Proteomic profiling reveals region-specific neuroimmune and apoptotic signatures induced by Bothrops jararaca venom toxins in the murine brain.

Cerebrovascular pathology and neuronal network dysfunction are early features of Alzheimers disease (AD) associated with neuroinflammation and cognitive decline, but the vascular and immune triggers of neuronal hyperactivity remain largely unknown. Here, we show that the blood coagulation protein fibrin disrupts microglia-neuron interactions, promoting neuronal hyperactivity in an AD mouse model. Genetic elimination of the fibrin inflammatory domain reduced neuronal hyperactivity, restored dynamic microglial interactions with active neurons and protected from high-risk decision making in 5XFAD mice. Leveraging the transcriptional signatures of microglia and inhibitory and excitatory neurons, a ligand-receptor atlas revealed fibrin-dependent disruption of innate immune and glutamatergic signaling between microglia and neurons in AD mice. Patients with AD also showed a correlation of cerebrospinal fluid (CSF) fibrinogen levels with biomarkers of inflammation, vascular and synaptic dysfunction. Thus, resilience to neuronal hyperactivity and restoration of the neuroimmune interactome by targeting fibrin may have therapeutic implications for Alzheimers disease and related conditions. There is a companion manuscript cited as Ref #62 submitted to bioRxiv (Lauderdale et al., 2026).

The middle cerebral artery (MCA) is critical for cerebral blood flow autoregulation and a primary site of cerebrovascular pathology in stroke, Alzheimer's disease, and vascular dementia. Pressure myography enables precise ex vivo quantification of MCA structure and function, but requires accurate anatomical identification and careful vessel handling to ensure reproducibility across diverse rat genetic models. This chapter provides a comprehensive, step-by-step protocol for isolating and cannulating the rat MCA M2 segment for pressure myography. We detail precise anatomical landmarks to ensure consistent vessel selection across strains. The protocol includes optimized solutions, cannulation techniques, and pressure protocols validated across multiple rat models, including transgenic (TgF344-AD), diabetic (T2DN), consomic (SS.5 BN , FHH.1 BN ), and genome-edited strains. Extensive troubleshooting notes address common technical challenges, including vessel viability assessment, pressure integrity, and strain-specific autoregulatory ranges. This methodology bridges molecular genetic findings with fundamental cerebrovascular physiology, enabling researchers to characterize myogenic reactivity, passive mechanical properties, and structural remodeling in rat models of cerebrovascular disease.

White matter hyperintensities (WMHs) are increasingly recognized as neuroimaging biomarkers of cerebrovascular pathology in Alzheimer's disease (AD), yet their temporal relationship with amyloid and tau accumulation remains unclear. While previous studies suggest bidirectional associations between WMHs and AD pathology, regional associations between WMHs and AD pathology have yet to be examined. This study investigated the temporal and regional associations between PET measures of amyloid (Aβ)and tau pathology and WMH burden in older adults. Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) included 1,241 older adults with Aβ and 636 with tau for cross-sectional analyses. Longitudinal analyses included 613 participants for Aβ change and 980 for WMH change (Aβ group), and 92 for tau change and 342 for WMH change (tau group). Linear models were used to i) assess associations between baseline regional WMH and Aβ and tau pathology, and ii) examine whether baseline pathology in one measure was associated with change in the other measure over two years. Baseline analyses revealed significant bidirectional associations between WMH burden and both Aβ (t = 2.29-3.70,p < .05) and tau pathology (t = 2.01-2.56, p < .05). Longitudinal analyses showed that baseline Aβ levels were associated with future WMH progression in frontal andparietal regionsand in anterior and posterior composite regions (t = 2.07-3.09, p < .04), while baseline tau was linked to WMH increases in parietal regions (t = 2.98, p < .03). However, baseline WMH burden was not associated with accumulation of Aβ or tau pathology in any region. These findings suggest that Aβ and tau pathology drive future WMH progression rather than the reverse, with distinct regional patterns for each pathology type.

Microglia are highly plastic cells that are capable of integrating subsequent insults. As the majority of Alzheimer's Disease (AD) patients also show cerebrovascular pathology, we here aimed to dissect the interactions between AD and ischemic brain injury on the microglial response to amyloid beta (Aβ) pathology. Unexpectedly, ischemic stroke in the context of cerebral β-amyloidosis drives the emergence of a neuroprotective microglial phenotype characterized by an ApoE-enriched transcriptional state and enhanced lipid handling. These microglia promote the rapid formation of highly compact Aβ plaques that are relatively inert and strikingly reminiscent of those observed in cognitively resilient AD patients. Our findings thus reveal that the microglial response to Aβ pathology is not a fixed trajectory toward dysfunction, but retains a capacity for beneficial reprogramming when engaged by the appropriate stimulus. Beyond characterizing this comorbid state, our data identify specific molecular pathways, centered on ApoE, complement activation, and lysosomal processing, that may be amenable to therapeutic targeting to promote protective microglial function in AD.

This historical review examines Dr. Harry J. Buncke's development of microsurgical instrumentation and anastomotic techniques for submillimeter vessels, discusses the 1966 Vermont Microvascular Surgery Conference where technical knowledge was exchanged between plastic surgeons and neurosurgeons, and highlights how Buncke's methods directly informed Dr. M. Gazi Yaşargil's cerebral revascularization procedures. Buncke's innovations in microsuture technology, jeweler's tool adaptation, vasospasm control protocols, and vessel repair techniques for arteries < 1 mm in diameter, demonstrated through successful rabbit ear replantation in 1964, provided the technical foundation for intracranial vessel anastomosis. The 1966 conference facilitated direct transmission of these peripheral vessel techniques to neurosurgical applications, with Yaşargil performing the first superficial temporal artery-to-middle cerebral artery bypass in 1967 using instruments and methods derived from Buncke's work. This cross-specialty collaboration established the laboratory training paradigm, atraumatic handling principles, and anastomotic protocols that remain fundamental to contemporary microneurosurgical practice, including current surgical management of moyamoya disease and complex cerebrovascular pathology.

Thyrotoxicosis is associated with heightened adrenergic activity, arrhythmogenic susceptibility, and procoagulant alterations; yet, its contribution to sudden death outside overt thyroid storm remains incompletely understood. We retrospectively screened 975 consecutive autopsies and identified 7 cases with biochemical evidence of thyroid hormone excess defined by elevated free T3 and/or free T4 levels. Clinical background, medication exposure, thyroid-related biomarkers, including thyroglobulin, thyroid autoantibodies, and interleukin-6, together with detailed histopathological examination of the thyroid gland and the cardiovascular system, were integrated to assess the potential contribution of thyroid hormone excess to the fatal outcome. Targeted genetic analysis was additionally performed in selected cases. Two cases fulfilled clinicopathological criteria for thyroid storm and showed markedly elevated IL-6 concentrations, suggesting severe systemic decompensation. In the remaining cases, death was attributed to structural cardiovascular or cerebrovascular pathology, including intracerebral hemorrhage, acute coronary thrombosis with plaque rupture, hydrocephalus, or presumed arrhythmic mechanisms. Biochemical thyrotoxicosis was observed even in the absence of thyroid-stimulating hormone suppression, and exogenous or treatment-associated thyrotoxicosis was sometimes accompanied by thyroid atrophy rather than hyperplasia. These findings indicate that thyroid hormone excess detected at autopsy represents a clinicopathological spectrum ranging from primary thyroid-driven death to contexts in which thyrotoxicosis functions as a physiological modifier that lowers the threshold for fatal cardiovascular events. Integrative interpretation of biochemical, pathological, and clinical findings may improve the understanding of thyroid hormone-mediated vulnerability in sudden death.

An International, Multi-Specialty Consensus Document on the Optimal Management of Patients with Internal Carotid Artery Occlusion.

Ischemic Stroke (IS) is a complex cerebrovascular disorder in which the gut microbiota has been identified as a key modulator. This study aims to explore the potential causal relationships between gut microbiota and three IS subtypes- Large-Artery Atherosclerosis (LAA), Small-Artery Stroke (SAS), and Cardiogenic Stroke (CES)-and to elucidate the mediating role of immune cells. We performed a two-sample bidirectional Mendelian Randomization (MR) analysis using multi-cohort data to examine the associations of 207 gut microbial taxa and 205 metabolic pathways with IS subtypes, further incorporating immune phenotypes as mediating factors. Specific gut microbial taxa and metabolic pathways showed significant associations with the three IS subtypes. Thirty immune cell phenotypes were identified as mediators in the gut microbiota-IS relationship. Among these, 14 mediating pathways explained more than 10% of the observed effects; for example, Parabacteroides johnsonii influenced LAA via HLA-DR on CD33-HLA-DR+ cells, with a mediation proportion of 11.34%. These findings reveal distinct immune-mediated mechanisms linking the gut microbiota to different IS subtypes, highlighting the complex tripartite interactions among the microbiota, immunity, and cerebrovascular pathology. This study provides evidence supporting immune-mediated associations between gut microbiota and IS subtypes. The results clarify potential mechanisms through which the microbiota contribute to different IS subtypes and offer new insights for developing therapeutic targets.

Heterozygous high temperature requirement serine peptidase A1 (HTRA1) mutations are associated with autosomal dominant cerebral small vessel disease (CSVD), but their pathogenic mechanisms remain elusive. In the present study, clinical data were collected from two families carrying heterozygous HTRA1 mutations, with pathogenic mutations verified through Sanger sequencing. Between January 2018 and December 2023, four patients with CSVD were recruited from the Department of Neurology, First Hospital of Shanxi Medical University (Taiyuan, China). Whole blood RNA sequencing (RNA-seq) was performed to identify differentially expressed genes. Lentiviral vectors were constructed for HtrA1 overexpression and knockdown in mouse brain microvascular endothelial bEnd.3 cells to assess cell viability, oxidative stress, tight junction integrity and apoptosis. Adeno-associated virus (AAV) technology was used to assess how HtrA1 gene interference affects the function of cerebral vascular endothelial cells in mice. Finally, the NOX4 inhibitor GLX351322 was administered to investigate its regulatory effects on cell permeability and apoptosis. Behavioral changes were assessed through open field and novel object recognition test and Morris water maze experiments to evaluate its impact on cognitive behavior in mice. The present study analyzed clinical data from two enrolled families with heterozygous HTRA1 mutations [c.854C>T (p.P285L) and c.905G>A (p.R302Q)] and observed stroke, cognitive decline and gait disturbances. RNA-seq of patient blood revealed downregulated HTRA1, occludin-like protein 1 and claudin 5, alongside upregulated NOX4, with apoptotic pathways prominently enriched. HtrA1 overexpression in bEnd.3 cells enhanced viability, decreased oxidative stress and apoptosis and elevated tight junction protein expression, whereas HtrA1 knockdown exacerbated these effects. In mice, AAV-mediated HtrA1 suppression in cerebrovascular endothelial cells increased NOX4 and caspase3 levels, disrupted blood-brain barrier (BBB) integrity and induced anxiety- and depressive-like behaviors, measured by the open field test, along with cognitive and memory impairment evaluated using the novel object recognition and Morris water maze tests. The NOX4 inhibitor GLX351322 partially restored endothelial function, mitigated BBB damage and alleviated behavioral impairment. The present findings demonstrated that heterozygous HTRA1 mutations promoted CSVD via NOX4-mediated oxidative stress, endothelial dysfunction and BBB breakdown. Targeting the HTRA1-NOX4 interaction using GLX351322 rescued cerebrovascular and cognitive pathology, offering preclinical validation for therapeutic intervention.

Automated detection of cerebral microbleeds on ex-vivo MRI scans of community-based older adults

Vascular dementia (VaD), a primary cognitive disorder caused by cerebrovascular pathology, features significant white matter damage from chronic cerebral hypoperfusion strongly correlated with cognitive decline. Myelin integrity disruption represents a core pathological foundation in VaD, with dysfunctional oligodendrocytes (OLs) and microglia (MG) forming a critical pathogenic nexus. OLs govern myelin formation and maintenance while MGs modulate myelination through cerebral microenvironment regulation. In the central nervous system, precise communication and synergistic interaction between cells are the basis for maintaining homeostasis and cognitive function. The complement system, cytokine network, and extracellular vesicles together form its core communication axis. The complement system is at the forefront of the rapid innate immune response, cytokines dynamically regulate the initiation and resolution of inflammation, as carriers of functional molecules between cells, extracellular vesicles target and deliver information of bioactive molecules, upgrading intercellular communication to an active and programmed network regulation system. The three work together to maintain the homeostasis of the neural microenvironment. Their dysregulation can lead to uncontrolled neuroinflammation and tissue damage, which is the core pathological link in diseases such as VaD. This review examines the interplay between OLs and MG in VaD demyelination, detailing their complex communication networks via the complement system (including C1q, C3, C5 fragments), key cytokines (TNF-α, IL-1β, IL-4, IL-10), and extracellular vesicle signaling. Notably, these pathways exhibit bidirectionality: moderate activation promotes repair mechanisms, whereas excessive responses exacerbate injury. Future research should elucidate the spatiotemporal dynamics of OLs-MG interactions and identify precise therapeutic targets to restore cellular equilibrium, thereby informing novel VaD intervention strategies.

The relationship between peripheral vascular health, including endothelia, cognitive decline, and Alzheimer's disease (AD) dementia risk is unclear. In this study, 2844 dementia-free Framingham Offspring participants (mean age 60.6 years, 53.2% women) had baseline brachial artery flow-mediated dilation (FMD%) and reactive hyperemia (RH). Participants were then followed for a median of 17 years for incident AD and underwent plasma biomarker testing and brain magnetic resonance imaging. FMD% (hazard ratio [HR]=0.83, 95% confidence interval [CI] 0.76 to 0.91, p<0.001) and RH (HR=0.89, 95% CI 0.79 to 0.99, p=0.049) were negatively associated with incident AD dementia after adjusting for confounders. Associations were stronger in individuals with elevated C-reactive protein. Poor vascular function correlated with higher plasma AD biomarkers, smaller brain volumes, greater white matter injury, and increased cerebral microbleeds. Poor FMD% and RH may serve as a prognostic biomarker for cerebrovascular pathology, including endothelial dysfunction in the AD brain.

BACKGROUND: Moyamoya disease (MMD) features progressive intracranial artery stenosis and collateralization. Growing evidence implicates a dysregulated gut–brain axis in cerebrovascular pathology. We aimed to identify MMD-associated gut microbes and delineate the molecular mechanisms linking intestinal signals to vascular inflammation in MMD. RESULTS: We profiled fecal microbiota using full-length 16S rRNA sequencing from 24 MMD patients and 20 matched controls, prioritizing taxa with LEfSe, LASSO, and random forest algorithms. A species-level diagnostic model showed robust discrimination in our cohort (ROC AUC = 0.9146), and DCA supported its clinical utility. To connect gut signals to host vascular responses, we integrated peripheral and vascular transcriptomes from GEO and a cross-disease cerebrovascular cohort. Differential expression, WGCNA, and LASSO analyses identified key MMD genes and their immune modules. We then intersected these with microbiome-derived, gut-related genes to nominate candidate mediators of gut–immune–vessel crosstalk. This multi-omics pipeline identified Fusobacterium nucleatum, Lachnoanaerobaculum cf. saburreum C27KA, and NK4A214_group as MMD-specific microbial markers. Crucially, these markers were associated with immune infiltration signatures and inflammatory pathway activation in diseased vessels. Further integration pinpointed QRFPR and HCAR2 as key mediators of gut-derived cerebrovascular inflammation, suggesting a potential microbiota–immune–vascular pathway along the gut–brain axis. CONCLUSION: We characterized an MMD-associated microbiota profile and proposed QRFPR and HCAR2 as candidate genes linking intestinal microbes to vascular immune activation. By mapping the gut–brain axis from microbial taxa to host receptors and vessel-wall transcriptional programs, this study uncovers potential disease mechanisms and highlights new avenues for microbiome-informed biomarkers and therapeutic targeting in MMD.

BACKGROUND:Cerebrovascular risk factors, a group of conditions that reduce or disrupt blood flow to the brain, often occur with Alzheimer’s disease (AD) and may contribute to the pathogenesis and cognitive decline. Hispanic individuals are at increased risk of vascular risk factors compared to non-Hispanic white counterpartsOBJECTIVE:We examined associations among vascular risk factors, including hypertension, diabetes, history of heart disease, and history of stroke, with plasma phosphorylated tau-181 (P-tau181) and cognition.METHODS:We pooled data from 2,159 two cohorts of older Hispanic adults. Vascular risk factors were self-reported. Plasma P-tau181 was measured using standardized protocols. Linear regression and mediation models assessed associations among vascular risk, P-tau181, and global cognition, stratified by cognitive status.RESULTS:Overall, P-tau181 was significantly associated with vascular risk factors and inversely associated with cognitive function. However, vascular risk factors were not independently associated with cognition. Among cognitively unimpaired individuals, vascular risk factors mediated the association between P-tau181 and cognition, while in cognitively impaired individuals, P-tau181 was strongly and independently associated with cognition, without mediation by vascular risk factors.CONCLUSIONS:Among elderly without dementia, vascular risk factors mediate the association between P-tau181 and cognition. However, among individuals with dementia there is no mediation, suggesting that the association between P-tau181 with dementia is independent of cerebrovascular pathology.

Arterial angiography remains the gold standard for the assessment of cerebrovascular anatomy and pathology. However, when arterial access is higher risk (patients with extreme tortuosity, type 4 Ehlers Danlos Syndrome, or the young pediatric population), and for long-term follow-up or intraoperative scenarios, intravenous 3-dimensional digital subtraction angiography (IV 3D-DSA) is an acceptable substitute. We assessed our experience in consecutive IV 3D-DSA procedures. Five hundred twenty-eight adult and 21 pediatric IV 3D-DSAs were performed at our institution on 2 state-of-the-art systems from January 2019 to March 2025. Imaging obtained on older angiography systems are not included. The cone-beam computed tomography (CBCT) data were reconstructed and displayed as 3D-DSA, CBCT without contrast, and CBCT angiography. Data were analyzed for indication, conversion to intra-arterial angiography, use of anesthesia, radiation dose, and complications. The primary indication in 408/528 adult and 9/21 pediatric patients was aneurysm evaluation, initial, postoperative, or follow-up. Other indications included vascular malformations, postoperative after revascularization surgeries, and other pathologies such as extracranial carotid disease and intracranial atherosclerotic disease. Seven of the 528 adult cases were significantly limited by motion artifact (1.3%), but only 3 of these were considered nondiagnostic (0.6%). Seventy-one adult and 2 pediatric acquisitions were performed intraoperatively in the hybrid operating room. 20/21 pediatric cases required general anesthesia. Eighty-six adult cases were performed under anesthesia, although most of these were performed intraoperatively under the same anesthetic as the index operation. There were no significant complications reported. With the newer, higher resolution, semirobotic biplane systems, IV 3D-DSA has become a tool in the angiography suite for rapid vascular assessment. It offers increased spatial resolution when compared with multidetector computed tomography, making it well suited to evaluate vasculature and endovascular devices, is noninvasive compared with catheter angiography, and can be used for intraoperative assessment of treatment.

White matter hyperintensities (WMH) detected on FLAIR MRI sequences serve as important biomarkers for cerebrovascular pathology, correlating with increased risks of cognitive decline, stroke, and demyelination. Contemporary automated segmentation approaches face substantial challenges in distinguishing pathological lesions from normal age-related periventricular hyperintensities, resulting in elevated false-positive rates that limit clinical utility. This investigation examines whether incorporating normal WMH as an explicit class during deep learning model training enhances pathological lesion detection compared to conventional binary segmentation approaches. We evaluated four established architectures (U-Net, Attention U-Net, DeepLabV3Plus, and Trans-U-Net) across two training paradigms using 2,750 FLAIR images from 115 patients with neurodegenerative diseases, sourced from local and public datasets with expert radiological annotations. The first paradigm employed traditional binary classification (background versus pathological WMH), while the second utilized multiclass classification incorporating normal periventricular hyperintensities as a distinct category. Statistical evaluation included paired comparative analysis and effect size quantification using Cohen’s d. The U-Net architecture demonstrated the most pronounced improvement with the multiclass approach, achieving 0.271 improvement in Dice coefficient (0.768 versus 0.497) and 1.9 improvement in Hausdorff distance (11.5 vs 13.4) (p < 0.0001, Cohen’s d = 0.5643). All architectures demonstrated medium practical effects (d = 0.44–0.57) beyond statistical significance. In the present data regime, convolutional neural network-based architectures demonstrated more stable training dynamics and larger performance improvements compared to the transformer-based models, though all architectures showed statistically significant benefits from multiclass training. The multiclass training methodology substantially improves pathological WMH identification while preserving clinical practicality, offering a robust framework for enhancing automated neuroimaging diagnostic capabilities.Trial Registration Number Tabriz University of Medical Sciences Research Ethics Committee (IR.TBZMED.REC.1402.902).

Vascular cognitive impairment and dementia (VCID) encompasses a heterogeneous group of disorders in which cerebrovascular pathology contributes to cognitive decline. Accumulating evidence from both clinical and basic studies suggests that neuroinflammation is one of the major mechanisms underlying VCID pathogenesis. However, its clinical evaluation remains challenging, and how it influences the process of VCID pathogenesis is still not fully understood. Experimental models of chronic cerebral hypoperfusion have demonstrated that decreased cerebral blood flow can activate innate immune responses and trigger inflammatory cascades. These cascades may contribute to white matter damage and cognitive deficits, and anti-inflammatory interventions have shown therapeutic potential in mitigating these outcomes. In this mini-review, we summarize recent findings on neuroinflammation from both clinical and basic studies, and discuss its role in VCID progression. A deeper understanding of the multifaceted mechanisms involved in inflammatory signaling will be essential for advancing VCID research and developing effective therapeutic strategies.

Dementia encompasses distinct subtypes characterized by different underlying mechanisms-most notably, Alzheimer's disease (AD), driven by neurodegeneration, and vascular dementia (VaD), stemming from cerebrovascular pathology. Growing evidence emphasizes the critical role of neuroinflammatory processes in both conditions, highlighting inflammatory biomarkers as potential tools for differential diagnosis. This study assesses the diagnostic accuracy of inflammatory biomarkers in distinguishing AD from VaD. A systematic search of PubMed, EMBASE, Web of Science, and Cochrane Library databases was conducted in November 2025 to identify eligible studies. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated to compare inflammatory marker levels between AD and VaD groups. Random-effects models were applied for all meta-analyses. Fifteen observational studies involving 1728 participants were included. Pooled analyses showed no significant differences in IL-6 (SMD: -0.13; 95% CI: -0.44 to 0.19; p = 0.433), TNF-α (SMD: -0.22; 95% CI: -0.71 to 0.28; p = 0.388), or CRP (SMD: 0.73; 95% CI: -0.17 to 1.62; p = 0.111) between AD and VaD overall. However, subgroup analyses indicated context-dependent variations: IL-6 and TNF-α levels were lower in patients with AD in studies conducted in Eastern regions, with larger sample sizes (≥100 participants), older populations (≥70 years), or higher methodological quality. CRP showed similar patterns in larger or higher-quality studies. Importantly, IL-1β levels were significantly higher in patients with AD compared to patients with VaD (SMD: 0.48; 95% CI: 0.18 to 0.79; p = 0.002). Exploratory analyses suggest IL-1β as a promising candidate for differentiating AD from VaD, warranting validation in larger, prospective studies.Thepreliminary, context-dependent signalsfor IL-1β, IL-6, and TNF-α indicate that inflammatory pathways differ between these dementias but are substantially influenced by methodological and population factors. INPLASY platform (number: INPLASY202570068).

INTRODUCTIONCerebrovascular pathology contributes to dementia but lacks standardized quantification for multicenter datasets. We developed harmonized indices to quantify small vessel disease (SVD) and vascular cognitive impairment (VCI) likelihood using National Alzheimer's Coordinating Center Neuropathology 11 data.METHODSSix cerebrovascular domains were scored (0 to 3) and aggregated into a SVD index (0 to 18), with proportional scaling when ≥5 domains were available. A vascular cognitive impairment neuropathology guideline (VCING)‐Lite proxy substituted global for occipital‐specific ratings. A principal component analysis‐derived global‐cognition factor and clinical dementia status were modeled against vascular indices. Coherence was tested across complete, domain‐complete, and Alzheimer's disease neuropathologic change (ADNC)‐limited subsets.RESULTSSVD scores were consistent across datasets, with lower values only in the ADNC‐limited subset (p < 0.003). SVD–VCING‐Lite correlations remained strong after adjustment (r = 0.72, p < 0.001). Both were associated with worse global cognition and higher odds of dementia.DISCUSSIONThis framework links cerebrovascular pathology to in‐life outcomes and enables reproducible modeling of vascular contributions in mixed dementias.