Search Results (7,037)

Neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are becoming more prevalent and still lack effective disease-modifying therapies (DMTs). However, translational efficiency remains critically low. For example, a ClinicalTrials.gov analysis of AD programs (2002–2012) estimated ~99.6% attrition, while PD programs (1999–2019) achieved an overall success rate of ~14.9%. In vitro platforms are assessed, ranging from immortalized neuronal lines and primary cultures to human-induced pluripotent stem cell (iPSC)-derived neurons/glia, neuron–glia co-cultures (including neuroinflammation paradigms), 3D spheroids, organoids, and blood–brain barrier (BBB)-on-chip systems. Complementary in vivo toxin, pharmacological, and genetic models are discussed for systems-level validation and central nervous system (CNS) exposure realism. The therapeutic synthesis focuses on AD, covering symptomatic drugs, anti-amyloid immunotherapies, tau-directed approaches, and repurposed drug classes that target metabolism, neuroinflammation, and network dysfunction. This review links experimental models to translational decision-making, focusing primarily on AD and providing a brief comparative context from other NDDs. It also covers emerging targeted protein degradation (PROTACs). Key priorities include neuroimmune/neurovascular human models, biomarker-anchored adaptive trials, mechanism-guided combination DMTs, and CNS PK/PD-driven development for brain-directed degraders. 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

Short-range internal timing supports coordinated movement, attention, and physiological regulation, yet distortions of time experience are frequently reported across clinical and high-arousal states. Patients with anxiety or acute stress often describe an apparent acceleration of time, whereas depressive states are more commonly associated with a slowing of subjective time. Neurological conditions, including Parkinson’s disease and epilepsy, further demonstrate alterations in temporal processing that cannot be reduced to a single mechanism. This narrative review synthesizes evidence from experimental timing paradigms, subjective passage-of-time judgments, and chronobiological approaches to examine how internal timing varies across biological states. In this study, we highlight the distinction between experiential time distortion and performance-based interval timing and discuss how task characteristics, arousal level, and neural context contribute to heterogeneous findings. Historical and methodological foundations are reviewed, including early chronobiological work linking subjective time estimation to biological rhythms. The reviewed evidence suggests that many timing distortions observed in stress-related, affective, and neurological conditions reflect state-dependent reconfiguration rather than irreversible dysfunction. Framing timing variability as a potential marker of internal state may help reconcile inconsistent results across paradigms and inform future clinical and translational research on temporal processing. Full article

Neurodegenerative disorders are increasingly linked to a progressive decline in lysosomal function. Activating Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, has therefore emerged as a promising therapeutic strategy to enhance cellular clearance in these conditions. In this study, we identified KHS-101 as a novel TFEB activator through a high-throughput screen of blood–brain-barrier-permeable small molecules. We demonstrated that KHS-101 promotes TFEB nuclear translocation, enhances lysosomal biogenesis and proteolytic activity, and increases autophagic flux. Furthermore, KHS-101 significantly accelerates the degradation of pathogenic A53T mutant α-synuclein in a cellular model of Parkinson’s disease, suggesting its potential to mitigate α-synuclein-mediated proteotoxicity and hold neuroprotective potential. Our findings identify KHS-101 as a potent TFEB activator and highlight the therapeutic potential of modulating the autophagy-lysosomal pathway for treating Parkinson’s disease and related disorders. 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

Neurodegenerative disorders are characterized by progressive neuronal loss and dysfunction, yet increasing evidence indicates that glial cells are central mediators of both disease initiation and progression. Astrocytes, microglia, and oligodendrocyte lineage cells modulate neuronal survival by regulating neuroinflammation, metabolic support, synaptic maintenance, and proteostasis. However, dysregulated glial responses, including chronic microglial activation, impaired phagocytosis, altered cytokine production, and mitochondrial dysfunction, contribute to persistent inflammation and structural degeneration observed across Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease and multiple sclerosis. Recent advances in single-cell and spatial omics have revealed extensive glial heterogeneity and dynamic shifts between neuroprotective and neurotoxic phenotypes, emphasizing the context-dependent nature of glial activity. This review summarizes current knowledge regarding the multifaceted involvement of glial cells in neurodegenerative disorders. 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

Background/Objectives: Parkinson’s disease is the second most common neurodegenerative disorder, affecting patients’ daily lives in multiple domains, including functional status, health-related quality of life, and psychological well-being. This study examined the relationship between self-reported global activity level, functional status, Health Related QoL (HRQoL), and psychological state among patients with Parkinson’s disease in Greece. Methods: Thirty volunteers (mean age = 69.07, SD = 11.24), members of the Greek Parkinson’s Patients and Caregivers Association, completed (a) the Parkinson’s Disease Questionnaire to evaluate HRQoL and (b) the Hospital Anxiety and Depression Scale (HADS) to assess psychological state. Participants then performed (a) the Five Times Sit to Stand Test (FTSST) and (b) the Berg Balance Scale (BBS) to evaluate functional status. All questionnaires and the test used in the present study have been validated in Greek. Correlation analysis with Spearman r tests with Bonferroni correction was performed between the above variables. Subsequent linear regression models were used to identify independent predictors of HRQoL and balance using SPSS 29.0.2.0. Results: Participants reported elevated anxiety (M = 9.67, SD = 4.44) and depressive symptoms (M = 8.97, SD = 4.08), alongside relatively high HRQoL scores (M = 40.09, SD = 18.40). Impaired functional performance was observed, with 22 participants failing to complete the FTSST within 16 s and 16 scoring below 40 on the BBS. Functional status was strongly correlated with HRQoL (r = −0.696, p < 0.001) and activity level (r = −0.521, p < 0.008). Depression was also significantly associated with poorer HRQoL (r = 0.618, p < 0.008) and lower activity levels (r = −0.545, p < 0.008). Regression analyses revealed that balance (β = −0.526), disease duration (β = 0.437), anxiety (β = 0.411), and lower limb function (β = −0.351) were significant independent predictors of HRQoL (R² = 0.785; F(9, 20) = 12.69; p < 0.001), while HRQoL (β = −0.738) and lower limb function (β = −0.391) independently predicted balance (R² = 0.699; F(9, 20) = 4.72; p = 0.002), suggesting a bidirectional relationship between physical function and subjective well-being. Conclusions: Activity level, HRQoL, functional status, and psychological state in patients with Parkinson’s disease are interrelated factors. Increased levels of anxiety and depression, as well as reduced HRQoL, were observed. The findings point to a potentially reinforcing cycle between poor balance and diminished quality of life, with anxiety and age playing key roles. Overall, the results illustrate that functional, psychological, and HRQoL measures interact in complex ways, emphasizing the multidimensional profile of patients with Parkinson’s disease. Further studies with larger samples are required to confirm these findings. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by the degeneration of dopaminergic neurons in the substantia nigra, resulting in cardinal motor symptoms such as tremor, rigidity, and bradykinesia. Neuroinflammation is increasingly recognized as a central driver of PD onset and progression in which oligodendrocytes, astrocytes, and microglia engage in complex bidirectional crosstalk that shapes the inflammatory milieu of the central nervous system. Pathological activation of glial cells triggers the release of pro-inflammatory cytokines, chemokines, and reactive oxygen species, thereby exacerbating neuronal injury and contributing to sustained disease progression. Modulating maladaptive glial activation states and their intercellular communication represents a promising therapeutic avenue aimed at mitigating neuroinflammation and slowing PD pathology. This review synthesizes current knowledge on neuroinflammation in PD, focusing on the distinct roles of microglia, astrocytes, and oligodendrocytes, their interaction networks, and emerging therapeutic strategies. 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

Background/Objectives: Patients with deep brain stimulation (DBS) require regular follow-up. When a sudden loss of therapeutic effect occurs, impedance abnormalities are often the underlying cause. If reprogramming cannot restore clinical benefit, revision surgery may be necessary to replace defective hardware. Since all three major manufacturers are used at our center, we analyzed our patient cohort to determine the incidence and causes of impedance abnormalities. Methods: All 601 patients who underwent de novo DBS implantation in Hamm between 2009 and 2025 were evaluated for impedance abnormalities. In cases requiring revision surgery, the specific cause was identified. The manufacturer, electrodes, and contacts involved were systematically analyzed. Results: A total of 25 of 601 patients required revision surgery. Revision rates were 2.67% in patients with Parkinson’s disease, 6.19% in those with a tremor, and 5.71% in those with dystonia. Across manufacturers, 7.6% of patients with a Medtronic system required revision surgery, compared with 3.4% of patients with an Abbott system and no patients with a Boston Scientific system. The primary causes of revision were electrode-related problems (19/25), followed by extension defects (6/25), connector issues (4/25), and, in one case, a generator defect (1/25). Conclusions: Only 4.16% of patients required revision surgery due to impedance abnormalities. Patients with a tremor and non-segmented electrodes showed a higher incidence than those with Parkinson’s disease or dystonia. Predominantly older Medtronic systems had the highest revision rate, whereas no Boston Scientific systems required revision. In most cases, the electrodes were the primary source of impedance abnormalities. A total of 52% of revisions were performed within two years and 92% were performed within six years of implantation. 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

Fine-grained action detection remains a challenging and actively studied problem. While previous methods predominantly rely on convolutional neural networks (CNNs), their limited modeling capacity and high computational cost restrict their effectiveness in fine-grained settings. To overcome these challenges, we propose Action-JointsLLM, a novel framework that leverages joints extracted from visual data and large language models (LLMs) for accurate and efficient fine-grained action detection. Specifically, we introduce a Joint2Text module that transforms sequences of human joints into natural language descriptions, enabling direct compatibility with LLMs. Additionally, we design an attn-pooling mechanism to identify the contributions of each joint and time step across the motion sequence, enabling more accurate action analysis. Our approach demonstrates strong generalization across different LLM backbones and achieves state-of-the-art performance on the PD-WALK dataset, using Parkinson’s disease detection as a representative fine-grained action recognition task. Full article

Exercise-induced myokines have emerged as crucial mediators of the beneficial effects of physical activity on neurodegenerative diseases through complex molecular mechanisms involving oxidative stress reduction, neuroinflammation suppression, and synaptic plasticity enhancement. Among these myokines, irisin, encoded by the FNDC5 gene, has gained significant attention as a potential therapeutic target in neurodegenerative conditions due to its ability to cross the blood–brain barrier and exert pleiotropic neuroprotective effects. This review synthesizes current evidence from both preclinical and clinical studies examining the role of exercise-induced irisin in neurodegeneration, with particular emphasis on translational potential and therapeutic applications. A comprehensive search was conducted across PubMed, Web of Science, Scopus, and EMBASE databases (spanning January 2015 to December 2024) to identify peer-reviewed articles investigating irisin’s neuroprotective mechanisms in neurodegenerative diseases. Ten studies met the inclusion criteria (five rodent/primate model studies and five human clinical investigations), which were analyzed for methodological rigor, intervention protocols, biomarker quantification methods, and reported outcomes. Reviewed studies consistently demonstrated that exercise-induced endogenous irisin elevation correlates with improved cognitive function, reduced neuroinflammatory markers, enhanced synaptic plasticity, and modulation of neurodegenerative pathways, with exogenous irisin administration reproducing several neuroprotective benefits observed with exercise training in animal models. However, substantial heterogeneity exists regarding exercise prescription parameters (intensity, duration, frequency, modality), training-induced irisin quantification methodologies (ELISA versus mass spectrometry), and study designs (ranging from uncontrolled human observations to randomized controlled trials in animal models). Critical appraisal reveals that human studies lack adequate control for confounding variables including baseline physical fitness, comorbidities, concurrent medications, and potential sources of bias, while biochemical studies indicate distinct pharmacokinetics between endogenous training-induced irisin and exogenous bolus dosing, necessitating careful interpretation of therapeutic applicability. The translational potential of irisin as a therapeutic agent or drug target depends on resolving methodological standardization in biomarker measurement, conducting well-designed clinical trials with rigorous control for confounders, and integrating findings from molecular/biochemical studies to elucidate mechanisms linking irisin to disease modification. Future research should prioritize establishing clinical trial frameworks that harmonize exercise prescriptions, employ robust biomarker quantification (mass spectrometry), and stratify participants based on disease stage, comorbidities, and genetic predisposition to clarify irisin’s role as a potential therapeutic intervention in neurodegenerative disease management. Full article