To explore pathological and immune cell infiltration characteristics of pigmented pretibial patches in diabetic patients. Forty-two diabetic patients undergoing thigh amputation at Tianjin Medical University Chu Hsien-I Memorial Hospital were enrolled. Before the operation, the pretibial skin of the patients were examined and sampled for HE and Masson staining. The thickness of the epidermis and the density of blood vessels in the dermis were compared between patients with and without pigmented pretibial patches. The expressions of VEGFA and VEGFR2 in the skin tissues were detected using Western blotting, and CD4+ and CD8+ cells and the CD4/CD8 ratio were analyzed with immunohistochemical staining. Compared with the patients without pigmented pretibial patches, the patients with pigmented pretibial patches showed obvious thickening of the epidermal spinous layer, irregular downward extension of the epidermal projections, hyperkeratosis, melanin deposition in the basal layer, increased capillaries in the dermis, and localized, well-defined inflammatory cell infiltration around the blood vessels. In pigmented pretibial patches group, Masson staining revealed irregular arrangement, thickening and hyaline degeneration of collagen fibers, significantly increased epidermal thickness and blood vessel density in the dermis, increased CD4+ cells and the CD4/CD8 ratio, and reduced CD8+ cells. The pigmented pretibial patches in diabetic patients show obvious pathological changes possibly due to vascular and immune abnormalities.

To evaluate the therapeutic effects of ranibizumab on optic disc and macular microvascular perfusion in central retinal vein occlusion (CRVO) with macular edema (ME). Optical coherence tomography angiology (OCTA) parameters, including optic disc vessel density (VD; including whole-disc VD, intra-disc VD, and peripapillary VD), superficial/deep capillary plexus (SCP/DCP) VD, and central macular thickness (CMT) were analyzed. Additional assessments included best-corrected visual acuity (BCVA) via Early Treatment Diabetic Retinopathy Study (ETDRS) chart and hemorheological profiling. CRVO patients received monthly intravitreal ranibizumab injections for three consecutive months. Pre- and post-treatment parameters were statistically compared. The study comprised 60 CRVO-ME patients (28 males; 32 females), aged 50-78y (mean 63.3±7.6y) and 60 age-/sex-matched healthy controls. As compared with participants exhibiting normal funduscopic findings, CRVO patients demonstrated significantly elevated levels of low-shear-rate whole blood viscosity (LSR-WBV), high-shear-rate whole blood viscosity (HSR-WBV), and aggregation index (AI, all P<0.05). In CRVO-affected eyes, vertical cup-to-disc (C/D) ratio and optic cup volume were significantly smaller, whereas retinal nerve fiber layer (RNFL) thickness was significantly greater, compared to both unaffected contralateral eyes and normal control eyes (all P<0.05). Following treatment, VD of the entire optic disc (P<0.05), intra-disc VD (P<0.05), and peripapillary VD (P<0.05) all increased significantly relative to baseline. CMT decreased significantly (P<0.05), whereas macular SCP-VD and macular DCP-VD showed non-significant slight reductions (P>0.05). At baseline, BCVA of CRVO eyes correlated with whole-disc VD (r=-0.276, P=0.033), intra-disc VD (r=-0.342, P=0.009), and peripapillary VD (r=-0.335, P=0.007), with intra-disc VD demonstrating the strongest association. Besides, BCVA improvement, after the treatment, correlated positively with whole-disc VD (r=0.342, P=0.008) and intra-disc VD (r=0.396, P=0.002). Optic disc blood perfusion is more closely associated with visual acuity than macular perfusion, suggesting intra-disc VD may serve as a potential biomarker for monitoring visual acuity changes in CRVO. Multiple ranibizumab injections significantly improve optic disc perfusion but may have exerted detrimental effects on the macula. CRVO patients shows higher hemorheological parameters than those with normal fundi. Reduced vertical C/D ratio and optic cup volume may be linked to CRVO incidence, potentially acting as susceptibility factors.

Novel OCT Angiography Parameters for Analyzing Microvascular Changes in Proliferative Diabetic Retinopathy After Intravitreal Conbercept Loading Injections.

Purpose The study aims to investigate the relationship between pancreatic β-cell function and macular vascular structure and blood flow in patients with type 2 diabetes mellitus (DM) without clinical signs of diabetic retinopathy (DR). Methods This prospective cross-sectional study enrolled 121 type 2 DM patients without clinical DR, representing a total of 240 eyes. The area under the C-peptide release curve (AUCC) derived from the oral glucose tolerance test, fasting serum C-peptide level and the updated Homeostasis Model Assessment (HOMA2) model were utilized to reflect pancreatic β-cell function. Insulin resistance (IR) was assessed by HOMA2 model. The macular vascular and blood flow parameters of patients were measured by optical coherence tomography angiography (OCTA). Separate Linear Mixed-Effects Models were employed to analyze the relationship between pancreatic β-cell function indicators and OCTA metrics. Results In separate multivariate models, AUCC, fasting serum C-peptide level, and HOMA2 estimates of β-cell function (HOMA2-B) each demonstrated a significant positive association with vessel density (VD) measures in the deep capillary plexus (DCP), including total DCP VD, parafoveal DCP VD, and perifoveal DCP VD. Conclusions The impaired pancreatic β-cell function is significantly associated with adverse macular vasculature alterations, suggesting that these vascular changes may occur prior to the clinical manifestation of DR in patients with compromised β-cell function. β-cell function markers might help identify patients at risk of early subclinical retinal microvascular changes.

The neurovascular pathophysiology of migraine may extend to the retinal microvasculature. This study aimed to investigate structural and microvascular changes in migraine patients using optical coherence tomography angiography (OCT-A), focusing on the impact of migraine itself, independent of potential confounding factors. In this prospective, observational study, 54 migraine patients and 55 age- and sex-matched healthy controls underwent comprehensive OCT-A imaging. Peripapillary retinal nerve fiber layer (RNFL) thickness, ganglion cell complex (GCC) thickness, and macular vessel density (VD) in the superficial (SCP), deep (DCP), and choriocapillaris (CC) plexuses were compared. Multivariable regression analysis was employed to control for age, sex, spherical equivalent, and blood pressure. Migraine patients exhibited significantly reduced vessel density in the inferior quadrants of both the SCP and DCP compared to controls (p < 0.05). Notably, migraine status emerged as a significant independent predictor of reduced inferior DCP vessel density (β = -2.443, p = 0.044) after adjustment for confounders. Female sex was also an independent predictor of reduced VD. Strong negative correlations were observed between inferior DCP VD and clinical severity markers, including monthly attack frequency and MIDAS scores (p < 0.01). A paradoxical increase in nasal CC VD was detected. No significant differences were found in RNFL, GCC, or central macular thickness. This study identifies microvascular impairment in the inferior deep capillary plexus as a key, independent feature of migraine, strongly correlated with disease severity. OCT-A presents a promising tool for detecting objective biomarkers of migraine-related microvascular dysfunction.

BackgroundThe eye has been considered a ‘window to the brain’ and to several neurodegenerative brain disorders including Alzheimer's disease (AD) that display alterations in the eye, especially the retina. Plasma levels of AD biomarkers, including Aβ42/Aβ40 ratio, pTau 181, glial fibrillary acidic protein (GFAP), total Tau (tTau), and Neurofilament lightchain (NfL) are significantly altered in AD patients. We sought to evaluate the association of retinal perfusion measured using optical coherence tomography angiography (OCTA) with plasma biomarkers of AD.MethodParticipants (31; 5 mild cognitive decline/AD, 6 subjective cognitive decline and 20 cognitively normal) underwent ophthalmological evaluation including OCTA and a blood sample. Single molecule array (Simoa) assays were used to measure plasma concentrations of Aβ42, and Aβ40, pTau181, GFAP, Ttau, and NfL. Partial Pearson correlations, covaried for age and sex, were used to compare retinal vessel and perfusion density with plasma level of the Aβ42/Aβ40 ratio, pTau181, GFAP, tTau and NfL.ResultPlasma Aβ42/Aβ40 showed a significant positive association with retinal vessel density (r=0.398 p = 0.036) and perfusion density (r = 0.384 p = 0.044). pTau 181 showed a significant negative association with retinal perfusion density (r=‐0.499 p = 0.041). GFAP showed a significant positive association with foveal avascular zone area in the superficial capillary plexus (r=0.554 p = 0.021).ConclusionThe majority of the sample was cognitively normal or mildly impaired, suggesting that retinal perfusion may be a useful tool for early diagnosis of AD‐related pathophysiology. Future longitudinal studies in larger samples and evaluating the utility of combining retinal and plasma biomarkers for predicting future progression to AD are needed.

Early detection of ophthalmological and kidney complications of hypertension in children and adolescents may play a significant role in prophylaxis and prevent irreversible organ damage. This study aimed to assess standard kidney injury markers (creatinine, urea, uric acid, cystatin C, 24-h microalbuminuria), as well as potential ophthalmological changes using optical coherence tomography (OCT) and optical coherence tomography angiography (OCT-A) in the early course of newly diagnosed hypertension in children and adolescents. The study group consisted of 56 children and adolescents with newly diagnosed hypertension who had not received antihypertensive treatment prior to the study. Fifteen individuals served as controls. The ECHO, abdominal ultrasound, ophthalmological examination, urine and blood tests were performed. The concentration of cystatin C was increased in patients with hypertension. Children and adolescents with hypertension had decreased values of GFR (90.31 ± 13.00ml/min/1.73 m2), estimated by the Filler equation, compared to subjects with optimal values of blood pressure (99.00 ± 9.27ml/min/1.73 m2). The data revealed statistically significant differences in the retinal vessel density analyzed by OCT-A, which was decreased in the control group compared with the study group. Pediatric patients with newly diagnosed hypertension have increased concentrations of cystatin C and hypofiltration estimated by the Filler equation. OCT-A might be considered a diagnostic tool for better understanding the early process of microvascular changes and the influence of concomitant comorbidities in newly diagnosed systemic hypertension.

Effects of Laughter Exercise on Intraocular Pressure, Schlemm's Canal and Chorioretinal Parameters in Healthy Adults.

This study aimed to determine whether optical coherence tomography (OCT) with enhanced axial resolution improves structural characterization of the disorganization of the retinal inner layers (DRIL) in diabetic retinal disease (DRD) and its association with functional and vascular alterations. In this prospective cross-sectional study, 55 diabetic patients, 27 with DRIL (age: 57.1 ± 14.6 years) and 28 eyes without DRIL with diabetes mellitus (DM) type I/II (age: 58.2 ± 13.0 years), were examined with conventional spectral-domain OCT (SD-OCT), High-Resolution (High-Res) OCT, OCT angiography (OCTA), and microperimetry. DRIL areas were significantly smaller on High-Res OCT compared to SD-OCT (mean ± standard deviation, 0.3 ± 0.3 vs. 1.3 ± 1.2 mm2, p < 0.001). OCTA analyses demonstrated persistent group differences in superficial and deep vessel density and FAZ circularity between DRIL eyes and eyes without DRIL, even after adjustment for clinical diabetic retinopathy severity score (DRSS, all p < 0.05). Within DRIL eyes, intra-eye analysis revealed a stepwise reduction in retinal sensitivity from areas with DRIL detected on both OCT modalities (Zone I: 13.1 ± 1.3 dB) to areas with DRIL only on SD-OCT (Zone II: 20.6 ± 0.8 dB) and to unaffected retina (Zone III: 23.1 ± 0.7 dB, overall p < 0.001). OCT with enhanced axial resolution refines DRIL detection, aligning more precisely with localized functional and vascular impairment.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-34931-2.

Secondary lymphedema is characterized by limb swelling following lymphatic disruption. This results in decreased lymph flow through the collecting ducts and dermal backflow in the subdermal lymphatics. The role of dermal lymphatics in the development of lymphedema is poorly understood. The purpose of this study is to evaluate the effect of dermal lymphatic preservation in the development of lymphedema in a murine tail experimental model. A standard murine lymphedema tail model was used as the study control. A 3mm circumferential excision was performed 20mm from the base of the tail. Both collecting lymphatics adjacent to the veins were transected (Full Dermal Disruption (FDD), control, n = 6). The experimental group was a modification of the standard model consisting of two hemi circumferential skin excision and collecting lymphatics transection with 3mm interval (Partial Dermal Disruption (PDD), experimental, n = 8) maintaining continuity of capillary lymphatics. Tail volume measurements, lymphatic clearance with near Infrared Indocyanine Green (ICG) laser lymphangiography, and histology were assessed. The PDD group had lower tail volumes compared to FDD till day 28 (p < 0.001). ICG lymphangiography demonstrated better lymphatic clearance in the PDD when compared to FDD (p < 0.001). Reduced dermal thickness (p = 0.004) and collagen deposition (p = 0.008) were observed in PDD. Podoplanin-positive lymphatic vessel density was higher in PDD at the unadjusted level (p = 0.014) but did not meet Bonferroni-corrected significance (α = 0.010). This study demonstrates dermal lymphatics can preserve lymphatic function despite injury to transporting lymphatic channels. Dermal lymphatics may have the potential for lymphedema prevention at the lymphatic injury site.

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy in which cervical lymph node metastasis critically determines patient prognosis. Despite advances in clinical staging based on tumor size, depth of invasion, and nodal status, these parameters fail to capture the biological heterogeneity of HNSCC, leading to overtreatment or undertreatment, and significant morbidity. Emerging evidence implicates small extracellular vesicles (SEVs) as key mediators of tumor progression and promising biomarkers for metastatic potential. In this study, we performed iTRAQ-based proteomic profiling of SEVs from metastatic (MOC2) and nonmetastatic (MOC1) HNSCC mouse cell lines and identified multiple cargoes associated with metastatic processes, including angiogenesis, extracellular matrix remodeling, immune modulation, and perineural invasion. Further, we employed an immune-competent orthotopic mouse oral carcinoma (MOC) model to investigate how exosome biogenesis affects HNSCC metastasis. Loss of the exosome/SEV biogenesis protein HRS in MOC2 HNSCC cells impaired SEV formation in vitro and tumor growth and metastasis in vivo. Consistent with the SEV cargoes enriched in MOC2 EVs, immunohistochemical analyses of MOC2 tumors revealed reduced blood vessel and nerve density in HRS-deficient tumors. Analysis of candidate biomarker SEV cargoes in the circulating EVs from HPV-negative HNSCC patients revealed significant correlations of these proteins with metastatic status. Collectively, these findings identify SEV cargoes as potential functional mediators of metastasis and liquid biopsy biomarkers in HNSCC.

Longitudinal Evaluation of Microvascular Changes and Imaging Biomarkers Associated with Visual Prognosis in Retinal Artery Occlusion.

This study compared microcirculatory measures using sidestream dark field (SDF) videomicroscopy at sublingual and sublabial regions, examining whether novice examiners can achieve comparable reliability to experienced operators and the effect of operator experience on sublabial image quality. Microcirculatory imaging was performed using SDF videomicroscopy at the sublingual and sublabial regions. Sublingually, the probe was placed under the tongue on the mucosa of the floor of the mouth, in a stable, flat position to minimize tissue distortion. Sub-labially, the probe was positioned on the mucosa medial to the superior labial frenulum and stabilized between the central and lateral incisors. Participants were positioned at a 40-degree incline. Both novice and experienced operators captured images, and manually analyzed clips in AVA 3.2 software. All images were evaluated using the microcirculatory image quality score. Total vessel density, perfused vessel density, portion of perfused vessels, microvascular flow index, and heterogeneity index were calculated. No statistically significant differences in image quality scores were found between observers at the sublabial site. Vessel density measures demonstrated reliable inter-observer agreement, while some flow indices showed proportional bias (MFI, p = 0.01). No significant differences were detected between sublingual and sublabial regions for most measures, except for the microvascular flow index. The sublabial site is a valid alternative to the sublingual region for measuring certain microcirculatory parameters, though it requires further evaluation in flow metrics.

To evaluate the morphometric changes in macular neovascularization (MNV) architecture after faricimab treatment in neovascular age-related macular degeneration, comparing treatment-naive and previously treated eyes. Prospective study analyzing 45 eyes (18 treatment naive, 27 switched) with neovascular age-related macular degeneration undergoing faricimab treatment. Optical coherence tomography angiography images were exported and the quantification of changes in MNV area, vessel area, vessel density, number of junctions, branching index, total vessel length, end points, and lacunarity was performed using AngioTool v0.6a. Follow-ups at baseline (V0), at the end of the loading phase (V1), and at 1 year (V2) were collected. Baseline MNV characteristics differed significantly between treatment-naive and switched eyes. Switched eyes exhibited greater MNV area ( P < 0.001), vessel area ( P < 0.001), junction count ( P = 0.004), vessel length ( P < 0.001), average vessel length ( P = 0.02), end point count ( P = 0.002), and lacunarity ( P = 0.04). Conversely, naive eyes had higher vessel density ( P < 0.001) and branching index ( P = 0.007). Posttreatment, MNV area ( P < 0.001), vessel area ( P < 0.001), junction count ( P = 0.001), and total vessel length ( P < 0.001) decreased, whereas lacunarity increased ( P = 0.001). Greater changes were observed in naive eyes, but the end point count only reduced in switched eyes ( P = 0.01), being stable in naive eyes. At V2, switched eyes still had larger MNV area ( P = 0.007), vessel area ( P = 0.004), junction count ( P = 0.002), vessel length ( P = 0.004), and end points ( P = 0.007). Faricimab induces significant and sustained remodeling of the MNV network in neovascular age-related macular degeneration, with more pronounced changes in treatment-naive eyes. These changes were primarily driven by the loading phase, but then remained stable toward the 1-year follow-up.

Association between posterior vitreous detachment stage and quantitative neovascularization morphology in proliferative diabetic retinopathy using wide-field swept-source optical coherence tomography angiography.

Longitudinal Neural and Microvascular Changes in Type 2 Diabetic Patients Without Retinopathy: A 2-Year Prospective Cohort Study.

Optical coherence tomography angiography (OCTA) is widely used for evaluating retinal vessels. The aim of this study was to assess the influence of OCTA quality, as measured by the previously introduced OSCAR-MP criteria, on OCTA outcome parameters and the reliability of test-retest results. In this prospective longitudinal cohort study, we performed retinal OCTA at baseline and within 24 hours in 54 participants, including 42 healthy individuals and 12 patients with demyelinating CNS disease. We performed reliability testing on OCTA outcome parameters based on QC status according to the OSCAR-MP criteria. Retinal vessel density measurements remained consistent between baseline and follow-up scans when both passed quality control. By contrast, vessel densities were significantly higher in high-quality images than in paired lower quality ones. Reliability measures, such as intraclass correlation coefficient (ICC) and Pearson r, were higher in pairs where both images met quality standards, with a lower coefficient of repeatability and minimal detectable change observed. Poor OCTA image quality negatively affects retinal vessel density measurements. Implementing OSCAR-MP quality criteria demonstrated strong test-retest reliability in high-quality OCTA images, indicating its potential role as reliable quality criteria for OCTA in future clinical trials and research settings.

Background/Objectives: Thyroid eye disease (TED) can lead to structural and microvascular changes in the orbit and retina. This study aimed to investigate the associations between Clinical Activity Score (CAS), orbital magnetic resonance imaging (MRI) measurements, and retinal microvascular changes in TED patients. Methods: This cross-sectional study included 38 patients (76 eyes) with TED. Each patient underwent a comprehensive ophthalmological evaluation, CAS assessment, and a detailed medical history. Optical coherence tomography angiography (OCTA) was performed to quantify vessel density (VD) in the superficial and deep capillary plexus (SCP and DCP). Exophthalmos, extraocular muscle thickness and orbital fat thickness were measured on MRI scans to evaluate structural changes. Laboratory analyses included thyroid hormone levels, thyrotropin receptor antibodies (TRAb), anti-thyroid peroxidase antibodies (anti-TPO), and lipid profile. Results: Active TED patients (CAS ≥ 3) had significantly higher TRAb levels (p < 0.001), while anti-TPO did not differ between groups. Active eyes showed significantly higher DCP VD in the whole image (p = 0.013), parafovea (p = 0.012), and perifovea (p = 0.009) across all quadrants, with no difference in SCP or the foveal avascular zone (FAZ). In linear mixed model regression analyses, after adjusting for previous glucocorticosteroid therapy, higher triglycerides, greater medial rectus thickness, and whole-image DCP VD independently predicted higher CAS values (R2 = 42, p < 0.001). After adjusting for age and sex, CAS remained significantly positive predictor of DCP VD in the parafovea (R2 = 0.22, p < 0.001). Conclusions: Changes in DCP VD reflect TED activity and structural orbital involvement.

Early Peripapillary and Macular Microvascular Changes Following Ruthenium-106 Plaque Brachytherapy For Uveal Melanomas.

Rationale: The efficacy of drug delivery to the brain is constrained by the impermeability of the blood-brain barrier (BBB) in healthy tissues and the heterogeneous permeability of the blood-tumor barrier (BTB) in gliomas. Focused ultrasound (FUS) has emerged as a promising technique to transiently modulate vascular permeability, however its effects vary across different brain tissues. This study systematically evaluates the effects of FUS-induced vascular permeability modulation in the gray matter (GM), white matter (WM), and brain tumors, considering their distinct tissue architectures, vascular densities, and permeability profile. Additionally, we compare the delivery of bevacizumab (antiangiogenic monoclonal antibody) and methotrexate (small-molecule chemotherapeutic) to determine how molecular size influences vascular-level permeability and extravasation distances.Methods: A total of n = 48 Fischer-344 rats, including both healthy and tumor-bearing cohorts, underwent magnetic resonance imaging (MRI)-guided FUS using a feedback-controlled algorithm to modulate microbubble pressure based on microbubble emissions. Tumors were either untreated or received a single FUS exposure, while healthy tissues, including GM and WM, were treated with either a single exposure, or a repeated exposure administered 30 minutes after the first one. MR images were used to assess contrast enhancement before and after sonication. Drug deposition was quantified via fluorescence microscopy in terms of local signal intensities and distances of extravasation. Tissue-specific vascular characteristics, including vessel diameters, densities, and inter-vessel distances, were also analysed.Results: The lack of MRI contrast enhancement in untreated tissues suggested a healthy permeability status of the BBB in GM and WM, while a compromised BTB was observed in tumors. Following FUS treatments, contrast enhancement significantly increased in all tissues, with tumors exhibiting the most pronounced effects. Repeated FUS further enhanced permeability in GM and WM, achieving drug deposition levels comparable to those observed in tumors after a single treatment. At the vascular level, FUS exposure led to significant increases in drug extravasation distances, particularly in tumors. Vascular densities were approximately threefold higher in GM, compared to WM and tumors (GM:WM:Tumor 3.2:1:1), yet both drug signal intensities and extravasation distance correlated more strongly with the number of treatments than with baseline vascularity. Fluorescence microscopy revealed that bevacizumab extravasation was primarily localized near vessel lumens, whereas methotrexate exhibited significantly greater extravascular diffusion, reaching distances spanning entire inter-vessel spaces, consistent with its lower molecular weight. At the individual vessel level, white matter showed significantly lower drug signal intensity than gray matter following a single treatment.Conclusion: This study provides vascular-level insights into how FUS-mediated drug delivery is influenced by tissue architecture, vascular properties, treatment regimen, and drug molecular weight. Notably, at the individual vessel level, drug extravasation varies between the different tissue types, and thus vascular density is not the sole driver of differences in drug deposition in these tissues. The study findings highlight the potential of repeated FUS exposures for enhancing the deposition of therapeutics across the physiologically intact BBB of both the gray and white matter, reaching levels comparable to those observed in the pathologically compromised BTB of gliomas. Thus, sonications prescribed over previously permeabilized tissues facilitate deeper drug penetration into interstitial compartments, allowing therapeutics to reach cells further from vessel lumens despite inherent tissue-specific differences.