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.

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.

MicroRNA Candidate Biomarkers for Parkinson’s Disease and Idiopathic REM Sleep Behavior Disorder

Background: Parkinson’s disease (PD), a severe neurodegenerative disorder, and idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD), a parasomnia recognized as the prodromal stage of synucleinopathies (including PD), both lack reliable, non-invasive biomarker tests for early intervention and management. Objectives: To investigate whether plasma extracellular vesicle (EV)-associated sncRNAs could discriminate PD and/or iRBD patients from healthy individuals.Methods: We optimized a cDNA library construction method, EVsmall-seq, for high throughput sequencing of sncRNAs associated with plasma EVs. We profiled EV-sncRNAs from the plasma of 60 normal controls, 56 iRBD patients, and 53 PD patients, and constructed a support vector machine (SVM) classifier to identify the informative miRNA features to distinguish PD and/or iRBD patients from healthy individuals. Results: First, a sixteen-miRNA signature was found to distinguish PD patients from healthy individuals with 88% sensitivity, 90.43% specificity, and 89.13% accuracy. Second, a three-miRNA signature was found to distinguish iRBD patients from healthy individuals with 96% sensitivity, 86.36% specificity, and 91.49% accuracy. Third, tweenty 20 miRNAs were found consistently increased or decreased in expression from healthy subjects to iRBD to PD patients, which might be linked to PD development through iRBD.Conclusions: Current study provides a valuable and highly informative dataset of EV-associated sncRNAs from plasma of iRBD and PD patients. We identified miRNA signature features that could serve as minimally-invasive, blood-based surveillance biomarkers for distinguishing iRBD or PD from healthy individuals with high sensitivity, specificity, and accuracy.

Abnormal REM Sleep Atonia Control in Chronic Post-Traumatic Stress Disorder

Study Objectives Post-traumatic stress disorder (PTSD) and REM sleep behavior disorder (RBD) share some common features including prominent nightmares and sleep disturbances. We aimed to comparatively analyze REM sleep without atonia (RSWA) between patients with chronic PTSD with and without dream enactment behavior (DEB), isolated RBD (iRBD), and controls. Methods In this retrospective study, we comparatively analyzed 18 PTSD with DEB (PTSD+DEB), 18 PTSD without DEB, 15 iRBD, and 51 controls matched for age and sex. We reviewed medical records to determine PTSD clinical features and quantitatively analyzed RSWA. We used non-parametric analyses to compare clinical and polysomnographic features. Results PTSD patients, both with and without DEB, had significantly higher RSWA than controls (all p < 0.025, excepting submentalis phasic duration in PTSD+DEB). Most RSWA measures were also higher in PTSD+DEB than in PTSD without DEB patients (all p <0.025). Conclusions PTSD patients have higher RSWA than controls, whether DEB is present or not, indicating that REM sleep atonia control is abnormal in chronic PTSD. Further prospective studies are needed to determine whether neurodegenerative risk and disease markers similar to RBD might occur in PTSD patients.

Cognition and Driving Ability in Isolated and Symptomatic REM Sleep Behavior Disorder

Study Objectives To analyze cognitive deficits leading to unsafe driving in patients with REM Sleep Behavior Disorder (RBD), strongly associated with cognitive impairment and synucleinopathy-related neurodegeneration. Methods Twenty isolated RBD (iRBD), 10 symptomatic RBD (sRBD), and 20 age- and education-matched controls participated in a prospective case-control driving simulation study. Group mean differences were compared with correlations between cognitive and driving-safety measures. Results iRBD and sRBD patients were more cognitively impaired than controls in global neurocognitive functioning, processing speeds, visuospatial attention, and distractibility (p<0.05). sRBD patients drove slower with more collisions than iRBD patients and controls (p<0.05), required more warnings, and had greater difficulty following and matching speed of a lead car during simulated car-following tasks (p<0.05). Driving-safety measures were similar between iRBD patients and controls. Slower psychomotor speed correlated with more off-road accidents (r=0.65) while processing speed (-0.88), executive function (-0.90) and visuospatial impairment (0.74) correlated with safety warnings in sRBD patients. Slower stimulus recognition was associated with more signal-light (0.64) and stop-sign (0.56) infractions in iRBD patients. Conclusions iRBD and sRBD patients have greater selective cognitive impairments than controls, particularly visuospatial abilities and processing speed. sRBD patients exhibited unsafe driving behaviors, associated with processing speed, visuospatial awareness, and attentional impairments. Our results suggest that iRBD patients have similar driving-simulator performance as healthy controls but that driving capabilities regress as RBD progresses to symptomatic RBD with overt signs of cognitive, autonomic, and motor impairment. Longitudinal studies with serial driving simulator evaluations and objective on-road driving performance are needed.

Objective Sleep Profile in LGI1/CASPR2 Autoimmunity

Study Objectives Rapid eye movement (REM) sleep behavior disorder (RBD) and other sleep disturbances are frequent in leucine-rich, glioma inactivated protein 1-IgG (LGI1) and contactin-associated protein 2-IgG (CASPR2) autoimmunity, yet polysomnographic analyses of these disorders remain limited. We aimed to characterize clinical presentations and analyze polysomnographic manifestations, especially quantitative REM sleep without atonia (RSWA) in LGI1/CASPR2-IgG seropositive (LGI/CASPR2+) patients. Methods We retrospectively analyzed clinical and polysomnographic features and quantitative RSWA between LGI1+/CASPR2+ patients and age-sex matched controls. Groups were compared with Wilcoxon rank-sum and chi-square tests. Combined submentalis and anterior tibialis (SM+AT) RSWA was the primary outcome Results Among 11 (LGI1+, n=9; CASPR2+, n=2) patients, Morvan syndrome sleep features were present in 7 (63.6%) LGI1+/CASPR2+ patients, with simultaneous insomnia and DEB in 3 (27.3%), and the most common presenting sleep disturbances were dream enactment behavior (DEB, n=5), insomnia (n=5), and sleep apnea (n=8; median apnea hypopnea index=15/hour). Median Epworth Sleepiness Scale (ESS) was 9 (range 3-24; n=10), with hypersomnia in 4 (36.4%). LGI1+/CASPR2+ patients had increased N1 sleep (p=0.02), decreased REM sleep (p=0.001), and higher levels of SM+AT any RSWA (p < 0.001). Eight of 9 (89%) LGI1+ exceeded RBD RSWA thresholds (DEB, n=5; isolated RSWA, n=3). RSWA was greater in anterior tibialis than submentalis. All 10 LGI1+/CASPR2+ patients treated with immunotherapy benefitted, and 5/10 had improved sleep disturbances. Conclusion LGI1/CASPR2-IgG autoimmunity is associated with prominent dream enactment, insomnia, RSWA, sleep apnea, and shallower sleep. Polysomnography provides objective disease markers in LGI1+/CASPR2+ autoimmunity and immunotherapy may benefit associated sleep disturbances.

Validation of Visually Identified Muscle Potentials during Human Sleep Using High Frequency/Low Frequency Spectral Power Ratios

Surface electromyography (EMG), typically recorded from muscle groups such as the mentalis (chin/mentum) and anterior tibialis (lower leg/crus), is often performed in human subjects undergoing overnight polysomnography. Such signals have great importance, not only in aiding in the definitions of normal sleep stages, but also in defining certain disease states with abnormal EMG activity during rapid eye movement (REM) sleep, e.g., REM sleep behavior disorder and parkinsonism. Gold standard approaches to evaluation of such EMG signals in the clinical realm are typically qualitative, and therefore burdensome and subject to individual interpretation. We originally developed a digitized, signal processing method using the ratio of high frequency to low frequency spectral power and validated this method against expert human scorer interpretation of transient muscle activation of the EMG signal. Herein, we further refine and validate our initial approach, applying this to EMG activity across 1,618,842 s of polysomnography recorded REM sleep acquired from 461 human participants. These data demonstrate a significant association between visual interpretation and the spectrally processed signals, indicating a highly accurate approach to detecting and quantifying abnormally high levels of EMG activity during REM sleep. Accordingly, our automated approach to EMG quantification during human sleep recording is practical, feasible, and may provide a much-needed clinical tool for the screening of REM sleep behavior disorder and parkinsonism.