Retinal degenerative diseases, including age-related macular degeneration and retinitis pigmentosa, have led to vision loss for millions worldwide. While stem/progenitor cell transplantation shows promise, its clinical application is limited by poor survival, efflux, and low integration of transplanted cells. Biopolymer scaffolds have been explored to improve viability and differentiation, but most in vitro assessments rely on simplified or endpoint analyses that fail to capture dynamic behaviors. Retinal explant models, which preserve tissue architecture and neuronal connections, provide a more physiologically relevant platform. However, conventional explant models are often limited to endpoint analyses and lack real-time monitoring capabilities. Here, we developed a novel explant model for human retinal progenitor cell (hRPC) transplantation using porcine retinal tissue slice, agarose hydrogel, and confocal microscope with an incubation cage. Retinal tissue slices exhibited comparable viability before and after imaging. Alginate-based hydrogels containing hRPCs were injected adjacent to photoreceptor or ganglion cell layer of cross-sectional retinal tissue slices, enabling visualization of the cells' position relative to retinal tissue slice over time. Real-time confocal imaging tracked key cellular behaviors, including migration, attachment, invasion, viability, and apoptosis. Injected hRPCs displayed random movement within the bulk alginate hydrogel and localized attachment or invasion at the hydrogel-tissue interface. Notably, laminin-incorporated alginate hydrogels promoted cell clustering and facilitated deeper invasion into retinal tissue compared with single cells.

Retinal degeneration is the leading cause of blindness worldwide. Subretinal implantation of human retinal progenitor cells (hRPCs) has shown great promise in models of retinal degeneration for restoration of vision but is limited by extremely low (< 2%) integration into the retina. Successful integration of implanted cells requires their migration from the site of implantation into the degenerating retina. Little is known about what cues promote RPC migration in the context of the postimplantation microenvironment, such as cues presented by a biomaterial carrier. We utilized a high-throughput assay to study the migration of hRPCs in three-dimensional hydrogel matrices of varying chemical composition and stiffness and, with exposure to different soluble factors, to identify cues important for hRPC migration and associated cell signaling events driving migration. Collagen type I, collagen type I methacrylate, and hyaluronic acid glycidyl methacrylate gels were developed with variable stiffness. The impact of key growth factors in neural development, regeneration, and cell migration such as epidermal growth factor (EGF), fibroblast growth factor (FGF), stromal cell-derived factor (SDF), and hepatocyte growth factor (HGF) was studied using hRPCs in 2 mg/mL collagen type I gels. Migration of the hRPCs varied significantly in gels of different composition and stiffness, with higher levels of mean migration distance after 48 h in nonphoto crosslinked collagen-based gels with higher concentrations of gel components and associated compressive moduli. In addition, the presence of SDF and HGF in collagen gels increased hRPC migration compared to media alone. Key signaling nodes correlating with hRPC migration were identified in Akt and MAPK signaltransduction pathways using bead-based multiplex ELISA and partial least-squares regression (PLSR) modeling. These results motivate the further exploration of material stiffness and co-delivery of soluble factors as important design parameters in cell delivery vehicles to promote transplanted hRPC migration and successful integration into degenerating retina.

Background The estimated incidence of chronic subdural hematomas (cSDH) in the general population is projected to nearly double over the next decade, likely making it the most commonly treated cranial neurosurgical condition in adults by 2030. We investigated the outcomes of middle meningeal artery embolization (MMAe) as either a primary or adjunctive treatment for cSDH in nonagenarian patients. Methods We retrospectively reviewed all patients 90 years of age or older treated with middle meningeal artery embolization for cSDH from 2018 to 2024 at two academic institutions. Statistical analysis was performed on patient demographics, baseline functional status, intervention, cSDH size, recurrence rate, reintervention rate, and follow-up functional status. Results Twenty-one patients aged 90 or older were identified who were treated with MMAe for cSDH. Hematoma thickness ranged from 10mm to 34mm with a mean midline shift of 4.6mm. Eighteen patients were treated with MMAe alone, while three patients underwent surgery followed by MMAe. A total of 20 patients had radiological follow up, with no evidence of growth or recurrence in 95 % of the patients. There was one recurrent cSDH in our cohort in the setting of new trauma after hospital discharge. There was one complication related to the MMAe procedure which was a femoral artery pseudoaneurysm that resolved without further treatment. Median baseline mRS was 3 prior to MMAe and median follow-up mRS after treatment was 2. Conclusion MMAe is a safe and efficacious treatment for nonagenarian patients with cSDH, and shows promise as a potential primary treatment modality.

Intracranial hemorrhages are highly concerning but underreported complications related to flow diversion (FD) treatment of intracranial aneurysms. Herein, we aimed to characterize these complications and the factors influencing their occurrence. We retrospectively reviewed patients treated with FD from 2013 to 2023 at a single U.S. institution, analyzing aneurysm characteristics, comorbidities, antiplatelet and anticoagulation use, and hemorrhage imaging features. Risk factors for intraparenchymal hemorrhages (IPHs) were assessed with univariate analysis. There were 622 patients harboring 788 aneurysms treated in 690 procedures during the study period. Within 7 months of follow-up, 15 intracranial hemorrhages were identified (2.2

BACKGROUND: The Matsushima grade has traditionally been used to evaluate vessel ingrowth from the superficial temporal artery after encephalo-duro-arterio-synangiosis (EDAS) for Moyamoya disease (MMD) patients. However, this grading is subjective and prone to measurement variability. Herein, we propose the orbital grading system quantifying leptomeningeal and burr hole-related vessel-ingrowth from the superficial temporal artery and/or middle meningeal artery to the middle and anterior cerebral arteries post EDAS in MMD patients. METHODS: An anatomical classification was developed by reference to 2 parallel vertical lines from the bony landmarks of the orbit, categorized from Grade 0-3. Regression models were used to compare clinical and functional outcomes of our grading system with the Matsushima scale. RESULTS: Forty MMD patients, with median age of 48 years, mostly females (72.5%), underwent 56 EDAS procedures. Presentation included ischemic events (65.0%), hemorrhage (22.5%), and seizures (7.5%). Most patients were categorized as Suzuki double dagger IV (69.5%). Fifty EDAS (89.9%) had concurrent burr holes placed (parietal and frontal regions). At a median follow-up of 13.7 months, collateral growth was graded as follows: grade 0 (6; 10.8%), grade 1 (12; 21.4%), grade 2 (23; 41.1%), and grade 3 (15; 26.8%). Linear regression showed similarities in the distribution between the orbital grading system and Matsushima grading (r = 0.86; P < 0.01). Ischemic events were fewer in hemispheres categorized as grade 2-3 compared to grade 0-1 (P = 0.047) as well as in Matsushima grading A or B compared to C (P = 0.047). CONCLUSIONS: The orbital grading system demonstrated agreement in identifying postoperative ischemic events as the Matsushima grade and provides a more practical and objective evaluation of collateral vessel ingrowth after EDAS with and without burr holes.

The use of surgical procedures for the treatment of blinding conditions has a long history, most notably for cataract. In the modern era, refinements in ophthalmologic techniques and pharmacology have greatly expanded the range of available interventions for a host of ocular conditions. Nevertheless, conditions involving the loss of cell types that lack the ability to regenerate remain a persistent therapeutic challenge. In the case of diseases involving the loss of corneal endothelial cells, tissue transplantation has proven successful, although the limited availability of donor corneas restricts the use of this approach (Fu and Hollick, 2024). More problematic are diseases involving the loss of retinal neurons and retinal pigment epithelial (RPE) cells where few, if any, options are currently available to the treating clinician. As a group, neural retinal degenerative diseases are common and examples include age-related macular degeneration, Stargardt Disease, retinitis pigmentosa, as well as various forms of optic neuropathy, including glaucoma. In addition, common retinal vascular diseases such as diabetic retinopathy and vascular occlusive disease frequently involve retinal cell loss. Given the prevalence of visual disability resulting from these conditions, novel methods of both preserving and replacing retinal neurons are needed.

BACKGROUND AND OBJECTIVES:Flow diversion (FD) for posterior circulation aneurysms, such as proximal posterior inferior cerebellar artery (PICA) aneurysms, remains "off-label" and controversial. Although there are reports of using FD in the vertebral artery (VA) to treat PICA aneurysms, the differences between structural PICA-origin variants have not been explored. We analyzed PICA aneurysms treated with FD, assessed radiographic and clinical outcomes, and presented a novel classification of the PICA origin in relationship to aneurysm anatomy.METHODS:We performed a retrospective study of prospective data for intracranial aneurysms treated with FD at a major academic institution from 2013 to 2022. Proximal PICA aneurysms that underwent FD placement in the V4 segment of the vertebral artery were included for analysis. A literature review was performed on PubMed to evaluate previously published cases. The PICA origin was characterized by 4 distinct subtypes. Type 1 describes the PICA originating adjacent/separate to the aneurysm neck, Type 2 with the PICA originating from the aneurysm neck, Type 3 with the PICA originating from the aneurysm dome, and Type 4 (True PICA aneurysm) with the aneurysm located proximally on PICA, distal to the PICA-VA junction.RESULTS:Thirteen proximal PICA aneurysms were identified and included in the analysis. Patients were primarily female (76.9%), with a median age of 62 years. The aneurysm median maximum diameter was 5.8 mm. From the total sample (institutional and literature review cases), type 1 had a 100% complete and near-complete occlusion rate, type 2 had 75.0%, type 3 had 88.9%, and type 4 had 75%. The overall complete and near-complete occlusion rate was 83.3% (20/24).CONCLUSION:FD in the V4 VA segment is an effective way to treat proximal PICA aneurysms. Exploring the relationship between PICA origin is a helpful method in predicting occlusion rates for proximal PICA aneurysms and may lead to improved treatment considerations.

INTRODUCTION: Most cavernous carotid aneurysms (CCAs) are asymptomatic benign lesions; therefore, they are frequently detected during routine clinical diagnostic processes. Most providers recommend routine surveillance instead of immediate management for CCAs given a natural history with a low risk of life-threatening complications. However, the cost-effectiveness of such care and the optimal follow-up interval remains unknown. METHODS: A decision analysis study was performed utilizing a Markov model with Monte Carlo simulations to simulate patients undergoing treatment or routine surveillance at different time intervals (half, 1-,2-,3-, 5-and 7-year intervals) for different size of CCAs (=<12 mm, 13- 24 mm, >=25 mm ). Input data for the model was extracted from the current literature. Probabilistic and deterministic sensitivity analyses were performed to evaluate the robustness of the Model. RESULTS: On base case analysis, following-up every 2 years with noninvasive imaging is the most cost-effective strategy for CCAs =< 12 mm, while annual follow up is cost-effective for large/giant (13-24 mm, >=25 mm) CCAs. The conclusions remain robust in probabilistic sensitivity and deterministic sensitivity analyses. As the risk of thrombo-embolic event gets higher and annual growth risk and annual rupture risk of CCAs increases, immediate treatment for large/giant (13- 24 mm, >=25 mm ) CCAs and annual follow up even prompt treatment for CCAs =< 12 mm is optimal. CONCLUSIONS: The most cost-effective management strategy for CCAs=< 12 mm and large/giant CCAs are following up every 2 years and following up every year, respectively. More frequent follow-up strategies or prompt preventive treatment for CCAs =< 12 mm and immediate treatment for large/giant CCAs would be more appropriate in patients with higher risk factors for cerebral ischemia, aneurysm growth and aneurysm rupture.

INTRODUCTION: Thromboembolic (TE) events are among the most feared complications after flow diversion (FD) and reported to occur even with adequate dual antiplatelet therapy. METHODS: A retrospective analysis of aneurysms treated with FD at a single institution in the US was performed from 2013 to 2023. We documented the emergence of intraprocedural and postoperative TE events. A survival analysis and a Cox regression model was conducted to identify predictors associated with these events. RESULTS: We included 651 procedures performed on 593 patients to treat 748 aneurysms. TE events occurred in 38 of performed procedures (5.8%), causing permanent morbidity in 20 patients, four of whom died. Eleven cases presented with acute stent thrombosis, 11 with large vessel occlusion, and 9 with perforator strokes. At a median follow-up of 9.5 months, 66.7% of patients with an ischemic event had an mRS = 2. Three of the deaths were secondary to occlusion at the basilar trunk and vertebral artery. In the anterior circulation, six out of ten patients with MCA occlusion and eight out of eleven patients with ICA occlusion achieved independence. Time-to-event Cox regression analysis demonstrated that TE events were more frequent in patients exhibiting aspirin resistance (HR=2.66; 95% CI=1.10-6.70), and when multiple devices were used (HR=3.25; 95% CI=1.00-11.00). CONCLUSIONS: TE events after FD result from multiple factors, including age, aneurysm characteristics, aneurysm location, antiplatelet resistance, and procedural factors. In our cohort, we found the highest morbidity for patients with TE events presenting with LVO at the middle cerebral artery, and vertebrobasilar system.

BACKGROUND:The long-term outcomes after stereotactic radiosurgery (SRS) for pediatric brain arteriovenous malformations (AVMs) remain poorly understood given the paucity of longitudinal studies. A systematic review was conducted to pool cumulative incidences for all outcomes. METHODS:PubMed, Embase, and Web of Science were queried to systematically extract potential references. The articles relating to AVMs treated via SRS were required to be written in English, involve pediatric patients (<18 years of age), and include a mean follow-up period of >5 years. Individual patient data were obtained to construct a pooled Kaplan-Meier plot on obliteration rates over time. RESULTS:Among the 6 studies involving 1315 pediatric patients averaging a follow-up period of 86.6 months (range, 6-276), AVM obliteration was observed in 66.1% with cumulative probabilities of 48.28% (95% confidence interval [CI], 41.89-54.68), 76.11% (95% CI, 67.50-84.72), 77.48% (95% CI, 66.37-88.59) over 3, 5, and 10 years, respectively. The cumulative incidence of post-SRS hemorrhage, tumors, cysts, and de novo seizures was 7.2%, 0.3%, 1.6%, and 1.5%, respectively. The cumulative incidence of radiation-induced necrosis, edema, radiologic radiation-induced changes (RICs), symptomatic RICs, and permanent RICs were 8.0%, 1.4%, 28.0%, 8.7%, and 4.9%, respectively. CONCLUSIONS:Studies assessing long-term outcomes after SRS are moderate in quality and retrospective. Thus, interpretation with caution is advised given the variable degree of loss to follow-up, which suggests that complication rates may be higher than the values stated in the literature. Future prospective studies are needed to validate these findings.

This comprehensive review explores the multifaceted role of endothelial progenitor cells (EPCs) in vascular diseases, focusing on their involvement in the pathogenesis and their contributions to enhancing the efficacy of endovascular treatments for intracranial aneurysms (IAs). Initially discovered as CD34+ bone marrow-derived cells implicated in angiogenesis, EPCs have been linked to vascular repair, vasculogenesis, and angiogenic microenvironments. The origin and differentiation of EPCs have been subject to debate, challenging the conventional notion of bone marrow origin. Quantification methods, including CD34+ , CD133+ , and various assays, reveal the influence of factors, like age, gender, and comorbidities on EPC levels. Cellular mechanisms highlight the interplay between bone marrow and angiogenic microenvironments, involving growth factors, matrix metalloproteinases, and signaling pathways, such as phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK). In the context of the pathogenesis of IAs, EPCs play a role in maintaining vascular integrity by replacing injured and dysfunctional endothelial cells. Recent research has also suggested the therapeutic potential of EPCs after coil embolization and flow diversion, and this has led the development of device surface modifications aimed to enhance endothelialization. The comprehensive insights underscore the importance of further research on EPCs as both therapeutic targets and biomarkers in IAs.

In recent years there has been a significant shift in the management of intracranial aneurysms, as most, both ruptured and unruptured, are being treated through an endovascular approach.1-3 However, there are still instances in which open surgical clipping is the best option for definitive management. Both patient factors, such as age and comorbidities, and aneurysm characteristics, such as size, morphology, and location, must be taken into consideration when treating aneurysms. This is especially true for anterior1 communicating artery aneurysms, as these have been treated successfully using multiple different techniques.4,5 There are no absolute guidelines indicating how a particular aneurysm should be treated and, therefore, one must be able to determine how to best manage a patient based on their own skill set, knowledge, and experience. We present a case of a 61-year-old woman who presented with a ruptured anterior communicating artery aneurysm. Initially she was brought to the angiography suite to undergo possible endovascular treatment of the aneurysm, but after reviewing the morphology and size of the aneurysm, we believed that this aneurysm could not be treated safely through an endovascular approach and surgical clipping was the better option. The patient consented to the procedure. In this operative video, we describe the technical aspects of the surgical procedure and the benefits of our approach (Video 1).

Beta (β)-adrenergic G-protein-coupled receptors (GPCRs) are primarily responsible for signaling in the sympathetic nervous system and control numerous body functions, including increased heart rate, pupil dilation, glycogen metabolism, and adrenaline secretion. Using its ligand, isoproterenol, bound β1-AR structure (PDB ID:7S0F), we synthesized a blue light (405 nm) sensitive, novel inactive isoproterenol derivative (OptoIso) with optically deprotectable groups. The goal was to control cell surface and endomembrane β1-AR signaling using light. Our results show that OptoIso efficiently activates β1AR signaling, as indicated by the miniGs protein and nanobody80 (Nb-80) recruitment to the activated cell surface receptor, G-beta gamma translocation, and cAMP production only upon exposure of cells to a few pulses of blue light in the presence of OptoIso. Due to its enhanced cell permeability, OptoIso efficiently entered cells, and blue light exposure after washing cells induced endomembrane-exclusive β1-AR activation at user-defined subcellular endomembrane regions. Given the disease relevance of β1-AR in general, and deep-organelle β1-AR in particular, OptoIso will be a valuable tool for decoding pathological β adrenergic signaling. NIH NIGMS for funding (1R01GM140191).

Dural arteriovenous fistulas (dAVFs) are vascular malformations of the central nervous system that feature an arteriovenous shunt fed by dural arteries and can be intracranial or spinal.(1-3) Spinal dAVFs are classically found at the nerve root sleeve.(3) The arterial supply can often be predicted by the fistula location, whereas the symptomatology and risk of hemorrhage is determined by the venous drainage pattern.(1-3) Craniocervical fistulas, a subset of dAVFs, may arise in association with the anterior condylar venous confluence or more dorsally in association with the transdural segment of the vertebral artery.(1-3) This latter type of fistula typically has spinal venous drainage and may present with myelopathy from spinal cord venous congestion.We present a 61-year-old man who presented with a 2-week history of neck pain and paraparesis. Magnetic resonance imaging of the cervical spine revealed diffuse T2 hyperintensity of the cord from the pons to the level of the T1 vertebra. A computed tomography angiogram showed a possible dAVF at the craniocervical junction on the left. Because of the unclear nature of the patient's spinal cord lesion, a cerebral angiogram was performed. It confirmed a dAVF associated with the transdural segment of the left vertebral artery, with small dural feeders from the left vertebral artery and venous drainage into the anterior spinal vein. The patient underwent a modified suboccipital craniectomy and C1 laminectomy for dAVF ligation (Video 1). He was extubated postoperatively and discharged to a rehabilitation unit with improvement in lower extremity strength.

Microglia shift toward an inflammatory phenotype during aging that is thought to exacerbate age-related neurodegeneration. The molecular and cellular signals that resolve neuroinflammation post-injury are largely undefined. Here, we exploit systems genetics methods based on the extended BXD murine reference family and identify IGFBPL1 as an upstream cis-regulator of microglia-specific genes to switch off inflammation. IGFBPL1 is expressed by mouse and human microglia, and higher levels of its expression resolve lipopolysaccharide-induced neuroinflammation by resetting the transcriptome signature back to a homeostatic state via IGF1R signaling. Conversely, IGFBPL1 deficiency or selective deletion of IGF1R in microglia shifts these cells to an inflammatory landscape and induces early manifestation of brain tauopathy and retinal neurodegeneration. Therapeutic administration of IGFBPL1 drives pro-homeostatic microglia and prevents glaucomatous neurodegeneration and vision loss in mice. These results identify IGFBPL1 as a master driver of the counter-inflammatory microglial modulator that presents an endogenous resolution of neuroinflammation to prevent neurodegeneration in eye and brain.

Ocular retinoblastoma malignancies, which develop into metastatic phenotypes, result in poor prognosis and survival for infant and child patients. To improve the prognosis of metastatic retinoblastoma, it is important to identify novel compounds with less toxic side effects and higher therapeutic efficacy compared to existing chemotherapeutics. Piperlongumine (PL), a neuroprotective, plant-derived compound has been explored for its anticancer activities both in vitro and in vivo. Here, we analyze the potential efficacy of PL for metastatic retinoblastoma cell treatment. Our data reveal that PL treatment significantly inhibits cell proliferation in metastatic retinoblastoma Y79 cells compared to the commonly used retinoblastoma chemotherapeutic drugs carboplatin, etoposide, and vincristine. PL treatment also significantly increases cell death compared to treatment with other chemotherapeutic drugs. PL-induced cell-death signaling was associated with significantly higher caspase 3/7 activities and greater loss of mitochondrial membrane potential. PL was also internalized into Y79 cells with an estimated concentration of 0.310pM and expression analysis revealed reduced MYCN oncogene levels. We next examined extracellular vesicles derived from PL-treated Y79 cells. Extracellular vesicles in other cancers are pro-oncogenic, mediating systemic toxicities via the encapsulation of chemotherapeutic drugs. Within metastatic Y79 EV samples, an estimated PL concentration of 0.026pM was detected. PL treatment significantly downregulated Y79 EV cargo of the oncogene MYCN transcript. Interestingly, non-PL-treated Y79 cells incubated with EVs from PL-treated cells exhibited significantly reduced cell growth. These findings indicate that in metastatic Y79 cells, PL exhibits potent anti-proliferation effects and oncogene downregulation. Importantly, PL is also incorporated into extracellular vesicles released from treated metastatic cells with measurable anti-cancer effects on target cells at a distance from the site of primary treatment. The use of PL in the treatment of metastatic retinoblastoma may reduce primary tumor proliferation and inhibit metastatic cancer activity systemically via extracellular vesicle circulation.

Abstract Background Retinal ganglion cell (RGCs) loss underlies several retinal degenerative diseases, including Glaucoma and NF1-OPG. RGCs are essential cells in the visual pathway. These cells transmit the signal gathered from the retinal photoreceptors to the brain via the optic nerve and loss of these cells leads to permanent loss of vision. Presently there is no treatment, however, in the last decade cell replacement has shown potential to restore vision in these conditions. Materials and Methods In this study, we have established protocol with a dose dependent response differentiating porcine retinal progenitors (pRPCs) into retinal ganglion cells (RGC) with DAPT and Forskolin treatments. Cells were initially treated with a known concentration of DAPT and Forskolin that has been widely used to culture RGCs. Results We identify the optimal concentration and time course that yields the highest expression of RGCs, pRPCs were cultured for 4 weeks in 25 different concentrations of small molecules. At week 2 and 3 approximately 40% of the pRPCs population expressed the neuronal marker TUJ1 and RGCs markers such as RBPMS and Thy1.1. Differentiated cells showed the lowest proliferative index as indicated by Ki-67 expression. Conclusion This data demonstrates that specific concentrations of DAPT and Forskolin can induce RPCs to undergo differentiation into RGCs linage.