Search Results (51)

(1) Background and Objectives: Parkinson’s disease’s (PD) underlying pathophysiology still remains incompletely understood, with Braak’s hypothesis of ASyn pathology propagation being the most widely accepted. Recently, a novel model has been introduced, proposing two distinct ASyn propagation pathways: a bottom-up trajectory termed Body-first PD, and a central nervous system (CNS)-initiated pathway termed Brain-first PD. This distinction introduces new perspectives in the PD literature landscape regarding diagnosis, prognostic factors and patient management. This study set out to systematically synthesize the current literature comparing Brain-first and Body-first PD, with a focus on clinical characteristics and disease progression, diagnostic biomarkers, and management approaches. (2) Materials and Methods: A systematic literature search was conducted in March 2025 using PubMed, Cochrane Library, DOAJ and Google Scholar. Human observational, diagnostic, and interventional studies published between 2019 and March 2025, including patients with de novo or early PD, were eligible. Pre-motor REM sleep behavioral disorder (RBD) was used as the primary differentiation criterion. Risk of bias was evaluated using the Joanna Briggs Institute (JBI) critical appraisal checklists. Results were synthesized using a narrative approach. (3) Results: Sixteen studies comprising 2107 PD patients met the inclusion criteria. Body-first PD was associated with a higher non-motor symptom (NMS) burden, faster disease progression, and a higher prevalence of cognitive impairment. Additionally, Body-first PD patients exhibited more widespread and symmetrical neurodegeneration, along with electrophysiological and metabolic differences. Distinct biomarker and microbiome profiles were also observed between subtypes. No eligible studies addressing management approaches were identified. (4) Conclusions: In conclusion, the available evidence suggests that Brain-first and Body-first PD may represent two distinct pathophysiological entities, a proposal with great significance for the diagnosis, prognosis and management of PD patients. However, the predominantly cross-sectional nature of the current literature limits causal inference. Future longitudinal and interventional studies are required to clarify the potential clinical implications of this subtype classification theory. Full article

Background: Electromyography (EMG), video-polysomnography (vPSG), and wrist actigraphy are each used to develop diagnostic algorithms for rapid-eye-movement sleep behavior disorder (RBD). However, the extent to which they capture overlapping versus distinct motor phenomena remains unknown. We evaluated the respective contributions of actigraphy, EMG and vPSG to the measurement of REM sleep motor activity. Methods: Seventeen adults with RBD (Mount Sinai n = 9; Stanford n = 8) and eight control participants from an open Newcastle dataset underwent vPSG and concomitant wrist actigraphy. Flexor digitorum superficialis EMG activity and video-detected movements were manually scored in 3 s mini epochs. Actigraphy was quantified using an acceleration-magnitude-based activity count model. Statistical and agreement analyses were performed to assess the motor events captured by all three, any two, or by each modality independently during REM sleep. Results: In participants with RBD, actigraphy-derived movement load was significantly higher during REM sleep than during non-REM stages, a pattern not observed in control participants. REM movement load was also higher in RBD participants compared to controls, although this difference did not remain significant after correction for multiple comparisons. Across 12,941 3 s mini epochs, EMG, actigraphy, and video detected 1703, 1613, and 811 motor events, of which 413 were detected concurrently by all three modalities. Pairwise agreement was moderate and increased from EMG–actigraphy (κ = 0.27 ± 0.10) to actigraphy–video (κ = 0.41 ± 0.12) and EMG–video (κ = 0.45 ± 0.15). Of EMG-detected events, 49.0% were also detected by actigraphy; of actigraphy-detected events, 37.2% were detected by EMG and 34.9% by video. Actigraphy activity counts were highest for events detected by all three modalities and lowest for actigraphy-only events. Conclusions: Actigraphy-measured REM-related motor activity was elevated in RBD but not in controls. EMG, actigraphy, and video captured partially overlapping motor events in RBD patients, with actigraphy showing the highest sensitivity and manually scored video the lowest. Full article

Parkinson’s disease (PD) and associated synucleinopathies are preceded by a prolonged prodromal phase during which neurodegenerative processes evolve years before the onset of motor or cognitive symptoms. Identifying biologically specific and accessible biomarkers during this window is critical for early diagnosis, risk stratification, and the development of disease-modifying therapies. Increasing evidence supports the skin as a key peripheral tissue involved in synucleinopathy, offering a minimally invasive source for in vivo detection of pathological α-synuclein. This review summarizes current evidence on skin-derived biomarkers across the prodromal continuum of PD, with particular emphasis on skin biopsy-based detection of phosphorylated α-synuclein and α-synuclein seed amplification assays (SAAs). Findings in high-risk prodromal phenotypes, including idiopathic REM sleep behavior disorder (iRBD) and pure autonomic failure (PAF), are critically reviewed. Emerging data suggest that cutaneous α-synuclein pathology may precede nigrostriatal dopaminergic degeneration and may predict phenoconversion to overt synucleinopathies. Important knowledge gaps are highlighted, including the lack of data in other prodromal phenotypes such as hyposmia. Overall, skin-based biomarkers appear to represent promising, scalable tools for biological diagnosis, prognostication, and enrichment of prodromal PD cohorts in clinical trials. Full article

Rapid eye movement sleep (REM) is a critical sleep stage associated with several sleep disorders, including sleep apnea and rapid eye movement sleep behavior disorder. Polysomnography (PSG) is the gold standard for identifying REM periods and diagnosing sleep disorders. However, PSG is typically conducted in sleep medicine centers using specialized equipment, where sleep experts assess sleep conditions through measurements such as brain activity, respiration, heart activity, and eye movements. An overnight stay in a sleep laboratory can adversely affect a patient’s natural sleep quality, introducing the risk of iatrogenic sleep disturbances. Recent studies have explored sleep stage detection using lightweight wearable devices, such as smartwatches, which offer lower cost but rely on a limited set of psychological signals. In this study, we propose a machine learning approach for REM sleep staging based solely on breathing rate (BR) and heart rate (HR), without relying on PSG recordings. Experimental evaluations conducted on the Dreamt dataset demonstrate the feasibility of the proposed approach and its potential to provide meaningful information for sleep staging. Future work will focus on developing a fully non-contact REM detection framework by integrating video-based estimation of HR and BR. Full article

Background: Rapid Eye Movement (REM) sleep behavior disorder (RBD) is a parasomnia resulting from degeneration of pontine and medullary circuits responsible for muscle atonia during REM sleep, leading to dream-enactment behaviors and vocalizations. It is strongly linked to α-synucleinopathies, particularly Parkinson’s disease. Current biomarkers such as neurophysiological measures and imaging support diagnosis and monitoring, but remain invasive or costly. Aim: This study aims to evaluate vocal and speech alterations as exploratory, non-validated candidate biomarkers of REM sleep behavior disorder. Methods: A systematic review was conducted according to PRISMA 2020 guidelines. PubMed, IEEE Digital Library Web of Science, Embase and the Cochrane Library were systematically searched for studies published from database inception to November 2025, as preregistered on the Open Science Framework. Studies were selected through a multi-step screening process and underwent qualitative quality assessment. Results: Twelve studies met inclusion criteria. Individuals with RBD exhibited abnormal nocturnal vocalizations and early lexical, syntactic, and narrative disruptions despite preserved perceptual speech. Quantitative analyses identified consistent deficits in prosody, phonation stability, timing, and articulation, with significant group differences and diagnostic accuracy up to 96% sensitivity. Multilingual cohorts demonstrated progression over time, while digital phenotyping detected emerging Parkinsonian signs with AUC > 0.70. Conclusions: Speech and vocal abnormalities in iRBD reflect early neurodegenerative changes and show promising but still exploratory diagnostic and prognostic potential. Integrating vocal markers with established biomarkers may enhance early detection; however, further research is required to validate a reliable and reproducible vocal signature of prodromal synucleinopathies. Full article

REM sleep behavioral disorder (RBD) is of increasing interest in Parkinson’s disease (PD). Previous studies exploring the association between REM sleep without atonia (RWA) and clinical PD features or other objective sleep metrics are scarce and have used PSG findings. A mobile electroencephalography (EEG)/electrooculography (EOG) recording system with two channels can objectively measure sleep parameters, including RWA, during natural sleep at home. We investigated whether RWA measured on a portable recording device at home could be associated with clinical PD features or other sleep metrics using baseline data from the ZEAL study. Differences between patients with and without RWA was analyzed using ANCOVA test. REM sleep length was significantly longer in patients with RWA than in those without RWA. A multivariate comparison using ANCOVA showed a significant difference in log-transformed REM sleep duration of patients with RWA after adjustment for potential confounders (adjusted mean difference of 1.203; 95% confidence interval 0.468 to 1.937; p = 0.003). The strength of this study was that it evaluated the association between RWA during natural sleep at home and clinical variables as well as other sleep metrics. The major result was that patients with and without RWA did not differ in their clinical variables, and there was no relation between RWA and objective sleep metrics other than REM sleep. The duration of REM sleep may be associated with RWA during natural sleep at home. Full article

REM sleep behavior disorder (RBD) represents a prodromal manifestation of Parkinson’s disease (PD), reflecting the breakdown of inhibitory networks extending from the brainstem to the cortex. This review synthesizes pathological, physiological, and behavioral evidence to illustrate how early α-synuclein pathology disrupts REM-sleep atonia and motor automaticity through degeneration of pontomedullary and cholinergic–inhibitory circuits. The resulting failure of inhibitory precision links nocturnal REM sleep without atonia to daytime gait and postural abnormalities, framing RBD as a dynamic systems disorder rather than a purely sleep-related phenomenon. By examining this continuum across neurophysiological, behavioral, and clinical domains, the review highlights current knowledge gaps, particularly regarding the temporal dynamics of degeneration and compensation. It further integrates multimodal biomarkers that capture these transitions in vivo and discusses therapeutic strategies aimed at preserving inhibitory network integrity and delaying phenoconversion to overt Parkinsonian syndromes. Full article

L1 cell adhesion molecule (L1CAM)-positive extracellular vesicles (EVs) are being explored as a potential source of biomarkers for Parkinson’s disease (PD) in peripheral blood. However, their utility remains controversial. In this study, we sought to investigate the proteome composition of L1CAM⁺-EVs isolated from human blood plasma and evaluate their potential as biomarkers for PD. L1CAM⁺-EVs were extracted from blood plasma using direct immunoprecipitation by employing magnetic beads coupled to an anti-L1CAM antibody. The Proximity Extension Assay platform, Olink Explore 3072, was used to analyze samples from 60 individuals: 20 healthy controls (HC), 20 patients with isolated REM sleep behavior disorder (iRBD), and 20 PD patients. Targeted proteomic analysis identified 2841 proteins in L1CAM⁺-EVs, of which 203 exhibited differential expression across groups. Although these changes were not statistically significant, after correction for multiple testing, a combination of 12 proteins could discriminate between PD and HC. Moreover, several proteins displayed trends toward upregulation or downregulation in PD and iRBD when compared with HC. These preliminary findings suggest that L1CAM⁺-EVs proteins show some potential as biomarkers for PD; however, further investigation and validation studies are required. Full article

Parkinson’s disease (PD) is a multisystem disorder, with early changes extending beyond basal ganglia circuitries and involving non-dopaminergic pathways, including cerebellar networks. Whether cerebellar dysfunction reflects a compensatory mechanism or an intrinsic hallmark of disease progression remains unresolved. In this cross-sectional study, we examined how cerebellar γ-aminobutyric acid (GABA) and glutamate/glutamine (Glx) systems, as well as their excitatory/inhibitory (E/I) balance, are modulated along the disease course. As to ascertain how these mechanisms contribute to motor and non-motor features in the premotor and early stages of PD, 18 individuals with isolated REM sleep behavior disorder (iRBD), 20 de novo, drug-naïve PD (dnPD), and 18 matched healthy controls underwent clinical, cognitive, and neuropsychiatric assessments alongside cerebellar magnetic resonance spectroscopy (MRS, MEGA-PRESS, 3T). While cerebellar neurotransmitter levels did not differ significantly across groups, dnPD patients exhibited a shift toward hyperexcitability in the E/I ratio, without correlation to clinical or cognitive measures. In contrast, in iRBD, an inverse relationship between heightened GABAergic activity and neuropsychiatric symptoms emerged. These findings suggest an early, dynamic cerebellar involvement, potentially reflecting compensatory modulation of altered basal ganglia output. Our results support cerebellar GABA MRS as a promising biomarker and open perspectives for targeting non-dopaminergic pathways in PD. Full article

Background: This study aims to investigate the association between the presence and severity of non-motor symptoms (constipation, REM sleep behavior disorder [RBD], hyposmia, and depression) and the severity of motor impairment in Parkinson’s disease (PD). Methods: We used data from Parkinson’s Progression Markers Initiative (PPMI), comprising patients with established PD, prodromal PD, and healthy controls. Motor disability was evaluated with the MDS-UPDRS part III. Non-motor symptoms were assessed with standardized scales for constipation (MDS-UPDRS part I sub-item), depression (15-item GDS), RBD questionnaire (RBDQ), and hyposmia (UPSIT). The relationships between non-motor symptoms and motor severity were explored using linear regression models (adjusted for age/sex). Results: Constipation was significantly more prevalent in PD and prodromal PD and independently associated with greater motor severity in both groups (p < 0.001). Constipation also correlated with increased freezing and falls. Depressive symptoms were similar across groups, but in prodromal PD, higher GDS scores were associated with worse UPDRS III scores (p = 0.02), as well as higher freezing and fall scores. Hyposmia was strongly reduced in PD and prodromal PD compared with controls but was not independently associated with motor severity. Higher RBDQ scores were associated with worse motor impairment in PD, but not in prodromal PD after adjustment. Conclusions: Constipation and REM sleep behavioral disorder were independent correlates of worse motor severity in prodromal and established PD, whereas depressive symptoms predicted more severe parkinsonism only within the prodromal phase. Full article

Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is recognized as a precursor to neurodegenerative diseases. This study aimed to develop predictive models for the timing and subtype of phenoconversion in iRBD. We analyzed comprehensive clinical data from 178 individuals with iRBD over a median follow-up of 3.6 years and applied machine learning models to predict when phenoconversion would occur and whether progression would present with motor- or cognition-first symptoms. During follow-up, 30 patients developed a neurodegenerative disorder, and the extreme gradient boosting survival embeddings–Kaplan neighbors (XGBSE-KN) model demonstrated the best performance for timing (concordance index: 0.823; integrated Brier score: 0.123). Age, antidepressant use, and Movement Disorder Society–Unified Parkinson’s Disease Rating Scale Part III scores correlated with higher phenoconversion risk, while coffee consumption was protective. For subtype classification, the RandomForestClassifier achieved the highest performance (Matthews correlation coefficient: 0.697), indicating that higher Montreal Cognitive Assessment scores and younger age predicted motor-first progression, whereas longer total sleep time was associated with cognition-first outcomes. These findings highlight the utility of machine learning in guiding prognosis and tailored interventions for iRBD. Future research should include additional biomarkers, extend follow-up, and validate these models in external cohorts to ensure generalizability. Full article

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by loss of muscle atonia and abnormal behaviors occurring during REM sleep. Idiopathic RBD (iRBD) is recognized as the strongest prodromal hallmark of α-synucleinopathies, with an established conversion rate to a neurodegenerative condition that reaches up to 96.6% at 15 years of follow-up. Moreover, RBD-converters display a more severe clinical trajectory compared to those that do not present with RBD. However, the extent to which iRBD represents a distinct genetic entity or an early manifestation of neurodegeneration remains unclear. To address this, we applied Genomic Structural Equation Modeling (GenomicSEM) using a GWAS-by-subtraction approach to disentangle the genetic architecture of iRBD from the shared genomic liability across α-synucleinopathies. Our findings highlight the SNCA locus as a key genetic regulator of iRBD susceptibility. While iRBD exhibits a partially distinct genetic signature, residual genomic overlap with neurodegenerative traits suggests that its genetic architecture exists along a continuum of α-synucleinopathy risk. In this scenario, the associations with neuroanatomical correlates may serve as early indicators of a trajectory toward future neurodegeneration. These findings provide a framework for identifying biomarkers that could aid in disease stratification and risk prediction, potentially improving early intervention strategies. Full article

Alpha-synuclein has been associated with neurodegeneration, especially in Parkinson’s disease (PD). This study aimed to review clinical, biochemical, and neuroimaging markers and management of prodromal synucleinopathies. The prodromal state of synucleinopathies can be better understood with PD pathophysiology, and it can be separated into premotor and pre-diagnostic phases. The incidence of PD in patients with prodromal phase symptoms ranges from 0.07 to 14.30, and the most frequently studied pathology is the REM behavioral disorder (RBD). Neuroimaging markers are related to dopamine denervation, brain perfusion changes, gross anatomy changes, and peripheral abnormalities. α-synuclein assays (SAA) in CSF revealed high sensitivity (up to 97%) and high specificity (up to 92%); in the last decade, there was the development of other matrices (blood, skin, and olfactory mucosa) for obtaining quantitative and qualitative α-synuclein. Other biomarkers are neurofilament light chain, DOPA decarboxylase, and multiplexed mass spectrometry assay. Regarding genetic counseling in α-synucleinopathies, it is an important topic in clinical practice to discuss with patients with high-risk individuals and should involve basic principles of autonomy, beneficence, and non-maleficence. Some of the themes that should be reviewed are the involvement of physical activity, diet (including alcohol, coffee, and vitamin supplementation), smoking, sleep, and stress in the pathophysiology of synucleinopathies. The number of trials related to prodromal symptoms is still scarce, and the number of studies evaluating intervention is even lower. Full article

(1) Background: Phasic events in rapid eye movement (REM) sleep are a core feature of isolated REM behavior disorder (iRBD), which is often associated with emotion dysregulation. This study explores the relationship between sleep and the overnight habituation of emotional reactivity in healthy controls (HCs) and iRBD patients, focusing on the role of REM phasic events and a specific non-REM waveform, namely sleep spindles. (2) Methods: Participants underwent polysomnography and completed arousal rating tasks and mood scales before and after sleep. In total, eight HCs (4 M, mean age 60.62 ± 6.8) and eight iRBD patients (7 M, mean age 68.25 ± 5.12) were included in the analyses. (3) Results: In HCs, longer REM sleep duration correlated positively with overnight habituation. In the whole sample, overnight habituation negatively correlated with REM sleep latency and wake-after-sleep onset, and positively with N2 sleep. Higher overnight habituation was associated with fewer REM arousals and awakenings in the whole sample, and with greater N2 sleep spindle density in HCs. (4) Conclusions: Our preliminary results suggest that REM sleep and spindles in N2 play critical roles in emotional processing. The study confirms the relationship between emotion dysregulation and REM phasic events, enhancing our understanding of how sleep impacts emotional reactivity and also in the prodromal phase of neurodegenerative disease. Full article

Alpha-synuclein (α-syn) is a 140-amino-acid, intrinsically disordered, soluble protein that is abundantly present in the brain. It plays a crucial role in maintaining cellular structures and organelle functions, particularly in supporting synaptic plasticity and regulating neurotransmitter turnover. However, for reasons not yet fully understood, α-syn can lose its physiological role and begin to aggregate. This altered α-syn disrupts dopaminergic transmission and causes both presynaptic and postsynaptic dysfunction, ultimately leading to cell death. A group of neurodegenerative diseases known as α-synucleinopathies is characterized by the intracellular accumulation of α-syn deposits in specific neuronal and glial cells within certain brain regions. In addition to Parkinson’s disease (PD), these conditions include dementia with Lewy bodies (DLBs), multiple system atrophy (MSA), pure autonomic failure (PAF), and REM sleep behavior disorder (RBD). Given that these disorders are associated with α-syn-related neuroinflammation—and considering that SARS-CoV-2 infection has been shown to affect the nervous system, with COVID-19 patients experiencing neurological symptoms—it has been proposed that COVID-19 may contribute to neurodegeneration in PD and other α-synucleinopathies by promoting α-syn misfolding and aggregation. In this review, we focus on whether SARS-CoV-2 could act as an environmental trigger that facilitates the onset or progression of α-synucleinopathies. Specifically, we present new evidence on the potential role of SARS-CoV-2 in modulating α-syn function and discuss the causal relationship between SARS-CoV-2 infection and the development of parkinsonism-like symptoms. Full article