REM Sleep Behavior Disorder Research Articles

Analysis of striatal connectivity corresponding to striosomes and matrix in de novo Parkinson’s disease and isolated REM behavior disorder

Striosomes and matrix are two compartments that comprise the striatum, each having its own distinct immunohistochemical properties, function, and connectivity. It is currently not clear whether prodromal or early manifest Parkinson’s disease (PD) is associated with any striatal matrix or striosomal abnormality. Recently, a method of striatal parcellation using probabilistic tractography has been described and validated, using the distinct connectivity of these two compartments to identify voxels with striosome- and matrix-like connectivity. The goal of this study was to use this approach in tandem with DAT-SPECT, a method used to quantify the level of nigrostriatal denervation, to analyze the striatum in populations of de novo diagnosed, treatment-naïve patients with PD, isolated REM behavioral disorder (iRBD) patients, and healthy controls. We discovered a shift in striatal connectivity, which showed correlation with nigrostriatal denervation. Patients with PD exhibited a significantly higher matrix-like volume and associated connectivity than healthy controls and higher matrix-associated connectivity than iRBD patients. In contrast, the side with less pronounced nigrostriatal denervation in PD and iRBD patients showed a decrease in striosome-like volume and associated connectivity indices. These findings could point to a compensatory neuroplastic mechanism in the context of nigrostriatal denervation and open a new avenue in the investigation of the pathophysiology of Parkinson’s disease.

An Event Detection Mechanism with Deep Feature Extraction and Optimal Loss Function Based XGBoost Classifier

Purpose: Interoceptions are a combination of sensation, integration, and interpretation of internal bodily signals. Interoceptions are bidirectionally related to the human being mental and physiological health, and well-being. Sleep and different interoceptive modalities are proven to share common relations. Heartbeat Evoked Potential (HEP) is known as a robust readout to interoceptive processes. In this study, we focused on the relation between HEP modulations and sleep-related disorders. Materials and Methods: We investigated four different sleep-related disorders, including insomnia, rapid eye movement behavior disorder, periodic limb movements and nocturnal frontal lobe epilepsy, and provided HEP signals of multiple Electroencephalogram (EEG) channels over the right hemisphere to compare these disorders with the control group. Here, we investigated and compared the results of 35 subjects, including seven subjects for the control group and seven subjects for each of above-mentioned sleep disorders. Results: By comparing HEP responses of the control group with sleep-related patients’ groups, statistically significant HEP differences were detected over right hemisphere EEG channels, including FP2, F4, C4, P4, and O2 channels. These significant differences were also observed over the grand average HEP amplitude activity of channels over the right hemisphere in the sleep-related disorders as well. Conclusion: Our results between the control group and groups of patients suffering from sleep-related disorders demonstrated that during different stages of sleep, HEPs show significant differences over multiple right hemisphere EEG channels. Interestingly, by comparing different sleep disorders with each other, we observed that each of these HEP differences’ patterns over specific channels and during certain sleep stages bear considerable resemblances to each other.

Investigation of Heartbeat Evoked Potential (HEP) Response During Different Stages of Sleep in Sleep Disorders

Purpose: Interoceptions are a combination of sensation, integration, and interpretation of internal bodily signals. Interoceptions are bidirectionally related to the human being mental and physiological health, and well-being. Sleep and different interoceptive modalities are proven to share common relations. Heartbeat Evoked Potential (HEP) is known as a robust readout to interoceptive processes. In this study, we focused on the relation between HEP modulations and sleep-related disorders. Materials and Methods: We investigated four different sleep-related disorders, including insomnia, rapid eye movement behavior disorder, periodic limb movements and nocturnal frontal lobe epilepsy, and provided HEP signals of multiple Electroencephalogram (EEG) channels over the right hemisphere to compare these disorders with the control group. Here, we investigated and compared the results of 35 subjects, including seven subjects for the control group and seven subjects for each of above-mentioned sleep disorders. Results: By comparing HEP responses of the control group with sleep-related patients’ groups, statistically significant HEP differences were detected over right hemisphere EEG channels, including FP2, F4, C4, P4, and O2 channels. These significant differences were also observed over the grand average HEP amplitude activity of channels over the right hemisphere in the sleep-related disorders as well. Conclusion: Our results between the control group and groups of patients suffering from sleep-related disorders demonstrated that during different stages of sleep, HEPs show significant differences over multiple right hemisphere EEG channels. Interestingly, by comparing different sleep disorders with each other, we observed that each of these HEP differences’ patterns over specific channels and during certain sleep stages bear considerable resemblances to each other.

Distinctive sleep complaints and polysomnographic findings in antibody subgroups of autoimmune limbic encephalitis

IntroductionSleep disturbances are being increasingly recognized in association with autoimmune encephalitis (AIE). We investigated the prevalence of sleep-related symptoms and polysomnographic features of patients with AIE and the long-term outcomes in these patients in a multi-center, prospective study from Turkey.MethodsWe prospectively evaluated patients with definite AIE in a common database including demographics, AIE-related and sleep-related symptomatology. Maximum and latest modified Rankin scores (mRS) and Liverpool Outcome Score (LOS) were noted.ResultsOf 142 patients, 87 patients (61.3%) fulfilled the criteria for definite AIE (mean age, 46.8+18.8 years; 51.7% women; mean disease duration, 21.0+38.4 months). 78.9% of patients had at least one or more new onset or worsened sleep-related symptomatology: insomnia (55.3%), excessive daytime sleepiness (EDS, 28.0%), sleep apnea (18.7%), REM sleep behavior disorder (RBD, 17.3%), restless legs syndrome (10.7%) and oneiric stupor (9.3%). Sleep efficiency, N3 and REM sleep were decreased and N1 sleep was increased in patients with Ab[+] AIE. LOS points were highest in those with insomnia and sleep apnea, and lowest in those with EDS, RBD and oneiric stupor. RBD and sleep apnea were more common in anti-LG1 Ab[+] group than anti-NMDAR Ab[+] group. Index of periodic leg movements was highest in anti-LG1 Ab[+] group. Patients with EDS and oneiric stupor had more common memory problems. Maximum and latest mRS scores were positively correlated with EDS and oneiric stupor. EDS, RBD and oneiric stupor were negatively correlated with LOS points.ConclusionOur study emphasizes the presence and importance of early diagnosis of sleep disturbances in AIE in regard to their deteriorative influences on disease prognosis.

Plasma proteomics identify biomarkers predicting Parkinson’s disease up to 7 years before symptom onset

Parkinson’s disease is increasingly prevalent. It progresses from the pre-motor stage (characterised by non-motor symptoms like REM sleep behaviour disorder), to the disabling motor stage. We need objective biomarkers for early/pre-motor disease stages to be able to intervene and slow the underlying neurodegenerative process. Here, we validate a targeted multiplexed mass spectrometry assay for blood samples from recently diagnosed motor Parkinson’s patients (n = 99), pre-motor individuals with isolated REM sleep behaviour disorder (two cohorts: n = 18 and n = 54 longitudinally), and healthy controls (n = 36). Our machine-learning model accurately identifies all Parkinson patients and classifies 79% of the pre-motor individuals up to 7 years before motor onset by analysing the expression of eight proteins—Granulin precursor, Mannan-binding-lectin-serine-peptidase-2, Endoplasmatic-reticulum-chaperone-BiP, Prostaglaindin-H2-D-isomaerase, Interceullular-adhesion-molecule-1, Complement C3, Dickkopf-WNT-signalling pathway-inhibitor-3, and Plasma-protease-C1-inhibitor. Many of these biomarkers correlate with symptom severity. This specific blood panel indicates molecular events in early stages and could help identify at-risk participants for clinical trials aimed at slowing/preventing motor Parkinson’s disease.

Developing disease-modifying interventions in idiopathic REM sleep behavior disorder and early synucleinopathy

Alpha-synucleinopathies are prevalent neurological disorders that cause significant disability, leading to progressive clinical deterioration that is currently managed solely through symptomatic treatment. Efforts to evaluate disease-modifying therapies during the established stage of the disease have not yielded positive outcomes in terms of clinical or imaging efficacy endpoints. However, alpha-synucleinopathies have a long prodromal phase that presents a promising opportunity for intervention with disease-modifying therapies. The presence of polysomnography-confirmed REM sleep behavior disorder (RBD) is the most reliable risk factor for identifying individuals in the prodromal stage of alpha-synucleinopathy. This paper discusses the rationale behind targeting idiopathic/isolated RBD in disease-modifying trials and outlines possible study designs, including strategies for patient stratification, selection of biomarkers to assess disease progression and patient eligibility, as well as the identification of suitable endpoints. Additionally, the potential targets for disease-modifying treatment in alpha-synucleinopathies are summarized.

REM sleep and neurodegeneration.

Several brainstem, subcortical and cortical areas are involved in the generation of rapid eye movement (REM) sleep. The alteration of these structures as a result of a neurodegenerative process may therefore lead to REMsleep anomalies. REM sleep behaviour disorder is associated with nightmares, dream-enacting behaviours and increased electromyographic activity in REM sleep. Its isolated form is a harbinger of synucleinopathies such as Parkinson's disease or dementia with Lewy bodies, and neuroprotective interventions are advocated. This link might also be present in patients taking antidepressants, with post-traumatic stress disorder, or with a history of repeated traumatic head injury. REM sleep likely contributes to normal memory processes. Its alteration has also been proposed to be part of the neuropathological changes occurring in Alzheimer's disease.

Nonmotor Symptoms and Impulse Control Disorders in Parkinson's Disease Patients in India: A Cross-sectional Study.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder with significant nonmotor symptom (NMS) burden, including impulse control disorders. This study aimed to comprehensively evaluate NMS and impulse control disorders in PD patients under primary care. A descriptive cross-sectional study was conducted on 32 PD patients and evaluated using standardized assessment tools. Demographics, comorbidities, and symptom burdens were recorded. Evaluation tools included the Hoehn and Yahr Scale, REM Sleep Behavior Disorder assessment, Geriatric Depression Scale, Montreal Cognitive Assessment scale for cognitive impairment, NMS scale, and identification of impulse control disorders. In PD, comorbidities were prevalent (84%), and most were at Hoehn and Yahr Stages 2 and 3. REM Sleep Behavior Disorder was present in 28.12%, with 5 receiving clonazepam treatment. Depression affected 28.12%, with 5 receiving pharmacological treatment. Cognitive impairment was notable in 9 patients. NMS burden was high, with varying severity. Impulse control disorders were limited, whereas one case of dopamine dysregulation syndrome was identified. This primary care-based study in India assessed NMS and impulse control disorders in PD patients, highlighting comorbidities and management opportunities. The study's strength lies in evaluating an unselected primary care population, whereas limitations include small sample size. This study emphasizes the importance of primary care physicians in monitoring and managing NMS in PD patients. Impulse control disorders and cognitive impairment are critical aspects that need attention. The findings support an integrated approach involving health-care professionals across various disciplines to provide holistic care for PD patients.

Symmetric and Profound Monoaminergic Degeneration in Parkinson's Disease with Premotor REM Sleep Behavior Disorder.

Rapid eye movement sleep behavior disorder (RBD) may precede or follow motor symptoms in Parkinson's disease (PD). While over 70% of idiopathic RBD cases phenoconvert within a decade, a small subset develops PD after a more extended period or remains nonconverted. These heterogeneous manifestations of RBD in PD prompt subtype investigations. Premotor RBD may signify "body-first" PD with bottom-up, symmetric synucleinopathy propagation. Explore brainstem and nigrostriatal monoaminergic degeneration pattern differences based on premotor RBD presence and duration in de novo PD patients. In a cross-sectional analysis of de novo PD patients (n = 150) undergoing FP-CIT PET and RBD Single-Question Screen, the cohort was categorized into groups with and without premotor RBD (PDRBD+/-), with further classification of PDRBD+ based on a 10-year duration of premotor RBD. Analysis of FP-CIT binding in the striatum and pons, striatal asymmetry, and striatum-to-pons ratios compared patterns of nigrostriatal and brainstem monoaminergic degeneration. PDRBD+ exhibited more severe and symmetrical striatal dopaminergic denervation compared to PDRBD-, with the difference in severity accentuated in the least-affected hemisphere. The PDRBD+<10Y subgroup displayed the most prominent striatal symmetry, supporting a more homogeneous "body-first" subtype. Pontine uptakes remained lower in PDRBD+ even after adjusting for striatal uptake, suggesting early degeneration of pontine monoaminergic nuclei. Premotor RBD in PD is associated with severe, symmetrical nigrostriatal and brainstem monoaminergic degeneration, especially in cases with PD onset within 10 years of RBD. This supports the concept of a "widespread, bottom-up" pathophysiological mechanism associated with premotor RBD in PD.

A Machine Learning Approach for Early Identification of Prodromal Parkinson's Disease.

Parkinson's disease (PD) affects approximately 6 million people worldwide. Data analysis of early PD symptoms using machine learning (ML) models may provide an inexpensive, non-invasive, and simple method for the remote diagnosis of early PD. The aim of this project was to analyze voice, computer keystrokes, spiral drawings, and gait data involving PD patients and controls available in public databases using ML models and identify early PD characteristics that are more pronounced than others. An ML model was developed using Random Forest to analyze existing clinical data for PD patients, prodromal PD patients with REM (rapid eye movement) sleep behavior disorder (RBD) symptoms, and non-PD healthy controls. We reviewed and collected data from the UCI (University of California Irvine) Machine Learning Repository, PPMI (Parkinson's Progression Markers Initiative), and Kaggle databases. ML analysis was carried out on voice samples in PD and RBD patients, computer keystroke data, spiral drawings, and gait datasets. The ML prediction model developed may be helpful in improving risk prediction for PD, enabling early intervention and resource prioritization. The ML study suggests that voice analysis is the most robust test, followed by computer keystroke data, spiral drawings, and gait analysis, in that order. Voice is affected even in RBD patients, revealing that it is a sensitive and early measure of prodromal PD. The low accuracy of the analysis indicates that several PD-positive samples may remain undetected and unclassified. Combining all four features, that is, voice analysis, computer keystroke data, spiral drawings, and gait analysis, may improve the overall accuracy.

Evaluating the Impacts of Parasomnias on Sleep and Exploring Their Therapeutic Interventions

Sleep disorders are topics of important discussion as they apply to a function crucial for the growth and development of individuals. Sleep plays a pivotal role in one's long-term health but various disorders may limit or prevent high-quality sleep for children and adults. One of these common disorder groups is parasomnias. As there is still much to learn in medicine when it comes to parasomnias and their treatments, it is of utmost importance to understand the processes behind the occurrence of parasomnias and their associated conditions. This review breaks down the most common parasomnias, categorizing them based on the onset of disease during rapid eye movement (REM) or non-rapid eye movement (NREM) sleep stages. This includes somnambulism (sleepwalking), confusional arousals, night terrors, REM behavior disorder (RBD), nightmare disorder, and others. It highlights the characteristics of diagnosis for these individual disorders and attempts to evaluate them through an etiological, epidemiological, and pathophysiological lens. This review also presents the current pharmacological and non-pharmacological interventions for these disorders.

Sleep and circadian rhythm dysfunctions in movement disorders beyond Parkinson's disease and atypical parkinsonisms.

This review aimed to comprehensively outline sleep and circadian rhythm abnormalities in hyperkinetic movement disorders beyond Parkinson's disease and atypical parkinsonisms, including tremor, dystonia, choreiform movements, tics, and ataxia disorders. Insomnia, poor sleep quality, and excessive daytime sleepiness (EDS) are commonly reported in essential tremor, Wilson's disease, tics or Tourette's syndrome, and spinocerebellar ataxia (SCA). REM sleep behavior disorder (RBD) have been observed in Wilson's disease and SCA. A combination of REM and non-REM parasomnias, along with nocturnal stridor with the initiation of sleep and re-entering after awakening, are characterized by undifferentiated Non-REM and poorly structured N2 in anti-IgLON5 disease. Restless legs syndrome (RLS) has been reported commonly in SCAs. Sleep-related dyskinesia has been reported in ADCY5-related disease and GNAO1-related movement disorder. Sleep problems can manifest as a result of movement disorders, either through direct motor disturbances or secondary nonmotor symptoms. Medication effects must be considered, as certain medications for movement disorders can exacerbate or alleviate sleep disturbances. Distinguishing sleep problems in some diseases might involve pathognomonic symptoms and signs, aiding in the diagnosis of movement disorders.

Genetic analysis and natural history of Parkinson's disease due to the LRRK2 G2019S variant.

The LRRK2 G2019S variant is the most common cause of monogenic Parkinson's disease (PD); however, questions remain regarding the penetrance, clinical phenotype and natural history of carriers. We performed a 3.5-year prospective longitudinal online study in a large number of 1286 genotyped LRRK2 G2019S carriers and 109 154 controls, with and without PD, recruited from the 23andMe Research Cohort. We collected self-reported motor and non-motor symptoms every 6 months, as well as demographics, family histories and environmental risk factors. Incident cases of PD (phenoconverters) were identified at follow-up. We determined lifetime risk of PD using accelerated failure time modelling and explored the impact of polygenic risk on penetrance. We also computed the genetic ancestry of all LRRK2 G2019S carriers in the 23andMe database and identified regions of the world where carrier frequencies are highest. We observed that despite a 1 year longer disease duration (P = 0.016), LRRK2 G2019S carriers with PD had similar burden of motor symptoms, yet significantly fewer non-motor symptoms including cognitive difficulties, REM sleep behaviour disorder (RBD) and hyposmia (all P-values ≤ 0.0002). The cumulative incidence of PD in G2019S carriers by age 80 was 49%. G2019S carriers had a 10-fold risk of developing PD versus non-carriers. This rose to a 27-fold risk in G2019S carriers with a PD polygenic risk score in the top 25% versus non-carriers in the bottom 25%. In addition to identifying ancient founding events in people of North African and Ashkenazi descent, our genetic ancestry analyses infer that the G2019S variant was later introduced to Spanish colonial territories in the Americas. Our results suggest LRRK2 G2019S PD appears to be a slowly progressive predominantly motor subtype of PD with a lower prevalence of hyposmia, RBD and cognitive impairment. This suggests that the current prodromal criteria, which are based on idiopathic PD, may lack sensitivity to detect the early phases of LRRK2 PD in G2019S carriers. We show that polygenic burden may contribute to the development of PD in the LRRK2 G2019S carrier population. Collectively, the results should help support screening programmes and candidate enrichment strategies for upcoming trials of LRRK2 inhibitors in early-stage disease.

Metacognitive accuracy differences in Parkinson's disease and REM sleep behavioral disorder relative to healthy controls.

Metacognition is the ability to monitor and self-assess cognitive performance. It can be impaired in neurodegenerative diseases, with implications for daily function, and the ability of patients to reliably report their symptoms to health professionals. However, metacognition has not been systematically assessed in early-mid stage Parkinson's disease (PD) and REM sleep behavioral disorder (RBD), a prodrome of PD. This study aimed to evaluate metacognitive accuracy and self-confidence in PD and RBD patients across various cognitive tasks. We conducted detailed computerized cognitive assessments with 19 cognitive tasks within an established PD and RBD cohort. Participants self-rated their performance post-task. Metacognitive accuracy was calculated by comparing these ratings against objective performance and further analyzed against clinical and mental health factors. PD and RBD patients' metacognitive accuracy aligned with control subjects. However, they exhibited lower confidence across cognitive domains, reflecting their reduced cognitive performance. A notable inverse correlation was observed between their confidence and MDS-UPDRS I and II scales and HADS anxiety and depression scores. Our findings indicate that patients with early to mid-stage PD and RBD are generally aware of their cognitive status, differing from other neurological disorders. The inverse relationship between patient confidence and symptoms of depression, anxiety, and daily life challenges underscores the impact of emotional and functional difficulties on their self-perception of cognitive abilities. This insight could be significant for understanding how these conditions affect mental health, aiding clinicians in developing more effective patient care strategies.

Decreased heart rate variability in sympathetic dominant states in Parkinson's disease and isolated REM sleep behavior disorder

IntroductionParkinson's disease (PD) presents with decreased heart rate variability (HRV) from its early stages. However, most of its evidence originates from HRV measurements in parasympathetic dominant states. In this study, we aimed to examine whether HRV in sympathetic dominant states during the head-up tilt table test (HUT) serves as a marker of autonomic dysfunction in PD and isolated REM sleep behavior disorder (iRBD). MethodsWe retrospectively assessed 102 patients with PD, 10 patients with iRBD, and 43 healthy controls. We then measured the coefficient of variation of RR intervals as an HRV parameter in sympathetic dominant states (CVRR-S) and parasympathetic dominant states (CVRR-P). Furthermore, we evaluated parameters of cardiac autonomic function, including HUT and the heart-to-mediastinum (H/M) ratio of cardiac metaiodobenzylguanidine scintigraphy. ResultsPatients with iRBD and PD at Hoehn and Yahr stage I exhibited a significantly decreased CVRR-S compared to healthy controls (controls vs. iRBD vs. PD; 1.82 ± 0.64 % vs. 1.13 ± 0.41 % vs. 1.15 ± 0.51 %, p < 0.001), although no further deterioration was observed in PD at more severe Hoehn and Yahr stages. CVRR-S showed a significant correlation with the H/M ratio in PD (r = 0.51, p < 0.001). Additionally, receiver operating characteristic (ROC) analysis revealed a larger area under the ROC curve in CVRR-S compared to that in CVRR-P for discriminating PD or iRBD from healthy controls. ConclusionHRV in sympathetic dominant states shows the potential to be a marker of autonomic dysfunction in iRBD and early-stage PD, aiding in early diagnosis and patient stratification.

REM sleep behaviour disorder (RBD): Personal perspectives and research priorities.

The formal identification and naming of rapid eye movement (REM) sleep behaviour disorder (RBD) in 1985-1987 is described; the historical background of RBD from 1966 to 1985 is briefly discussed; and RBD milestones are presented. Current knowledge on RBD is identified with reference to recent comprehensive reviews, allowing for a focus on research priorities for RBD: factors and predictors of neurodegenerative phenoconversion from isolated RBD and patient enrolment in neuroprotective trials; isolated RBD clinical research cohorts; epidemiology of RBD; traumatic brain injury, post-traumatic stress disorder, RBD and neurodegeneration; depression, RBD and synucleinopathy; evolution of prodromal RBD to neurodegeneration; gut microbiome dysbiosis and colonic synuclein histopathology in isolated RBD; other alpha-synuclein research in isolated RBD; narcolepsy-RBD; dreams and nightmares in RBD; phasic REM sleep in isolated RBD; RBD, periodic limb movements, periodic limb movement disorder pseudo-RBD; other neurophysiology research in RBD; cardiac scintigraphy (123I-MIBG) in isolated RBD; brain magnetic resonance imaging biomarkers in isolated RBD; microRNAs as biomarkers in isolated RBD; actigraphic, other automated digital monitoring and machine learning research in RBD; prognostic counselling and ethical considerations in isolated RBD; and REM sleep basic science research. RBD research is flourishing, and is strategically situated at an ever-expanding crossroads of clinical (sleep) medicine, neurology, psychiatry and neuroscience.

Genetic associations between Rapid Eye Movement (REM) sleep behavior disorder and cardiovascular diseases.

Previous studies revealed that sleep disorders are potential risk factors for cardiovascular diseases, such as obstructive sleep apnea and rapid eye movement (REM) sleep behavior disorder (RBD). However, the causal associations between RBD and cardiovascular diseases remained unknown. We used the latest and largest summary-level genome-wide association studies of RBD, stroke and its subtypes, coronary artery disease (CAD), myocardial infarction (MI), and heart failure (HF) to select genetic variants as the instrumental variables. Mendelian randomization (MR) analysis was performed to test the causal associations between RBD and the cardiovascular diseases above. Inverse variance weighted method was used as the main analysis. After multiple comparisons, genetically predicted RBD was significantly associated with the risk of HF [odds ratio (OR) = 1.033, 95% CI 1.013-1.052, p = 0.001]. Leave-one-out analysis further supported the robustness of the causal association. Furthermore, we identified a suggestive association between genetically predicted MI and RBD (OR = 0.716, 95% CI 0.546-0.940, p = 0.016). However, in our study no associations were identified of RBD with CAD or stroke and its subtypes. Our study highlighted the potential associations between RBD and cardiovascular diseases at genetic level, including HF and MI. More studies were required to clarify the biological mechanisms involved the associations.

Molecular beacon-based detection of circulating microRNA-containing extracellular vesicle as an α-synucleinopathy biomarker.

Early and precise diagnosis of α-synucleinopathies is challenging but critical. In this study, we developed a molecular beacon-based assay to evaluate microRNA-containing extracellular vesicles (EVs) in plasma. We recruited 1203 participants including healthy controls (HCs) and patients with isolated REM sleep behavior disorder (iRBD), α-synucleinopathies, or non-α-synucleinopathies from eight centers across China. Plasma miR-44438-containing EV levels were significantly increased in α-synucleinopathies, including those in the prodromal stage (e.g., iRBD), compared to both non-α-synucleinopathy patients and HCs. However, there are no significant differences between Parkinson's disease (PD) and multiple system atrophy. The miR-44438-containing EV levels negatively correlated with age and the Hoehn and Yahr stage of PD patients, suggesting a potential association with disease progression. Furthermore, a longitudinal analysis over 16.3 months demonstrated a significant decline in miR-44438-containing EV levels in patients with PD. These results highlight the potential of plasma miR-44438-containing EV as a biomarker for early detection and progress monitoring of α-synucleinopathies.

Lysosomal and synaptic dysfunction markers in longitudinal cerebrospinal fluid of de novo Parkinson’s disease

Lysosomal and synaptic dysfunctions are hallmarks in neurodegeneration and potentially relevant as biomarkers, but data on early Parkinson’s disease (PD) is lacking. We performed targeted mass spectrometry with an established protein panel, assessing autophagy and synaptic function in cerebrospinal fluid (CSF) of drug-naïve de novo PD, and sex-/age-matched healthy controls (HC) cross-sectionally (88 PD, 46 HC) and longitudinally (104 PD, 58 HC) over 10 years. Multiple markers of autophagy, synaptic plasticity, and secretory pathways were reduced in PD. We added samples from prodromal subjects (9 cross-sectional, 12 longitudinal) with isolated REM sleep behavior disorder, revealing secretogranin-2 already decreased compared to controls. Machine learning identified neuronal pentraxin receptor and neurosecretory protein VGF as most relevant for discriminating between groups. CSF levels of LAMP2, neuronal pentraxins, and syntaxins in PD correlated with clinical progression, showing predictive potential for motor- and non-motor symptoms as a valid basis for future drug trials.

Glutamate Signaling in Patients With Parkinson Disease With REM Sleep Behavior Disorder.

Clinical heterogeneity of patients with Parkinson disease (PD) is well recognized. PD with REM sleep behavior disorder (RBD) is a more malignant phenotype with faster motor progression and higher nonmotor symptom burden. However, the neural mechanisms underlying this clinical divergence concerning imbalances in neurotransmitter systems remain elusive. Combining magnetic resonance (MR) spectroscopy and [11C]ABP688 PET on a PET/MR hybrid system, we simultaneously investigated two different mechanisms of glutamate signaling in patients with PD. Patients were grouped according to their RBD status in overnight video-polysomnography and compared with age-matched and sex-matched healthy control (HC) participants. Total volumes of distribution (VT) of [11C]ABP688 were estimated with metabolite-corrected plasma concentrations during steady-state conditions between 45 and 60 minutes of the scan following a bolus-infusion protocol. Glutamate, glutamine, and glutathione levels were investigated with single-voxel stimulated echo acquisition mode MR spectroscopy of the left basal ganglia. We measured globally elevated VT of [11C]ABP688 in 16 patients with PD and RBD compared with 17 patients without RBD and 15 HC participants (F(2,45) = 5.579, p = 0.007). Conversely, glutamatergic metabolites did not differ between groups and did not correlate with the regional VT of [11C]ABP688. VT of [11C]ABP688 correlated with the amount of REM sleep without atonia (F(1,42) = 5.600, p = 0.023) and with dopaminergic treatment response in patients with PD (F(1,30) = 5.823, p = 0.022). Our results suggest that patients with PD and RBD exhibit altered glutamatergic signaling indicated by higher VT of [11C]ABP688 despite unaffected glutamate levels. The imbalance of glutamate receptors and MR spectroscopy glutamate metabolite levels indicates a novel mechanism contributing to the heterogeneity of PD and warrants further investigation of drugs targeting mGluR5.