Search Results (803)

Background: Multiple sclerosis (MS) lacks a single invariant phenotypic core. Patients accumulate heterogeneous combinations of sensory, motor, cognitive, and autonomic impairments over time, reflecting lesions that are disseminated in time and space. Standard scales such as the Expanded Disability Status Scale (EDSS) distribute disability across functional systems, but do not explicitly represent MS phenotype as a mixture of latent symptom modules. Methods: We analyzed 4617 de-identified neurology progress notes from 577 patients with MS at a single academic medical center. A large language model (GPT-5.2) categorized each note with respect to 17 non-mutually-exclusive neurological phenotype features, and note-level features were aggregated to patient-level binary vectors. Non-negative matrix factorization (NMF) was applied to generate three-, four-, and five-module solutions. For each rank, we computed approximate variance captured, relative reconstruction error, and module-level feature loadings. In the preferred four-module solution, we derived patient-level module percentages, identified highly dominant (≥55%) and archetypal (≥70%) module profiles, and quantified admixture using Shannon entropy and the effective number of modules. Results: Three-, four-, and five-module NMF solutions showed similar approximate variance captured (52.7–54.3%) and reconstruction error (0.47–0.53), but the four-module solution provided the clearest clinical interpretation. The four latent modules were sensory-visual-pain, ataxic-spastic-falls, cognitive-psychologic-fatigue, and autonomic-bladder-bowel, aligning closely with established functional systems in MS. Most patients exhibited admixed phenotypes, with module entropies ranging from 0 (single-module dominance) to 1.386 (equal mixture) and effective modules spanning approximately 1 to 4. Using pre-specified thresholds, 154 patients (26.6%) were highly dominant in a single module and 72 (12.5%) were archetypal; these purer phenotypes were most often in the sensory-visual-pain module. Conclusions: MS phenotypic diversity in routine clinical practice can be parsimoniously represented as mixtures of four latent symptom modules rather than as positions along a single severity axis. Most patients show substantial admixture of sensory, motor, cognitive, and autonomic involvement, but a minority exhibit relatively pure or strongly dominant module patterns. This modular representation provides an interpretable framework for quantifying MS phenotype and for generating testable hypotheses about MS subtypes whose biological relevance remains to be established. Full article

Background and Objectives: Parkinson’s disease is a multidimensional neurodegenerative disorder in which motor and non-motor manifestations frequently coexist. This study aimed to evaluate the association between Hoehn and Yahr stage and non-motor symptom burden among patients with Parkinson’s disease in Peru. Materials and Methods: An analytical cross-sectional study was conducted in 92 patients with Parkinson’s disease registered or followed at Hospital San Juan Bautista de Huaral, Lima region, Peru, during 2025. Non-motor symptom burden was assessed using MDS-UPDRS Part I and categorized as mild, moderate, or severe. Clinical stage was assessed using the Hoehn and Yahr scale and grouped as early, intermediate, or advanced. Crude and adjusted ordinal odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using ordinal logistic regression. Results: The median age was 65.0 years, 67.4% were male, and the median disease duration was 6.0 years. Moderate and severe non-motor symptoms were observed in 58.7% and 23.9% of patients, respectively. In the adjusted model, intermediate stage (adjusted OR = 5.89; 95% CI: 1.83–18.98) and advanced stage (adjusted OR = 27.74; 95% CI: 6.74–114.18) were associated with greater non-motor symptom severity. Conclusions: Higher Hoehn and Yahr stage was independently associated with greater non-motor symptom severity. These findings support systematic non-motor assessment, particularly in intermediate and advanced stages. Full article

Background and Objective: Depression is frequent in Parkinson’s disease (PD), but it is unclear how mood changes and impacts patient’s quality of life (QoL) over time. Our objective was to analyze the frequency of depression and mood changes in people with PD (PwP) over 5 years of follow-up, comparing it with a control group, as well as its relationship with the patients’ QoL. Patients and Methods: PwP and healthy controls (HC) recruited from the COPPADIS cohort from January/2016 to November/2017 were included in this 5-year follow-up study. Mood was assessed by the Beck Depression Inventory II (BDI-II), and participants were classified as having major depression, minor depression, subthreshold depression, or non-depression at baseline and at 2, 4, and 5 years of follow-up. Correlation analysis and linear regression models were applied. Results: The BDI-II total score increased from 8.1 ± 6.2 at baseline to 10.3 ± 8.1 at the 5-year follow-up visit in PwP (p < 0.0001) but not in HC (from 4.1 ± 5.2 to 4.0 ± 5.7 [p = 0.896]). The prevalence of depression remained around 50–54% in the PwP group and 21–25% in the HC group throughout the follow-up period, but the mood state showed variability for each patient between visits. Patients’ QoL was associated with the depressive state throughout the entire follow-up period (p < 0.0001). Worsening QoL, sleep, longer disease duration, and an increase in neuropsychiatric symptoms were identified as independent factors associated with a worsening of mood over time in PwP (N = 348). Conclusions: Mood change over time in PwP is associated with QoL. Full article

Background and Objectives: Parkinson’s disease (PD) includes a prodromal phase characterized by non-motor symptoms (NMS). We investigated whether sleep disturbances co-aggregate with other NMS in suspected prodromal PD (p-PD) to refine early phenotyping and risk stratification. Materials and Methods: A population-based survey was conducted in Kaunas, Lithuania. Participants from the Kaunas City preventive health screening cohort (2024–2025) were screened using the Innsbruck REM Sleep Behaviour Disorder Inventory (RBD-I). Sixty-two individuals were included: 31 with suspected p-PD and 31 controls. Demographic characteristics, clinical features, sleep symptoms, olfactory function, autonomic symptoms, cognition, and mood were assessed. Between-group comparisons and within-group correlation analyses were performed. Results: Groups did not differ in age, sex, education, lifestyle exposures, or family history (all p > 0.05). Compared with controls, individuals with suspected p-PD had a higher prevalence of insomnia (71.0% vs. 12.9%, p < 0.001), pathological daytime sleepiness (22.6% vs. 0%, p = 0.005), cognitive impairment (54.8% vs. 16.1%, p = 0.001), and constipation (32.3% vs. 0%, p = 0.002). As expected from the predefined enrichment strategy, hyposmia and orthostatic hypotension (OH) were observed only among suspected p-PD participants. Within the suspected p-PD group, the Non-Motor Symptoms Questionnaire (NMSQ) scores correlated with depressive/anxiety symptoms (r = 0.578, p = 0.001). Olfactory dysfunction correlated with cognitive impairment (r = 0.410, p = 0.001) and depressive/anxiety symptoms (r = 0.396, p = 0.001). Conclusions: Sleep disturbances, particularly insomnia and excessive daytime sleepiness, co-occurred with cognitive, affective, and gastrointestinal non-motor manifestations in individuals with suspected p-PD, supporting the concept of a broader prodromal phenotype. Comprehensive screening in individuals with RBD symptoms may improve early PD risk stratification beyond single-marker approaches. Full article

Parkinson’s disease (PD), impacting millions worldwide, leads to motor deficits and various non-motor symptoms. Although there is no cure, treatment primarily involves dopamine replacement therapy, especially L-dopa for motor symptoms, and additional drugs are required to address non-motor effects. This underscores the increasing demand for dual-acting drugs that can effectively target both symptom types in PD. This study explored the potential effects of a standardised Mesembryanthemum tortuosum extract, Zembrin^®, in treating PD, utilising in vivo and in silico models. Zebrafish larvae were subjected to pre-treatment with reserpine, followed by exposure to Zembrin^®, with selegiline and L-dopa as positive controls. The in vivo component of this study monitored locomotion and oxidative stress, while the in silico component identified potential drug targets for the treatment of PD. Reserpine induced hypolocomotion and oxidative stress in zebrafish larvae, and Zembrin^® (12.5 µg/mL) effectively enhanced locomotion and reduced oxidative stress. The molecular docking, molecular dynamics simulations, and binding free energy calculations revealed that four mesembrine alkaloids (mesembranol, mesembrenol, mesembrenone, and mesembrine) form stable and energetically favourable complexes with monoamine oxidase B (MAO-B) and dopamine transporter (DAT), which are significant targets for addressing both the motor and non-motor effects of PD. Full article

Background/Objectives: Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a rare neurometabolic disorder with an expanding clinical spectrum, including mild and non-classical presentations. We report a boy with severe transient neonatal hyperkalemia, bilateral congenital cataracts, and later subtle neurological and neurocognitive symptoms, in whom genomic testing supported the diagnosis of mild GLUT1DS. Methods: This single-patient case report describes clinical follow-up from birth to nine years of age, including neurological, metabolic, neuropsychological, imaging, and genetic investigations. Whole-exome sequencing using next-generation sequencing technology was performed. Results: The patient required intensive care immediately after birth because of severe transient hyperkalemia of unclear etiology. Bilateral congenital cataracts were surgically corrected during infancy. Later, he developed two brief seizure episodes, reduced exercise tolerance, episodic fatigue, attentional difficulties, motor restlessness, and mild graphomotor impairment. Neuropsychological assessment showed overall average intellectual functioning, below-average verbal abilities, low-average non-verbal abilities, and attention-deficit/hyperactivity disorder. Repeated metabolic investigations, electroencephalography, and brain magnetic resonance imaging were unrevealing. Whole-exome sequencing identified an apparently de novo heterozygous SLC2A1 variant, NM_006516.4.1333_1335del, p.(Phe445del), supporting the diagnosis of mild GLUT1DS. Because of the mild phenotype and preserved everyday functioning, ketogenic diet therapy was not initiated. Conclusions: This case highlights the diagnostic challenges of mild GLUT1DS and the value of genomic testing in children with unexplained neurological or neurocognitive symptoms despite normal routine investigations. Although neonatal hyperkalemia and GLUT1DS coexisted in this patient, current evidence is insufficient to establish a causal relationship. Full article

Background/Objectives: Non-motor symptoms (NMS) are highly prevalent in advanced Parkinson’s disease (PD) and substantially affect quality of life. Continuous infusion therapies are established treatment options for motor fluctuations not controlled by oral medication, but their effects on NMS remain incompletely characterized. We aimed to evaluate the effects of continuous infusion therapies on NMS in advanced PD. Methods: A systematic review was conducted according to PRISMA guidelines. PubMed, Embase, and Cochrane were searched for English-language original studies published between January 2005 and 1 March 2026. Eligible studies included patients with PD treated with levodopa–carbidopa intestinal gel (LCIG), continuous subcutaneous apomorphine infusion (CSAI), subcutaneous levodopa formulations, or levodopa–entacapone–carbidopa intestinal gel (LECIG) and reported quantitative NMS outcomes. Due to methodological heterogeneity, results were synthesized qualitatively. Results: Fifty-four studies were included. Most evaluated LCIG (n = 38), followed by CSAI (n = 14), subcutaneous levodopa formulations (n = 6), and LECIG (n = 2). Overall, 4157 patients were assessed at baseline and 2919 at follow-up. Global non-motor burden improved in 33/45 (73.3%) baseline-to-follow-up comparisons. NMSS total score decreased from 84.4 ± 35.2 to 54.9 ± 17.6. The most consistent benefits were observed for sleep/fatigue and gastrointestinal symptoms. Sleep/fatigue outcomes improved in 26/31 (83.9%) baseline-to-follow-up comparisons. Cognitive outcomes were mostly stable, while cardiovascular, urinary, sexual, and mood-specific outcomes showed less consistent benefit. Conclusions: Continuous infusion therapies may be associated with reduced global non-motor burden in advanced PD, particularly sleep/fatigue and gastrointestinal symptoms. Evidence is strongest for LCIG, while data for CSAI, LECIG, and subcutaneous levodopa formulations remain limited. Full article

Schizophrenia remains a debilitating global health challenge where pharmacologic treatment has been stagnant for over seventy years, relying almost exclusively on the blockade of dopamine receptors. While this mechanism controls positive psychosis, it frequently fails to address negative symptoms or cognitive impairment and carries a significant burden of metabolic and motor adverse effects. This review evaluates the scientific and clinical validation of xanomeline–trospium (Cobenfy^®; investigational name KarXT), the first approved antipsychotic with a completely non-dopaminergic mechanism of action. We synthesize data ranging from the unique structural biology of the bitopic M1/M4 muscarinic receptor agonist xanomeline to the pharmacokinetic innovation of using the peripheral antagonist trospium chloride to mitigate systemic toxicity. Comprehensive analyses of the EMERGENT clinical trial program demonstrate that this combination significantly reduces heterogeneous schizophrenia symptoms with a safety profile distinct from current standards of care, specifically avoiding weight gain and extrapyramidal movement disorders. Furthermore, we contrast this success with the recent failures of other novel mechanisms and explore the potential for precision medicine through the identification of muscarinic receptor deficit biotypes. We conclude that M1/M4 muscarinic receptor agonism represents an important advance toward circuit-based therapeutics that may help overcome some of the limitations inherent to dopamine-centered pharmacotherapy. Full article

Background and Clinical Significanc: Neuropathic corneal pain is a debilitating condition characterized by ocular pain disproportionate to clinical signs, often resulting from peripheral and central sensitization of the corneal somatosensory pathway. Emerging evidence suggests that chronic involuntary muscle contraction in blepharospasm may lead to irritation of trigeminal afferents and corneal neurogenic inflammation, potentially predisposing patients to neuropathic corneal pain. Given its debilitating nature, early recognition can prevent the progression of neuropathic sequelae. This study examines the potential role of blepharospasm as a predisposing factor contributing to neuropathic corneal pain. Case Presentation: This retrospective case series describes three cases (median age: 50 years) of neuropathic corneal pain in association with blepharospasm and their clinical course following multimodal treatment over a median follow-up period of one year. Ocular surface was evaluated using slit-lamp biomicroscopy, while corneal nerve structure and morphology were assessed with in vivo confocal microscopy. All the three subjects presented with minimal ocular surface staining but disproportionate ocular pain characterized by burning sensation and photophobia. Proparacaine challenge testing was performed to determine the subtype of neuropathic corneal pain. Pain symptoms and quality of life were evaluated using the Ocular Pain Assessment Survey and Ocular Surface Disease Index questionnaires. In vivo confocal microscopy demonstrated characteristic corneal nerve abnormalities including reduced corneal nerve density, increased nerve tortuosity, and the presence of microneuromas. Treatment included oral Pregabalin or Gabapentin, topical lubricants, Cyclosporine 0.05% (1 case), and 20% autologous serum eye drops (1 case). Two of the three cases received four to five injections of botulinum toxin for blepharospasm, whereas one had undergone a single injection prior to review. All patients also received weekly periorbital quantum molecular resonance electrotherapy for two months. Improvements were observed across multiple domains of the Ocular Pain Assessment Survey and Ocular Surface Disease Index evaluation, including ocular pain, photophobia, non-ocular pain, and quality-of-life measures following multimodal treatment. The co-existence of blepharospasm and neuropathic corneal pain observed in our cases supports a possible association between chronic periocular muscle hyperactivity and corneal nociceptor sensitization. Proposed mechanisms include chronic trigeminal nerve irritation, neurogenic inflammation, and sensitization mediated by pro-inflammatory neuropeptides. Multimodal treatment targeting both motor hyperactivity and neuropathic pain pathways appeared to provide symptomatic relief, including the use of quantum molecular resonance electrotherapy, which might modulate pain pathways, block nociceptor neurotransmission, and accelerate corneal nerve regeneration. Given the complexity of the neural pathways responsible for ocular discomfort, further studies are required to elucidate the relationship between neuropathic corneal pain and blepharospasm in larger cohorts, as well as refine existing therapeutic approaches, including evaluating the therapeutic role of electrotherapy. Conclusions: Blepharospasm may represent a potential predisposing factor of neuropathic corneal pain. Early recognition and concurrent treatment of blepharospasm and neuropathic corneal pain can effectively relieve symptoms and improve quality of life. Adopting a multimodal treatment approach is therefore recommended. Full article

α-Synuclein (α-Syn) is a key presynaptic protein, primarily known for its role in the pathogenesis of Parkinson’s disease (PD) and other synucleinopathies, including dementia with Lewy bodies (DLB). Although much of the research has focused on the nigrostriatal dopamine (DA) pathway, there is growing recognition that the accumulation of misfolded α-Syn in the prefrontal cortex (PFC) is a critical driver of non-motor symptoms and cognitive deficits in PD and DLB. This review examines the dual role of α-Syn in the PFC circuitry, initially exploring its regulation of synaptic vesicle (SV) dynamics and recycling to maintain stable neurotransmission. We highlight its contribution to the modulation of glutamatergic (Glu) and GABAergic (γ-aminobutyric acid, GABA) synapses, which ensures the functional excitatory/inhibitory (E/I) balance of prefrontal circuits. Conversely, in PD and DLB, the transition of functional α-Syn monomers to pathological oligomers triggers a cascade of synaptic failures. We analyze how α-Syn aggregation causes pathology in dendritic spines, leads to a progressive reduction in the density of synaptic markers, and impairs cortical plasticity. Synthesizing evidence from neuroimaging studies, post-mortem human cortical samples, and animal models, this review emphasizes the PFC as a vulnerable brain region where α-Syn-mediated synaptic dysfunction translates into cognitive and emotional deficits. Deciphering these early synaptic alterations is essential for developing neuroprotective strategies that preserve cortical function in PD and DLB. Full article

Extrapyramidal symptoms (EPS) are motor side effects commonly induced by antipsychotic medications and can lead to measurable changes in handwriting patterns. These symptoms affect both the spatial and temporal characteristics of writing, including stroke thickness, direction and the rate of directional change. To model these complex variations, we propose a novel Liquid Generative Adversarial Network (LiquidGAN), which combines the adaptive dynamics of liquid neural networks with the data generation capability of GANs. Handwriting data were collected from 94 patients with confirmed EPS and 30 healthy controls using Archimedean spiral patterns drawn with both hands. A total of 211 images were processed for both binary and multiclass classification using a pretrained ResNet50 model. The pretrained ResNet50 achieved 92% accuracy and 97% precision in the binary classification task; however, its performance dropped significantly to 57% accuracy in multiclass classification, indicating limited capability in capturing fine-grained EPS severity variations. In contrast, the proposed LiquidGAN demonstrated excellent performance in the binary classification task, achieving 97% accuracy and 98% precision. More importantly, LiquidGAN substantially outperformed the baseline in the more challenging multiclass setting, achieving 70% accuracy and precision across four classes (mild, moderate, severe, and control). This shows that the diverse dataset from the liquidGAN significantly improves the HOG-ANN classification and effectively captures complex and subtle handwriting variations associated with different EPS severity levels that conventional models such as ResNet50 fail to distinguish. In addition, LiquidGAN generated diverse and realistic synthetic handwriting samples, yielding improved Fréchet Inception Distance (FID), precision, and recall compared with style GAN. These findings demonstrate that handwriting biomarkers, when analyzed through dynamic generative learning, offer an effective and non-invasive approach for monitoring extrapyramidal side effects in clinical settings. Full article

The dopamine D₃ receptor (D₃R) has long been considered a secondary target in the treatment of Parkinson’s disease (PD), with therapeutic strategies primarily focused on D₂ receptor–mediated motor control. However, accumulating evidence now supports D₃R as a functionally distinct dopaminergic receptor subtype with specific relevance to non-motor symptom domains and dopaminergic signaling under hypodopaminergic conditions. Recent advances in high-resolution structural biology have elucidated the molecular basis of D₃R/D₂R discrimination, revealing how subtle residue-level and microstructural differences within a conserved G protein–coupled receptor framework shape ligand recognition and receptor activation. In parallel, the emergence of ligand-dependent biased signaling has refined current understanding of D₃R pharmacology. Selected ligands can preferentially engage Gα_i/o-mediated pathways while limiting β-arrestin recruitment and associated regulatory processes, providing a mechanistic rationale for more stable modulation of mesolimbic dopaminergic circuits involved in affective and motivational regulation. Beyond symptomatic modulation, preclinical studies suggest that D₃R signaling may influence neuronal resilience, synaptic plasticity, and adaptive responses to dopaminergic injury; however, such effects remain experimental and have not been demonstrated in clinical PD. This review integrates recent structural, signaling, and functional insights into D₃R biology, with particular emphasis on biased agonism and emerging therapeutic concepts. Although D₃R-targeted strategies do not currently represent disease-modifying interventions, they offer a rational framework for the development of next-generation dopaminergic therapies aimed at improving precision, tolerability, and long-term signaling stability in Parkinson’s disease. Full article

Background: Both neuromodulation and physical therapy have been shown to mitigate motor and non-motor symptoms of Parkinson’s disease. To date, no studies have examined the integration of transcutaneous auricular vagus nerve stimulation (taVNS) with physical therapy approaches for improving Parkinsonian symptoms. The purpose of this study was to investigate the safety, tolerability, and feasibility of combining taVNS with physical therapy to enhance the therapeutic benefits of exercise as medicine in a clinical setting. Methods: Participants were randomly assigned to receive active or sham bilateral taVNS in combination with PT for 12 visits over 6 weeks. Safety, tolerability, and feasibility outcomes were primary. Secondly, exploratory analyses of changes in cardiovascular and motor function over time were also performed. Results: Overall, taVNS was safe and well-tolerated prior to PT. Cardiovascular analyses suggest that active taVNS may augment HR response to exercise compared to sham. For motor outcomes, both groups showed significant overall improvements; however, no significant between-group differences were found. Conclusions: The preliminary results obtained in this pilot trial confirm that taVNS combined with physical therapy for individuals with PD is safe and feasible. The exploratory cardiovascular and motor findings support the need for larger, adequately powered clinical trials investigating the integration of taVNS into PT and exercise methods for improving PD symptomology. Trial registration: ClinicalTrials.gov NCT05871151. Full article

Spinal cord injury (SCI) is frequently accompanied by abnormal muscle tone and spasticity, which impair voluntary motor control, mobility, and quality of life. Although classically defined as velocity-dependent hyperreflexia, tone abnormalities after SCI encompass a broader spectrum, including sustained muscle activation, co-contraction, clonus, and non–velocity-dependent resistance to movement. These manifestations arise from distributed changes across spinal and supraspinal motor systems. At the segmental level, SCI induces maladaptive plasticity involving motoneurons, interneurons, sensory afferents, and muscle, including dysregulated persistent inward currents, altered inhibitory neurotransmission, afferent hyperexcitability, synaptic reorganization, and structural muscle remodeling. In parallel, supraspinal adaptations—including cortical motor map reorganization, reduced intracortical inhibition, corticospinal–reticulospinal imbalance, loss of monoaminergic modulation, and altered brainstem and cerebellar regulation—further amplify spinal circuit gain and impair inhibitory control of tone. Current pharmacologic treatments largely suppress symptoms without addressing these underlying circuit changes, while invasive neuromodulatory strategies are limited by surgical risk or state-dependent effects. This review synthesizes emerging insights into the multilevel mechanisms regulating abnormal tone after SCI and examines neuromodulatory approaches targeting spinal and supraspinal networks. Particular attention is given to transcutaneous spinal cord stimulation (TcSCS), a non-invasive method capable of modulating segmental reflex circuits and descending control pathways. Advances in transcriptomic and epigenetic profiling may further enable mechanism-based therapies and biomarker-guided strategies for treating spasticity. Full article

Oculomotor dysfunction is an eye movement disorder frequently experienced in patients with Parkinson’s disease. Many patients tend to experience visual symptoms, and this can exacerbate cognitive symptoms when visual tasks become more demanding. The purpose of this review is to characterize oculomotor dysfunction in patients with Parkinson’s disease based on the distinct types of ocular motor deficits and their corresponding impact on the patient’s symptoms, visual perception, activities of daily living, and quality-of-life. A systematic literature search was conducted to identify relevant articles. The results from the sensorimotor framework analysis are categorized in five domains: visual-sensory, visual-motor, visual-perceptual, cognitive processing, and psychosocial challenges. The findings suggest that clinical evaluation and neurorehabilitation should move beyond speed-dependent metrics, but focus on specific non-speed-dependent ocular motor deficits. By fostering interdisciplinary collaboration, healthcare professionals can take proactive steps to address the vision-related challenges faced by patients with Parkinson’s disease. Full article