Search Results (2,139)

Background/Objectives: Respiratory dysfunction in Parkinson’s disease (PD) is frequently underrecognized, particularly when resting oxygen saturation is preserved. Dynamic stress testing, however, may reveal exercise-induced oxygen desaturation, reflecting a latent functional respiratory impairment. The relationship between exertional oxygen desaturation and cognitive performance in PD remains insufficiently explored. Objective: To investigate the association between exercise-induced oxygen desaturation and global cognitive performance in patients with PD, and to explore the contribution of pulmonary gas exchange impairment assessed by diffusing capacity of the lung for carbon monoxide (DLCO). Methods: This prospective, cross-sectional, single-center observational study with consecutive enrollment included 50 patients with idiopathic Parkinson’s disease undergoing multidisciplinary respiratory evaluation following neurological assessment. Participants underwent cognitive evaluation using the Romanian version of the Montreal Cognitive Assessment (MoCA), pulmonary function testing including DLCO and total lung capacity (TLC), and a supervised 6-min walk test (6MWT) with continuous pulse oximetry. Exercise-induced oxygen desaturation was defined as a decrease in SpO₂ of ≥4% from baseline. Correlation analyses and multivariable regression models were applied. Results: Exercise-induced oxygen desaturation was frequent, with 60% of patients exhibiting a ≥4% decrease in SpO₂ during the 6MWT. Greater desaturation was significantly associated with lower MoCA scores (Spearman’s r = −0.383, p = 0.006). No significant associations were found between exertional desaturation and resting pulmonary function parameters, including DLCO and TLC. In multivariable analysis, lower MoCA score and levodopa–carbidopa intestinal gel treatment independently predicted greater oxygen desaturation during exercise. Conclusions: Exercise-induced oxygen desaturation is common in patients with PD despite preserved resting oxygenation and is associated with poorer cognitive performance. These findings suggest that exertional desaturation may reflect a dynamic functional impairment and may be associated with increased physiological vulnerability. Functional exercise testing with oxygen saturation monitoring may provide complementary information beyond resting pulmonary assessments. Full article

Background/Objectives: Parkinson’s disease (PD) is one of the most prevalent neurodegenerative disorders. Despite its multifactorial etiology, PD pathophysiology shared specific features such as cytoplasmic α-synuclein inclusions, oxidative stress, mitochondrial dysfunction, and impaired autophagy. Bromodomain and Extra-Terminal domain (BET) proteins, functioning as epigenetic readers, have recently emerged as promising therapeutic targets due to their regulatory role in redox homeostasis, neuroinflammation, and autophagy. However, their potential involvement in PD pathophysiology remains largely unexplored. Therefore, we aimed at evaluating whether BET modulation could ameliorate the parkinsonian phenotype in two cellular models. Methods: Differentiated SH-SY5Y and N1E-115 neuronal cells were exposed to rotenone toxin to mimic PD phenotype and co-treated with the small BET inhibitor JQ1. Results: BET inhibition significantly counteracted rotenone-induced cell death, neuromorphological alterations, and α-synuclein accumulation. These protective effects were accompanied by restoration of redox balance, as indicated by enhanced activation of the antioxidant system and suppression of the pro-oxidant NADPH oxidase complex. Moreover, JQ1 treatment alleviated mitochondrial dysfunction and corrected autophagy impairments triggered by rotenone. Conclusions: These data highlight a novel role for BET proteins in neurodegeneration, suggesting that their modulation may represent a promising approach to counteract PD neuropathology. Full article

Mitochondrial dysfunction is a key early pathological process in neurodegenerative diseases (NDs), leading to oxidative stress, impaired energy metabolism, and neuronal apoptosis prior to the onset of clinical symptoms. Although mitochondria represent important therapeutic targets, effective interventions targeting mitochondrial function remain limited. This review summarizes current evidence regarding the mechanisms by which melatonin protects mitochondria and evaluates its therapeutic relevance, with a primary focus on Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease—the major protagonists of NDs—while briefly covering other NDs such as amyotrophic lateral sclerosis, multiple sclerosis, and prion diseases. Melatonin selectively accumulates in neuronal mitochondria and exerts neuroprotection through multiple pathways: (1) direct scavenging of reactive oxygen species (ROS); (2) transcriptional activation of antioxidant defenses via the SIRT3 and Nrf2 pathways; (3) regulation of mitochondrial dynamics through DRP1 and OPA1; and (4) promotion of PINK1- and Parkin-mediated mitophagy. Additionally, melatonin exhibits context-dependent pleiotropy: under conditions of mild mitochondrial stress, it restores mitochondrial homeostasis; under conditions of severe mitochondrial damage, it promotes pro-survival autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby conferring stage-specific therapeutic advantages. Overall, melatonin offers a sophisticated mitochondria-targeting strategy for the treatment of NDs. However, successful clinical translation requires clarification of receptor-dependent signaling pathways, development of standardized dosing strategies, and validation in large-scale randomized controlled trials. Full article

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by motor dysfunction and non-motor symptoms, including cognitive decline. Animal models that replicate PD’s clinical features are essential for therapeutic research. The widely used subacute 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP)-induced mouse model effectively mimics motor deficits but fails to fully represent aging-related non-motor symptoms. In this study, we established an aging-associated PD mouse model by combining MPTP with D-galactose treatment. Compared to mice treated with MPTP alone, MPTP + D-galactose-treated mice exhibited typical motor impairments alongside cognitive deficits in the Morris water maze and Y-maze tests. D-galactose alone induced cognitive impairment without motor dysfunction. Pathological analysis showed that the MPTP + D-galactose treatment caused tyrosine hydroxylase-positive neuron loss similar to MPTP, while D-galactose did not damage these neurons. Additionally, Micro-CT revealed bone loss in both the MPTP + D-galactose and D-galactose groups. This model recapitulates both the motor and aging-related non-motor symptoms of PD, including cognitive impairment and bone loss, providing a more comprehensive tool for studying PD pathogenesis and evaluating potential therapies. Full article

This review summarizes the role of nuclear factor erythroid 2–related factor 2 (Nrf2) as a common link between aging, neurodegeneration, and neuropathic pain. Aging is characterized by oxidative stress and constant inflammation, which coincides with reduced Nrf2 activity and weaker antioxidant responses, increasing vulnerability to diseases. In neurodegenerative disorders—including Alzheimer’s, Parkinson’s, Huntington’s disease, and amyotrophic lateral sclerosis—evidence indicates that impaired Nrf2 signaling contributes to oxidative damage, neuroinflammation, and mitochondrial dysfunction. Furthermore, in neuropathic pain, similar mechanisms are involved, and Nrf2 could play a role as a potential analgesic target because of its role in regulating cellular defense pathways. We also review natural Nrf2 modulators (e.g., flavonoids, other polyphenols, terpenoids, alkaloids), discussing their benefits alongside common translational limitations such as poor solubility, low oral bioavailability, rapid metabolism, and potential safety issues, including possible pro-oxidant effects and chemoresistance. We also outline future directions that should prioritize improving delivery systems, addressing NRF2/KEAP1 gene variations, evaluating combinations with standard therapies, exploring preventive applications, and defining dosing, treatment duration, and long-term safety. Overall, current evidence indicates that Nrf2 modulation is a practical, cross-cutting approach relevant to healthy aging and disease management. Full article

The blood–brain barrier (BBB) restricts therapeutic delivery to the central nervous system (CNS), hindering the treatment of neurological disorders, such as Alzheimer’s disease, Parkinson’s disease, brain cancers, and stroke. Aptamers, short single-stranded DNA or RNA oligonucleotides that can fold into unique 3D shapes and bind to specific target molecules, offer high affinity and specificity, low immunogenicity, and promising BBB penetration via receptor-mediated transcytosis targeting receptors such as the transferrin receptor (TfR) and low-density lipoprotein receptor-related protein 1 (LRP1). This review examines aptamer design through the Systematic Evolution of Ligands by Exponential Enrichment (SELEX) and its variants, mechanisms of BBB crossing, and applications in CNS disorders. Recent advances, including in silico optimization, in vivo SELEX, BBB chip-based MPS-SELEX, and nanoparticle–aptamer hybrids, have identified brain-penetrating aptamers and enhanced the brain delivery efficiency. This review highlights the potential of aptamers to transform CNS-targeted therapies. Full article

Background/Objectives: Neurodegenerative diseases are driven by multiple interconnected pathological mechanisms involving both intrinsic and extrinsic molecular and cellular processes. Efficient bidirectional intracellular transport is essential for neuronal survival and function, enabling the movement of organelles, proteins, and vesicles between the neuronal soma and distal compartments. This process is primarily mediated by kinesin-dependent anterograde transport and dynein-dependent retrograde transport. Disruption of either motor protein compromises endosome–lysosome recycling, leading to cellular dysfunction and neurodegeneration. However, the mechanisms underlying motor protein impairment in Parkinson’s disease (PD) remain incompletely understood. Methods: We investigated the involvement of kinesin and dynein in intracellular transport dysfunction using both in vitro and in vivo models of PD. Cultured neuronal cells were exposed to MPP+ (1-methyl-4-phenylpyridinium) to model PD-associated neurotoxicity, and motor protein function, vesicular trafficking, and endosomal recycling were assessed. In parallel, an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced mouse model of PD was used to evaluate dynein-positive fiber density in the spinal cord. The role of calpain-2 was examined by co-treatment with the selective calpain-2 inhibitor zLLYCH2F in both experimental systems. Results: MPP+ exposure disrupted kinesin- and dynein-mediated transport in neuronal cytoplasm, resulting in impaired vesicular trafficking and defective endosome–lysosome recycling. These alterations led to abnormal accumulation of vesicles in both perinuclear regions and at the cell periphery. Pharmacological inhibition of calpain-2 with zLLYCH2F restored motor protein function and normalized vesicle distribution in MPP+-treated cells. Consistent with in vitro findings, MPTP-treated mice exhibited a significant reduction in dynein-positive fiber density within the spinal cord, which was prevented by co-treatment with zLLYCH2F. Conclusions: Our findings demonstrate that calpain-2 activation contributes to kinesin and dynein dysfunction following MPP+/MPTP exposure, leading to impaired intracellular transport and vesicle recycling in PD models. Inhibition of calpain-2 preserves motor protein function, maintains cytoskeletal integrity, and supports normal intracellular trafficking. These results identify calpain-2 as a critical regulator of motor protein stability and suggest that targeting calpain-2 may represent a promising therapeutic strategy for mitigating intracellular transport defects in Parkinson’s disease. Full article

Parkinson’s disease (PD), the second most common neurodegenerative disorder globally, relies primarily on dopamine replacement therapy for conventional treatment. This approach fails to reverse core pathological processes and is associated with long-term side effects. Recent research on the microbiota-gut-brain axis (MGBA) has revealed that PD pathology may originate in the gut, forming a vicious cycle from the gut to brain through α-synuclein propagation, gut dysbiosis, intestinal barrier disruption, and neuroinflammation. This offers a novel perspective for managing PD through dietary interventions that modulate the gut microbiome. However, single probiotic or prebiotic interventions show limited efficacy. This review systematically introduces the novel concept of “synbiotics combining medicinal plant polysaccharides with probiotics,” aiming to integrate traditional “medicinal food” wisdom with modern microbiome science. The article systematically elucidates the pathological mechanisms of MGBA dysfunction in PD and the intervention mechanisms of probiotics and emphasizes the structural and functional advantages of medicinal plant polysaccharide as superior prebiotics. The core section delves into the multifaceted synergistic mechanisms between these two components: enhancing probiotic colonization and vitality, optimizing microbial metabolic output, synergistically reinforcing the intestinal and blood-brain barriers, and jointly regulating immune and neuroinflammation. This approach targets the MGBA to achieve multi-level intervention for PD. Full article

Fucoidan, a complex sulfated polysaccharide derived from marine brown seaweeds, exhibits broad biological activities, including anticoagulant, antitumor, antiviral, anti-inflammatory and lipid-lowering effects. Fucoidan confers neuroprotection in animal models of a broad spectrum of brain disorders such as Parkinson’s disease (PD) and depression. However, the effect of fucoidan on gut-derived neuroinflammation and associated behavioral changes has been scarcely investigated. In comparison to fucoidan from other brown seaweeds, that from Fucus vesiculosus exhibited a better neuroprotective effect in vivo and more potent radical scavenging activity in vitro. Fucoidan from Laminaria japonica ameliorates behavioral disorders related to acute ulcerative colitis (UC) in aged mice. It is of interest to assess the effects of fucoidan administration on intestinal and brain inflammation in the acute colitis mouse model. Fucoidan treatment ameliorated DSS-induced intestinal pathology, reduced the inflammatory mediator expression in the gut and brain, and activated intestinal macrophages and cortical microglia in the UC mice. It also protected the intestinal mucosal barrier and blood–brain barrier as well as prevented neuronal damage, while alleviating anxiety-like behavior in UC mice. These results suggest fucoidan supplementation may help prevent brain disorders, such as depression and PD, potentially involving gut–brain axis-related mechanisms, as fucoidan suppresses gut-derived neuroinflammation. Full article

Parkinson’s disease is a neurodegenerative disorder that affects the elderly population worldwide. Rotenone (ROT) is an environmental toxin that impairs mitochondrial dynamics by inhibiting respiratory chain complex I and thus inducing oxidative stress. Farnesol (FSL) is a dietary sesquiterpene with antioxidant and anti-inflammatory properties reported in various in vivo models. To evaluate the efficacy of FSL in the management of PD, Wistar rats were injected with ROT (2.5 mg/kg, i.p) and pretreated with FSL. Immunohistochemical staining measured tyrosine hydroxylase-positive cells in the substantia nigra and striatum. Western blotting was employed to determine protein expression of inflammatory, apoptotic, and autophagic markers. Our results indicate that FSL significantly protected against ROT-induced inflammation by suppressing microglial and astrocytic activation through the downregulation of Toll-Like receptor 4 (TLR4), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), inhibitor of kappa B (IkB), inducible nitric oxide synthase (iNOS), cyclooxygenase (COX), matrix metalloproteinase-9 (MMP-9) expression. FSL has also demonstrated an antioxidant effect by enhancing the activity of superoxide dismutase and catalase while reducing the level of Malondialdehyde and nitric oxide. Moreover, it restored homeostasis in ROT-induced imbalance between pro- and anti-apoptotic proteins. Impaired autophagy observed in ROT-injected rats was corrected by FSL treatment, which upregulated phosphorylated mammalian target of rapamycin (p-mTOR) expression and downregulated P62, an autophagosome marker. The protective effect of FSL was further supported by preserving the brain-derived neurotrophic factor (BDNF) and tyrosine hydroxylase in the brain. These findings demonstrate the neuroprotective ability of FSL and its potential to be developed as a pharmaceutical or nutraceutical agent for the prevention and treatment of PD by mitigating neuropathological changes observed in dopaminergic neurodegeneration. Full article

Psychosis is a frequent and disabling non-motor complication of Parkinson’s disease (PD). Clozapine and quetiapine are widely used in the treatment of Parkinson’s disease psychosis (PDP). We conducted an exploratory study to compare patient experiences with physician prescribing practices. Patients with PDP hospitalized at a university center completed semi-structured interviews on perceived efficacy, adverse effects, and daily functioning. Neurologists and geriatricians attending training sessions completed a structured questionnaire on prescribing patterns, attitudes toward clozapine, and perceived treatment burden. Data were analyzed thematically and triangulated across cohorts. Eleven patients (mean age 81 years; nine treated with quetiapine, two with clozapine) were included. Most quetiapine-treated patients reported persistent hallucinations, sedation, dizziness, and reduced autonomy. Fourteen physicians completed the survey and most preferred quetiapine, citing monitoring logistics and agranulocytosis risk as barriers to clozapine. Overall, patient priorities centered on symptom control and independence, whereas physician decisions emphasized feasibility and safety. Facilitating clozapine monitoring and incorporating patient-reported outcomes into routine care may improve patient-centered PDP management. Full article

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by age-dependent degeneration of dopaminergic neurons in the substantia nigra, a process mediated by α-synuclein aggregation, mitochondrial dysfunction, and impaired proteostasis. While BAP31—an endoplasmic reticulum protein critical for protein trafficking and degradation—has been implicated in neuronal processes, its role in PD pathogenesis remains poorly understood. To investigate the impact of BAP31 deficiency on PD progression, we generated dopamine neuron-specific BAP31 conditional knockout with DAT-Cre (cKO) mice (Slc6a3cre-BAP31^fl/fl) and subjected them to MPTP-lesioned Parkinsonian models. Compared to BAP31^fl/fl controls, Slc6a3cre-BAP31^fl/fl mice exhibited exacerbated motor deficits following MPTP treatment, including impaired rotarod performance, reduced balance beam traversal time, and diminished climbing and voluntary motor capacity abilities. BAP31 conditional deletion showed no baseline phenotype, with deficits emerging only after MPTP. Our results indicate that these behavioral impairments correlated with neuropathological hallmarks: decreased NeuN neuronal counts, elevated GFAP astrogliosis, reduced tyrosine hydroxylase levels in the substantia nigra, and aggravated dopaminergic neurodegeneration. Mechanistically, BAP31 deficiency disrupted mitochondrial homeostasis by suppressing the PINK1–Parkin mitophagy pathway. Further analysis revealed that BAP31 regulates PINK1 transcription via the transcription factor Engrailed Homeobox 1. Collectively, our findings identify BAP31 as a neuroprotective modulator that mitigates PD-associated motor dysfunction by preserving mitochondrial stability, underscoring its therapeutic potential as a target for neurodegenerative disorders. Full article

Dysphagia and dysarthria are common, co-occurring manifestations in neurodegenerative diseases, resulting from damage to distributed neural networks involving cortical, subcortical, cerebellar, and brainstem regions. These disorders profoundly affect patient health and quality of life through complex sensorimotor impairments. Objective: The aims was to provide a comprehensive, evidence-based review of the neuroanatomical substrates, pathophysiology, diagnostic approaches, and management strategies for dysphagia and dysarthria in neurodegenerative diseases with emphasis on their multisystem nature and integrated treatment approaches. Methods: A narrative literature review was conducted using PubMed, Scopus, and Web of Science databases (2000–2024), focusing on Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). Search terms included “dysphagia”, “dysarthria”, “neurodegenerative diseases”, “neural networks”, “swallowing control” and “speech production.” Studies on neuroanatomy, pathophysiology, diagnostic tools, and therapeutic interventions were included. Results: Contemporary neuroscience demonstrates that swallowing and speech control involve extensive neural networks beyond the brainstem, including bilateral sensorimotor cortex, insula, cingulate gyrus, basal ganglia, and cerebellum. Disease-specific patterns reflect multisystem involvement: PD affects basal ganglia and multiple brainstem nuclei; ALS involves cortical and brainstem motor neurons; MSA causes widespread autonomic and motor degeneration; PSP produces tau-related damage across multiple brain regions. Diagnostic approaches combining fiberoptic endoscopic evaluation, videofluoroscopy, acoustic analysis, and neuroimaging enable precise characterization. Management requires multidisciplinary Integrated teams implementing coordinated speech-swallowing therapy, pharmacological interventions, and assistive technologies. Conclusions: Dysphagia and dysarthria in neurodegenerative diseases result from multifocal brain damage affecting distributed neural networks. Understanding this multisystem pathophysiology enables more effective integrated assessment and treatment approaches, enhancing patient outcomes and quality of life. Full article

Motor disorders are increasingly recognized as a significant complication of chronic kidney disease (CKD), yet they remain underdiagnosed, undertreated, and often overlooked in clinical practice. Patients with CKD experience a broad spectrum of motor disturbances, including restless legs syndrome, myoclonus, flapping tremor, periodic limb movements in sleep, Parkinsonism, and peripheral neuropathy. These disorders arise from complex and often overlapping mechanisms such as uremic neurotoxicity, vascular injury, electrolyte and hormonal imbalances, or inflammatory processes, reflecting the systemic impact of impaired renal function on the central and peripheral nervous systems. The presence of motor disorders in CKD is associated with substantial clinical consequences for quality of life, contributing to impaired mobility, persistent insomnia, daytime fatigue, higher fall risk, and diminished independence. Moreover, these disturbances have been linked to increased cardiovascular morbidity and mortality, further exacerbating the already high burden of disease in this population. Current management approaches focus on optimizing kidney function through dialysis or transplantation, pharmacological therapies such as dopaminergic agents, gabapentinoids, and iron supplementation, as well as non-pharmacological interventions including structured exercise programs and sleep hygiene measures. Despite these strategies, robust evidence on long-term outcomes, comparative effectiveness, and optimal treatment algorithms remains limited. Greater recognition of the clinical impact of motor disorders in CKD, combined with targeted research efforts, is urgently needed to improve patient-centered outcomes and guide evidence-based care. Full article

Neurodegeneration—driven by oxidative stress, chronic inflammation, and protein aggregation—underlies disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and stroke. Current pharmacological treatments are largely symptomatic and do not restore lost neural circuitry, motivating regenerative approaches. Mesenchymal stem cells (MSCs) provide neurotrophic and immunomodulatory benefits and can support synaptic repair, yet robust conversion into mature, electrophysiologically functional neurons remain challenging and often depends on complex inducer cocktails with translational limitations. Crocin, a saffron-derived carotenoid, is reported to enhance neurogenesis and neuroprotection in preclinical models through pathways including Wnt/β-catenin, Notch1, CREB/BDNF, and modulation of GSK-3β, while reducing apoptosis and inflammatory signaling. Here, we synthesize evidence supporting crocin’s neuroprotective and proneurogenic activity and propose a testable hypothesis that crocin-based or crocin-modified formulations could be evaluated as adjuncts to guide MSC neuronal lineage commitment. Importantly, direct evidence that crocin alone can drive MSC trans-differentiation into fully functional neurons is currently insufficient; future work should define functional benchmarks (electrophysiology, synaptogenesis, and phenotypic stability) and rigorously validate safety, dosing, and delivery strategies for neuroregenerative translation. Full article