Search Results (13,931)

GM1 gangliosidosis and Morquio B are rare lysosomal storage disorders (LSDs) with significant unmet medical needs. These disorders result from mutations in the galactosidase beta 1 (GLB1) gene, leading to impaired β-galactosidase (β-Gal) activity and toxic substrate accumulation. The lack of approved disease-modifying therapies for GM1 gangliosidosis and Morquio B, along with the challenges of achieving effective central nervous system delivery, has driven interest in small-molecule pharmacological chaperones (PCs) to restore β-Gal stability and function. Using Gain Therapeutics’ Magellan™ platform, a novel allosteric binding site on β-Gal was identified, enabling the discovery of a new class of Structurally Targeted Allosteric Regulators (STARs). Medicinal chemistry optimization produced a structurally unique STAR compound series, demonstrating broad β-Gal stabilizing effects. The therapeutic potential of these compounds was evaluated in vitro using a canine fibroblast model of GM1 gangliosidosis, where they were shown to significantly reduce toxic GM1 ganglioside accumulation. Immunocytochemistry-based assays confirmed substrate clearance and provided reliable structure–activity relationships, guiding further compound development. Notably, STARs achieved greater substrate clearance than the competitive PC N-nonyl-deoxygalactonojirimycin (NN-DGJ) under the conditions tested, as demonstrated by immunocytochemistry-based assays. While these findings are encouraging, further in vivo studies are required to validate the therapeutic efficacy of these few STAR compounds, particularly in addressing the neurodegenerative aspects of GM1 gangliosidosis. This study underscores the potential of the Magellan platform in identifying STAR molecules and provides a strong foundation for further optimization and preclinical validation in GLB1-related disorders, particularly GM1 gangliosidosis. Full article

Glucagon-like peptide-1 (GLP-1) and dual GIP/GLP-1 receptor agonists, originally introduced for the management of type 2 diabetes mellitus and obesity, are increasingly recognized for their broader actions within the central nervous system, with emerging implications in neuropsychiatry and neurodegeneration. This review integrates current preclinical and clinical evidence, emphasizing their pharmacodynamic profile, central receptor distribution, and the molecular pathways linking metabolic signaling to neural function. Evidence suggests that GLP-1 receptor activation across key brain regions involved in energy balance and reward modulates multiple neurotransmitter systems, including dopamine and serotonin, as well as glutamatergic and GABAergic transmission, thereby influencing behavior, affective processes, and cognitive function. In parallel, these agents exhibit neuroprotective properties through improved neuronal insulin sensitivity, attenuation of neuroinflammatory pathways, and support of neuroplasticity, alongside effects on limiting pathological protein aggregation. Dual GIP/GLP-1 agonism may further potentiate these central actions through complementary metabolic and synaptic mechanisms. Although pharmacovigilance data have identified isolated neuropsychiatric adverse events, current clinical evidence does not support a consistent causal association. Collectively, incretin-based therapies represent a promising translational approach at the interface of metabolic and neuropsychiatric disorders, warranting further investigation into their long-term central safety, therapeutic efficacy, and clinical relevance. Full article

Alphaviruses are mosquito-borne viruses that can infect the central nervous system (CNS) and cause encephalomyelitis, which is a rare but dangerous complication from infection. In mice, this can be studied in a model of infection with Sindbis virus (SINV), which infects neurons and causes neurological disease. Due to the non-renewable nature of neurons, the immune response in the CNS is specialized to prevent neuronal damage or death, even if they are infected. Therefore, insights into the nuances of antiviral immunity in the CNS provide a better understanding of disease pathogenesis and mechanisms of recovery. Type I interferons (IFNs) are critically important for survival; they are an innate antiviral defense mechanism that consists mainly of IFNα and IFNβ. Although both use the same receptor, type-specific differences between IFNα and IFNβ have been described in other contexts. To this end, Ifnb^−/− mice were used to elucidate the role of IFNβ in recovery from alphavirus encephalomyelitis. IFNβ-deficient mice have intact IFNα expression and downstream signaling, but symptomatic disease occurs earlier and is more severe. This is accompanied by increased virus replication in the early stages of infection. Microgliosis is reduced in Ifnb^−/− mice compared to wildtype, but inflammatory cytokine/chemokine levels are higher and associated with alterations in monocyte and NK cell recruitment into the CNS. Ifnb^−/− mice have no deficiencies in the expression of factors known to be required for viral clearance. Therefore, IFNβ modulates the early stages of the immune response and facilitates restriction of virus replication, contributing to delayed disease onset. Full article

Neuropsychiatric conditions constitute a major and growing global health burden, with prevalence rates that continue to rise worldwide. Although these disorders have traditionally been studied primarily from a neuronal perspective, accumulating evidence indicates that immune dysregulation and inflammatory processes play a central role in their pathophysiology. In this review, we advance the hypothesis that nitric oxide (NO)-mediated alterations in blood–brain barrier (BBB) integrity represent a critical mechanistic link between inflammation and central nervous system dysfunction in neuropsychiatric disorders. NO is a gaseous multifunctional signaling molecule involved in vascular homeostasis and immune responses, and its dysregulated production, together with aberrant protein S-nitrosylation, has been implicated in several neuropsychiatric conditions. However, the specific mechanisms by which NO signaling contributes to BBB dysfunction remain incompletely defined. Here, we synthesize current evidence supporting a role for NO-dependent vascular and inflammatory pathways in BBB disruption and discuss how these processes may contribute to the onset and progression of neuropsychiatric conditions. Clarifying these mechanisms may provide novel insights into disease pathogenesis and identify therapeutic targets aimed at preserving BBB integrity and limiting neuroinflammation. Full article

Kynurenic acid (KYNA), a metabolite of the L-kynurenine pathway of L-tryptophan degradation, is an endogenous blocker of glutamate ionotropic excitatory amino acid (EAA) receptors and nicotinic acetylcholine receptors (nAChRs). KYNA plays a significant role in various neuropsychiatric disorders and the aging process. Some researchers have suggested that KYNA may contribute to memory impairment. In this study, we examined the impact of L-kynurenine (a KYNA substrate) and the anti-dementia drugs D-cycloserine and Cerebrolysin on kynurenine aminotransferase (KAT) activity, an enzyme forming KYNA, in liver homogenates of Helix pomatia snails. Furthermore, a memory model was established using these snails, wherein tentacle shortening served as an indicator of learning activity. In vitro experiments on Helix pomatia demonstrated the significant impact of L-kynurenine and anti-dementia drugs on KYNA synthesis. KYNA levels increased significantly in the presence of L-kynurenine in liver homogenate. However, KYNA formation decreased when anti-dementia drugs, including Cerebrolysin or D-cycloserine, were administered to the snails’ liver homogenate. L-kynurenine has been shown to impair the learning process in vivo in snails, but an anti-dementia drug has been demonstrated to reverse this effect. Significant inhibition of tentacle lowering was observed in response to L-kynurenine treatment, which corresponded with elevated KYNA levels in the central nervous system. Administering D-cycloserine or Cerebrolysin alongside L-kynurenine reversed its effects. The Helix pomatia memory model is a valuable tool for studying learning and memory formation in various conditions and in the presence of different pharmacological agents. A drug or natural extract that blocks KYNA synthesis has the ability to increase tentacle lowering and could be considered an anti-dementia agent. Furthermore, this metabolite may also protect against aging and delay damage to the central nervous system related to memory. Full article

Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterized by abnormal aggregation of β-amyloid (Aβ) peptides, tau proteins, and neuroinflammation in the central nervous system (CNS). While most AD research has focused on the brain, the molecular pathology of the spinal cord remains poorly understood. In this study, we investigated amyloid pathology, neurodegeneration, neuroinflammation, and cholesterol metabolism across distinct regions of the spinal cord and examined sex-specific differences using a model of AD, 5xFAD mice. Our data reveal that Aβ accumulation was restricted to the cervical spinal cord at 3 months but was evident in all areas of the spinal cord by 9 months, with similar patterns in both female and male animals. Despite this early and progressive Aβ deposition, no significant neuronal loss was observed in the ventral horn of the cervical spinal cord in either sex at 3 or 9 months of age. In contrast, there was a significant positive correlation between Aβ deposition and Iba1+ cell density in the spinal cord of 5xFAD mice. The number of Iba1+ cells in both the grey and white matter was significantly increased in female and male 5xFAD mice compared with age-matched wild-type (WT) littermates at 9 months of age. Astrocytic responses, however, were sex-specific: female, but not male, 5xFAD mice exhibited a significant increase in GFAP+ astrocytes in the grey matter of the thoracic and lumber spinal cord at 9 months compared with 3 months and relative to age-matched WT controls in the cervical and thoracic spinal cord. Furthermore, GFAP+ area in the thoracic spinal cord was significantly higher in female 9-month-old 5xFAD mice compared with their male counterparts, indicating a female-specific astrocytic response in AD spinal cord pathology. Our data also show an increase in free cholesterol (Filipin+ area) in 5xFAD mice at 9 months relative to WT controls, accompanied by altered expression of cholesterol metabolism genes, including downregulation of Abca1, Cyp46a1 and Cyp27a1. Collectively, these findings provide new insights into AD progression in the spinal cord, highlighting molecular pathology of AD extending beyond the brain. Full article

Heart rate variability (HRV) is a key physiological marker for autonomic nervous system function and cardiovascular health. Photoplethysmography (PPG) is commonly used to derive HRV metrics in wearable and low-cost monitoring systems. This study presents a comparative assessment of basic HRV metrics obtained from a MAX30102 optical sensor and a custom analog circuitry with an ADS1115 analog-to-digital converter (ADC). Both measurement pathways were carefully aligned using analog high-pass and low-pass filters and a consistent digital filtering pipeline, ensuring that the frequency bands relevant to HRV were preserved. PPG signals were recorded simultaneously, and inter-beat intervals were extracted to calculate the Standard Deviation of NN intervals (SDNN), Root Mean Square of Successive Differences (RMSSD), and Percentage of successive NN intervals >50 ms (pNN50) across multiple 30-s windows. Bland–Altman analysis was employed to evaluate agreement between the two methods. Results indicate that the analog circuit with an ADS1115 achieves comparable HRV basic metrics to the MAX30102 sensor, with improved Signal-to-Noise Ratio (SNR) due to high-resolution ADC and low-noise analog amplification. These findings demonstrate that a carefully designed analog acquisition system can reliably reproduce HRV basic parameters from PPG signals, providing an alternative approach for low-cost, flexible biosensing platforms. Full article

Heart rate variability (HRV) has emerged as a key biomarker for assessing autonomic nervous system activity, stress, fatigue, and emotional states. With the rapid development of wearable sensor technologies, HRV analysis has expanded from clinical environments to real-world, continuous monitoring. This review summarizes current applications of HRV metrics in wearable devices, including fitness tracking, mental stress assessment, sleep quality evaluation, and early detection of physiological or psychological disorders. Recent advances in photoplethysmography (PPG)-based HRV estimation have enabled noninvasive and user-friendly measurement, though challenges remain in accuracy under motion and variable environmental conditions. We also discuss methodological considerations, such as artifact correction, data segmentation, and the integration of HRV with other biosignals for multimodal analysis. Emerging research suggests that combining HRV with metrics such as respiration rate, skin conductance, and accelerometry can enhance robustness and interpretability in dynamic settings. Finally, future directions are proposed toward personalized health analytics, emotion-aware computing, and real-time adaptive feedback systems. This review highlights the growing potential of wearable HRV analysis as a foundation for preventive healthcare and human–machine symbiosis. Full article

Chronic pain is increasingly understood as a neuroimmune disorder rather than a purely neuronal condition, in which immune mediators and immune-like signaling within the nervous system regulate nociceptive gain across peripheral tissues, dorsal root ganglia (DRG), spinal cord, and supraspinal networks. Seminal and recent syntheses show that microglia, macrophages, cytokines/chemokines, and innate immune sensors can initiate and maintain maladaptive plasticity and central sensitization, helping explain the frequent clinical dissociation between structural pathology, systemic inflammatory markers, and pain severity. However, immune biology is bidirectional: alongside pronociceptive pathways, a growing literature describes active “pain-resolving” programs that terminate sensitization and restore homeostasis, including regulatory T cell (Treg)–IL-10 signaling and specialized pro-resolving mediators (SPMs). A structured search of PubMed/MEDLINE, supplemented by Europe PMC and PubMed Central, was performed, and citation chasing through broad scholarly indices was used to identify high-impact reviews, meta-analyses, and translational mechanistic studies. Systematic biomarker syntheses in low back pain, neck pain, and fibromyalgia indicate modest and heterogeneous systemic inflammatory signals, underscoring the need for mechanistic endotyping and stage-specific interventions. Based on this evidence, a clinically oriented framework is presented that distinguishes immune-driven pain amplification from impaired resolution and outlines practical implications for assessment, biomarker interpretation, and precision-oriented trial design. Full article

Background: Evaluation of chromosome aneuploidy and gene-level copy number alterations for diagnosis, prognosis, and therapeutic decision-making in solid tumors is the standard of care. Chromosomal microarray (CMA), next-generation sequencing (NGS), immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH) are the gold standard for detecting these variants in tumor tissue. In contrast to most solid tumors, cancers of the central nervous system (CNS) pose a unique challenge for effective detection via plasma due to the blood–brain barrier (BBB), with the additional challenges of brain biopsy or surgery being highly invasive and posing a significant risk to the patient. The Belay Ascent™ liquid biopsy test uses low-pass whole-genome sequencing (LP-WGS) to report on chromosome arm-level aneuploidy and gene-level copy number variants (CNVs) in cerebrospinal fluid (CSF) to inform diagnosis, prognosis, and therapeutic decision-making in CNS tumors. Methods: This study presents the equivalence of Ascent™ in detecting chromosome arm-level aneuploidy and gene-level CNVs using 48 tissue specimens followed by a clinical validation using a cohort of 32 CSF specimens with matched tissue-based tumor profiling information. Results: Equivalence of Ascent™ in detecting chromosome arm-level aneuploidy and gene-level CNVs using 48 tissue specimens was shown to have 100% and 97% positive percent agreement (PPA), respectively, compared to the gold standard of CMA/NGS. The validation cohort of 32 CSF specimens demonstrated 78% and 90% PPA for aneuploidy and gene-level CNVs, respectively. Clinical impact of Ascent™ was demonstrated, with 243 production cases able to inform the diagnosis and management of CNS tumors with high accuracy. Conclusions: Given the paucity of cells in CSF, limiting the use of karyotyping, CMA, IHC, and FISH, the Belay Ascent™ test provides a highly sensitive novel minimally invasive method for the evaluation of chromosome aneuploidy and gene-level CNVs in CSF. Full article

The microbiota–gut–brain axis (MGBA) is a complex bidirectional communication network integrating neural, endocrine, immune, and metabolic pathways linking intestinal microbiota to central nervous system function. Increasing evidence indicates that microbiota-derived signals are critical regulators of neurodevelopment and may contribute to vulnerability to neurodegenerative disorders across the lifespan. In this narrative review, we synthesize experimental and clinical evidence to define the key biological mechanisms underlying microbiota–brain interactions. Converging data indicate that immune activation, barrier dysfunction, and microbial metabolites, particularly short-chain fatty acids and tryptophan-derived compounds, represent central mediators linking gut dysbiosis to neuroinflammatory and neurodegenerative processes. Early-life microbial perturbations, driven by factors such as antibiotic exposure, diet, and psychosocial stress, appear to induce long-term immunometabolic programming that may increase susceptibility to neurological disorders later in life. Clinical studies consistently associate dysbiosis with neurodevelopmental conditions and major neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease; however, causal relationships remain incompletely defined due to heterogeneity and the predominance of observational data. Overall, the available evidence supports a lifespan model in which microbiota-driven immune and metabolic dysregulation contributes to both early neurodevelopmental trajectories and late-life neurodegeneration. While microbiome-based biomarkers and therapeutic strategies show promise, their clinical translation requires validation in longitudinal and interventional studies. Full article

(1) Background: Creutzfeldt–Jakob disease (CJD) is a progressive neurodegenerative disorder, characterized by cognitive decline, and motor and psychiatric symptoms; it primarily affects the central nervous system; however, peripheral nervous system involvement has rarely been described, particularly as an atypical presentation. (2) Methods: A 78-year-old Caucasian man, a retired farmer with no family history of neurological disease, presented with diarrhea followed by progressive lower limb weakness, which eventually evolved into encephalopathy and generalized areflexia. An initial diagnosis of inflammatory neuropathy was considered; the diagnostic assessment included blood and cerebrospinal fluid testing, a CT whole body scan, brain MRI, neuropsychological testing, electroencephalography, a nerve conduction study and electromyography. (3) Results: Neurophysiological studies demonstrated an acute asymmetrical sensorimotor, predominantly axonal polyneuropathy, initially suggestive of an axonal form of inflammatory polyradiculoneuritis. This pattern was confirmed on follow-up neurophysiological assessment performed three weeks later. Unexpectedly, the diagnostic course ultimately led to a diagnosis of sporadic Creutzfeldt–Jakob disease, confirmed by post-mortem neuropathological examination. Based on these findings, we conducted a literature review to summarize the current evidence on CJD-related neuropathy. (4) Conclusions: Our case emphasizes the importance of maintaining clinical suspicion for CJD even in patients presenting with progressive lower limb weakness and suggests that peripheral neuropathy may be concomitant or even precede the CNS manifestations. Careful consideration is required to avoid misdiagnosis of inflammatory neuropathy in the context of neurodegenerative diseases such as CJD. Full article

Introduction/Aims: Quantitative analysis of nerve echogenicity can support the diagnosis of mono- and polyneuropathies, for instance by distinguishing inflammatory-demyelinating from axonal damage. However, echogenicity is mainly assessed qualitatively and examiner-dependently. This study aimed to establish quantitative reference data for grayscale values of peripheral nerves in the upper and lower extremities of healthy children and adolescents to provide a clinical benchmark. Methods: We retrospectively analyzed ultrasound data from 211 healthy children aged two to seventeen years who had undergone standardized examinations of 15 peripheral nerve sites. Grayscale analysis (0–255 levels per pixel) was performed within manually defined regions of interest (ROIs) using ImageJ (version 1.52). Echogenicity values were correlated with age, weight, height, and body mass index (BMI). Results: Echogenicity showed no significant overall association with biometric parameters. Mean grayscale values ranged from 85.23 ± 2.16 for the tibial nerve at the medial malleolus to 134.62 ± 2.69 for the sural nerve. Gain settings below 60 resulted in significantly lower grayscale values, whereas measurements with gain ≥ 60 were stable and comparable. Discussion: We propose reference grayscale ranges for peripheral nerves in healthy children and adolescents as a practical benchmark for clinical use and future studies. Due to technical constraints—particularly retrospective image processing and non-lossless data export—each laboratory should establish its own reference dataset, or multicentric parameters should be established. As our sample consisted predominantly of Caucasian participants, ethnic differences should be considered when applying these values to other populations. Full article

Extracellular vesicles (EVs) facilitate intercellular communication in glioblastoma (GBM) by transferring microRNAs (miRNAs). GBM is the most aggressive primary brain tumor in adults, and despite multimodal therapy, the median survival remains approximately 15 months. Current diagnostic approaches, including contrast-enhanced MRI, are insufficient to reliably distinguish true tumor progression from pseudoprogression. Moreover, therapeutic efficacy is limited by intratumoral heterogeneity, acquired resistance, and the restrictive nature of the blood–brain barrier (BBB). In this context, EV-associated miRNAs (EV-miRNAs) contribute to GBM progression by regulating proliferation, angiogenesis, invasion, therapeutic resistance, and immune evasion. Notably, several EV-miRNAs are dysregulated in both GBM and neurodegenerative diseases (NDDs), suggesting shared molecular pathways across central nervous system (CNS) disorders. Circulating tumor-derived EV-miRNAs represent promising liquid biopsy biomarkers for diagnosis, prognosis, and longitudinal treatment monitoring. Beyond their biomarker potential, EVs can be engineered as nanocarriers capable of crossing the BBB to deliver therapeutic cargo, including inhibitors of oncogenic miRNAs (e.g., miR-21) or tumor-suppressive miRNAs (e.g., miR-124). This review summarizes the molecular functions, biomarker applications, and therapeutic strategies of EV-miRNAs in GBM. We further discuss current challenges related to methodological standardization, scalable production, and clinical translation. Collectively, advancing the understanding and clinical implementation of EV-miRNAs may provide new opportunities for precision diagnostics and therapeutic innovation in GBM. Full article

Beyond their classical role as “cellular powerhouses”, mitochondria are increasingly recognized as dynamic and interconnected networks whose architecture, quality control, and intercellular communication influence cellular and organismal homeostasis. Mitochondrial dynamics—including fusion–fission balance, mitophagy–biogenesis coupling, intracellular organization, and intercellular transfer via tunneling nanotubes, extracellular vesicles, or transient cell fusion—contribute to tissue adaptation and functional decline during aging. Focusing on cardiac muscle, skeletal muscle, and the nervous system, this narrative review synthesizes current evidence describing how aging disrupts mitochondrial network integrity through altered dynamics, impaired organelle positioning and transport, reduced mitophagy, mtDNA instability, and compromised metabolic coupling between cells. These alterations propagate across tissues, limiting energetic flexibility, stress resilience, and regenerative capacity. Building on these mechanisms, we discuss a systems-level perspective in which aging is associated with progressive loss of mitochondrial network coherence rather than solely cumulative molecular damage. Within this framework, mitochondrial connectivity functions as an integrative descriptor of cellular resilience: well-organized networks counteract metabolic perturbations, whereas functionally decoupled networks amplify stress and promote maladaptive aging trajectories. Emerging evidence indicates that physiological and pharmacological interventions, including endurance exercise, caloric restriction or mimetics, fusion-supporting pathways, and mitophagy-enhancing strategies, can partially restore network organization even later in life. Molecular, cellular, and tissue-level insights are integrated to highlight mitochondrial network dynamics as both a mechanistic contributor to aging and a potentially modifiable target for future preventive and therapeutic interventions. Full article