Early Daytime Sleepiness and Nighttime Slow-wave Sleep Disorganization in Progressive Macaque Model of Parkinson’s Disease

Parkinsonian patients often experience wake/sleep behavior disturbances, which can appear at an early stage of the disease in a way that is still not fully described. We aimed here at reproducing and characterizing these clinical signs in a progressive non-human primate model of the Parkinson’s disease to better understand the underlying physiopathology and to identify biomarkers of the disease. Three adult non-human primates (macaca fascicularis) were equipped with a polysomnographic telemetry system allowing the characterization of the wake/sleep behavior by long-term neurophysiological recordings and a modified multiple sleep latency test. Experiments were first performed in healthy animals and then during the progressive induction of a parkinsonian syndrome by chronic intramuscular injections of low doses of MPTP. We observed a significant early onset of wake/sleep behavior disturbances, before any motor symptoms, resulting in (i) a disorganization of nighttime sleep with more deep sleep and (ii) a disorganization of daytime naps with an excessive daytime sleepiness characterized by longer duration of naps, which occurred faster. These observations persisted and worsened in stable symptomatic state. In that latter state, we observed persistent excessive daytime sleepiness and more disorganized nighttime sleep architecture and continuity. Interpolating to the human condition, the present study suggests that nighttime and daytime sleep disorders may appear in early stage of the disease. They could thus be used as biomarkers of the disease for early stratification of patients who are at risk of developing Parkinson’s disease.

The Statin Target HMG-Coenzyme a Reductase (Hmgcr) Regulates Sleep Homeostasis in Drosophila

Statins, HMG Coenzyme A Reductase (HMGCR) inhibitors, are a first-line therapy, used to reduce hypercholesterolemia and the risk for cardiovascular events. While sleep disturbances are recognized as a side-effect of statin treatment, the impact of statins on sleep is under debate. Using Drosophila, we discovered a novel role for Hmgcr in sleep modulation. Loss of pan-neuronal Hmgcr expression affects fly sleep behavior, causing a decrease in sleep latency and an increase in sleep episode duration. We localized the pars intercerebralis (PI), equivalent to the mammalian hypothalamus, as the region within the fly brain requiring Hmgcr activity for proper sleep maintenance. Lack of Hmgcr expression in the PI insulin-producing cells recapitulates the sleep effects of pan-neuronal Hmgcr knockdown. Conversely, loss of Hmgcr in a different PI subpopulation, the corticotropin releasing factor (CRF) homologue-expressing neurons (DH44 neurons), increases sleep latency and decreases sleep duration. The requirement for Hmgcr activity in different neurons signifies its importance in sleep regulation. Interestingly, loss of Hmgcr in the PI does not affect circadian rhythm, suggesting that Hmgcr regulates sleep by pathways distinct from the circadian clock. Taken together, these findings suggest that Hmgcr activity in the PI is essential for proper sleep homeostasis in flies.

Progressive Prefrontal Cortex Dysfunction in Parkinson's Disease With Probable REM Sleep Behavior Disorder: A 3-Year Longitudinal Study

This study aimed to explore the disrupted prefrontal cortex activity specific to patients with Parkinson's disease (PD) with rapid eye movement sleep behavior disorder (RBD) compared with those without and to further examine the associations between these alterations and neuropsychological measurements. Ninety-six patients with early PD underwent both structural and functional MRI, and also neuropsychological assessments in the Parkinson's Progression Markers Initiative (PPMI) database. Of these, 46 patients who completed 1- and 3-year fMRI follow-up examinations were categorized as PD with probable RBD (PD-pRBD+) and without (PD-pRBD−). The left dorsolateral prefrontal cortex (DLPFC) seed-to-voxel functional connectivity analysis was conducted to evaluate the progressive neural alterations specific to PD-pRBD+ compared with PD-pRBD− over time. Furthermore, relationships between these alterations and neuropsychological performance were examined. Compared with patients with PD-pRBD−, patients with PD-pRBD+ initially exhibited connectivity deficits between the left DLPFC and the medial frontopolar cortex. Moreover, these patients further exhibited disrupted DLPFC connectivity in the lateral frontopolar cortex at the 3-year follow-up evaluation. Correlation analysis revealed that connectivity between the left DLPFC and frontopolar cortex was positively related to executive function in PD-pRBD+ after adjusting for nuisance variables. Progressive prefrontal cortex dysfunction associated with RBD in early PD may provide an effective subtype-specific biomarker of neurodegenerative progression, which may shed light on the neuropathological mechanisms underlying the clinical heterogeneity of this disease.

The cyclic interaction between daytime behavior and the sleep behavior of laboratory dogs

Sleep deprivation has been found to negatively affect an individual´s physical and psychological health. Sleep loss affects activity patterns, increases anxiety-like behaviors, decreases cognitive performance and is associated with depressive states. The activity/rest cycle of dogs has been investigated before, but little is known about the effects of sleep loss on the behavior of the species. Dogs are polyphasic sleepers, meaning the behavior is most observed at night, but bouts are also present during the day. However, sleep can vary with ecological and biological factors, such as age, sex, fitness, and even human presence. In this study, kennelled laboratory adult dogs’ sleep and diurnal behavior were recorded during 24-h, five-day assessment periods to investigate sleep quality and its effect on daily behavior. In total, 1560 h of data were analyzed, and sleep metrics and diurnal behavior were quantified. The relationship between sleeping patterns and behavior and the effect of age and sex were evaluated using non-parametric statistical tests and GLMM modelling. Dogs in our study slept substantially less than previously reported and presented a modified sleep architecture with fewer awakenings during the night and almost no sleep during the day. Sleep loss increased inactivity, decreased play and alert behaviors, while increased time spent eating during the day. Males appeared to be more affected by sleep fragmentation than females. Different age groups also experienced different effects of sleep loss. Overall, dogs appear to compensate for the lack of sleep during the night by remaining inactive during the day. With further investigations, the relationship between sleep loss and behavior has the potential to be used as a measure of animal welfare.

Cardiovascular Risk Factors and Phenoconversion to Neurodegenerative Synucleinopathies in Idiopathic REM Sleep Behavior Disorder

Several studies have suggested that atherosclerotic diseases and diabetes may be risk factors for α-synucleinopathies. This prospective cohort study evaluated whether cardiovascular diseases and metabolic risk factors alter the rate or type of phenoconversion from idiopathic/isolated REM sleep behavior disorder (iRBD) to parkinsonism or dementia. Polysomnography-confirmed iRBD patients recruited between 2004 and 2020 were followed annually. Baseline history of cardiovascular disorders, hypertension, hypercholesterolemia, and diabetes were compared among patients who developed outcomes versus those who remained outcome-free. No atherosclerotic risk factors were associated with development of α-synucleinopathies. Patients with hypercholesterolemia were somewhat more likely to develop dementia with Lewy bodies rather than Parkinson’s disease.

Sex Differences in Brain and Cognition in de novo Parkinson's Disease

Background and Objective: Brain atrophy and cognitive impairment in neurodegenerative diseases are influenced by sex. We aimed to investigate sex differences in brain atrophy and cognition in de novo Parkinson's disease (PD) patients.Methods: Clinical, neuropsychological and T1-weighted MRI data from 205 PD patients (127 males: 78 females) and 69 healthy controls (40 males: 29 females) were obtained from the PPMI dataset.Results: PD males had a greater motor and rapid eye movement sleep behavior disorder symptomatology than PD females. They also showed cortical thinning in postcentral and precentral regions, greater global cortical and subcortical atrophy and smaller volumes in thalamus, caudate, putamen, pallidum, hippocampus, and brainstem, compared with PD females. Healthy controls only showed reduced hippocampal volume in males compared to females. PD males performed worse than PD females in global cognition, immediate verbal recall, and mental processing speed. In both groups males performed worse than females in semantic verbal fluency and delayed verbal recall; as well as females performed worse than males in visuospatial function.Conclusions: Sex effect in brain and cognition is already evident in de novo PD not explained by age per se, being a relevant factor to consider in clinical and translational research in PD.

The Parkinson’s Disease Progression Neuroimaging Initiative

The Parkinson’s Disease Progressive Neuroimaging Initiative (PDPNI) is a longitudinal observational clinical study. In PDPNI, the clinical and imaging data of patients diagnosed with Parkinsonian syndromes and Idiopathic rapid eye movement sleep behavior disorder (RBD) were longitudinally followed every two years, aiming to identify progression biomarkers of Parkinsonian syndromes through functional imaging modalities including FDG-PET, DAT-PET imaging, ASL MRI, and fMRI, as well as the treatment conditions, clinical symptoms, and clinical assessment results of patients. From February 2012 to March 2019, 224 subjects (including 48 healthy subjects and 176 patients with confirmed PDS) have been enrolled in PDPNI. The detailed clinical information and clinical assessment scores of all subjects were collected by neurologists from Huashan Hospital, Fudan University. All subjects enrolled in PDPNI were scanned with 18F-FDG PET, 11C-CFT PET, and MRI scan sequence. All data were collected in strict accordance with standardized data collection protocols.