effects

Brain correlates of apathy in Kleine Levin syndrome: a mean apparent propagator study

International audienceSynopsis Kleine-Levin syndrome (KLS) is a rare neurological disorder characterized by episodes of severe hypersomnia, apathy, cognitive impairment, derealization and behavioral disturbances. Between episodes, patients have normal sleep, mood and behavior. Apathy is a prominent clinical feature of KLS but its pathophysiology is not known. Here we used mean apparent propagator to investigate white matter changes in KLS and correlated diffusion changes with apathy scores. Results showed that the corpus callosum was involved in KLS during episodes and mean RTAP measures in the corpus callosum correlated with apathy scores. Results were in accordance with known motivation-based circuits involving the orbitomedial frontal cortex. Purpose Kleine-Levin syndrome (KLS) is a rare neurological disorder that mainly affects adolescents. KLS is characterized by relapsing-remitting episodes of severe hypersomnia, apathy, cognitive impairment, derealization and behavioral disturbances. Between episodes, patients have normal sleep, mood and behavior [1]. Each episode is of brief duration varying from a week to 1-2 months. No definite cause has been identified [1]. Anatomical MRI scan is normal, but brain scintigraphy can be abnormal during and between episodes [2]. Apathy is a prominent clinical feature of KLS [3] but its pathophysiology in the disease remains to be established. The mechanisms responsible for apathy may involve several circuits connecting the frontal lobes to the basal ganglia [4]. Here, we performed TBSS analyses on the return-to-the-axis probability (RTAP) measures that may be linked to apparent axonal diameter and inflammation [5] to analyze the integrity of white matter (WM) microstructure of healthy volunteers (HV) compared to symptomatic (KLS-S) and asymptomatic (KLS-AS) patients. Methods We prospectively included 20 KLS-AS (mean age: 22.2 ± 8.9 years, 9 males) and 20 HV age and sex-matched one by one. Twelve of these 20 patients were also scanned during episodes (KLS-S). Apathy was assessed using the Starkstein Apathy score [6]. Diffusion-weighted images were acquired using a Siemens Verio 3T with a 12-channel head coil (GRAPPA=2; TR/TE=7.7s/92ms; voxel size: 2.5mm isotropic; 64, 32 and 8 gradient directions for b-values of 1800, 700, and 300 s/mm² respectively) and 8 images without diffusion weighting were also acquired. We preprocessed the images using FSL (fsl.fmrib.ox.ac.uk/fsl/fslwiki/) and included correction for susceptibility (topup) and for eddy current distortions (eddycor) and creation of a binary mask of the brain (bet). Then, we generated RTAP maps of all subjects [7]. Voxelwise statistical analyses were carried out using TBSS, part of the FSL comparing RTAP maps of HV versus KLS-AS, HV versus KLS-S and KLS-AS versus KLS-S (paired t-test). Finally, in the TBSS-based ROI, we computed correlations between clinical scores (disease duration and apathy scores) and mean RTAP measures in this ROI and performed tractography on one healthy subject to determine its projection fibers. Results were considered significant at p<0.05, fully corrected for multiple comparisons across space. Results There were no significant differences in RTAP between HV and KLS-AS. In KLS-S compared to KLS-AS, RTAP increased in the corpus callosum (CC). There was a correlation between apathy scores and mean RTAP in the CC of KLS-S (p=0.03, r=0.61) (see Figure 2). There were no other correlations with clinical scores in KLS-AS as well as in KLS-S. Using the TBSS-ROI as a seed for tractography, fibers passing through the CC with abnormal RTAP measures projected to medial orbitofrontal cortex (see Figure 3). Discussion and conclusion The results highlight the presence of structural changes correlated to the apathy score in the anterior portion of the CC during episodes, a region where fibers project onto the medial orbitofrontal cortex. As, these prefrontal regions are involved in motivation processes [4], this suggests that apathy in KLS could result from difficulties to provide the affective/motivational value of a given behavioral context

The myelin-weighted connectome in Parkinson’s disease

Background Even though Parkinson's disease (PD) is typically viewed as largely affecting gray matter, there is growing evidence that there are also structural changes in the white matter. Traditional connectomics methods that study PD may not be specific to underlying microstructural changes, such as myelin loss. Objective The primary objective of this study is to investigate the PD-induced changes in myelin content in the connections emerging from the basal ganglia and the brainstem. For the weighting of the connectome, we used the longitudinal relaxation rate as a biologically grounded myelin-sensitive metric. Methods We computed the myelin-weighted connectome in 35 healthy control subjects and 81 patients with PD. We used partial least squares to highlight the differences between patients with PD and healthy control subjects. Then, a ring analysis was performed on selected brainstem and subcortical regions to evaluate each node's potential role as an epicenter for disease propagation. Then, we used behavioral partial least squares to relate the myelin alterations with clinical scores. Results Most connections (~80%) emerging from the basal ganglia showed a reduced myelin content. The connections emerging from potential epicentral nodes (substantia nigra, nucleus basalis of Meynert, amygdala, hippocampus, and midbrain) showed significant decrease in the longitudinal relaxation rate (P < 0.05). This effect was not seen for the medulla and the pons. Conclusions The myelin-weighted connectome was able to identify alteration of the myelin content in PD in basal ganglia connections. This could provide a different view on the importance of myelination in neurodegeneration and disease progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Societ

GBA mutations are associated with Rapid eye movement sleep behavior disorder

Rapid eye movement sleep behavior disorder and GBA mutations are both associated with Parkinson’s disease. The GBA gene was sequenced in idiopathic rapid eye movement sleep behavior disorder patients (n = 265), and compared to controls (n = 2240). Rapid eye movement sleep behavior disorder questionnaire was performed in an independent Parkinson’s disease cohort (n = 120). GBA mutations carriers had an OR of 6.24 (10.2% in patients vs. 1.8% in controls, P < 0.0001) for rapid eye movement sleep behavior disorder, and among Parkinson’s disease patients, the OR for mutation carriers to have probable rapid eye movement sleep behavior disorder was 3.13 (P = 0.039). These results demonstrate that rapid eye movement sleep behavior disorder is associated with GBA mutations, and that combining genetic and prodromal data may assist in identifying individuals susceptible to Parkinson’s disease

The role of the melanoma gene MC1R in Parkinson disease and REM sleep behavior disorder

The MC1R gene, suggested to be involved in Parkinson disease (PD) and melanoma, was sequenced in PD patients (n=539) and controls (n=265) from New-York, and PD patients (n=551), rapid eye movement sleep behavior disorder (RBD) patients (n=351) and controls (n=956) of European ancestry. Sixty-eight MC1R variants were identified, including 7 common variants with frequency>0.01. None of the common variants was associated with PD or RBD in the different regression models. In a meta-analysis with fixed-effect model, the p.R160W variant was associated with an increased risk for PD (OR=1.22, 95%CI 1.02-1.47, p=0.03) but with significant heterogeneity (p=0.048). Removing one study that introduced the heterogeneity resulted in nonsignificant association (OR=1.11, 95%CI 0.92-1.35, p=0.27, heterogeneity p=0.57). Rare variants had similar frequencies in patients and controls (10.54% and 10.15%, respectively, p=0.75), and no cumulative effect of carrying more than one MC1R variant was found. The current study does not support a role for the MC1R p.R160W and other variants in susceptibility for PD or RBD

Evidence for the Re-Enactment of a Recently Learned Behavior during Sleepwalking

Animal studies have shown that sequenced patterns of neuronal activity may be replayed during sleep. However, the existence of such replay in humans has not yet been directly demonstrated. Here we studied patients who exhibit overt behaviors during sleep to test whether sequences of movements trained during the day may be spontaneously reenacted by the patients during sleep

GBA variants in REM sleep behavior disorder: a multicenter study

To study the role of GBA variants in the risk for isolated rapid-eye-movement (REM)-sleep behavior disorder (iRBD) and conversion to overt neurodegeneration

Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study

Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 \ub1 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing [hazard ratio (HR) = 3.16], objective motor examination (HR = 3.03), olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), an abnormal DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials