Non-motor Symptoms Research Articles

How to advance the pharmacological management of cognitive impairment in Parkinson's disease

Cognitive impairment is a common non-motor symptom in people with Parkinson's disease (PD) and is associated to poor clinical outcomes. Currently, rivastigmine is the only approved medication for PD dementia, and there are no treatments available for people with PD and mild cognitive impairment. To advance the pharmacological management of cognitive impairment in PD, it is essential to optimize clinical trial design. This includes refining cognitive outcome measures, ensuring longer study durations, and incorporating PD-specific cognitive assessments. Biomarkers offer valuable opportunities for screening, stratification, enrichment, and monitoring in trials, increasing the likelihood of detecting treatment effects. Additionally, adopting patient-centered approaches that prioritize inclusivity can enhance trial validity and address the current lack of diversity in PD studies. Digital cognitive assessments offer a promising tool for improving participation and enabling longitudinal monitoring, especially in underrepresented and mobility-challenged populations. By tackling these challenges, this review outlines strategies for advancing the pharmacological management of cognitive impairment in PD. It emphasizes the need for precise, inclusive, and biomarker-driven trials to accelerate drug development.

Challenges and Opportunities in Exploring Non-Motor Symptoms in 6-Hydroxydopamine Models of Parkinson's Disease: A Systematic Review.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of midbrain dopaminergic neurons, leading to motor symptoms such as tremors, rigidity, and bradykinesia. Non-motor symptoms, including depression, hyposmia, and sleep disturbances, often emerge in the early stages of PD, but their mechanisms remain poorly understood. The 6-hydroxydopamine (6-OHDA) rodent model is a well-established tool for preclinical research, replicating key motor and non-motor symptoms of PD. In this review, we systematically analyzed 135 studies that used 6-OHDA rodent models of PD to investigate non-motor symptoms. The review process adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Our analysis highlights the growing use of 6-OHDA PD models for experimental research of non-motor symptoms. It also reveals significant variability in methodologies, including choices of brain target, toxin dosage, lesion verification strategies, and behavioral assessment reporting. Factors that hinder reproducibility and comparability of findings across studies. We highlight the need for standardization in 6-OHDA-based models with particular emphasis on consistent evaluation of lesion extent and reporting of the co-occurrence of non-motor symptoms. By fostering methodological coherence, this framework aims to enhance the reproducibility, reliability, and translational value of 6-OHDA models in PD non-motor symptom research.

Effectiveness of 12 weeks of listening to Gayatri Mantra in the management of non-motor symptoms in patients with Parkinson’s disease: A pilot study

Background: Parkinson’s patients experience non-motor symptoms along with motor symptoms that include autonomic deregulation, insomnia, decline in cognition, and psychological distress. Although it is known that mantra chanting offers multiple beneficial effects, the scientific studies related to these are limited. Aims and Objectives: The present study aimed to observe the effectiveness of listening to the Gayatri Mantra in managing non-motor symptoms in patients with Parkinson’s disease. Materials and Methods: The present pilot study recruited 20 patients with Parkinson’s disease. The patients acted as self-controls. After recording the baseline values, the participants were asked to listen to the Gayatri Mantra 108 chanting twice a day for 12 weeks. After 12 weeks of listening, post-intervention values were recorded and analyzed. Sleep quality was assessed using the insomnia severity index. Stress levels were assessed using the perceived stress scale. Spatial and verbal memory tests were used to assess the memory scores. Blood pressure was recorded using the Diamond Original Mercurial Regular BP Monitor (Multicolor). The pulse rate was recorded manually in the radial artery. Results: There was a significant decrease in the perceived stress scores followed by the intervention (P<0.01). Sleep quality was improved in the participants followed by listening to the Gayatri Mantra chanting. There was an improvement in the spatial and verbal memory scores. Systolic and diastolic pressure was decreased and remained within normal limits followed by the intervention. The pulse rate was significantly decreased followed by the intervention. Conclusion: The study results provide preliminary evidence that listening to the Gayatri Mantra has positive effects on the management of the non-motor symptoms of Parkinson’s disease patients. However, there is a need for more studies with higher sample sizes to recommend the implementation of the Gayatri Mantra in the management of Parkinson’s disease.

Sleep spindle variation in patients with Parkinson's disease on first nights of sub-optimal deep brain stimulation.

Deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) is a common treatment for motor symptoms of Parkinson's disease but its influence on non-motor symptoms is less clear. Sleep spindles are known to be reduced in patients with Parkinson's disease, but the effect of STN DBS is unknown. The objective of our study was to address this knowledge gap. Polysomnograms were recorded for three consecutive nights in 15 patients with advanced Parkinson's disease (11 male, 4 female; age: 53-75years), including at least one night each of unilateral STN DBS stimulation ON and OFF. Stimulation ON was set to 70% of clinical amplitude to mitigate sleep being altered via changing motor symptoms or due to patient awareness of stimulation. Sleep spindles were detected in electroencephalogram (EEG) data by two previously published, validated automated sleep spindle detection algorithms: Ferrarelli et al. (2007) and Martin et al. (2013). Sleep spindle density was higher during stimulation ON than OFF nights in 11 of 12 subjects using either sleep spindle detection algorithm (p<=0.01, Wilcoxon rank sum). Stimulation ON versus OFF had no statistically significant effect on sleep spindle duration or amplitude. Our analysis indicates that a single night of sub-optimal STN stimulation significantly increases sleep spindle density in Parkinson's disease patients. These results further our understanding of how DBS impacts non-motor symptoms of Parkinson's disease.

Neurological and psychiatric characterization of rapid-onset dystonia-parkinsonism over time.

The onset of symptoms in Rapid-onset dystonia-parkinsonism (RDP) is typically over days to weeks and is often triggered by stressors like fever or childbirth. Limited information is available on how the motor and nonmotor symptoms evolve over the course of the disease. Our longitudinal study analyzed data from a cohort of RDP patients, documenting their symptoms across multiple visits. We characterized the phenotypic evolution of 14 individuals positive for ATP1A3 mutations (7 females, 7 males; mean examination age=37 years, mean age of onset=20 years). We focused on neurologic, cognitive, and neuropsychological data collected during in-person visits (mean interval between testing=5½ years). Initially, all participants exhibited bulbar symptoms. Headaches were noted in 50%, seizures in 31%, and tremors in 36%. At follow-up, 29% of those initially without headaches developed them, 22% without prior seizures experienced them, and 56% previously without tremors developed them. No improvements were seen in those with headaches; however, seizures and tremors improved in 25% and 80% of cases, respectively. For Burke-Fahn-Marsden Dystonia Rating Scale, Unified Parkinson's Disease Rating Scale, and International Cooperative Ataxia Rating Scale scores, improvement consisted of the reduction of the symptom. Cognitive functions improved from mildly impaired to low-average, and psychiatric evaluations indicated mild anxiety levels, slight increases in obsessive-compulsive behaviors, and decreased depression scores over time. This longitudinal analysis highlights the complex evolution of RDP, demonstrating significant variability in motor function and other symptoms such as headaches, seizures, and tremors.

The novel p.A30G SNCA pathogenic variant in Greek patients with familial and sporadic Parkinson's disease.

The p.A53T variant in the SNCA gene was considered, until recently, to be the only SNCA variant causing familial Parkinson's disease (PD) in the Greek population. We identified a novel heterozygous p.A30G (c.89 C>G) SNCA pathogenic variant in five affected individuals of three Greek families, leading to autosomal dominant PD. This study aims to further explore the presence and phenotypic expression of this variant in the Greek PD population. Restriction fragment length polymorphism (RFLPs) was used for genotyping of 664 Greek PD cases. Detailed clinical information was obtained for the carriers and p.A30G-positive samples underwent haplotype analysis. We identified 10 additional p.A30G-positive PD patients (1.5%), of whom 4 were sporadic cases (0.9%). They manifested typical Parkinsonian motor dysfunction, with a mean age of onset of 51.7 years (range: 33-62) and a broad spectrum of non-motor symptoms. The absence of affected first degree relatives in four out of ten index cases, and the presence of a phenocopy in an additional family, suggest that the p.A30G variant manifests reduced penetrance. The common haplotype among the p.A30G carriers confirmed a founder effect. Furthermore, two asymptomatic carriers were identified, with possible premotor manifestations. These findings underscore that the p.A30G SNCA pathogenic variant represents an important, albeit rare, cause of genetic PD in the Greek population. This is the first time in which a genetic synucleinopathy, with a variant in the SNCA gene, is clearly linked to an appreciable frequency of sporadic PD in a particular population.

Immediate effect of electrical vestibular stimulation on autonomic and respiratory parameters and reaction time in patients with Parkinson’s disease

Background: Both the electrical and natural vestibular stimulation were reported to alter both the blood pressure and motor output of respiration. After a thorough review of the literature, the studies observed the immediate effect of vestibular stimulation on autonomic and respiratory functions is sparse. Hence, the present study was undertaken. Aims and Objectives: The present study was undertaken to observe the immediate effect of electrical vestibular stimulation on autonomic and respiratory parameters in patients with Parkinson’s disease (PD). Materials and Methods: The present study recruited 30 patients with PD after obtaining written informed consent. After recording the baseline values, a single session of stimulation was administered to the participants and soon after recorded the participants. Blood pressure was recorded by Diamond BPDG 141 Deluxe Multicolor LED Mercury Free BP Monitor. Pulse rate and respiratory rate were recorded manually. Auditory and visual reaction times were recorded using the RT apparatus. Results: There was a significant decrease in the systolic (P=0.011) and diastolic blood pressure (P=0.002) after the stimulation. The pulse rate was decreased significantly (P=0.071) followed by the vestibular stimulation. No change in the respiratory rate was observed followed by the vestibular stimulation. There was a significant decrease in the visual reaction time for red (P=0.0087) and green light (P=0.0007), as a result of the intervention. Auditory reaction time for low pitch (P=0.0056) was significantly decreased followed by the intervention. Conclusion: The study results support that a single session of electrical vestibular stimulation has beneficial effects on blood pressure and reaction time in patients with PD. Further detailed studies are recommended with long-term administration of electrical stimulation to recommend the use of electrical vestibular nerve stimulation in the management of non-motor symptoms in PD patients.

Differential gait features across Parkinson's disease clinical subtypes.

Clinical subtypes in Parkinson's disease including non-motor manifestations may be more beneficial than subtypes based upon motor manifestations alone. Inclusion of gait metrics may help identity targets for rehabilitation and potentially predict development of non-motor symptoms for individuals with Parkinson's disease. This study aims to characterize gait differences across established multi-domain subtypes. "Motor Only", "Psychiatric & Motor" and "Cognitive & Motor" clinical subtypes were established through motor, cognitive, and psychiatric assessment. Walking was assessed in the "OFF" medication state. Multivariate analysis of variance identified differences in gait domains across clinical subtypes. The "Motor Only" subtype exhibited the fastest velocity, longest step length, and least timing variability (swing, step, stance), compared to "Psychiatric & Motor" and "Cognitive & Motor" subtypes. Stance time differed across subtypes; "Psychiatric & Motor" subtype had the longest stance time, followed by "Cognitive & Motor", then "Motor only". The "Psychiatric & Motor" group had different asymmetry from the "Cognitive & Motor" subtype, as "Psychiatric & Motor" walked with longer steps on their less-affected side while the "Cognitive & Motor" subtype displayed the opposite pattern. No differences were observed for swing time, step velocity variability, step length variability, width measures, or other asymmetry measures. Cognitive and Psychiatric subtypes displayed worse gait performance than the "Motor only" group. Stance time and step length asymmetry were different between Psychiatric and Cognitive subtypes, indicating gait deficits may be related to distinct aspects of non-motor manifestations. Gait signatures may help clinicians distinguish between non-motor subtypes, guiding personalized treatment.

Pramipexole decreases allodynia and hyperalgesia via NF-κB in astrocytes in rats with Parkinson's disease.

Pain is one of the principal non-motor symptoms of Parkinson's disease (PD), negatively impacting the patient's quality of life. This study aimed to demonstrate whether an effective dose of pramipexole (PPX) can modulate the NF-κB/p-p65 activation in glial cells (astrocytes and microglia) and diminish the hypersensitivity (allodynia and hyperalgesia) in male Wistar rats with PD. For this, 2μl of 6-hydroxydopamine (6-OHDA, 8μg/μL/0.2μl/min) was administered unilaterally in the Substantia Nigra of the Pars Compacta (SNpc) to establish a PD model rat. Motor behavioral tests were used to validate the PD model, and von Frey filaments were used to evaluate allodynia and hyperalgesia. Immunohistochemical and immunofluorescence were used to analyze the level of tyrosine hydroxylase in SNpc and striatum as well as the expression of GFAP, Iba-1, NF-κB/p-65 in the L4-L6 spinal cord dorsal horn. Unilateral 6-OHDA-lesion reduces motor capacity and produces long-term allodynia and hyperalgesia in both hind paws. L4-L6 spinal cord dorsal horn astrocytes and microglia were active in these 6-OHDA-lesioned rats. Moreover, PPX (1 and 3mg/Kg, i.p./10days, n=10 per group) inhibited the bilateral mechanical hypersensitivity, and PPX (3mg/Kg/i.p./10days) reduced 6-OHDA-induced astrocyte and microglia activation, as well as reduced NF-κB/p-p65 expression only in astrocytes of dorsal horn spinal cord in the L5-L6. These findings suggest that PPX could alleviate pain by decreasing the activation of microglia and astrocytes through the NF-κB/p-p65 pathway in the dorsal horn spinal cord. Therefore, PPX could be considered an optional tool for improving pain hypersensitivity in PD patients.

Prognostic factors for long-term outcomes of bilateral pallidal deep brain stimulation in the treatment of Meige syndrome.

This study aimed to investigate the effects of bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) on both motor and nonmotor symptoms in patients with Meige syndrome and to further explore prognostic factors for postoperative outcomes based on the long-term follow-up results. The authors retrospectively reviewed the medical records of a consecutive cohort of patients with refractory Meige syndrome who underwent GPi-DBS at their center from January 2016 to October 2023. Motor function, quality of life, neuropsychological status, and emotional state were assessed using standardized scales at baseline and every 3-6 months thereafter. Univariate and multivariate linear regression analyses were performed to identify independent risk factors affecting long-term motor function after GPi-DBS in patients with steady-state (stable) Meige syndrome. Fifty steady-state patients were ultimately included and assessed, with a mean follow-up duration of 62.9 ± 24.8 months. At the final postoperative evaluation, Burke-Fahn-Marsden Dystonia Rating Scale movement and disability scores showed improvements of 69% (p < 0.001) and 61% (p < 0.001), respectively. A significant improvement from baseline was observed in postoperative scores on the 36-item Short-Form General Health Survey. Throughout continuous neurostimulation, global cognitive function, neuropsychological status, and mood remained stable. Multivariate linear regression analysis revealed that longer disease duration (standardized β-coefficient -0.375, 95% CI -0.033 to -0.011; p < 0.001) and reduced volume of activated tissue within the sensorimotor subregion of the GPi (standardized β-coefficient 0.597, 95% CI 0.002-0.003; p < 0.001) were independently associated with worse long-term motor performance. Bilateral GPi-DBS is an effective, safe, and promising treatment option for intractable Meige syndrome and provides sustained benefits in motor function and quality of life without inducing cognitive or mood-related side effects. Early intervention and accurate electrode placement in the sensorimotor subregion of the GPi are essential for optimizing long-term therapeutic outcomes.

Non-motor symptoms in prodromal Parkinson's disease are linked to reduced quality of life

Non-motor symptoms in prodromal Parkinson's disease are linked to reduced quality of life

Effect of Botulinum toxin on non-motor symptoms in adult-onset idiopathic focal/segmental dystonia.

Non-motor symptoms, including depression, anxiety, sleep disturbances, pain and cognitive dysfunction, are a much more important predictor of quality of life than the severity of dystonia. To assess the effect of Botulinum toxin on non-motor symptoms and quality of life in patients with adult-onset idiopathic focal dystonia. Patients aged > 18years diagnosed with idiopathic focal dystonia were recruited in this longitudinal cohort study. The severity of dystonia, non-motor symptoms, and quality of life were evaluated using the BFMDRS, DNMSQuest, and EQ-5D at baseline and 1 and 3months after botulinum toxin. 65 patients were recruited with a median age of 59years. Blepharospasm was the most common phenomenology. 49.2% of patients had depression at baseline assessed using the Beck Depression Inventory (BDI). There was a significant negative correlation between baseline BFMDRS, DNMSQuest, BDI, and HAM-A scores and quality of life, but there was no relation with the type of focal dystonia. The mean percentage improvement in the BFMDRS-M, BFMDRS-D, DNMSQuest, BDI, HAM-A and EQ-5D was 25%, 52%, 16%,20%,23% and 23%, respectively, at one month. There was no statistically significant correlation between percentage change in motor scores compared to depression and quality of life scores at one month. Botulinum toxin improved motor and non-motor scores and quality of life at 1 and 3months after botulinum toxin therapy. The motor scores did not correlate with depression and DNMSQUEST scores but showed a weak positive correlation with anxiety scores.

Clinically probable RBD is an early predictor of malignant non-motor Parkinson’s disease phenotypes

Non-motor symptoms (NMS) in Parkinson’s disease (PD) significantly impact quality of life, especially in later stages. REM sleep behavior disorder (RBD) affects approximately 42% of all PD patients and frequently precedes motor PD symptoms. RBD is linked to increased rates of depression and cognitive decline. This study explores how early RBD can predict the development of NMS profiles in patients, comparing those with and without early RBD. We identified a unique NMS profile associated with early RBD. These patients had a higher rate of cognitive impairment (M2 = 326.84, p < 0.001), apathy (M2 = 332.93, p < 0.001), hallucinations (M2 = 480.05, p < 0.001), depression (M2 = 480.05, p < 0.0001), anxiety (corrected p < 0.01), impulse control disorders (M2 = 77.577, p < 0.001), and autonomic dysfunction (F = 251.8, p < 0001). A survival analysis revealed an association between early RBD and faster progression to cognitive impairment. These NMS profiles may play a critical role in stratifying patients for targeted interventions.

α-Phellandrene: A Promising Natural Remedy for Rotenone-Induced Parkinson's Disease.

Parkinson's Disease (PD) is a neurodegenerative disorder characterized by the pro-gressive loss of dopaminergic neurons in the substantia nigra, leading to motor dysfunction and non-motor symptoms. Current treatments primarily offer symptomatic relief without halt-ing disease progression. This has driven the exploration of natural compounds with neuropro-tective properties. In previous studies, α-phellandrene, a monoterpene present in essential oils of various aromatic plants, has shown promise in mitigating neurodegenerative processes. This study focuses on alpha-phellandrene's therapeutic potential in a rotenone-induced Parkinson's Disease model. Rotenone, a mitochondrial complex I inhibitor, is commonly used to induce PD-like symptoms in experimental models due to its ability to mimic the neurodegenerative processes observed in human PD. Our review explores the neuroprotective effects of alpha-phellandrene, focusing on its antioxidant, anti-inflammatory, and anti-apoptotic properties. Experimental groups of rodents received rotenone to induce PD-like symptoms, followed by alpha-phellandrene treatment. Biochemical analyses were performed to measure oxidative stress markers, inflammatory cytokines, and apoptotic signals in brain tissues. Results indi-cated that alpha-phellandrene administration significantly improved motor function and re-duced rotenone-induced oxidative stress, inflammation, and apoptosis in dopaminergic neu-rons. Histopathological examinations revealed a notable preservation of neuronal integrity in alpha-phellandrene-treated groups compared to controls. In conclusion, alpha-phellandrene demonstrates considerable neuroprotective effects in a rotenone-induced Parkinson's dmodel. These findings suggest that alpha-phellandrene could be a promising natural therapeutic agent for PD, warranting further investigation into its mechanisms of action and potential clinical applications. Specifically, our review indicates that alpha-phellandrene may exert neuropro-tective effects by various mechanisms, such as reducing oxidative stress, modulating neuro-transmitter levels, or inhibiting neuroinflammation. These mechanisms highlight its potential to alleviate PD symptoms and slow disease progression, underscoring the need for in-depth studies to validate these therapeutic effects in clinical settings.

Altered Intra- and Inter-Network Resting-State Functional Connectivity is Associated with Neuropsychological Functioning and Clinical Symptoms in Patients with Isolated Rapid Eye Movement Sleep Behavior Disorder.

Isolated rapid-eye movement (REM) sleep behavior disorder (iRBD) is characterized by abnormal behaviors in REM sleep and is considered as a prodromal symptom of alpha-synucleinopathies. Resting-state functional magnetic resonance imaging (rsfMRI) studies have unveiled altered functional connectivity (rsFC) in patients with iRBD. However, the associations between intra- and inter-network rsFC with clinical symptoms and neuropsychological functioning in iRBD remain unclear. To characterize intra- and inter-network rsFC in iRBD patients using a data-driven approach and to assess its associations with clinical features and cognitive functioning. Forty-two patients with iRBD and 45 healthy controls (HC) underwent rsfMRI and comprehensive neuropsychological testing. Resting-state networks were characterized using independent component analyses. Group differences in intra- and inter-network rsFC and their associations with clinical and neuropsychological data were studied. A threshold of corrected P < 0.05 was used in all the analyses. iRBD patients displayed lower intra-network rsFC within basal ganglia, visual, sensorimotor, and cerebellar networks, relative to HC. Mean rsFC strength within the basal ganglia network positively correlated with processing speed and negatively with the non-motor symptoms in iRBD patients. Reduced inter-network rsFC between sensorimotor and visual medial networks was observed in iRBD patients, which was associated with global cognitive status. iRBD is characterized by both reductions in intra-network rsFC in cortical and subcortical networks and inter-network dysconnectivity between sensorimotor and visual networks. Abnormalities in intra- and inter-network rsFC are associated with cognitive performance and non-motor symptoms, suggesting the utility of both rsFC measures as imaging markers in prodromal alpha-synucleinopathies. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Assessment of stigma among patients living with Parkinson's disease: an exploratory study.

This cross-sectional study aims to assess the levels of stigma among patients with Parkinson's disease (PD) and identify the demographic and clinical factors influencing both internal and external stigma. A total of 200 patients diagnosed with PD were recruited from Beijing Tiantan Hospital between June 2023 and June 2024 using convenience sampling. Data were collected through face-to-face interviews, including demographic information, disease severity assessed via the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), and stigma levels measured using the 24-item Stigma Scale for Chronic Illness (SSCI). Statistical analyses included t-tests, ANOVA, correlation analysis, and multivariate linear regression. The average SSCI score among PD patients was 58.74 ± 13.73, with significant variation based on age, gender, educational level, marital status, disease duration, and motor subtype. Patients aged under 60, male, with lower educational attainment, divorced or widowed, and with longer disease duration had higher SSCI scores. MDS-UPDRS Part I-III scores were positively correlated with both internal and external stigma (r = 0.4, 0.5, and 0.5, respectively, p < 0.001). Multivariate linear regression analysis identified MDS-UPDRS scores, age, self-care ability, marital status, disease duration, and motor subtype as independent predictors of stigma. Stigma in PD is influenced by a combination of demographic and disease-related factors, particularly disease severity. Targeted interventions focusing on reducing motor and non-motor symptoms, as well as addressing social determinants, may help alleviate the stigma experienced by PD patients. These findings underscore the need for comprehensive management strategies that incorporate both clinical treatment and psychosocial support.

Alterations in non-REM sleep and EEG spectra precede REM-sleep deficits in a model of synucleinopathy

Background Sleep disturbances often precede motor symptoms in neurodegenerative diseases like Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Neuroinflammation is implicated in PD pathophysiology and may contribute to non-motor symptoms such as sleep disturbances. The Thy1-αSyn mouse model, overexpressing human alpha-synuclein (αSyn), mimics key aspects of PD and DLB, making it valuable for studying related sleep disturbances and neuroinflammatory changes. Objective To investigate early-stage alterations in sleep architecture, electroencephalographic (EEG) patterns, and neuroinflammation in Thy1-αSyn mice. Methods We used telemetric EEG/electromyography (EMG) with video surveillance to compare sleep patterns and EEG spectral power between 2.5- and 4.5-month-old male Thy1-αSyn transgenic mice and wild-type littermates. Neuroinflammation was assessed by examining microglial (Iba1) and astrocytic (GFAP) activation in key sleep-regulating brain regions. Results Thy1-αSyn mice showed decreased resting wake time and increased non-REM sleep, with altered sleep bout frequency and length, indicating significant sleep architecture changes. Spectral analysis revealed a shift from higher to lower frequency bands, suggesting early neural circuitry disruptions due to αSyn overexpression. Significant microglial activation was observed at 3 months, with astrogliosis progressing by 5 months in key sleep-regulating regions, indicating that neuroinflammation may contribute to the observed sleep disturbances. Conclusions Early-stage Thy1-αSyn mice exhibit significant sleep architecture changes, EEG spectral shifts, and neuroinflammatory alterations. These findings suggest that neuroinflammation may play a role in the initial pathophysiological changes in PD and related synucleinopathies. Sleep, EEG, and neuroinflammatory changes could serve as early biomarkers for these diseases.

Synaptic phosphoproteome modifications and cortical circuit dysfunction are linked to the early-stage progression of alpha-synuclein aggregation.

Cortical dysfunction is increasingly recognized as a major contributor to the non-motor symptoms associated with Parkinson's disease (PD) and other synucleinopathies. Although functional alterations in cortical circuits have been observed in preclinical PD models, the underlying molecular mechanisms are unclear. To bridge this knowledge gap, we investigated tissue-level changes in the cortices of rats and mice treated with alpha-synuclein (aSyn) seeds using a multi-omics approach. Our study revealed significant phosphoproteomic changes, but not global proteomic or lipid profiling changes, in the rat sensorimotor cortex 3 months after intra-striatal injection with aSyn preformed fibrils (PFFs). Gene ontology analysis of the phosphoproteomic data indicated that PFF administration impacted pathways related to synaptic transmission and cytoskeletal organization. Similar phosphoproteomic perturbations were observed in the sensorimotor cortex of mice injected intrastriatally or intracortically with aSyn PFFs. Functional analyses demonstrated increased neuronal firing rates and enhanced spike-spike coherence in the sensorimotor cortices of PFF-treated mice, indicating seed-dependent cortical circuit dysfunction. Bioinformatic analysis of the altered phosphosites suggested the involvement of several kinases, including casein kinase-2 (CK2), which has been previously implicated in PD pathology. Collectively, these findings highlight the importance of phosphorylation-mediated signaling pathways in the cortical response to aSyn pathology spread in PD and related synucleinopathies, setting the stage for developing new therapeutic strategies.

Multiomics approach identifies dysregulated lipidomic and proteomic networks in Parkinson’s disease patients mutated in TMEM175

Parkinson’s disease (PD) represents one of the most frequent neurodegenerative disorders for which clinically useful biomarkers remain to be identified and validated. Here, we adopted an untargeted omics approach to disclose lipidomic, metabolomic and proteomic alterations in plasma and in dermal fibroblasts of PD patients carrying mutations in TMEM175 gene. We revealed a wide dysregulation of lysosome, autophagy, and mitochondrial pathways in these patients, supporting a role of this channel in regulating these cellular processes. The most significant altered lipid classes were Fatty acyls, Glycerophospholipids and Phosphosphingolipids. The plasma level of Phosphatidylcholines (PC) and Phosphatidylinositol (PI) 34:1 significantly correlated with an earlier age at onset of the disease in TMEM175 patients (p = 0.008; p = 0.006). In plasma we also observed altered amino acids metabolic pathways in PD patients. We highlighted that increased level of L-glutamate strongly correlated (p < 0.001) with the severity of motor and non-motor symptoms in PD_TMEM175 patients. In dermal fibroblasts, we disclosed alterations of proteins involved in lipids biosynthesis (PAG15, PP4P1, GALC, FYV1, PIGO, PGPS1, PLPP1), in the insulin pathway (IGF2R), in mitochondrial metabolism (ACD10, ACD11, ACADS) and autophagy (RAB7L). Interestingly, we quantified 43 lysosomal or lysosomal-related proteins, which were differentially modulated between TMEM175 patients and controls. Integrative correlation analysis of proteome and lipidome of PD_TMEM175 cellular models identified a strong positive correlation of 13 proteins involved in biosynthetic processes with PC and Ceramides. Altogether, these data provide novel insights into the molecular and metabolic alterations underlying TMEM175 mutations and may be relevant for PD prediction, diagnosis and treatment.

A PARK7 Mutation-Induced Early-Onset Parkinson's Disease in a Moroccan Family: Expanding the Geographic Spectrum.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and nonmotor symptoms, with a significant genetic component. Early-onset Parkinson's disease (EOPD), manifesting before age 45, is often linked to mutations in genes such as PARK2, PINK1, and PARK7, the latter coding for the protein DJ-1. We present the first reported cases of EOPD carrying a previously undescribed homozygous PARK7 mutation, p.Thr110Pro. Whole exom sequencing was performed on two inbred Moroccan siblings with early-onset Parkinson's disease (EOPD). Detailed clinical assessments, including neurological evaluations and cognitive testing, were conducted to understand the clinical presentation of the patients. Genetic analysis was also carried out to examine their genetic background. Therapeutic responses to treatments were monitored to assess the effectiveness of management strategies. The sequencing revealed that both siblings carried the homozygous PARK7 mutation, p.Thr110Pro. Both siblings presented with typical EOPD features, including motor and non-motor symptoms. The patients both presented with cognitive impairment, with the male sibling exhibiting more pronounced symptoms. He also developed compulsive behaviors, which underscore the varied clinical presentations and therapeutic responses associated with this genetic variant. This case study expands the genetic and geographic diversity of PD presentations, highlighting cognitive and behavioral challenges and variable therapeutic outcomes. It underscores the necessity for genetic screening and individualized management strategies for patients with PD.