Search Results (1,345)

Mild cognitive impairment (MCI) and sarcopenia are prevalent age-related conditions that often coexist and share common mechanisms such as chronic inflammation, reduced neuroplasticity, and impaired muscle function. Resistance exercise training (RET) has emerged as a promising non-pharmacological strategy capable of addressing both physical and cognitive decline. The aim of this narrative review is to synthesize preclinical and clinical evidence on the effects of RET in older adults with MCI and sarcopenia, with a specific focus on its impact on neuroinflammation, cognitive performance and structural brain changes. At the molecular level, RET activates anabolic pathways, including PI3K/Akt/mTOR, enhances neurotrophic support via BDNF, NT-3, and IGF-1, and promotes hippocampal neurogenesis through exercise-induced myokines such as irisin and cathepsin B. RET also exerts immunomodulatory actions by shifting microglia toward anti-inflammatory M2 phenotypes, attenuating reactive astrogliosis, and supporting oligodendrocyte precursor cell differentiation, thereby improving myelin integrity. Neuroimaging studies consistently report preservation of hippocampal and precuneus gray matter, as well as improved white matter connectivity following RET. Clinically, RET has demonstrated significant and sustained improvements in executive function, memory, and global cognition, with effects persisting for up to 18 months. Collectively, RET represents a multifaceted intervention with the potential to delay progression from MCI to Alzheimer’s disease by integrating neuroprotective, anti-inflammatory, and anabolic effects. Standardization of RET protocols and identification of biomarkers of responsiveness are needed to optimize its role within multimodal dementia-prevention strategies. Full article

Stress is a non-specific systemic response to internal or external challenges. Recent studies show that stress can disrupt iron metabolism and that iron dyshomeostasis is implicated in many diseases-particularly within the nervous system, where iron distribution and regulation intersect tightly with oxidative stress and inflammation. Activation of the hypothalamic–pituitary–adrenal (HPA) axis by stress can upregulate hepatic hepcidin and reprogram systemic iron fluxes, leading to functional iron deficiency and, in the brain, reduced iron availability, which affects myelination and neurotransmitter metabolism. Conversely, iron dyshomeostasis also contributes to neurodegenerative pathology. In this review, we synthesize recent evidence of how stress reprograms brain iron distribution and regulation, and we outline the mechanistic links between stress-induced iron dysregulation and neurological pathology. We also discuss the therapeutic implications (such as iron-chelation strategies) and highlight the three-way interplay among stress, iron metabolism, and neurodegeneration. These insights suggest that managing iron homeostasis may offer new therapeutic avenues for stress-related neural disorders. Full article

Differentiation of oligodendrocytes and myelination are enhanced by interleukin-4, an anti-inflammatory cytokine secreted from immune cells or injured neurons, and peroxisome proliferator-activated receptor γ serves as a central effector. While intracellular zinc concentrations have recently been reported to change dynamically during oligodendrocyte development, the role of zinc in interleukin-4-enhanced oligodendrocyte differentiation has not been studied. Using primary oligodendroglial cells and the oligodendroglial CG4 cell line, we show that intracellular zinc concentrations transiently increased 1 day after interleukin-4-induced differentiation and that intracellular as well as extracellular zinc chelators repressed the interleukin-4-dependent effects. Our analyses furthermore reveal that STAT6 activated the zinc transporter ZIP11 downstream of interleukin-4 in a phosphorylation-dependent manner and that siRNA-dependent knockdown of ZIP11 abolished the interleukin-4-enhanced oligodendrocyte differentiation. An antagonist of peroxisome proliferator-activated receptor γ similarly repressed the interleukin-4-dependent differentiation. However, agonists did not affect intracellular zinc concentrations. These findings indicate that interleukin-4 upregulates ZIP11 expression via activation of STAT6 and facilitates extracellular zinc uptake, which in turn activates peroxisome proliferator-activated receptor γ and thereby promotes oligodendrocytes differentiation. Our results argue that a modulation of zinc concentrations may be beneficial for promoting oligodendrocyte differentiation and remyelination under demyelinating conditions such as multiple sclerosis. Full article

Perineural invasion (PNI), defined by cancer spreading or invading into the nerve, links to severe pain, recurrence, and poor prognosis. PNI contributes to nerve damage, Schwann cell activation, and sensory neuron dysfunction. Soluble tumor necrosis factor α (solTNFα) binds to TNFR1 to drive inflammation and nerve injury, playing a key role in cancer progression and pain. This study, using a mouse sciatic nerve PNI model, explored whether blocking solTNFα-TNFR1 signaling via TNFR1 knockout or pharmacological inhibition by XPro1595 could reduce PNI-associated pain. Data showed that XPro1595, but not TNFR1 knockout, reduced tumor burden, alleviated mechanical allodynia, and improved muscle function and locomotion, primarily in females. Histological analysis in females showed that XPro1595 increased the number of myelin and dendritic cells while reducing axonal damage that resulted from PNI. In the tumor zone outside the nerve truck, XPro1595 reduced T cell and increased macrophage and dendritic cell numbers. Transcriptomic analysis revealed that XPro1595 in females with PNI upregulated mitochondrial, myelination, motor function, and immune regulation gene pathways while it downregulated inflammatory, extracellular matrix, and tumor progression pathways. Overall, we demonstrated that XPro1595 exhibited antitumor, neuroprotective, and analgesic properties in female mice, likely by promoting neuronal regeneration and mitochondrial function, while reducing inflammation and extracellular remodeling. Full article

Background: Intellectual disability (ID) is a heterogeneous condition caused by diverse genetic factors, including single-nucleotide variants (SNVs) and copy number variants (CNVs). Whole-exome sequencing (WES) and clinical exome sequencing (CES) have become essential tools for identifying pathogenic variants; however, their relative diagnostic performance in ID has not been fully characterized. Methods: Children diagnosed with ID or related neurodevelopmental disorders underwent WES or CES. Identified variants were classified according to ACMG/AMP and ClinGen guidelines, with segregation analysis performed when parental samples were available. Diagnostic yields were compared across demographic, prenatal, and phenotypic subgroups. A multidimensional semi-quantitative scoring system encompassing 15 clinical domains (e.g., age at onset, neuro-motor function, seizures, MRI findings, vision, and dysmorphic features) was developed. Z-scores were calculated for each parameter, followed by hierarchical cluster analysis (HCA) and correlation modeling to define genotype–phenotype associations and pathway-level clustering. Results: A broad spectrum of pathogenic and likely pathogenic variants across multiple genes and biological pathways was identified in our study. CNV-associated cases frequently exhibited prenatal anomalies or multisystem phenotypes associated with large chromosomal rearrangements. Monogenic variants and their corresponding phenotypic profiles were identified through clinical exome sequencing (CES) and whole-exome sequencing (WES). Phenotypic HCA based on Z-scores revealed three major biological groups of patients with coherent genotype–phenotype relationships: Group 1, severe multisystem neurodevelopmental disorders dominated by transcriptional and RNA-processing genes (POLR1C, TCF4, HNRNPU, NIPBL, ACTG1); Group 2, intermediate epileptic and metabolic forms associated with ion-channel and excitability-related genes (SCN2A, PAH, IQSEC2, GNPAT); and Group 3, milder or focal neurodevelopmental phenotypes involving myelination and signaling-related genes (NKX6-2, PLP1, PGAP3, SMAD6, ATP1A3). Gene distribution significantly differed among these biological categories (χ² = 54.566, df = 34, p = 0.0141), confirming non-random, biologically consistent grouping. Higher Z-scores correlated with earlier onset and greater neurological severity, underscoring the clinical relevance of the multidimensional analytical framework. Conclusions: This study highlights the genetic complexity and clinical heterogeneity of intellectual disability and demonstrates the superior diagnostic resolution of WES and CES. Integrating multidimensional phenotypic profiling with genomic analysis enhances genotype–phenotype integration and enables data-driven phenotype stratification and pathway-based re-analysis. This combined diagnostic and analytical framework offers a more comprehensive approach to diagnosing monogenic ID and provides a foundation for future predictive and functional studies. Full article

Major Depressive Disorder (MDD) remains a leading cause of disability worldwide, perpetuated by an incomplete understanding of its pathophysiology and the limited efficacy of conventional antidepressants. Historically, research has focused on neuron-centric models, particularly the monoamine hypothesis. However, the field is now recognizing the critical role of glial cells such as astrocytes, microglia, and oligodendrocytes, establishing them as key contributors to the molecular basis of depression. Rather than serving solely supportive roles, these cells actively modulate neuroinflammation, synaptic plasticity, neurotransmitter homeostasis, and metabolic regulation, processes disrupted in MDD. We discuss how stress-induced epigenetic modifications such as histone acetylation, methylation, and DNA methylation are linked to alterations in astrocytic glutamate transport, microglial inflammatory states, and oligodendrocyte-mediated myelination. Special emphasis is placed on the concept of glial transcriptional plasticity, whereby environmental adversity induces durable and cell type specific gene expression changes that underlie neuroinflammation, excitatory–inhibitory imbalance, and white matter deficits observed in MDD. By integrating findings from postmortem human tissue, single-cell omics, and stress-based animal models, this review highlights converging molecular mechanisms linking stress to glial dysfunction. We further outline how targeting glial transcriptional regulators may provide new therapeutic avenues beyond conventional monoaminergic approaches. Full article

Charcot–Marie–Tooth disease type 1A (CMT1A) is a hereditary condition caused by the duplication of the PMP22 gene. Overexpression of peripheral myelin protein 22 in Schwann cells leads to myelin sheath defects and axonal loss. We have produced a cell model to facilitate studies of the molecular mechanisms involved in PMP22 accumulation and clearance. Our model is a stably transfected, clonal, immortalised human Schwann cell line with overexpressed levels of PMP22 fusion protein. A control-transfected cell line (vector lacking PMP22) was also produced. PMP22-transfected cells had reduced levels of mitosis, with the PMP22 fusion protein concentrated in punctate aggregates in the cytoplasm and expressed at the plasma membranes, which were often irregular and spindly. In contrast, control cells (control-transfected and parent cell lines) generally had smooth and regular plasma membrane morphology. Culturing in the presence of NRG1 and forskolin lead to upregulation of markers of myelination potential in the control cells. These markers were more variable in the cells stably transfected with PMP22, including decreased levels of transcripts of SOX10, JUN, S100B and NGFR, but increased levels of MPZ and EGR2 compared to controls. Using proximity-dependent biotin identification (BioID2), several hundred proteins were identified in the proximity of the overexpressed PMP22, of which 291 significant proteins were only detected in the proximity of PMP22 and not in that of control pull-downs. Among the most significantly enriched PMP22-interacting proteins were integrins alpha-2 (ITGA2) and alpha-7 (ITGA7), which play a role in myelination via their interactions with the extracellular matrix. The presence of ITGA2 in just the PMP22-transfected fraction was confirmed by western blot. Some of the proteins were associated with several enriched molecular pathways, including molecular transport and protein trafficking, and may represent potential therapeutic targets for CMT1A by promoting the degradation and enhanced trafficking of PMP22. Full article

Among mouse models of neurological disease, Theiler’s murine encephalomyelitis virus (TMEV) provides a unique platform by using a naturally occurring viral trigger, paralleling the role of infections like Epstein–Barr virus in multiple sclerosis (MS). Just as not all individuals with predisposing viral infections develop the same neurological disease, not all mouse strains develop the same diseases following TMEV infection, so susceptibility is dictated by genetic background. For example, certain sets of alleles, called haplotypes, of the major histocompatibility complex (MHC) region have been associated with susceptibility to TMEV-induced demyelination (TVID) and MS. However, our previous work revealed that these MHC susceptibility haplotypes are not the sole contributors to TMEV-induced diseases in all mice. We infected mice from the genetically diverse Collaborative Cross (CC), a resource designed to reflect human population-level genetic variation. All 15 CC strains tested exhibited some form of neurological phenotype or CNS lesion following TMEV infection. However, chronic radiculoneuropathy characterized by axonal degeneration with myelin loss was observed in the CNS of only two strains, CC002 and CC023, which had markedly different immune responses and clinical profiles throughout the course of infection. Moreover, the pathology seen in CC002 and CC023 was not the same as what is typically seen in TVID. We used previous results from RNA sequencing of the hippocampus and spinal cord to test our hypothesis that myelin loss in these strains resulted from the convergent biological effects of multiple genetic risk variants, many previously unassociated with TMEV-induced diseases. These findings identify novel genetic targets and demonstrate the utility of genetically diverse models for uncovering complex neuroimmune interactions. Full article

The aim of this study was to investigate the pathology of hearing loss caused by cochleo-vestibular schwannoma. Surgical specimens have demonstrated that a tumor may displace normal nerve fibers of the cochlear nerve to one side (pushing pattern) or the neoplastic cells may invade the tumor and grow between normal nerve fibers (infiltrating pattern). The goal was to study the relationship of the tumor to the remaining fibers of the cochlear nerve. Nerve fibers within all 28 tumors showed positive anti-neurofilament (NF) labeling. Axons within tumors were sometimes turned orthogonal to their original plane. Onion bulb formations were observed in tumors giving rise to early Antoni B-like regions of degeneration. Positive anti-myelin protein zero (MPZ) labeling was demonstrated. No clear capsule was found between tumor and nerve. There was a comingling of tumor and nerve fibers either with the nerve of origin or with both the nerve of origin and surrounding internal auditory canal nerves. Iba1+ macrophages were prevalent within cochleovestibular schwannomas. Our results suggest that retro cochlear mechanisms of hearing loss go beyond compression of the eighth cranial nerve, involve both myelin and axon degeneration, and suggest an inflammatory component from the earliest stage of the disease. Full article

Diabetic neuropathy is characterized by nerve damage and chronic neuropathic pain and lacks effective treatment. Botulinum neurotoxin type A (BoNT/A), a neurotoxin with established therapeutic use in neurological disorders, has emerged as a potential analgesic agent. This study investigated the effects of a recombinant form of BoNT/A1 (rBoNT/A1) on neuropathic pain induced by spared nerve injury (SNI) in a diabetic mouse model. Thirty-two adult male C57BL/6JRj diabetic mice were subjected to SNI or sham surgery. Fourteen days post surgery, mice received an intraplantar dose of rBoNT/A1 or vehicle. Mechanical allodynia was assessed using von Frey filaments, and spinal cord and sciatic nerve tissues were analyzed via immunohistochemistry and transmission electron microscopy to evaluate glial activation, neurotransmitter receptor expression, and axonal morphology. The results demonstrated that rBoNT/A1 significantly alleviated mechanical allodynia and caused a marked reduction in Iba1-positive microglial activation in the spinal cord, whereas no significant changes were observed in astrocyte (GFAP) density or GABAAR subunit expression. Additionally, rBoNT/A1 treatment did not significantly alter axon diameter, myelin thickness, or C-fiber morphology. In conclusion, intraplantar administration of rBoNT/A1 reduced SNI-induced mechanical allodynia in diabetic mice, potentially by attenuating spinal microglial activation, supporting the therapeutic promise of rBoNT/A1 in managing diabetic neuropathic pain. Full article

The central nervous system is highly vulnerable to oxygen deprivation during the neonatal period, leading to long-term neurological damage. Growth hormone (GH) has shown neuroprotective and neuroregenerative effects in response to hypoxic injury. This study investigated GH effects on cell survival, inflammatory, and glial activation markers in the developing cerebellum, as well as its impact on motor coordination and anxiety-like behaviors in adulthood following neonatal hypoxia. Global hypoxia was induced in postnatal day 2 Wistar rats (8% O₂, 2 h), followed by subcutaneous GH treatment (0.1 mg/kg/d) for five days. Neonatal hypoxia triggered a sustained inflammatory response in the developing cerebellum, with increased expression of TLR-4, IL-1β, TNF-α, IL-6, COX-2, iNOS, and pNF-κB, persistent gliosis, myelin disruption, and Purkinje cell loss, leading to impaired adult behavior. GH exhibited a biphasic effect—initially proinflammatory, then anti-inflammatory—ultimately downregulating proinflammatory markers and activating prosurvival pathways (pStat5, pErk1/2, pAkt, Bcl-2, TNF-R2, IGF-1). GH also reduced microglial (Iba-1) and astrocytic (GFAP) hypertrophy, restored MBP and β-III tubulin levels, enhanced Purkinje cell survival, and improved motor coordination and anxiety-like behavior in adulthood. These findings demonstrate that GH modulates the cerebellar inflammatory response and supports its therapeutic potential to counteract neuroinflammation and dysfunction following neonatal hypoxic injury. Full article

Background: Amyloid positron emission tomography (PET) has been proposed as a tool to monitor myelination in multiple sclerosis (MS). We present baseline results from an ongoing prospective study, which is the first to include both early and standard phases of amyloid PET in patients with newly diagnosed MS. Methods: The prospective study includes patients with newly diagnosed MS (January 2023–February 2024). Clinical evaluation includes neurological disability (EDSS) and neuropsychological assessment. Brain MRI, early [¹⁸F]florbetaben (FBB) PET (eFBB; 0–5, 0–10 min post-injection), and standard FBB PET (sFBB; 90 min post-injection) were acquired. Normal-appearing white matter (NAWM) and damaged white matter (DWM) in MRI were segmented and co-registered with PET images. Results are presented as standardized uptake values (SUV), with the ratio using cerebellum as the reference region (SUVR) and the percentage of change between the DWM and NAWM. Results: Twenty patients were included (35.05 ± 10.72 years; 75% women). Both eFBB and sFBB acquisitions showed significantly lower SUVRmax and SUVRmean, and higher SUVRmin in the DWM compared to NAWM (p < 0.001) in all patients. SUV parameters in both DWM and NAWM from eFBB and sFBB PET correlated with the number of relapses and EDSS (r = −0.454 and r = −0.446, respectively; p < 0.05). Additionally, SUVR values in the DWM during eFBB correlated with cognitive impairment (SDMT; r = −0.516, p < 0.01), fatigue (MFIS-5; r = −0.450, p < 0.05), and quality of life (EQ-5D; r = −0.490, p < 0.05). Conclusions: Quantitative analysis of dual-phase FBB PET demonstrates differential uptake between DWM and NAWM, which is probably associated with demyelination and neurodegeneration. These preliminary findings suggest that amyloid PET may have predictive value for disease activity and progression, supporting its potential as a biomarker in MS. Follow-up data from this study are needed to support the baseline results. Full article

Extracellular vesicles (EVs) have emerged as potential therapeutic agents for neurological disorders. Their molecular cargo may reflect the clinical status of the donor and has been identified as a biomarker for the cellular damage and repair processes underlying intracerebral hemorrhage (ICH). It has been shown that EVs from patients with favorable outcomes carry a distinct proteomic signature, compared to those from poor outcome patients, which may promote recovery in preclinical models of ICH. We investigated whether intravenously administered EVs isolated from patients with poor outcomes after ICH provide any benefit in a preclinical ICH model. No significant differences were observed in lesion volume between the placebo and treatment groups at 24 h, 72 h, or 28 days post-ICH. Functional assessments using the Rogers and tapered beam walking tests revealed no improvement in motor performance in the treatment group at 24 h, 72 h, 7 d, 14 d and 28 d. Histological analysis at 28 days showed no significant differences in immunofluorescence markers of myelin preservation (MOG, Olig-2), astroglial activation (GFAP), or angiogenesis (VEGF) between groups. In conclusion, EVs derived from patients with poor outcomes after ICH failed to promote functional recovery or modulate markers of injury and repair in a rat model, suggesting few endogenous repair mechanisms. Full article

Background: The ways in which peripheral sensory nerves interact with osteosarcomas are important to understand because it could lead to development of new approaches to treat bone cancer pain. This study aimed to determine how cancer affects sensory nerve density and distribution in a murine model of osteosarcoma-induced bone pain. Methods: The femoral marrow cavities of male C3H/HeNHsd mice were injected with either NCTC 2472 primary osteosarcoma (cancer) cells or phosphate buffered saline (control). Pain behavior was assessed using limb use score and static weight bearing assays. At the experimental endpoint, femurs were collected, decalcified, immunolabeled, cleared and imaged using light sheet microscopy (Ultramicroscope Blaze, Miltenyi Biotec). The distribution of sensory nerves was traced through the marrow cavity of the proximal femur and the periosteum overlying the third trochanter (Imaris, Bitplane). Results: Weight bearing on the injected limb was decreased in osteosarcoma-injected but not saline-injected mice. Filament tracing revealed a reduced density of neurofilament 200 kDa-positive (NF200+; myelinated nerve marker) but not calcitonin gene-related peptide-positive (CGRP+; peptidergic nerve marker) sensory nerves in the marrow cavity of osteosarcoma-injected relative to saline-injected mice. There was increased density of CGRP+ but not NF200+ nerves in the periosteum of osteosarcoma-injected relative to saline-injected mice. Conclusions: Osteosarcoma differentially affects the density and distribution of different subtypes of peripheral sensory nerves in bone. Understanding how osteosarcomas affect different populations of sensory nerves could lead to more targeted mechanism-based treatments for bone cancer-induced pain. Full article

Background: Neuromyelitis optica spectrum disorder (NMOSD) causes severe optic nerve (ON) inflammation and vision loss. Current treatments remain limited, prompting exploration of new therapeutic strategies. This study evaluated the efficacy of ITRI-E-(S)4046 (ITRI-ES), a dual ROCK1/2 and MYLK4 kinase inhibitor, in a rat model of NMOSD optic neuritis. Methods: NMOSD-like optic neuritis was induced in rats by applying NMOSD patient serum-soaked sponges around the ON. Rats received intravitreal injections of either 0.2% ITRI-ES, phosphate-buffered saline (PBS), or intraperitoneal methylprednisolone (MP). Visual function was assessed using flash visual-evoked potentials (fVEP). Retinal ganglion cell (RGC) survival and apoptosis were quantified using FluoroGold retrograde labeling and TUNEL assay. ON inflammation and demyelination were evaluated via immunohistochemistry and Western blot analysis of aquaporin-4 (AQP4), myelin basic protein (MBP), glial fibrillary acidic protein (GFAP), and inflammatory markers. Results: ITRI-ES significantly preserved visual function, restoring fVEP amplitudes (~36 μV vs. ~21 μV in PBS-treated, p < 0.05) and RGC density (~85% of normal vs. ~37% PBS). RGC apoptosis was reduced (~2.3-fold lower vs. PBS, p < 0.05). PBS-treated rats showed decreased AQP4 and MBP (2.5–2.8-fold vs. sham) and increased GFAP (2.8-fold). ITRI-ES maintained higher AQP4 (~3.5-fold) and MBP (~1.5-fold) levels, suppressed GFAP (~5.5-fold vs. PBS), reduced NF-κB, IL-1β, TNF-α, microglia activation, and macrophage infiltration, and increased anti-inflammatory Arg1 and CD206 markers (~3-fold vs. PBS). Conclusions: ITRI-ES alleviates optic nerve inflammation, preserves retinal integrity, and maintains visual function in NMOSD-associated optic neuritis, underscoring kinase inhibition as a promising therapeutic strategy. Full article