Search Results (170)

Glioblastoma and diffuse gliomas pose major therapeutic challenges due to marked intratumoral heterogeneity, limited tissue accessibility, and the blood–brain barrier. Tissue-based next-generation sequencing (NGS) remains essential for WHO CNS5 molecular classification, yet it is invasive and poorly suited to serial monitoring. Two complementary non- or minimally invasive approaches have advanced rapidly: radiogenomics, which correlates multiparametric MRI features with genomic alterations, and cerebrospinal fluid (CSF) liquid biopsy sequencing, which detects circulating tumor DNA with high tissue concordance. This review examines the independent progress and synergistic integration of radiogenomics and CSF-NGS. Imaging signatures can non-invasively predict key drivers (IDH1/2, EGFR, TERT, PTEN, TP53) and molecular subtypes, while CSF-ctDNA sequencing enables real-time assessment of clonal evolution, therapy resistance (including post-temozolomide hypermutation), and residual disease. We discuss technical considerations, performance metrics, multimodal artificial-intelligence fusion, and emerging clinical applications for diagnosis, prognosis, treatment selection, and longitudinal surveillance. Critical challenges, standardization, prospective validation, and workflow integration are highlighted. By combining the spatial phenotypic information of radiogenomics with the temporal genomic resolution of CSF sequencing, this multimodal strategy offers a promising path toward precision neuro-oncology and reduced reliance on repeated invasive sampling. Full article

Circulating small extracellular vesicles (sEVs) released from the placenta carry bioactive compounds. Placental sEVs (psEVs) have been implicated as drivers of pathology in preeclampsia, a common disorder of pregnancy. This study investigates the hypothesis that psEVs are detectable in cerebrospinal fluid (CSF) during pregnancy, and are present at higher concentrations in preeclamptic and eclamptic pregnancies. Two techniques were used to search for psEVs. Firstly, the ExoCounter assay was performed on neat CSF from normotensive, preeclamptic and eclamptic pregnancies, and non-pregnant controls (n = 11, 12, 10 and 4, respectively). Quantitative PCR was used to search for psEV-associated microRNAs in the CSF of pregnant women. Neither assay found evidence of psEVs in the CSF of pregnant women, regardless of whether they had preeclampsia or eclampsia. This study suggests that psEVs do not reside in CSF during pregnancy and may be more likely to impact central nervous tissues through peripheral changes or interaction with the blood–brain barrier without crossing. Full article

Chronic kidney disease is associated with neurovascular complications including cognitive impairment, potentially involving blood–brain barrier (BBB) impairment. The protein-bound uremic toxin indoxyl sulfate (IS) promotes endothelial injury, but its effects on human brain microvascular endothelial cells remain incompletely understood. Human cerebral microvascular endothelial cells (hCMEC/D3) were exposed to IS 200 and 900 μM. BBB integrity was assessed by the FITC-dextran (4 kDa) transwell permeability assay and claudin-5 immunofluorescence. Transcriptional responses were quantified by qPCR for aryl hydrocarbon (AhR) target genes, oxidative stress-associated and inflammatory markers, senescence, and junction-associated genes. Senescence-associated phenotypic changes were evaluated by SA-β-galactosidase staining and cytokine array profiling. IS increased endothelial permeability at 24 and 48 h (~1.5-fold relative to control) without evidence of cytotoxicity and reduced claudin-5 staining intensity. IS strongly upregulated AhR target genes, including CYP1A1, CYP1B1, and CYP1A2. NFE2L2 and IDO1 increased, while NFKB1 remained unchanged. SA-β-gal positivity increased, accompanied by elevated GM-CSF and G-CSF secretion, while CDKN1A decreased at IS 900 µM and CDKN2A remained unchanged. CDH5 was downregulated, TJP1 increased at 900 µM, and CLDN5 remained unchanged. These findings indicate that IS exposure is associated with impaired BBB integrity, AhR-related transcriptional responses, oxidative stress-associated transcriptional changes, junctional remodeling, and senescence-like endothelial features. However, causal attribution to individual pathways requires inhibition or knockdown studies. Full article

Over time, our understanding of the central nervous system (CNS) as an immunologically privileged site where immune-cell infiltration takes place has changed; research has transformed the dominant view, showing that the CNS is an immunologically specialized tissue featuring complex interactions between the immune system and CNS processes, where the choroid plexus (CP) has an essential role in regulating neuronal tissue homeostasis and immune-cell trafficking. Although immune-cell entry into the CNS is tightly controlled, small numbers of antigen-experienced lymphocytes can access cerebrospinal fluid (CSF) compartments for immune surveillance under normal conditions. During an injury, such as cerebral ischemia or spinal cord damage, dendritic cell precursors infiltrate the CNS, suggesting their involvement in modulating lymphocyte activity. However, the immunoregulatory function of the CP alone is insufficient to prevent damage. Injury can trigger a cascade of events including activation of microglia toward a pro-inflammatory M1 phenotype, infiltration of peripheral immune cells across the blood–brain barrier (BBB), and uncontrolled neuroinflammation. T cells play a critical role in this process. Th1 cells exacerbate inflammation upon recognizing neural antigens, whereas Th2 cells promote recovery by releasing neurotrophic factors. This highlights the dual role of inflammation in CNS injury and repair. Full article

Major depressive disorder (MDD) is not reducible to a single neurotransmitter deficit. Current explanations commonly involve monoaminergic dysfunction, hypothalamic–pituitary–adrenal axis dysregulation, immune-inflammatory activation, impaired neuroplasticity and synaptic dysfunction, together with metabolic and neurovascular abnormalities. Lipidomic studies have repeatedly identified glycerophospholipid abnormalities in MDD, but their mechanistic meaning remains unresolved because changes in bulk lipid abundance do not explain how altered lipid metabolism becomes a receptor-level neural signal. This review develops a testable interpretation of the lysophosphatidylcholine (LPC)–autotaxin (ATX)–lysophosphatidic acid (LPA)–LPA receptor (LPAR) axis in which LPC species generated during phospholipid turnover provide ATX substrates, ATX activity determines local LPA generation, LPA production and inactivation shape ligand availability, and LPAR signaling links the lipid product to neural output. This structure shifts the focus from total lipid abundance to matched assessment of lipid species, enzyme activity, anatomical site and receptor subtype. Human studies report lower serum and cerebrospinal fluid (CSF) ATX in MDD, lower CSF LPA 22:6 in MDD and schizophrenia, and negative total LPA findings that caution against biomarker oversimplification. Depression-relevant and broader stress- or anxiety-related experimental studies show that ATX, LPA and LPAR perturbation can affect hippocampal function, synaptic physiology, emotional behavior and stress resilience. The key unresolved issue is whether brain-accessible LPC species, active ATX, locally generated LPA, LPA inactivation capacity and receptor-specific output can be demonstrated within the same MDD-relevant fluid, brain-interface site or neural circuit. Future work should therefore move from fluid-level association toward pathway closure through targeted and spatial lipidomics, anatomical ATX activity mapping, LPA inactivation assays, blood–brain barrier (BBB)/interface analysis, LPAR perturbation and matched circuit or behavioral readouts. Full article

Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological disorder characterized by gait disturbance, cognitive impairment, and urinary incontinence; however, its diagnosis and prediction of shunt responsiveness remain challenging. This systematic review aimed to synthesize current evidence on cerebrospinal fluid (CSF) proteomic biomarkers in iNPH and to identify molecular patterns with diagnostic and prognostic relevance. A PRISMA-guided search of PubMed, Web of Science, and Google Scholar identified 14 eligible studies comprising 1171 iNPH patients. Proteomic analyses revealed substantial heterogeneity in study design and detected proteins; however, consistent patterns emerged. iNPH is associated with upregulation of inflammatory and extracellular matrix-related proteins and relative downregulation of synaptic and neuronal markers. Neurodegenerative proteins, including amyloid-β, tau, and neurofilament light chain, demonstrated value in differentiating iNPH from comorbid neurodegenerative diseases and in predicting response to ventriculoperitoneal shunting (VPS). These findings support a multifactorial model of iNPH involving impaired glymphatic clearance, neuroinflammation, blood–brain barrier dysfunction, and mechanical axonal stress. Multidimensional biomarker profiles, rather than single proteins, appear to provide the greatest clinical utility, highlighting the need for standardized proteomic panels and integrative predictive models. However, given the substantial heterogeneity of the included studies and the predominantly exploratory nature of current proteomic evidence, the identified proteins should be interpreted as candidate biomarkers rather than clinically validated diagnostic or prognostic tools. Multidimensional biomarker profiles appear biologically plausible and may offer greater explanatory value than single proteins, but their clinical utility requires validation in standardized prospective cohorts. The authors therefore propose a conceptual iNPH proteomic “Vulnerability Model” integrating CSF biomarkers to reflect the balance between reversible and irreversible pathology; this is currently a hypothetical model that requires rigorous statistical and clinical validation through large-scale prospective cohort studies before it can fulfill its potential for improving patient stratification and prediction of postoperative outcomes. Full article

Propolis is a natural resinous product with a broad spectrum of biological activities, including immunomodulatory and anti-inflammatory effects. Increasing evidence suggests that propolis may influence pathways involved in tissue remodeling and fibrosis; however, comparative studies evaluating different propolis types in endothelial models remain limited. Brain microvascular endothelial cells, as a key component of the blood–brain barrier, constitute a relevant in vitro model for studying anti-inflammatory and neurovascular responses under both physiological and pathological conditions. The aim of this study was to compare the effects of Brazilian green propolis (EEP-BRA) and Polish brown propolis extracts (EEP-PL) on the immunological and fibrotic responses of brain microvascular endothelial cells. Human brain microvascular endothelial cells (hCMEC/D3-BBB) were exposed to propolis extracts (EEP-BRA and EEP-PL) under normoxic and hypoxic conditions to reflect diverse microenvironmental states. The analysis focused on the modulation of release of selected cytokines, including IL-10, IL-4, IL-6, IFN-γ, GM-CSF, TNF-α, IL-2, IL-8, and TGF-β, with particular emphasis on TGF-β as a key regulator of fibrosis. Results: Both propolis extracts significantly modulated cytokine production, although their effects differed depending on the origin of the propolis and oxygen conditions. Under the hypoxia condition followed by IFN-α stimulation, EEP-PL-50 was associated with reduced TNF-α (0.54 vs. 3.61 pg/mL; Hedges g = −6.78; large effect size, p > 0.05) and decreased TGF-β1, IL-8 and TGF-β2/β3. EEP-BRA-50 elicited a distinct profile characterized by increased IL-6 (171.58 vs. 27.63 pg/mL; p < 0.001; g = +6.15) and GM-CSF, while reducing TGF-β1. Both extracts preserved viability > 70% (ISO 10993-5). In conclusion, the results demonstrate that EEP-BRA and EEP-PL exert distinct immunomodulatory effects on brain endothelial cells. These findings highlight the importance of propolis origin in determining its biological activity and support its potential application in modulating inflammation and neurovascular responses. Full article

The cribriform plate (CP) functions as a dynamic neuroimmune interface through which olfactory nerve bundles exit the brain within a specialized perineural microenvironment (cpPME). While traditionally viewed as a passive structural barrier, emerging evidence positions the CP as a central hub for cerebrospinal fluid (CSF) drainage, glymphatic–lymphatic clearance, and antigen presentation. This review provides a comprehensive understanding of recent advances in cpPME research, highlighting the adaptive remodeling of the immune landscape in response to neuroinflammation and aging. We critically evaluate the translational gap between rodent models and human physiology, discussing the implications for neurodegenerative diagnostics, neuroinflammatory conditions, infectious diseases and “nose-to-brain” therapeutic delivery. By integrating anatomical, physiological, and immunological perspectives, we offer a comprehensive framework for understanding the CP’s role in CNS homeostasis and its potential as a transformative diagnostic and therapeutic target. Full article

Mechanisms of arboviral neuroinvasion are still incompletely resolved, despite longstanding emphasis on the blood-brain barrier (BBB) as the principal interface for central nervous system (CNS) entry. While BBB-centered models have been highly informative, they may underrepresent the contribution of other CNS border structures, particularly the choroid plexus and the blood-cerebrospinal fluid barrier (BCSFB). Here, we re-examine the BCSFB as a relevant but unevenly supported neuroinvasion interface in arboviral encephalitis. The strongest direct evidence is currently available for Zika virus (ZIKV), for which experimental studies support infection of choroid plexus-associated cells and CNS access through the blood-CSF axis. Semliki Forest virus (SFV) provides additional direct, although still limited, support for this concept. In contrast, for West Nile virus (WNV), Japanese encephalitis virus (JEV), and tick-borne encephalitis virus (TBEV), evidence for choroid plexus involvement remains indirect or insufficiently resolved, even though neuroinvasion itself is well established. We therefore argue not for replacement of BBB-centered models, but for broader integration of the BCSFB into current frameworks of arboviral CNS invasion. This evidence-based perspective supports a hierarchical, virus-dependent view of choroid plexus involvement and highlights the need for mechanistic studies that directly test when and how this interface contributes to encephalitic disease. Full article

Background: Dragon’s blood (dried resin of Dracaena cochinchinensis (Lour.) S.C.Chen) is a classic traditional medicine for treating ischemic stroke, yet its bioactive components capable of penetrating the blood–brain barrier (BBB) remain ill-defined. This study aims to elucidate its material basis and the synergistic mechanism of Borneol as a “guide drug.” Methods: A systematic strategy integrating UHPLC-Q-TOF-MS/MS and metabolomics was employed to map the chemical profile of dragon’s blood and identify its migrating constituents in rats. Results: A total of 96 compounds were characterized in vitro. In vivo analysis of the cerebrospinal fluid (CSF) revealed a brain-penetrating profile that was significantly enriched by Borneol, with the number of detected constituents increasing from 11 in the DB group to 16 in the DB + B group. The results demonstrated that demethylation, glycoside hydrolysis, and oxidation are primary metabolic pathways, validating a “pro-drug” mechanism where aglycones and hydroxylated derivatives act as the central effectors. Notably, Borneol not only enhanced the BBB permeability of lipophilic flavonoids but also facilitated unique metabolic transformations, such as the cyclization of berberrubine to coptisine. Conclusions: This study elucidates the brain-penetrating material basis of dragon’s blood and reveals the dual synergistic mechanism of Borneol involving both physical permeation enhancement and metabolic modulation, offering scientific evidence for its clinical application in central nervous system diseases. Full article

Background: Vascular dysfunction and neurovascular inflammation are increasingly recognized as contributors to Alzheimer’s disease (AD) pathophysiology, particularly through interactions with tau-related neurodegeneration. Endothelial adhesion molecules, including vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), play key roles in blood–brain barrier regulation and immune-vascular crosstalk, yet their relevance to long-term disease progression and established AD biomarkers remains incompletely understood. Methods: Using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we examined associations between baseline cerebrospinal fluid (CSF) levels of VCAM-1 and ICAM-1 and clinical progression, CSF biomarkers, neuroimaging measures, and cognitive outcomes over up to 10 years of follow-up. This study included 294 participants (87 cognitively normal, 129 with mild cognitive impairment, and 78 with AD). Multivariable logistic regression was used to assess associations with diagnostic progression, and linear regression models examined relationships with baseline and longitudinal measures of tau, amyloid-β, hippocampal volume, Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) metabolism, and cognition. Models were adjusted for age, sex, apolipoprotein E epsilon 4 (APOE ε4) status, baseline diagnosis, and baseline CSF amyloid-β, with false discovery rate correction applied for multiple comparisons. Results: Baseline CSF VCAM-1 and ICAM-1 levels did not differ across diagnostic groups. However, higher baseline levels of both markers were nominally associated with increased odds of disease progression. Notably, ICAM-1 showed a strong and robust association with baseline CSF phosphorylated tau, which remained significant after multiple-comparison correction. VCAM-1 was also associated with tau pathology, though this did not survive correction. Neither marker was associated with baseline or longitudinal changes in hippocampal volume, FDG-PET metabolism, or cognitive performance. Conclusion: CSF VCAM-1 and ICAM-1 appear to reflect neurovascular inflammatory processes linked to tau pathology rather than markers of clinical stage or longitudinal neurodegeneration. These findings support a role for endothelial activation in AD pathophysiology and highlight vascular–immune mechanisms as potential contributors to tau-related disease vulnerability. 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

Cerebral small vessel disease (CSVD) is a leading cause of stroke, cognitive impairment, and vascular dementia, yet disease-modifying therapeutic strategies remain limited. Emerging evidence suggests that sleep fragmentation (SF), a common and often under-recognized feature of aging and cardiometabolic disorders, plays a pivotal role in CSVD pathogenesis by disrupting the glymphatic system, the brain’s primary waste clearance pathway. Sleep-dependent glymphatic function facilitates the removal of neurotoxic metabolites and maintains neurovascular homeostasis. In contrast, SF impairs cerebrospinal fluid (CSF)–interstitial fluid (ISF) exchange, promotes perivascular space enlargement, endothelial dysfunction, blood–brain barrier (BBB) breakdown, and chronic neuroinflammation, hallmarks of CSVD. This review synthesizes current mechanistic, preclinical, and clinical evidence linking SF to glymphatic dysfunction and small vessel pathology, framing these interactions as a sleep–glymphatic–vascular continuum underlying CSVD progression and cognitive decline. We further explore the emerging therapeutic potential of tocotrienols (T3), vitamin E isoforms with potent antioxidant, anti-inflammatory, and vasculoprotective properties, as modulators of neurovascular integrity within this continuum. Although direct evidence linking T3 to glymphatic regulation remains limited, converging data support their capacity to preserve endothelial function, attenuate oxidative stress, and stabilize astrocytic and BBB dynamics, mechanisms highly relevant to glymphatic and microvascular health. By integrating sleep biology, glymphatic neuroscience, and nutritional vascular protection, this review highlights hypothesis-generating preventive and therapeutic avenues for CSVD and delineates key knowledge gaps, including the need for longitudinal human studies, standardized glymphatic imaging, objective sleep phenotyping, and interventional trials to establish causal and translational relevance. Full article

The glymphatic system is a fluid-transport framework in which cerebrospinal fluid (CSF) enters the brain along perivascular routes, exchanges with interstitial fluid (ISF), and exits toward venous, perineural, and meningeal lymphatic pathways enabling waste clearance. Recent studies have clarified the anatomical components that regulate solute movement. The perivascular astrocyte endfeet, which are enriched in polarized aquaporin-4 (AQP4) expression, create a high-permeability water interface that facilitates CSF–ISF exchange. Multiscale physical drivers such as cardiac pulsation, arteriolar vasomotion, and brain-state changes during sleep regulate the timing and efficiency of the glymphatic transport. A broad spectrum of solutes is transported through this pathway, from small metabolites to extracellular proteins including amyloid-β and tau, as well as exogenous tracers and some lipid-associated species. Glymphatic redistribution may interface with other clearance systems, including the brain-to-blood efflux via blood–brain barrier (BBB) transport, intramural periarterial drainage (IPAD) that clears along vascular basement membranes and the meningeal lymphatic pathways that drain macromolecules to deep cervical lymph nodes. These different routes may be interconnected and may represent a waste clearance network with complementary roles assigned to different mechanisms. Moreover, state dependence (notably sleep) and vascular health modulate glymphatic flux, offering plausible links between glymphatic system dysfunction, aging and neurodegeneration. Methodological advances—from intrathecal contrast magnetic resonance imaging (MRI) to in vivo two-photon imaging and tracer-kinetic modeling—have provided new insights into the anatomical scaffold and kinetics of the glymphatic system. Advances in glymphatic anatomy, together with growing evidence implicating glymphatic dysfunction in neurodegeneration, point towards a unifying framework that is urgently needed. Our synthesis spans glymphatic structure, fluid routing, and the repertoire of transported solutes and links to complementary clearance routes, supporting a unified model in which glymphatic clearance represents an important contributor of cerebral homeostasis. Understanding glymphatic dysfunction may guide the establishment of diagnostic imaging biomarkers that have the potential to assist in therapeutic modulation of neurodegenerative diseases. Full article

Glioblastoma (GBM) remains one of the most treatment-resistant human malignancies, largely due to the interplay between disrupted fluid dynamics, immune evasion, and the structural complexity of the tumor microenvironment; in addition to these, treatment resistance is also driven by intratumoral heterogeneity, glioma stem cell persistence, hypoxia-induced metabolic and epigenetic plasticity, adaptive oncogenic signaling, and profound immunosuppression within the tumor microenvironment. Emerging evidence shows that dysfunction of the glymphatic system, mislocalization of aquaporin-4, and increased intracranial pressure compromise cerebrospinal fluid–interstitial fluid exchange and impair antigen drainage to meningeal lymphatics, thereby weakening immunosurveillance. GBM simultaneously remodels the blood–brain barrier into a heterogeneous and permeable blood–tumor barrier that restricts uniform drug penetration yet enables tumor progression. These alterations intersect with profound immunosuppression mediated by pericytes, tumor-associated macrophages, and hypoxic niches. Advances in imaging, including DCE-MRI, DTI-ALPS, CSF-tracing PET, and elastography, now allow in vivo characterization of glymphatic function and interstitial flow. Therapeutic strategies targeting the fluid-immune interface are rapidly expanding, including convection-enhanced delivery, intrathecal and intranasal approaches, focused ultrasound, nanoparticle systems, and lymphatic-modulating immunotherapies such as VEGF-C and STING agonists. Integrating barrier modulation with immunotherapy and nanomedicine holds promise for overcoming treatment resistance. Our review synthesizes the mechanistic, microenvironmental, and translational advances that position the glymphatic–immune axis as a new frontier in glioblastoma research. Full article