Search Results (2,199)

Neuroinvasive free-living amoebae (FLA), particularly Naegleria fowleri and Acanthamoeba spp., are responsible for rare but devastating infections of the central nervous system (CNS). Approximately 480 cases of primary amoebic meningoencephalitis (PAM) and fewer than 200 well-documented cases of Acanthamoeba-associated granulomatous amoebic encephalitis (GAE) have been reported worldwide. Mortality rates frequently exceed 90%. PAM typically develops following exposure to warm freshwater contaminated with N. fowleri and progresses rapidly in otherwise healthy individuals. In contrast, GAE usually follows a more indolent course and occurs predominantly in immunocompromised hosts. Despite their distinct clinical courses, both infections are characterized by CNS invasion, amoeba-mediated tissue destruction, blood–brain barrier (BBB) disruption, and host inflammatory responses. These processes drive neuroinflammation, neuronal injury, and neurological deterioration. Early diagnosis remains challenging because clinical manifestations are nonspecific and disease progression can be either fulminant or initially subtle. Therapeutic management is hindered by poor CNS drug penetration, limited efficacy of currently available therapies, treatment-related toxicity, and the absence of standardized treatment protocols or controlled clinical trials. This narrative review critically synthesizes current evidence on CNS invasion, neuroinflammation, neuropathology, diagnostic challenges, and therapeutic strategies in neuroinvasive FLA infections. It also highlights key translational priorities, including earlier diagnosis, standardized treatment protocols, stronger clinical evidence, and improved CNS-targeted drug delivery. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and significant neuropathological changes. Early and accurate diagnosis remains a major challenge, highlighting the need for reliable, minimally invasive biomarkers. MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression, have emerged as promising candidates. Their expression is altered in the brains of AD patients, reflecting disease-specific pathological processes, and they are detectable in peripheral biofluids. However, discrepancies in miRNA profiles between the brain and the circulation, and between patient populations remain a significant limitation, raising questions about their origin, transport across the blood–brain barrier, and their reliability in reflecting central nervous system pathology. This review provides a comprehensive overview of current research comparing miRNA expression profiles in brain tissue and blood in AD, with a focus on their biological relevance, mechanisms of release and transport, and diagnostic potential. We also discuss the challenges associated with cross-tissue variability, methodological inconsistencies, and the need for standardized approaches. Finally, we highlight future directions, including multi-tissue analyses and integration with other noninvasive modalities, to improve the clinical utility of miRNA-based biomarkers in AD. Full article

Background: Accumulating evidence suggests that environmental light cues influence brain function and neurodegenerative processes; however, the underlying cellular mechanisms remain incompletely understood. Methods: Here, using a Tau-overexpressing Drosophila model, we investigated how light exposure modulates neurodegeneration-associated phenotypes, with a particular focus on adenosine signaling and mitochondrial homeostasis. We performed behavioral assays, biochemical measurements, genetic interference targeting the adenosine receptor, and mito-QC reporter analysis to assess mitochondrial quality control. Results: We show that light exposure ameliorates Tau-induced behavioral impairments and neuropathological features, reducing climbing time by approximately 29% in males and 45% in females, and extending median lifespan by ~29% in males and ~26% in females. Notably, biochemical analyses revealed that light exposure significantly increases brain adenosine levels at ZT12 by approximately 5 to 6 nmol/L in both sexes (p < 0.01), suggesting a light-dependent modulation of adenosine availability. To further examine the role of adenosine signaling, we performed genetic interference experiments targeting the adenosine receptor. These results indicate that adenosine receptor-associated signaling is functionally involved in the beneficial effects of light, as disruption of this pathway attenuates the light-induced improvements in behavioral and mitochondrial phenotypes. Using a mito-QC reporter system, we further show that light exposure enhances mitochondrial quality control, as reflected by a ~2.3-fold increase in mitolysosome density (p < 0.001). Importantly, this effect is modulated by the functional state of adenosine signaling, suggesting a potential interaction between these processes. Conclusions: Together, our findings indicate that light exposure is associated with coordinated changes in adenosine signaling and mitochondrial quality control, which may contribute to the attenuation of Tau-induced deficits in Drosophila. This work provides insight into how environmental light cues may influence neurodegeneration-related cellular processes and highlights the potential relevance of light-based interventions for future mechanistic and translational studies. Full article

Background and Clinical Significance: Beta-propeller protein–associated neurodegeneration (BPAN), also known as static encephalopathy of childhood with neurodegeneration in adulthood (SENDA), is a subtype of neurodegeneration with brain iron accumulation caused by pathogenic variants in WDR45. Although its clinical course and neuroimaging features are increasingly recognized, detailed neuropathological characterization, especially at its terminal stage, remains limited. Case presentation: We report a 68-year-old woman with a heterozygous WDR45 splice-site variant (NM_007075.4:c.830+1G>A), representing the longest-surviving case of SENDA/BPAN described to date. After static developmental delay in childhood, she rapidly developed progressive parkinsonism, dystonia, and cognitive decline in early adulthood, ultimately becoming bedridden with profound motor and autonomic dysfunction. Serial MRI demonstrated progressive cerebral and cerebellar atrophy with iron-related signal changes in the globus pallidus and substantia nigra. She died of sepsis at the age of 68 and was subjected to an autopsy including the brain. Neuropathological findings: Autopsy revealed severe, diffuse neuronal loss and gliosis throughout the central nervous system, with marked iron deposition and complete neuronal loss in the globus pallidus and substantia nigra. Immunohistochemistry demonstrated widespread tau pathology. Notably, neuronal tau inclusions contained both four-repeat (4R) and three-repeat (3R) isoforms, whereas glial tau was predominantly 4R-positive, indicating a mixed neuronal 4R/3R and glial 4R-dominant tauopathy. Perivascular and subpial 4R-tau–dominant deposits consistent with aging-related tau astrogliopathy were also present. LC3-positive and ferritin-positive cells suggested impaired autophagic flux, supporting the proposed autophagy-related pathogenesis of SENDA/BPAN. Conclusions: This case provides comprehensive clinicopathological insight into end-stage SENDA/BPAN, highlighting distinctive tau isoform patterns in neurons versus glia and pathological evidence of autophagy dysfunction. These findings expand the neuropathological spectrum of SENDA/BPAN and may inform future mechanistic and therapeutic research. Full article

High homocysteine levels are a key risk factor for cognitive impairment, a major public health concern in aging societies. Although betaine is known to reduce Hcy levels, its effects on hyperhomocysteinemia (hHcy)-induced cognitive impairment and the underlying mechanisms remain unclear. Here, we established an hHcy-induced cognitive impairment mouse model by feeding mice a high-methionine diet for 8 weeks, followed by betaine supplementation for 14 days. Betaine treatment attenuated hHcy-induced cognitive impairment. This improvement was accompanied by alleviation of neuropathological alterations and enhancement of antioxidant capacity. Notably, betaine suppressed reactive oxygen species (ROS) accumulation, neuronal apoptosis, and Tau hyperphosphorylation at Ser396 and Thr231 in both mouse hippocampus and HT-22 cells. Mechanistically, betaine-induced activation of the PI3K/AKT/GSK-3β pathway was effectively blocked by the PI3K inhibitor LY294002. Notably, treatment with the ROS scavenger N-acetylcysteine (NAC) alone phenocopied this activation, suggesting that ROS functions as an upstream regulator of this signaling cascade. Collectively, our data demonstrate that betaine attenuates hHcy-induced cognitive impairment by suppressing oxidative stress-driven apoptosis and Tau pathology through modulation of the PI3K/AKT/GSK-3β signaling pathway. These findings suggest that betaine may hold promise for further preclinical and clinical studies, although long-term efficacy and safety evaluations remain necessary. Full article

The term ‘dementia’ encompasses a diverse group of progressive neurodegenerative disorders, the common feature of which is the deterioration of higher cortical functions. This process not only involves memory deficits and language communication disorders, but also executive dysfunction and loss of emotional control, which ultimately leads to a complete loss of the patient’s independence. Within this group of disorders, Alzheimer’s disease (AD) presents the most serious clinical challenge, characterized by a unique neuropathological triad: the presence of extracellular β-amyloid plaques, intracellular neurofibrillary tangles of tau protein, and widespread dysfunction of cholinergic transmission. The cholinergic hypothesis remains the cornerstone of the current understanding of cognitive impairment in AD. It posits that progressive dementia is caused by the selective degeneration of neurons in the anterior basal forebrain, resulting in a drastic reduction in acetylcholine (ACh) levels in the synaptic cleft. In the absence of a causal treatment, acetylcholinesterase inhibitors (AChEIs) remain the standard of care. Their pharmacological action is based on the inhibition of the AChE enzyme, which allows neurotransmission deficits to be compensated for by prolonging the half-life of acetylcholine at the synapse. This literature review presents a synthesis of the efficacy and safety of classic and novel AChEIs. A comprehensive search of the PubMed, Scopus, and Cochrane Library databases was conducted for clinical data published up to 2026. Evidence from key trials indicates that standard AChEIs induce significant cognitive stabilization compared to placebo, with rivastigmine maximizing daily living parameters via transdermal delivery. However, their therapeutic impact remains strictly symptomatic without arresting neurodegeneration. Conversely, emerging agents like huperzine A and the translation-blocker Posiphen demonstrate disease-modifying potential by modulating CSF biomarkers associated with amyloid and tau proteins. Clinically, while traditional regimens are limited by gastrointestinal toxicities, transitioning toward innovative multi-target structures represents a necessary shift to address both cognitive decline and neurodegeneration. Full article

Hypoxia is a prevalent characteristic of neurological diseases, including ischemic injury, neurodegeneration and infectious disease complications. Concurrently, hypoxia shapes both protective and pathological responses within the central nervous system (CNS). Central to this process is hypoxia-inducible factor 1α (HIF1α), a transcription factor that regulates cellular adaptation to reduced oxygen availability through coordinated glycolytic, inflammatory and cell survival pathways. Under hypoxic conditions, HIF1α transcriptional activity influences microglial activation, mitochondrial quality control, and cytokine production, thereby modulating neuroinflammation and neuroprotection. Preclinical evidence points toward hypoxia preconditioning being neuroprotective through HIF1α-dependent mechanisms in a context-dependent matter. This review synthesizes the current understanding of the role of HIF1α across neurological disease contexts, highlighting the intersection of hypoxia, neuroinflammation and neuronal survival. Ultimately, defining the cell-specific and context-dependent involvement of HIF1α will be critical for targeted therapeutic approaches to alleviate neuronal death and slow disease progression. Full article

Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder caused by glutaryl-CoA dehydrogenase (GCDH) deficiency, leading to the accumulation of neurotoxic metabolites that can cause both acute encephalopathic crises and progressive, insidious brain injury. Current management primarily relies on a protein-restricted diet, which remains therapeutically insufficient and burdensome for patients, highlighting the need for disease-modifying therapies. In this study, we established a novel GA1 mouse model using CRISPR/Cas9 technology and evaluated the preclinical efficacy of systemic recombinant adeno-associated virus (rAAV)-mediated gene therapy. Under standard dietary conditions without high-lysine challenge, our GA1 model exhibited sustained cerebral and hepatic glutaric acid (GA) accumulation and distinct chronic vacuolation in the hippocampus and cerebellum, mirroring the insidious-onset GA1 phenotype. Five-week-old mice received a single intravenous injection of rAAV-hGCDH using either rAAV2/8 or rAAV2/9 serotypes. Systemic rAAV-mediated gene therapy significantly reduced GA accumulation and attenuated chronic neuropathological changes in this GA1 mouse model for both serotypes. Our findings support the hypothesis that peripheral metabolic correction may play an important role in preventing the chronic neuropathological changes associated with GCDH deficiency. However, further investigation using tissue-specific expression systems is required to definitively delineate the relative contributions of hepatic versus central GCDH restoration to the observed neuroprotection. Full article

Background/Objectives: COVID-19, caused by the SARS-CoV-2 virus, can lead to widespread neurological and cognitive complications, even in the absence of significant structural brain abnormalities. Understanding the evolving health concerns in the context of viral infections is critical to service member readiness, fitness, and mission completion. The potential neuroprotective effects of SARS-CoV-2 vaccination remain underexplored. Methods: Using a cross-sectional, non-human primate model (female cynomolgus macaques), we employed magnetoencephalography (MEG) to assess resting-state brain activity following vaccination with escalating doses of a novel psoralen-inactivated SARS-CoV-2 vaccine (PsIV) or a combination of PsIV and a DNA vaccine (prime boost), and subsequent challenge with the Delta variant (SARS-CoV-2 B.1.617.2). MEG scans were acquired 41 days after inoculation. Source series were constructed for 42 regions of interest for each subject, and band power was computed. Results: Band power demonstrated substantial preservation of neural activity across multiple brain regions in vaccinated subjects compared to unvaccinated controls following viral challenge. Significantly lower power was observed across the brain at all bandwidths in the unvaccinated group relative to the prime boost group. As PsIV concentration increased, spectral power increased, with the prime boost group having the greatest power. Conclusions: This approach not only underscores the role of vaccination in mitigating neuropathology but also highlights the capability of MEG to detect subtle yet significant changes in brain function that may be overlooked by other imaging modalities. These findings advance our understanding of vaccine-induced neuroprotection and establish MEG as a powerful tool for monitoring brain function in the context of viral infections. Full article

Background: Acute carbon monoxide (CO) poisoning can cause delayed neuropsychiatric sequelae (DNS) after a latent period, yet its pathophysiology remains poorly understood because of the lack of reproducible experimental models. Methods: We established a rat model of DNS using acute CO poisoning (6500 ppm for 25 min). Behavioral assessments evaluated cognition, locomotion, sensorimotor function, exploratory behavior, and reward responsiveness. Histopathological analyses assessed brain injury, and regional monoamine concentrations were quantified using high-performance liquid chromatography. Results: CO-exposed rats developed delayed and progressive behavioral abnormalities, including impaired spatial working memory, reduced locomotor activity, sensorimotor dysfunction, and diminished exploratory behavior. At 4 weeks, CO-exposed rats showed reduced Y-maze alternation (49.3% vs. 72.2%, p < 0.0001), complete loss of tape-removal success (0% vs. 100%, p < 0.001), reduced digging behavior (10.1 ± 6.9 vs. 27.4 ± 3.9, p < 0.01), and decreased locomotor activity (330.5 ± 172.1 vs. 730.5 ± 139.5 cm, p < 0.01). In contrast, olfactory discrimination, sucrose preference, and grip strength were preserved. Histopathology demonstrated persistent neuronal and inflammatory alterations. Dopamine concentrations were significantly reduced in the cortex and basal ganglia, whereas thalamic serotonin levels were increased following CO poisoning. Conclusion: Acute CO poisoning induces a reproducible DNS characterized by progressive behavioral impairment, persistent histopathological abnormalities, and regional monoaminergic dysregulation. These findings support the concept that DNS is an evolving neuropathological process and identify dopaminergic pathways as potential therapeutic targets. Full article

Alzheimer’s disease (AD) and metabolic syndrome often occur together, sharing characteristics such as insulin resistance, dyslipidemia, and chronic inflammation. Metabolic dysfunction frequently precedes cognitive decline, indicating that early intervention might alter the disease’s progression. We investigated whether the GLP-1 receptor agonist semaglutide (SMGL) influences metabolic impairment and AD pathology in an AD mouse model. Male and female 5xFAD and wild-type (WT) mice on regular (RD) or high-fat diets (HFD) were administered SMGL for 13 weeks. SMGL-treated groups exhibited significant, context-dependent effects. In metabolically challenged 5xFAD HFD mice, treatment led to reduced body weight, improved glucose tolerance, normalized cholesterol levels, and a restored balance of adiponectin and leptin. These improvements were associated with reduced Aβ40 and Aβ42 levels, restored GLP-1 receptor expression, increased synaptophysin and βIII-tubulin levels, and enhanced spatial memory. SMGL also decreased Iba1 and CD68 immunoreactivity in the hippocampus and cortex, reduced macrophage infiltration, and lowered CD36 expression in visceral adipose tissue (VAT), indicating coordinated anti-inflammatory effects. WT RD mice showed minimal metabolic responses and a modest decline in Y-maze performance, suggesting that excessive GLP-1 receptor activation may disrupt neuronal homeostasis when metabolic status is normal. SMGL acts as a context-specific metabolic and neuroprotective agent, offering the greatest benefits under conditions of metabolic dysfunction. These findings in a preclinical model suggest that targeting early metabolic disturbances provides a testable hypothesis for attenuating AD-related neurodegeneration, though further translational studies are required. Full article

Background: Previous work from our group demonstrated an association between immunohistochemical detection of Human cytomegalovirus (HCMV) late antigen and poor event-free survival (EFS) in pediatric medulloblastoma. Whole-genome sequencing (WGS) further identified increased abundance of HCMV-aligned reads at the UL88 locus, particularly in Group 3 tumors, a molecular subgroup associated with aggressive clinical behavior and poor prognosis. Methods: We performed an integrated multi-omics analysis of pediatric medulloblastoma using WGS (n = 39) and RNA sequencing (RNA-seq; n = 28) datasets. RNA-seq data were filtered using stringent alignment criteria (MAPQ ≥ 20) and compared with fetal brain (n = 12), adult brain (n = 12), and HCMV-infected cell culture controls (n = 3). Only high-confidence uniquely aligned reads were retained to reduce nonspecific and multi-mapped viral alignments. Sequencing reads were aligned to the HCMV Merlin reference genome (NC_006273.2) using a standardized analytical pipeline. A subset of 28 cases with matched tumor WGS, tumor RNA-seq, and germline WGS data was used for integrated multi-omics analyses. Orthogonal validation analyses were performed in Group 3 tumors using independent genomic and transcriptomic approaches. Exploratory survival analyses were conducted in a combined cohort (n = 84) integrating genomic and immunohistochemical datasets. Results: Recurrent low-level HCMV-aligned molecular signals were identified across medulloblastoma datasets. Reads aligning to UL76, UL88, and UL99 were the most consistently detected HCMV-associated late-gene signals across RNA-seq and WGS datasets. A composite HCMV late-gene signature (UL76–UL88–UL99) showed higher levels in Group 3 tumors than in other molecular subgroups (p < 0.05 in WGS analyses). Orthogonal analyses demonstrated concordant low-level HCMV-associated genomic and transcriptomic signals enriched in tumors with MYC-associated activation and chromosome 17 imbalance. In the combined cohort (n = 84), elevated HCMV-associated signal assessed by immunohistochemistry and genomic profiling was associated with reduced EFS (median 55 vs. 147 months; log-rank p < 0.001). The subgroup classified as HCMV-high Group 3 demonstrated the strongest association with adverse outcome in exploratory multivariable analyses (HR = 6.43, p = 0.002). Conclusions: This study identifies recurrent low-level HCMV-associated genomic and transcriptomic signals across pediatric medulloblastoma datasets, with preferential enrichment in biologically aggressive Group 3 tumors. Although the extremely low abundance of viral-aligned reads precludes definitive evidence of productive viral infection, the reproducible detection of HCMV-associated molecular signatures across independent sequencing platforms supports further investigation into a potential oncomodulatory association in pediatric medulloblastoma. Additional validation using optimized viral detection methodologies, independent cohorts, and mechanistic studies will be necessary to clarify the biological and clinical significance of these findings. Full article

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) and the accumulation of tau in the brain, which triggers robust innate immune responses. Growing evidence indicates that neuroinflammation contributes to AD progression by overactivating microglia through the release of cytokines and chemokines. In general, chemokines can disrupt neuronal communication and promote blood–brain barrier permeability. Peripheral immune cells are mobilized into the brain by a gradient of chemokines. These processes link peripheral immune responses with substantial T-cell infiltration into the CNS parenchyma, leptomeninges and cerebrospinal fluid of both AD mice and AD patients. This finding underscores the relevance of the adaptive immune system, particularly T and B cells, in AD neuropathology. T-cell infiltration into the brain can influence amyloid clearance through chemokine signalling. However, chemokines play a critical role in AD by either promoting or suppressing disease progression. The infiltration of peripheral T and B cells into the brain parenchyma can exacerbate neuronal loss, yet it may also exert neuroprotective effects. Despite the presence of CD4⁺ and CD8⁺ T cells in postmortem brains of AD patients, debate continues about their role in AD brains, in terms of whether they are protective or detrimental. Understanding the complex role of chemokines in controlling innate and adaptive immune responses by modulating neuron–glia interactions (involving astrocytes and microglia) may provide novel therapeutic approaches for AD. Targeting chemokine signalling or treating with drugs that can prevent the recruitment of immune cells may be promising strategies for treating AD neuropathology. Therapies that prevent the overactivation of T cells in the brain could lead to protective strategies against AD. In fact, regulatory T cells (Tregs) could delay the onset of cognitive symptoms, because they suppress inflammation and slow the accumulation of Aβ plaques and p-Tau in the brain. Complementary strategies, such as photobiomodulation, nanoparticle, and T-cell-based approaches, could mitigate AD progression in patients. Full article

α-synuclein (α-syn) aggregation in dopaminergic neurons is a central event in Parkinson’s disease (PD) pathogenesis. Immunotherapeutic strategies targeting α-syn, including passive and active approaches, aim to inhibit aggregation, propagation, and toxicity of pathological species while promoting their clearance via immune mechanisms. This review summarizes α-syn directed immunotherapies evaluated in in silico, in vitro, and in vivo models, as well as early phase clinical trials, focusing on how epitope selection and antibody formats influence efficacy, safety, and target engagement. Data on monoclonal antibody, peptide, and protein-based vaccines, and structure-guided immunogens were analyzed, integrating behavioral, neuropathological, proteomic, and structural outcomes alongside biomarker development for α-syn species in cerebrospinal fluid and peripheral compartments. Clinical evidence indicates that several candidates induce sustained anti-α-syn antibody responses with acceptable safety profiles and signs of pharmacodynamic engagement, including reductions in free or oligomeric α-syn. However, consistent long-term clinical benefits remain unproven, highlighting the gap between preclinical success and disease modification in humans. Advances in structural biology and proteomics support rational epitope selection and improved immunogen design, reinforcing α-syn-targeted immunotherapy as a promising yet experimental strategy for PD, and highlighting the need for mechanistically oriented, biomarker-driven clinical trials initiated in well-characterized prodromal and early-stage cohorts. Full article

Human herpesvirus-6 consists of a pair of viral species, HHV-6A and HHV-6B, which are neurotropic with the ability to invade, persist, and reactivate within the nervous system. Accumulating evidence links HHV-6 to epilepsy and other neuropathologies, including: multiple sclerosis, chronic fatigue syndrome, and neurodegeneration. Yet, mechanisms by which these viruses induce neurological disorders, including their role in epileptogenesis, remain unknown. It has been demonstrated that HHV-6 exhibits tropism for astrocytes, oligodendrocytes, and neurons. Thus, HHV-6 can perturb cellular homeostasis, neuronal signaling, and immune regulation, astrocytic glutamate clearance, GABAergic inhibition, and cholinergic or monoaminergic neurotransmission yielding network hyperexcitability. It is also reported that HHV-6 can activate neuroinflammation through Toll-Like Receptor (TLR), cytokine, and/or NF-$\kappa$B activation, which facilitates neuronal injury and network instability. Indeed, a suite of converging processes suggest a multifactorial nature for HHV-6 related neuropathology. Despite robust experimental and clinical data, definitive causal relationships between HHV-6 and epilepsy (or induction of neurodegeneration) remain elusive. This review discusses evidence for roseolovirus-induced neurological dysfunction and disorders commonly associated with HHV-6A and HHV-6B infections. A preponderance of clinical and experimental evidence suggests that differential tropism for distinct neuronal neurotransmitter chemotypes and glia as well as systemic effects are involved in roseolovirus-mediated neurological disease. Full article