Search Results (869)

Traumatic brain injury (TBI) is a global public health problem which causes long-term neurologic damage caused by both primary mechanical injury and secondary pathological processes. Extracellular vesicles (EVs) such as exosomes, microvesicles (MVs) and apoptotic bodies (ApoBDs) serve as critical vehicles mediating intercellular communication in the central nervous system (CNS) following TBI. The biogenesis and the content of EVs, including proteins, lipids and RNAs, are greatly changed and involved in the evolution of inflammation or tissue repairing after TBI. In this overview, we recapitulate the cellular origin of EVs and the function of EVs in the neuroinflammatory process after TBI, highlighting the dual regulatory roles of EVs in the biological response to TBI, whereby certain EV populations amplify secondary injury cascades, while others promote endogenous repair and recovery processes. We next investigate the progress in EV engineering and targeted delivery systems and report the potential mechanisms, emphasize the prospects and potential of engineered EVs for therapy, and comment on challenges and perspectives for clinical application in TBI. Full article

(1) Background and Objectives: Parkinson’s disease’s (PD) underlying pathophysiology still remains incompletely understood, with Braak’s hypothesis of ASyn pathology propagation being the most widely accepted. Recently, a novel model has been introduced, proposing two distinct ASyn propagation pathways: a bottom-up trajectory termed Body-first PD, and a central nervous system (CNS)-initiated pathway termed Brain-first PD. This distinction introduces new perspectives in the PD literature landscape regarding diagnosis, prognostic factors and patient management. This study set out to systematically synthesize the current literature comparing Brain-first and Body-first PD, with a focus on clinical characteristics and disease progression, diagnostic biomarkers, and management approaches. (2) Materials and Methods: A systematic literature search was conducted in March 2025 using PubMed, Cochrane Library, DOAJ and Google Scholar. Human observational, diagnostic, and interventional studies published between 2019 and March 2025, including patients with de novo or early PD, were eligible. Pre-motor REM sleep behavioral disorder (RBD) was used as the primary differentiation criterion. Risk of bias was evaluated using the Joanna Briggs Institute (JBI) critical appraisal checklists. Results were synthesized using a narrative approach. (3) Results: Sixteen studies comprising 2107 PD patients met the inclusion criteria. Body-first PD was associated with a higher non-motor symptom (NMS) burden, faster disease progression, and a higher prevalence of cognitive impairment. Additionally, Body-first PD patients exhibited more widespread and symmetrical neurodegeneration, along with electrophysiological and metabolic differences. Distinct biomarker and microbiome profiles were also observed between subtypes. No eligible studies addressing management approaches were identified. (4) Conclusions: In conclusion, the available evidence suggests that Brain-first and Body-first PD may represent two distinct pathophysiological entities, a proposal with great significance for the diagnosis, prognosis and management of PD patients. However, the predominantly cross-sectional nature of the current literature limits causal inference. Future longitudinal and interventional studies are required to clarify the potential clinical implications of this subtype classification theory. Full article

Background: Blood-based biomarkers offer an accessible alternative to cerebrospinal fluid or positron emission tomography (PET) imaging for Alzheimer’s disease (AD) screening and diagnosis. This study evaluated the diagnostic performance of the fully automated HISCL plasma Aβ42/40 assay in a real-world clinical setting. Methods: We retrospectively enrolled 127 participants, stratified into cognitively normal (CN), mild cognitive impairment (MCI), AD, and Non-AD subgroups. Plasma Aβ42/40 levels were quantified using the HISCL and Simoa platforms. Additionally, plasma oligomerized Aβ (OAβ), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were measured. Results: The HISCL plasma Aβ42/40 ratio was significantly lower in the AD continuum (MCI + AD) compared to the CN subgroup (p < 0.001). The HISCL assay demonstrated robust diagnostic performance (AUC = 0.747), yielding a comparably higher AUC value compared to the Simoa Aβ42/40 ratio (AUC = 0.687). Although method comparison showed a proportional difference between HISCL and Simoa, the HISCL assay maintained high discriminative capability. Notably, integrating plasma GFAP and NfL with the HISCL Aβ42/40 ratio significantly enhanced the diagnostic accuracy (AUC = 0.823, p = 0.046). Method comparison between heparinized and EDTA plasma in the HISCL assay confirmed assay stability, showing a significant correlation and a regression slope near unity. Conclusions: The HISCL plasma Aβ42/40 assay demonstrates reliable diagnostic performance for identifying AD pathology in clinical practice, showing stability across sample types. Furthermore, its combination with neurodegeneration markers significantly improves predictive accuracy, supporting its utility as a robust screening tool and foundational component of future multimarker diagnostic panels. Full article

Background: Plasma biomarkers are promoted as scalable tools for the staging of Alzheimer’s disease (AD), yet head-to-head comparisons against the clinical scales used to define diagnostic labels remain scarce. Reported gains from machine learning fusion of clinical and biomarker features may reflect label circularity rather than biological signals, and quantifying this circularity is a central aim of the present work. Methods: From the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we assembled 655 participants (CN = 296, MCI = 168, and AD = 191) with concurrent plasma biomarkers (pT217, A$\beta$42/40, NfL, and GFAP), clinical scales (MMSE, CDR-SB, and FAQ), APOE genotype, and demographics. Three pre-specified feature sets (clinical-only, biomarker plus demographic–genetic, and full fusion) were compared across four classifiers (Logistic Regression, SVM, Random Forest, and XGBoost) using repeated, nested cross-validation (5-fold × 3 outer, 5-fold inner) with balanced class weighting. Because the external Center for Neurodegeneration and Translational Neuroscience (CNTN) cohort ($n=130$) measures pT181 rather than pT217 and lacks A$\beta$42/40, external evaluation used a separate reduced feature panel (NfL, GFAP, APOE, age, sex, and education), not the proposed pT217-inclusive panel. Results: Clinical scales alone reached a three-class AUC-OVR of $0.9539\pm 0.0041$, and fusion reached $0.9559\pm 0.0046$, an indistinguishable gain. Because MMSE, CDR-SB, and FAQ partly determine ADNI diagnostic labels, both estimates are circularity-inflated upper bounds and do not reflect independent classification power. Independent of this circularity, the internal plasma plus demographic–genetic model still achieved AUC-OVR $=0.7455\pm 0.0150$, with pT217 as the dominant contributor. Pairwise discrimination was excellent for CN vs. AD ($1.0000$) and MCI vs. AD ($0.9739$) but markedly weaker for CN vs. MCI ($0.9302$ for fused and $0.6972$ for plasma only). The separate reduced-feature model, which contains neither pT217 nor A$\beta$42/40, transferred to CNTN with AUC-OVR $=0.702$ (95% CI $0.635$–$0.764$). Conclusions: Apparent fusion gains in ADNI are largely a consequence of label circularity. After removing the circular clinical features, the internal pT217-inclusive plasma model supports three-class CN/MCI/AD screening at AUC $\approx 0.74$ and a reduced panel without pT217 transfers to an independent cohort at AUC $\approx 0.70$. These values provide a realistic performance estimate for blood-based AD staging under the current feature set, diagnostic label structure, and cohort design, and richer feature sets or pathology-anchored labels may shift this estimate. MCI detection remains the principal bottleneck. Full article

Background: In the immunotherapy era, cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) is increasingly performed after neoadjuvant immune checkpoint inhibitor (ICI)-based therapy. Examination of the nephrectomy specimen may capture the depth of treatment-induced tumor clearance more accurately than size-based radiological criteria alone. However, pathological reporting is highly heterogeneous across studies: residual viable tumor (RVT), necrosis, pT stage, and binary downstaging have all been used, limiting reproducible cross-study comparison. We aimed to characterize this heterogeneity, assess its implications for evidence synthesis, and propose a pragmatic framework for qualitative interpretation. Methods: PRISMA-compliant systematic review of studies reporting pathological response and oncological outcomes in mRCC patients undergoing CN after neoadjuvant systemic therapy (PROSPERO CRD420251154068). A qualitative synthesis was performed. A three-category Pathological Response Category (PRC) framework is proposed to harmonize heterogeneous metrics. Results: Seven retrospective studies (n = 408) were included. Pathological reporting metrics were inconsistent across all studies, preventing formal meta-analysis. Nevertheless, across cohorts reporting survival outcomes, deeper pathological response was directionally associated with more favorable oncologic outcomes. A discordance between radiological and pathological response was observed, including near-complete tumor clearance in patients classified as radiologically stable, reflecting the non-size-based mechanisms of ICI-induced tumor killing. Conclusions: The central finding of this review is not that pathological response predicts survival—which is expected—but that current pathological reporting in the mRCC surgical setting is too heterogeneous to quantify the frequency, depth, or prognostic significance of that response in a reproducible way. Prospective adoption of standardized pathological reporting protocols is the most critical next step for this field. Full article

Oligodendrocytes (OLs) are specialized glial cells essential for the formation and maintenance of the myelin sheath within the central nervous system (CNS). Historically, OLs were considered a functionally homogeneous population. However, the advent and widespread application of single-cell and single-nucleus RNA sequencing (scRNA-seq/snRNA-seq) technologies since 2015 have revealed substantial transcriptional heterogeneity, varying according to developmental stage, anatomical region, and disease state. In this review, we synthesized current advances in the understanding of OL heterogeneity. Nine OL cell classes have been identified in the mouse somatosensory cortex and hippocampal CA1 region, later expanding to 13 distinct subpopulations across ten CNS regions. Furthermore, we characterized disease-associated oligodendrocytes (DAOs)/disease-associated oligodendrocyte lineages (DOLs), identified in various neurological diseases, including multiple sclerosis (MS), Alzheimer’s disease (AD), and spinal cord injury, focusing on their molecular markers, spatial distribution, and pathophysiological roles. We summarized key transcriptional regulatory networks underlying DAO induction, including the signal transducer and activator of transcription (STAT)/interferon regulatory factor (IRF) family, the Yin Yang 1 (YY1)/nuclear factor kappa B (NF-κB) axis, and the SOX9/SOX10 regulatory system. The utility of region-specific brain analyses using spatial transcriptomics (ST) in conjunction with these approaches was also discussed. Finally, we compiled the implications of patient stratification according to white matter glial response patterns derived from large-scale snRNA-seq analyses of patients with progressive MS. Our synthesis shows that oligodendrocytes consist of multiple distinct subtypes that vary across development, brain regions, and disease conditions. In pathological states, they adopt specific disease-associated programs that reflect context-dependent responses and may influence disease progression and repair. This work provides a framework for understanding how oligodendrocyte diversity contributes to neurological disease and may support the development of targeted remyelination therapies. Full article

Typhus (FBT), caused by Rickettsia typhi, rarely causes neurological disease. Herein, we describe neurological involvement in two cases of FBT. In the first case, an adult presented with persistent fever which deteriorated into status epilepticus. He was successfully treated with doxycycline and made a complete recovery. In the second case, a patient suffered an ischemic stroke and had a protracted clinical course but ultimately made a near complete recovery. In addition to these cases, we conducted a comprehensive narrative review of 43 cases of neurologic involvement in FBT reported from 1989 to 2025. Cases were excluded if there were pathologic discrepancies with typical cases of FBT. Presentations ranged from cranial nerve palsies to meningitis and fulminant encephalitis. This review highlights the spectrum of CNS complications associated with FBT and underscores the importance of early recognition and treatment with doxycycline to improve outcomes. Given the potential severity of neurologic involvement, clinicians in endemic areas should maintain a high index of suspicion for FBT in patients presenting with a febrile illness and neurologic symptoms. Full article

Background: Acetamiprid (ACMP) exposure mediates a variety of pathological complications, including testicular toxicity. Berberine (BBR) is a plant-derived alkaloid with potential pharmacological properties. This study sought to evaluate the ameliorative effects of BBR against ACMP-induced testicular toxicity. Methods: Male Wistar rats were divided into four groups: control, BBR-treated, ACMP-exposed, and BBR+ACMP co-treated, and were administered with BBR (150 mg/kg b.wt) and ACMP (21.7 mg/kg b.wt) for 21 days. Biochemical and FTIR analyses, RT-PCR, computational analyses, and histopathological examination were conducted to assess alterations in lipid and protein profiles, as well as apoptotic and structural changes. Results: ACMP exposure was associated with oxidative injury, functional alterations (stretching of -OH, -CH₂, -NH, C=O, C-N, -COO-, -PO₂⁻), and compositional changes in proteins and lipids. Pre-treatment of BBR (2 h prior) was associated with attenuation of the functional and compositional alterations in proteins and lipids in co-treated rats. RT-PCR and computational analysis showed increased Bax and caspase-3 and decreased Bcl-2 mRNA expression, suggesting a potential modulation of ACMP-induced apoptosis by BBR. Histological examination showed that pre-treatment with BBR prevented ACMP-induced structural alterations, including cellular disorganization and alteration in seminiferous tubules. Conclusions: The study suggested that the BBR may exert ameliorative effects against ACMP-induced testicular toxicity by modulating lipid and protein changes and the anti-apoptotic pathway. Thus, BBR could be used as a potential ameliorative agent against oxidative stress. However, more mechanistic studies are needed for broader biological relevance and validity. Full article

The hallmarks of allergic diseases are Type 2 immunity, including IL-4 and IL-13 production, IgE antibody generation, mast cell and basophil activation, histamine release, and eosinophil activation. There are many routes by which such mediators can influence CNS biology, including cytokine entry or signaling via brain barrier receptors; leukocyte trafficking across activated barriers; cytokine signaling via circumventricular organ sites or dural immune compartments; vagus nerve afferent signaling; mast cell degranulation; and histamine neuromodulation. Neuroinflammation is a common hallmark of many neurodegenerative diseases, but whether and to what degree allergic/type 2 immune biology may be involved depends on the specific disease stage and pathology. Here, we assess studies connecting the roles of IL-4/IL-13 signaling, IgE/mast cell activation, eosinophil-attractive chemokines, and histamines in Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, dementia with Lewy bodies, Huntington’s disease, prion disease, and tauopathy/atypical parkinsonism. Mechanisms appear most clear in the case of Parkinson’s disease, where epidemiology suggests an important role in dementia/Alzheimer’s disease, while for other neurodegenerative conditions the evidence is less compelling and may be either mechanistic or modulatory. Confounding issues include sex differences, drug exposures, comorbid conditions, socioeconomic factors, and coexisting inflammatory diseases. Finally, we suggest a strategy based on longitudinal immune phenotyping, CNS biomarkers, and pathway manipulation to assess the relationship between allergic immune signaling and neurodegeneration. Full article

Gaucher disease is a prototypical lysosomal sphingolipid storage disorder caused by pathogenic variants in GBA1, resulting in glucocerebrosidase deficiency and accumulation of bioactive lipids, including glucosylceramide and glucosylsphingosine (lyso-Gb1). While non-neuronopathic Gaucher disease is effectively managed with enzyme replacement and substrate reduction therapies, neuronopathic forms remain largely refractory to treatment due to progressive central nervous system (CNS) involvement and limited penetration of current therapies across the blood–brain barrier. Disease pathobiology extends beyond lysosomal substrate accumulation to encompass dysregulated sphingolipid signaling, particularly sphingosine-1-phosphate (S1P)-mediated “inside-out” signaling, alongside neuroinflammation, oxidative stress, and glial activation, which collectively drive neurodegeneration. In this review, we synthesize current knowledge on sphingolipid metabolism and signaling in neuronopathic Gaucher disease and integrate these mechanisms into a three-tier, CNS-focused biomarker framework. The first tier comprises substrate-proximal markers of lysosomal burden (lyso-Gb1), which reflect GCase deficiency and correlate with systemic disease severity but incompletely capture CNS pathology. The second tier comprises markers of glial activation and neuroinflammation (glial fibrillary acidic protein [GFAP], glycoprotein non-metastatic melanoma protein B [GPNMB]), which reflect the downstream neuroimmune response to sphingolipid accumulation. The third tier comprises markers of neuroaxonal injury (neurofilament light chain [NfL]), which index irreversible neuronal damage as the terminal consequence of uncontrolled CNS disease. Together, these tiers map distinct but mechanistically interconnected stages of disease progression, from lysosomal dysfunction through glial activation to neuroaxonal loss, enabling stage-specific interpretation of biomarker signals that single-analyte approaches cannot provide. We further examine how S1P-mediated inside-out signaling links intracellular lipid dysregulation to extracellular neuroimmune and neurovascular responses and how the blood–brain barrier shapes compartment-dependent biomarker behavior across cerebrospinal fluid and blood. By grounding biomarker selection in this mechanistic cascade, the framework provides explicit criteria for pairing analytes across tiers, interpreting discordance between peripheral and CNS compartments, and designing multi-modal endpoints for clinical trials of CNS-penetrant therapies. Despite these advances, significant challenges remain, including limited longitudinal datasets, variability in assay methodologies, and incomplete validation of biomarkers as surrogates of CNS disease progression. Addressing these gaps will require harmonized, multi-modal approaches integrating biochemical, functional, and imaging measures. By positioning neuronopathic Gaucher disease as a model of sphingolipid-driven neurodegeneration, this review highlights opportunities for biomarker-guided therapeutic development relevant to Gaucher disease and the broader spectrum of sphingolipid-associated neurological disorders. Full article

Background: Understanding lymph node involvement in head and neck cancers is crucial for developing effective treatment strategies and improving patient outcomes. Accurate identification of nodal metastases can enhance prognostic assessment, improve survival rates, and reduce the risk of recurrence. This study aimed to evaluate the association of lymph node metastases with primary tumor characteristics, with a particular focus on tumor stage and primary tumor location in head and neck squamous cell carcinoma (HNSCC). Methods: The study included 170 patients diagnosed with HNSCC at a single medical center between 2022 and 2025. Clinical and pathological assessments of the size and extent of primary tumors were performed according to the American Joint Committee on Cancer TNM classification, version 8. Results: The study cohort consisted of adult patients with a mean age of 61.9 years, of whom 40.6% were female. The tongue was the most common primary tumor site (54.7%), followed by the floor of the mouth (22.4%) and the jaw (8.8%). Clinical staging identified lymph node metastases (cN1 or higher) in 32.4% of patients, whereas pathological evaluation revealed nodal involvement in 38.9%. A statistically significant association was observed between tumor stage and the presence of lymph node metastases (p < 0.001). Additionally, the frequency of nodal metastases varied by anatomical site, with the highest rates observed in tumors of the floor of the mouth and the tongue. Conclusions: These findings suggest that both tumor stage and primary tumor location are associated with an increased risk of lymph node metastases. The results underscore the limitations of clinical staging in detecting nodal disease and highlight the prognostic significance of tumor stage and anatomical site in assessing metastatic risk. Full article

Neuroscience is a rapidly advancing field; however, a comprehensive understanding of brain function at the molecular, cellular, and systems levels remains incomplete. Neurological and psychiatric disorders represent a major global health burden, highlighting the need for improved diagnostic and therapeutic strategies. Cerebrospinal fluid (CSF) is one of the most informative biofluids for investigating central nervous system (CNS) pathology due to its close biochemical relationship with brain tissue. Recent advances in neurometabolomics, defined as the comprehensive analysis of small-molecule metabolites in CSF, have been driven by the development of highly sensitive and informative mass spectrometry-based techniques. These approaches enable the identification of disease-associated metabolic signatures. This review summarizes current chromatography–mass spectrometry-based methods used in both untargeted and targeted CSF metabolomics, with particular emphasis on their analytical performance, reproducibility, and limitations. Special attention is given to method standardization and validation, as well as to the identification of reliable metabolic biomarkers for the diagnosis and monitoring of neurological disorders, including neurodegenerative, psychiatric, oncological, and neuroinflammatory diseases. Full article

Impairment in blood supply to the brain deprives its cells of the much-needed nutrients and molecules such as oxygen and glucose necessary for its development, growth and survival. This will set up a host of pathological processes such as impaired homeostasis, energy failure, excitotoxicity, oxidative stress, impaired protein synthesis, inflammation, cytokine-mediated toxicity and impairment of blood–brain barrier. These pathological processes will result in the damage or death of the cells depending on the extent of the deprivation. Similarly, they will impair synthesis of acetylcholine (Ach) and norepinephrine (NE), which are important neurotransmitters in the cholinergic and adrenergic systems responsible for cellular communication and functions. Thus, interventions to help arrest and/or modulate the initial and subsequent pathological states and help recover the functions of the brain are needed. One of such interventions is vagus nerve stimulation, which helps activate the cholinergic and the adrenergic systems via projections of the afferent fibers of the vagus nerve to the nucleus of the solitary tract (NTS). Activation of the cholinergic and the adrenergic systems results in reduction in pro-inflammatory factors such as tumor necrosis α, increase in pro-angiogenic factors and increase in firing of adrenergic neurons in the central nervous system (CNS). Full article

Background: The prognostic significance of histological transformation (HT) in treatment-naive diffuse large B-cell lymphoma (DLBCL) remains controversial. This study aimed to evaluate the clinical outcomes and failure patterns of treatment-naive transformed DLBCL (trDLBCL) compared with de novo DLBCL using a large-scale cohort. Methods: We retrospectively analyzed 1735 consecutively enrolled treatment-naive DLBCL patients (118 trDLBCL and 1617 de novo). Propensity score matching (PSM) was performed to balance baseline characteristics. Survival outcomes were assessed using Kaplan–Meier and Cox proportional hazards models. Subgroups were defined by pathology (t-FL vs. t-MZL) and pattern: concurrent (synchronous indolent lymphoma and DLBCL components at diagnosis) vs. pure transformation (DLBCL occurring as the sole histology in patients with a prior history of untreated indolent lymphoma). Results: In the overall cohort, trDLBCL was associated with significantly inferior progression-free survival (PFS) compared with de novo disease and remained an independent adverse prognostic factor in multivariable analysis (HR 1.754, p < 0.001). These findings were confirmed in a 1:1 propensity score-matched cohort (108 pairs), where trDLBCL continued to show worse PFS (p < 0.01), while overall survival (OS) was comparable (p = 0.99). Within trDLBCL patients, the underlying indolent subtype (t-FL vs. t-MZL) did not significantly affect survival (PFS p = 0.17, OS p = 0.35), whereas “pure transformation” was associated with markedly inferior PFS (p = 0.005) and OS (HR 2.56, p = 0.02) compared with concurrent transformation. Failure pattern analysis revealed a higher risk of early progression in trDLBCL (POD24: 30.56% vs. 18.52%; OR 1.94, 95% CI: 1.05–3.56), whereas central nervous system (CNS) involvement was low and comparable between groups (2.78% vs. 0.93%, p = 0.62). Conclusions: Treatment-naive trDLBCL is associated with inferior PFS driven by early progression, whereas OS is comparable due to effective salvage therapies. Pure transformation appeared to define a higher-risk subgroup with inferior disease control, supporting the need for future prospective studies to evaluate risk-adapted frontline, consolidation, or maintenance strategies. Full article

Tauopathies, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal lobar degeneration with tau pathology, are unified by pathogenic tau misfolding, post-translational modification, aggregation, and network-level spread. Yet decades of drug development that predominantly pursued single nodes (e.g., one kinase, one aggregation inhibitor, one monoclonal antibody epitope) have repeatedly delivered late-stage disappointments, underscoring a central lesson: tauopathy behaves less like a linear pathway and more like a coupled system of proteostasis failure, neuroinflammation, synaptic-mitochondrial stress, and metabolic dysregulation. This review examines rhizomes (notably Zingiberaceae genera such as Curcuma, Zingiber, Alpinia, Kaempferia, and Boesenbergia) as chemically diverse “multi-target platforms” whose bioactives can engage several tau-relevant nodes simultaneously. We synthesise evidence across tau phosphorylation (GSK-3β/CDK5 and upstream stress signalling), tau aggregation and seeding, autophagy-lysosome and proteasome pathways, redox-mitochondrial resilience, neuroinflammatory circuits (NF-κB/NLRP3), and neuro-metabolic signalling (insulin-PI3K-AKT, AMPK-mTOR). A translational lens is applied throughout, focusing on drug-likeness and CNS multiparameter optimisation; BBB permeability and efflux; metabolism and bioavailability constraints; and formulation strategies (nanoparticles, phytosomes, engineered exosomes) that may render rhizome-derived scaffolds more clinically plausible. We conclude that rhizomes offer credible mechanistic hypotheses for tau modulation, but progress depends on rigorous standardisation, realistic exposure matching, biomarker-driven study design, and a shift from “single-compound optimism” to network pharmacology with translational discipline. Full article