Search Results (7,631)

Parkinson’s disease (PD) is characterized by oxidative stress, mitochondrial dysfunction, and dopaminergic neuron loss, for which effective treatments remain unavailable. Here, we report CL0179, a fungal-derived decahydrofluorene alkaloid with antioxidant-associated neuroprotective properties, and evaluate its effects across cellular and animal PD models. CL0179 exhibited a favorable safety profile and protected SHSY5Y against 6-hydroxydopamine- (6-OHDA), rotenone-, and 1-Methyl-4-phenylpyridinium-iodide (MPP⁺)-induced neurotoxicity by preserving mitochondrial membrane potential and network integrity. Transcriptomic analyses revealed selective restoration of gene-expression programs associated with oxidative phosphorylation, mitochondrial bioenergetics, and stress adaptation disrupted by MPP⁺. CL0179 also enhanced SIRT1 activity under MPP⁺ stress, whereas pharmacological SIRT1 inhibition partially attenuated protection of mitochondrial membrane potential and cell viability. In LRRK2-G2019S astrocytes, CL0179 reduced ROS and α-synuclein accumulation and restored mitochondrial organization, while in human dopaminergic neurons, it attenuated toxin-induced mitochondrial depolarization and preserved neuronal architecture. To overcome the low production of CL0179, we generated the structurally related analogue CL0670. Both compounds crossed the blood–brain barrier and protected mouse primary cortical neurons, while CL0670 improved motor deficits in a 6-OHDA mouse model. Collectively, these compounds promote mitochondrial resilience and stress-adaptive neuroprotection, supporting their potential for PD and related neurodegenerative disorders. Full article

Neurodegenerative diseases share features of neuronal loss, neuroinflammation, and protein aggregation. The cGAS-STING pathway, a key DNA sensor, mediates neuroinflammation via TBK1-IRF3 and IKK-NF-κB axes, inducing type I interferons and pro-inflammatory cytokines. This pathway upregulates ZBP1, promotes PANoptosome assembly, and triggers PANoptosis, releasing DAMPs and creating a self-amplifying “inflammation–death” cycle. In Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis, pathological proteins (Aβ, Tau, α-synuclein, TDP-43) or genetic defects (e.g., C9orf72 repeats) cause mitochondrial DNA leakage or genomic instability, activating this axis. This review highlights the cGAS-STING-PANoptotic cascade as a shared pathogenic mechanism and discusses the current evidence and remaining challenges in confirming this hypothesis. Full article

Failure of axonal maintenance is proposed as a mechanism shared by Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). We reanalysed three public post-mortem resources under one rule set: bulk RNA-seq of 1242 samples from 319 donors (GSE153960) and midbrain single-nucleus RNA-seq (GSE157783, GSE178265). As a contributing project, a second batch variable tracked diagnosis in both cord segments and was completely separated from it in three cortical regions, which we removed. Adjusting for this removed a third of the naive differential expression. In ALS cord, the dominant depleted program was microtubule-based axonal transport (normalised enrichment score −2.40, FDR < 0.001); a regeneration-associated panel reached significance in none of ten fits. An ALS cord signature carried into the PD midbrain and scored highest on microglia in all 11 donors (+3.55 versus +0.73 next). Of 86 gene sets significant in both diseases, a translation block contained the GCN2 amino-acid-deficiency response. Both axes are compartment-level: within PD microglia, the complement panel is null (+0.21, p = 0.57). No GCN2 activity was measured, and the ALS cord is compared against PD midbrain. The axes that survive this control are glial and translational; the axonal question is not adjudicable in PD, where the panel score tracks dopaminergic content. Full article

Background: Progressive supranuclear palsy (PSP) and Parkinson’s disease (PD) frequently present with overlapping clinical features, creating diagnostic challenges, particularly during the early stages of disease. Structural MRI and peripheral inflammatory biomarkers may provide complementary information for differential diagnosis. Objective: To evaluate the diagnostic performance of automated pallidal volumetry and the neutrophil-to-lymphocyte ratio (NLR), individually and in combination, for distinguishing PSP from PD. Methods: This retrospective case–control study included 12 patients with PSP and 12 patients with PD. Automated brain volumetry was performed using the volBrain 2.0 platform. Total pallidal volume was selected as the primary imaging biomarker based on its established involvement in PSP pathology. NLR was calculated from routine blood counts. Diagnostic performance was assessed using receiver operating characteristic (ROC) analysis. A combined MRI–blood model was constructed using binary logistic regression. Results: Patients with PSP demonstrated lower normalized pallidal volumes than patients with PD. Pallidal volume showed high diagnostic performance for differentiating PSP from PD (AUC = 0.885), whereas NLR demonstrated only modest discriminatory ability (AUC = 0.715). The combined pallidal volume–NLR model achieved an AUC of 0.903 compared with 0.885 for pallidal volumetry alone, but this difference was not statistically significant (DeLong p = 0.732), and sensitivity, specificity and overall accuracy remained unchanged. Conclusions: Automated pallidal volumetry provided substantially better discrimination between PSP and PD than NLR alone. Although the combined model showed a small numerical increase in AUC, this improvement was not statistically significant and did not alter sensitivity, specificity or overall accuracy. These findings do not demonstrate incremental diagnostic value of NLR beyond pallidal volumetry in this cohort. Larger prospective studies are needed to determine the clinical utility of combined MRI–blood biomarker approaches in PSP. Full article

Emergency department providers may be challenged by the presentation of patients who exhibit movement abnormalities that could indicate conditions requiring interventions to reduce the risk of potential morbidity and mortality. Crucially, interventions for potential neurological diseases that require immediate intervention (e.g., stroke) are contraindicated in patients exhibiting movements that may be voluntary (e.g., emotional expressions and fabricated symptoms) or functional (e.g., functional movement disorders such as functional tremors or psychogenic nonepileptic seizures (PNES)). Current motor assessment relies on subjective visual observation by human examiners, which limits the speed and accuracy of this differentiation. We hypothesize that technology measuring the temporal and spatial characteristics of movement can provide quantifiable signatures to differentiate movement subtypes and reflect the distinct neural pathways underlying voluntary and involuntary movement. To assess clinical and commercial interest in such technology, we conducted exploratory interviews with 17 of 56 invited potential customers (neurologists, biomedical engineers, and other clinicians) through a National Science Foundation I-Corps program where interviewees confirmed motor assessments are often performed without instrumentation and expressed willingness to adopt inexpensive, validated technology. The findings support interest in our proposed approach; however, this evidence is still preliminary as the interview sample was a non-random convenience sample and no comparison of respondents and non-respondents was performed. The sensor-based technology also remains conceptual with no current prototype, indicating the need for further studies utilizing more rigorous sampling and prototype development before clinical application. Full article

Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological disorder characterized by gait impairment, cognitive decline, and urinary dysfunction. Despite improvements in diagnostic criteria and neuroimaging techniques, accurate diagnosis remains challenging due to clinical overlap with neurodegenerative diseases, particularly Alzheimer’s disease (AD) and synucleinopathies. Biomarkers capable of improving differential diagnosis, patient selection for shunt surgery, and prognostic assessment are therefore of considerable clinical interest, as has been in AD biomarkers. This review summarizes current evidence regarding the role of α-synuclein as a potential additional marker in iNPH, focusing on its association with concomitant neurodegenerative pathology, clinical manifestations, and treatment outcomes. Available studies indicate that α-synuclein pathology may coexist with iNPH in a substantial proportion of patients, with reported positivity rates ranging from approximately 14% to 33%, depending on the detection method used. Patients with concomitant α-synuclein pathology may exhibit clinical features atypical for pure iNPH, including upper limb rigidity, olfactory dysfunction, hallucinations, autonomic dysfunction, sleep disturbances, and fluctuating cognitive impairment. However, current evidence does not support α-synuclein positivity as an independent predictor of poor response to cerebrospinal fluid (CSF) drainage or shunt surgery. On the contrary, α-synuclein presence may provide additional information regarding mixed neurodegenerative pathology and contribute to personalized clinical management. Future studies should focus on standardized detection techniques, larger multicenter cohorts, longitudinal follow-up, and integration of α-synuclein assessment with established AD biomarkers, neuroimaging findings, and clinical evaluation. Overall, α-synuclein represents a promising complementary marker in iNPH, with potential value in being taken into consideration during clinical evaluation and understanding disease heterogeneity. Full article

Selenium-dependent antioxidant systems are critical for neuronal redox balance, but whether Parkinson’s disease (PD) involves systemic selenium deficiency or selective utilization impairment remains unclear. Using Parkinson’s Progression Markers Initiative (PPMI) proteomic data, we identified specific downregulation of glutathione peroxidase 3 (GPX3) in cerebrospinal fluid in PD, suggesting a compartment-specific alteration in GPX3-related antioxidant defense rather than a uniform systemic selenium deficit. Inorganic selenium sources suffer from low bioavailability and narrow therapeutic windows. We therefore developed a selenium-enriched peptide fraction (IPP-Se-F12) via controlled selenization of Idesia polycarpa Maxim. cake meal peptides, and characterized its selenium content, size distribution, and radical-scavenging activity. In SH-SY5Y and nematode models, IPP-Se-F12 attenuated 6-hydroxydopamine (6-OHDA)-induced cell death and rescued locomotor and dopamine-dependent behaviors more effectively than sodium selenite treatment. RNAseq further showed that IPP-Se-F12 treatment was associated with transcriptional changes in dephosphorylation, axon-guidance, and GPX3-centered antioxidant networks, including increased expression of gpx-3 and gpx-5. This study supports IPP-Se-F12 as a plant-derived selenium-associated peptide fraction with protective activity in cellular and nematode models and identifies GPX-related antioxidant regulation as a candidate mechanism for further investigation. Full article

3,4-dihydroxyphenethylamine, commonly known as dopamine (DA), is a neuromodulator that fine-tunes neuronal excitability, neurotransmitter release, and the effects of other neurotransmitters on postsynaptic neurons. DA, acting on D1 and D2 receptor families, is involved in myriad functions. In the striatum, it is mainly implicated in motor control, motivation, and reward mechanisms. In the cerebral cortex it participates in attention processes, working memory, long-term memory, etc. DA overproduction or deficits lead to neuronal circuit imbalance that underlies a number of neurological and psychiatric diseases, including Parkinson’s disease (PD), schizophrenia, Huntington’s disease (HD), and substance use disorders (SUDs), to name a few. DA regulates neuronal excitability by modulating ion channels, the release of excitatory (glutamate) and inhibitory (γ-aminobutyric acid, GABA) neurotransmitters, and postsynaptic interactions with glutamate and GABA receptors. Together, these pre- and postsynaptic actions of DA underlie a number of synergistic or antagonistic actions that have important implications for setting membrane potentials, improving the signal-to-noise ratio, and directing the sign of synaptic plasticity. In this review, I will first provide a historical overview of the many studies exploring DA actions in the brain, with particular focus on the striatum. Then, I will emphasize some of the contributions of our laboratory to the understanding of DA modulatory effects from an electrophysiological perspective. Finally, I will discuss the mechanistic and therapeutic implications of DA function and dysfunction. Full article

Neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by the progressive loss of specific neuronal cell populations and are associated with protein aggregates. Current therapeutic approaches are still limited due to the complexity and heterogeneity of these diseases, which points toward an urgent need to discover and develop new therapeutic agents. Natural compounds are a promising source of novel bioactive agents targeting multiple mechanisms of action implicated in neurodegeneration. Andrographolide (ANDRO) is a natural compound extracted from Andrographis paniculata, a traditional Chinese herb known for its anti-inflammatory and antioxidant properties, which has emerged as a potential neuroprotective agent due to its ability to cross the blood–brain barrier (BBB). ANDRO can exert neuroprotective effects by modulating numerous transcription factors and signaling pathways across different cell types in the central nervous system (CNS). It has been described that ANDRO reverses cognitive and/or motor impairments in AD and PD study models. However, the cellular and molecular mechanisms behind these protective effects are still being elucidated. In this review, we analyze the most recent findings on ANDRO, a neuroprotective agent with multiple biological targets that could reduce the progression of the most prevalent neurodegenerative diseases, AD and PD. Full article

Neurological disorders are a major cause of disability and mortality worldwide, and accessible methods for detecting tremor-related trajectory deviations remain an important research challenge. We present an augmented reality (AR)-based approach for evaluating trajectory deviations associated with tremor-related hand movements in Parkinson’s disease (PD) and neurological sequelae of traumatic brain injury (TBI). Unlike conventional surface-based drawing tests, the proposed approach removes the physical support point that may facilitate compensatory stabilization of hand movements during task performance. The method implementing this concept was preliminarily evaluated in a pilot cohort of 131 participants, including 50 healthy controls, 6 patients with PD, and 75 combat veterans with TBI, and was compared with a standard geometric figure drawing test. In the PD subgroup, the AR protocol flagged algorithmically detected trajectory deviations in all six participants. Given the small PD sample and the limited number of additional findings in the TBI group, these observations should be interpreted as preliminary and hypothesis-generating rather than as evidence of proof-of-concept accuracy or sensitivity. The results suggest that the anchor-free AR-based trajectory-assessment method may warrant further investigation as a potential approach for tremor-related movement analysis. Larger clinically validated studies with independent confirmation and standard concept metrics will be required to determine the clinical utility of the proposed method. Full article

Oxidative stress is strongly associated with neuronal damage in neurodegenerative diseases, such as Parkinson’s disease (PD). Fungal melanins are remarkable free radical scavengers; however, their capacity to protect neurons from reactive oxygen species (ROS)-induced damage remains understudied. This research evaluated the neuroprotective effects of fungal melanins and their arginine-modified counterparts on SH-SY5Y cells against neurotoxins, as well as their impact on ROS levels. Exposure to 0.6 mM H₂O₂ or 1 mM MPP⁺ markedly elevated ROS levels and reduced cell viability to approximately 56% and 60%, respectively. At 10 μg/mL, melanins from Apioperdon pyriforme, Russula nigricans, and Xylaria nigripes significantly protected cells against H₂O₂ cytotoxicity, whereas arginine-modified melanin from the skin of Scleroderma sinnamariense significantly attenuated MPP⁺ cytotoxicity. Further dose-dependent evaluation revealed that melanin from A. pyriforme (10–12 μg/mL) displayed activity comparable to the positive control (164 μg/mL N-Acetylcysteine (NAC)) against H₂O₂ by increasing cell viability up to 90%. Similarly, arginine-modified melanin from S. sinnamariense (6–10 μg/mL) and NAC showed a comparable protective effect against MPP⁺, boosting cell viability up to 80%. Both samples suppressed ROS to levels comparable to, or lower than, the untreated control. Melanin from A. pyriforme is a promising candidate for further research into complementary therapies for PD. Full article

Parkinson’s disease (PD) diagnosis relies on subjective clinical examination of motor signs that can be mild, intermittent, or absent early in the disease course, motivating objective, low-cost, non-invasive markers for earlier, more consistent detection. Voice recordings, acquirable with nothing more than a microphone, are a strong candidate, and this study develops a machine learning pipeline for voice-based PD screening built on the Competitive Swarm Optimizer (CSO), which jointly searches the acoustic feature subset, classifier configuration, and binarization transfer function, instead of optimizing the feature subset alone as most prior pipelines do. Evaluated on two public, subject-grouped voice datasets, Oxford and Naranjo, against five baselines under an identical protocol across 20 runs per method, our proposed pipeline attains the highest mean balanced accuracy on Naranjo with 0.847 and the second-highest on Oxford with 0.810, accuracies consistent with the wider voice-based PD screening literature; because this evidence comes from two small, single-recording-protocol, retrospective public datasets of 31 and 80 subjects each, we present it as an initial, encouraging step toward a first-pass triage or between-visit monitoring tool, pending external validation on a prospectively collected, multi-site cohort, not as a standalone diagnostic instrument. As an initial step toward clinical interpretability, we check which acoustic features are selected most consistently across 20 repeated runs of the proposed pipeline against established physiological correlates of Parkinsonian dysphonia; agreement between any two runs’ complete feature subsets is weak, but pitch period entropy, a nonlinear-dynamical measure of aperiodic pitch period variability, is selected far more often than chance on both datasets, consistent with the underlying pathophysiology and not merely predictive. These results support voice-based, metaheuristic-optimized screening as a plausible, interpretable, low-burden tool for telemedicine and home monitoring. Full article

Background and Objectives: The main neurodegenerative diseases (NDs)—Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS)—represent a growing global health burden with no available disease-modifying therapies. Curcumin, a polyphenol from Curcuma longa, is a promising candidate owing to its pleiotropic antioxidant, anti-inflammatory, and neuroprotective profile observed mainly in preclinical models, but the poor oral bioavailability (<1%) and negligible BBB penetration (<0.1%) have substantially limited curcumin’s clinical translation. The objective of this work was to critically examine the therapeutic potential of curcumin in NDs, focusing on advanced drug delivery systems (DDSs) designed to overcome its pharmacokinetic barriers. Methods: This is a narrative, non-systematic review of PubMed/MEDLINE, Scopus, and Web of Science. The review is organized around five complementary thematic areas selected to span the full translational pipeline of curcumin in neurodegeneration, from mechanistic rationale to clinical applicability: (1) molecular mechanisms, addressing the pleiotropic activities that justify therapeutic interest; (2) pharmacokinetic barriers, the principal obstacle to clinical translation; (3) the evolution of drug delivery systems (DDSs), documenting the technological strategies developed to overcome these barriers; (4) disease-specific applications, evaluating the available evidence across the four main NDs; and (5) translational limitations, identifying the methodological and regulatory gaps that must be closed to enable clinical implementation. Results: Curcumin exhibits neuroprotective activity in preclinical models of the four NDs analysed, acting on six interconnected mechanisms and the gut–brain axis. Four generations of DDSs have been developed, from phytosomes and clinically used lipid dispersions (Meriva^®, BCM-95^®, Longvida^®, and Theracurmin^®) to fourth-generation systems (biomimetic nanoparticles, MOFs, microneedles, 3D scaffolds, hydrogels, and carbon dots) that substantially increase the bioavailability in preclinical studies. Combination strategies, such as curcumin with resveratrol and dutasteride, show preliminary clinical signals in ALS. However, clinical translation remains limited: over 80% of positive animal findings have not been replicated in humans, formulation characterization is frequently incomplete, and most trials lack CNS-exposure biomarkers. Importantly, most of the reported bioavailability claims are based on total curcumin measurements (parent aglycone plus its inactive Phase II conjugates) rather than the active aglycone alone, a methodological limitation that should be considered when interpreting the magnitude of the bioavailability improvements reported for novel formulations. Conclusions: Curcumin exhibits pleiotropic neuroprotective activity in preclinical models of AD, PD, MS, and ALS, mediated by interconnected antioxidant, anti-inflammatory, anti-amyloidogenic, mitochondrial, and gut–brain axis mechanisms. However, its poor systemic bioavailability (<1%), minimal blood–brain barrier penetration, and extensive first-pass metabolism have limited clinical translation. Advanced drug delivery systems (including lipid-based carriers (liposomes, solid lipid nanoparticles, and nanostructured lipid carriers), polymeric nanoparticles (PLGA and chitosan), and bioinspired vesicles (exosomes)) are essential in order to overcome these barriers. Nevertheless, the formulation heterogeneity, limited long-term safety data, and reliance on preclinical models remain major obstacles; a definitive clinical translation will therefore require well-characterized formulations validated in phase II/III trials with cerebrospinal fluid exposure biomarkers, the pharmacokinetic monitoring of active aglycone (rather than total curcumin including inactive conjugates), and adaptive trial designs in neurological populations. Full article

Parkinson’s disease (PD) involves progressive basal ganglia dysfunction, with hyperexcitability of striatal indirect-pathway D2 medium spiny neurons (D2-MSNs) linked to motor impairment. Neuromotor rehabilitation is an important therapy, but its efficacy varies across interventions. This thematic review examines eleven rehabilitative strategies for PD, spanning forced and voluntary exercise (FE and VE respectively), non-invasive brain stimulation (rTMS, tDCS), and technology-based approaches such as exoskeletons, augmented reality, and dual-task training, within a framework distinguishing striatal recalibration from compensation via alternative motor networks. To formalize this distinction, a Bayesian ranking framework combines neurobiological plausibility with clinical evidence quality, identifying three functional clusters: a high-recalibration cluster (FE, p ≈ 0.80; LSVT BIG, p ≈ 0.62), an intermediate-uncertainty cluster (rTMS, HIIT, tDCS, treadmill, resistance training, Tai Chi/dance; 0.40–0.56), and a bypass/compensatory cluster (augmented reality, exoskeletons, dual-task training; p ≤ 0.33). This distinction between direct modulation of basal ganglia circuitry and recruitment of alternative motor networks, including the lateral premotor cortex, parieto-premotor circuits, and cerebello-thalamo-cortical pathways, supports a precision rehabilitation approach in PD. Full article

Efflux pumps are essential components of cellular detoxification mechanisms, regulating the intracellular accumulation of xenobiotics and endogenous compounds. Among them, P-glycoprotein (P-gp) plays a role in protecting the brain from potentially toxic molecules, and alterations in its function have been associated with neurodegenerative disorders, including Parkinson’s disease (PD). Although P-gp inhibitors have been extensively investigated in the context of multidrug resistance, their effects on neuronal cells remain poorly characterized. In the present study, we investigated the biological effects of the pyridoquinoxaline-based efflux pump inhibitor 2,2′-(pyrido[2,3-g]quinoxaline-2,3-diylbis(methylene))bis(oxy)bis(N-phenylbenzamide) (10d) in PC12 cells, a widely used dopaminergic neuronal model. The effects of 10d were evaluated by an MTT-based cell viability assay, while intracellular and extracellular dopamine (DA) levels and DA metabolites were quantified by high-performance liquid chromatography (HPLC). In addition, the ability of 10d to modulate MPTP-induced neurotoxicity was assessed, alone and in combination with amantadine (AMA), a known antiparkinsonian drug. Exposure to 10d (5 and 10 μM) reduced PC12 cell viability and markedly enhanced MPTP-induced cytotoxicity. Furthermore, 10d altered dopaminergic homeostasis by decreasing intracellular DA levels and modifying DA metabolite profiles, with more pronounced effects following co-treatment with MPTP. The combined administration of 10d, MPTP and AMA produced a stronger disruption of DA metabolism compared with individual treatments or 10d/MPTP co-exposure. Full article