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Amyloid-targeting therapies (ATTs), including donanemab and lecanemab, are FDA-approved disease-modifying therapies for Alzheimer’s disease in the mild cognitive impairment or mild dementia stages. Early initiation is important for optimal outcomes. This article summarizes practical strategies for implementing ATTs in clinical practice, focusing on leadership alignment and infrastructure development, as well as patient identification, diagnosis, and monitoring protocols. Key recommendations include establishing appropriate patient tracking systems, infusion and imaging protocols, and interprofessional collaboration. Approaches for systematic patient routing (e.g., hub-and-spoke models, fast-track mechanisms) and biomarker-integrated assessments are critical to facilitating timely diagnosis and treatment. Education for patients, care partners, and clinicians is crucial for managing the risks associated with amyloid-related imaging abnormalities. Successful ATT implementation requires coordinated systems, timely diagnosis, and robust safety monitoring. These measures can enable frameworks for ATT administration to optimize outcomes for patients, care partners, and health systems.

Abstract The liver is organized into tightly regulated zones with distinct metabolic functions but zonation erodes with age. Cellular senescence contributes to aging and liver diseases, however, its impact on aging biology is ill-defined. As part of The Cellular Senescence Network Consortium, we used multiple spatial transcriptomics approaches (GeoMx, Visium, CosMx) with snRNA-seq to profile senescence signatures, zonation markers, and metabolic pathways in livers from wild-type (WT) mice of multiple ages. We observed a loss of canonical zone signatures in aged mouse livers characterized by “expansion” of midlobular (zone 2) marker gene expression, accompanied by diminished expression of zone 3 marker genes by middle-age (18 months), indicative of loss of cell identity. Multiple analytic approaches identified distinct age-, zone- and sex-specific senescence signatures, which were significantly associated with zonation markers changes. This was recapitulated in Ercc1 mutant models of accelerated senescence, supporting a causal role of senescent cells in liver aging. A “no-zone” hepatocyte-like cluster expanded with age and with the strongest Senescence-Associated Secretory Phenotype (SASP) profile. Gene expression profiles from senescent hepatocytes implicate decreased WNT signaling and increased BMP as contributing to age-related loss of zonation. Together, these data elucidate the role of senescent cells in driving aging biology in non-diseased liver through disruption of cell:cell signaling and the loss of metabolic and cell identity gene expression necessary for hepatocyte function.

PURPOSE Cancer care capacity in sub-Saharan Africa (SSA) is constrained by late diagnosis and limited treatment access. Few funding mechanisms support innovative, locally led programs to address these challenges. A collaborative initiative was developed to strengthen oncology care through quality improvement (QI) projects. MATERIALS AND METHODS The program was developed by Global Bridges Oncology (GBO) at Mayo Clinic, Pfizer Global Medical Grants, and the African Organisation for Research and Training in Cancer. A committee composed primarily of African oncology experts guided the process. An RFP was disseminated across SSA in English, French, and Portuguese, inviting applications to improve diagnostic and therapeutic cancer care. Applications underwent a structured, two-stage review, with GBO providing technical support, expert guidance, and training resources. RESULTS The RFP generated 218 applications reflecting strong demand for oncology QI funding in SSA. After review, 17 projects representing 10 African countries were selected and awarded $1.1 million USD. Funded initiatives reflected four themes: oncology training and clinical practice improvements, early detection and accurate diagnostics, pediatric cancer care, and oncology nursing and palliative medicine. As of March 2026, 11 (65%) of 17 projects are complete, with 4,565 health care professionals engaged through direct training, conference dissemination, system adoption, and sensitization activities, and program-supported services were delivered to more than 47,300 patients. CONCLUSION This initiative demonstrates the feasibility of a competitive, regionally guided grant program to strengthen cancer care capacity. Early implementation outcomes, including measurable improvements in diagnostic delay, treatment adherence, and care network expansion, confirm that locally led QI initiatives can generate meaningful results across diverse institutional settings. By centering African leadership and supporting diverse QI projects, it advances equitable access to funding, capacity building, and sustainability planning.

Abstract To report clinical and functional outcomes, including patient-reported outcome measures (PROMs), complications, reoperation rates, and arthritic progression in patients who sustained a knee dislocation (KD) type V fracture dislocation at minimum 2-year follow-up. A retrospective review from a prospectively collected database was performed to identify all patients with a KD type V fracture dislocation between 2001 and 2022 at a single institution. Patient demographics, pre- and postoperative clinical examination findings, intraoperative details, and postoperative complication rates were obtained from medical records. PROMs, including Visual Analog Scale (VAS), Tegner Activity Scale, Lysholm score, and International Knee Documentation Committee Subjective (IKDC) score were analyzed. A total of 11 patients (mean age: 33.9 ± 7.6, mean BMI: 33.5 ± 6.4 kg/m2) were included with a mean follow-up of 6.4 ± 5.4 years. Seven patients (64%) had a tibial plateau fracture involving the weight-bearing surface. Four patients (36%) had a concomitant nerve injury, one patient (9%) had a concomitant vascular injury, three patients (27%) had a concomitant cartilage injury (ICRS grade 3 + ), and seven patients (64%) had a concomitant meniscus injury. In all, 10 patients (82%) underwent fracture fixation. The mean postoperative Kellgren-Lawrence (KL) grade was 3.0 ± 1.0. Postoperative PROMs included VAS at rest of 2.0 ± 2.3, VAS with activity of 3.3 ± 3.2, IKDC of 68.3 ± 22.1, Lysholm of 79.0 ± 23.6, and Tegner of 4.3 ± 1.7. Nine patients (83%) experienced a complication, with four (36%) patients requiring a subsequent reoperation. Patients with a KD V fracture dislocation who underwent surgical management demonstrated high complication and reoperation rates with advanced radiographic evidence of osteoarthritis but ultimately satisfactory functional outcomes at mid-term follow-up. These findings underscore the complexity of KD V injuries and the importance of early recognition, multidisciplinary surgical planning, and patient counseling regarding the prolonged recovery and likelihood of residual symptoms. Level of evidence is IV—retrospective case series.

Abstract Introduction Microglia are the resident immune cells of the central nervous system, classically studied for neuroinflammation. A specialized subset, vessel-associated microglia (VAM), whose somata directly contact capillaries, constitutes ∼30% of microglia in the naïve brain. Only recently have VAM been recognized as regulators of brain circulation, influencing blood—brain barrier (BBB) integrity and cerebral blood flow, yet their role in pathological vascular remodeling remains unclear. To address this gap, we used glioma models in which peritumoral capillaries undergo extensive vascular remodeling and BBB dysfunction, providing an in vivo platform to probe capillary vulnerability and vascular stability. Methods We combined pharmacological microglial ablation via CSF1R inhibitors with longitudinal in vivo two-photon imaging to visualize microglia—capillary interactions. Behavioral testing, survival analysis, T2-weighted MRI, and immunostaining were performed in parallel. Results Over half of the microglia-depleted mice developed acute, lethal paralysis by 15 days, whereas control tumor-bearing mice remained asymptomatic and survived 30 days. MRI revealed large intracranial hemorrhages and severe edema, and two-photon imaging showed nodular, abnormal vasculature at paralysis onset. The peritumoral region contained dense capillary networks with a marked increase in VAMs (>60%). Genetic lineage tracing confirmed these cells were microglia, exhibiting elongated, vessel-wrapping morphology, also observed following single-vessel photothrombosis and consistent with a response to capillary injury. Conclusion Our findings identify VAMs as critical neurovascular stabilizers that preserve peritumoral capillary integrity and prevent lethal hemorrhage in glioma, highlighting an essential immune role in brain vascular homeostasis. Notably, intracranial hemorrhage has repeatedly emerged across clinical trials of CSF1R inhibitors, raising important safety considerations for CSF1R-targeted therapies in the diseased brain. Funding Source AHA postdoc fellowship (26POST1560008) (J.Z.) Topic Categories Neuroimmunology (NEUR)

Abstract Introduction Cutaneous lichen planus (cLP) is a T cell—mediated skin disease in which cytotoxic CD8+ T cells attack basal keratinocytes at the dermo-epidermal junction. While studies have characterized T cell subsets in lesional tissue, circulating immune signatures in cLP are incompletely defined. We performed deep immunophenotyping of circulating T-cell subsets to map systemic alterations in cLP patients vs healthy controls. Methods We included 12 treatment-refractory cLP patients (mean age 63.6 ± 13.6 years) and 2 healthy controls (37.5 ± 10.6 years). Whole blood was profiled for 27 markers by flow cytometry. Sequential gating: singlets → live → CD3+ T cells → CD4+/CD8+/γδ; FOXP3+ Tregs were defined within CD4+. Frequencies were expressed as % of the immediate parent population. Group comparisons used two-tailed exact Mann—Whitney tests with Hodges—Lehmann median differences. Results Across frozen specimens, cLP patients exhibited broad T-cell activation. Proliferation increased in CD4 (Ki67+, p < 0.05), CD8 (6.785% vs 0.885%; Δ=5.90; p < 0.05), and Tregs (83.0% vs 46.8%; Δ=34.1; p < 0.05). Intracellular CTLA-4 was higher on CD4 (11.07% vs 2.615%; Δ=8.45; p < 0.05), CD8 (21.05% vs 9.30%; Δ=11.6; p < 0.05), and γδ T cells (47.20% vs 24.45%; Δ=22.75; p < 0.05). CXCL13+ cells expanded in CD4 (28.20% vs 12.45%; Δ=15.5; p < 0.05), CD8 (18.05% vs 3.595%; Δ=14.46; p < 0.05), γδ (2.805% vs 0.465%; Δ=2.285; p < 0.05), and Tregs (7.56% vs 1.17%; Δ=6.39; p < 0.05). Tregs were TBET-high (78.75% vs 61.55%; Δ=17.3; p < 0.05); GITR+ Tregs trended up (p = 0.1978). Conclusion cLP blood displays a CXCL13+, proliferative T-cell signature with increased intracellular CTLA-4 across CD4, CD8, γδ, and Treg compartments. CXCL13 elevation aligns with lesion-level literature implicating CXCL13+ CD8+ T cells that are suppressed in JAK-STAT therapy responders. Tregs exhibit a GITR upregulated, Th1-like phenotype that suggests loss of suppressive capacity, warranting further investigation on whether Treg dysfunction plays a causative role in cLP. Funding Source N/A Topic Categories Immune Mechanisms of Human Disease (HUM)

Abstract Introduction Bone marrow (BM) is the primary immune organ responsible for stem cell maintenance. Neurotropic infections elicit sequestration of T cells within the BM. Changes of the BM niche during brain viral infections are unknown. Intracranial infection with the neurotropic Theiler’s Murine Encephalomyelitis Virus (TMEV) in C57BL/6 mouse is cleared by 30 days due to generation of an antigen-specific CD8 T cell response. Methods We used brain viral infection and injury models to test T cell responses against brain antigens in the bone marrow. Results We determined that 1-10% of CD8 T cells present in the sternal, femoral, and cranial BM were virus antigen-specific 7 days post intracranial infection. Over 70% of these CD8 T cells were tissue resident. We determined antigen-specific CD8 T cells were generated in the BM within 4 days of infection. Continuous treatment with FTY720, which sequesters T cells outside of the blood, did not eliminate antigen-specific CD8 T cells in any BM compartment. CD8 T cells in the BM established durable memory populations and were reactivated upon antigen reencounter. In the memory phase (200 days post brain TMEV infection), bone marrow resident CD8 T cell could be reactivated upon cognate peptide delivery. Such reactivation of antigen specific memory CD8 T cells caused an increase in lineage-, Sca-1+, ckit + (LSK) cells in the BM in a CD8 dependent manner. Similarly, injection of the model antigen AF488-conjugated OVA mixed with Poly IC into the brain recapitulated antigen specific CD8 T cell generation within the bone marrow and further demonstrated the antigen presenting cell involved in the response to be a CD103 expressing myeloid DC. We conclude that viral infections and inflammatory stimulation in the brain induce in situ effector and memory T cell responses within the BM which is associated with significant stem cell dysregulation. Conclusion Our data paves the way for crucial studies of BM resident antigen-specific CD8 T cells in health and disease. Funding Source NIH K99/R00 Topic Categories Viral Immunology (VIR)

Abstract Introduction Peripheral nervous system innervation of various organs has been associated with the development and maintenance of the immune system. Yet, the intricate details of thymic innervation remain less well-studied. Interestingly, various neurological insults including brain tumors, and neurotropic infections have been shown to have profound impacts on thymic size and cellularity and T cell development. Methods We used flow cytometry, confocal microscopy, neuro tracers, and genetic knockout mice to evaluate developing T cell-neuron interactions within the thymus. Results We have identified neuronal cell bodies within the thymus. These cells express neuronal markers such as NeuN and tyrosine hydroxylase and lack TEC identifiers, such as EpCAM, UEA-1, and Ly51. Thymic neurons can be infected with a neurotropic rabies vector, further cementing their neuronal identity. Considering the thymus consists mostly of T cells, we next investigated a potential interaction between T cells and thymic neurons. Interestingly, loss of T cell development results in a lack of thymic neuron development indicating T cell-neuron coregulation during development. However, thymic neurons can be recovered following a bone marrow transplant, suggesting the provision of a differentiation and/or survival signal for neurons provided by the developing T cells. Using knockout mice lacking the T cell lineage at various stages of development, we determined that TCR beta selection is required for the development of thymic neurons. Finally, we determined that a lack of transition from DN4 to DP severely diminishes the development of thymic neurons. Analysis of the publicly available bulk RNA-sequencing data comparing thymic DP to DN cell populations indicates the potential involvement of IL34 in neuronal development in the thymus. Conclusion We describe a novel population of neuronal cells within the thymus that interact with developing thymocytes to establish optimal thymic architecture. Funding Source NIH K99/R00 Topic Categories Neuroimmunology (NEUR)

Abstract Introduction Glioblastoma is an aggressive brain cancer with poor prognosis for which immunotherapies have fared poorly. In part, the failure in immunotherapies is attributed to the existence of severe local and systemic immunosuppression in GBM. We determined that majority of hallmark features of systemic immunosuppression were linked to immunosuppressive factors in serum. Our data indicate that serum of glioma-bearing mice harbors heightened levels of cell-free DNA (CF-DNA). Methods We evaluated the extent to which CF-DNA contributes to systemic T cell dysfunction in mouse models of GBM and GBM patient plasma samples. Results We determined that majority of hallmark features of systemic immunosuppression were linked to immunosuppressive factors in serum. Our data indicate that serum of glioma-bearing mice harbors heightened levels of cell-free DNA (CF-DNA). Removing CF-DNA from serum improves T cell responses while adding CF-DNA derived from serum of glioma-bearing subjects to healthy T cells directly inhibits their functions. We have also verified that CF-DNA is detectible in sera isolated from patients with GBM. When compared to healthy controls, GBM patients have higher quantities of CF-DNA is their plasma. Interestingly, our preliminary data implicates neutrophil NETosis as the likely source of CF-DNA in sera of GBM patients. Moreover, we stained GBM tumor sections with citrullinated histone 3 (cit-H3) to evaluate the extent of NETosis in GBM patients. We determined evidence of significant NETosis within patient brain tumors. Systemic immunosuppression is detrimental to the success of immune-modulating therapies and patient survival. By identifying and removing the source of systemic immunosuppression, we will enhance immune responses against the tumor likely improving patient survival. Conclusion Glioblastoma causes immune suppression outside of the brain via the released CF-DNA. Our studies in GBM patients and mouse models help develop strategies to reverse immune dysfunction and improve outcomes. Funding Source NIH K99/R00 Topic Categories Immune Mechanisms of Human Disease (HUM)

Abstract Introduction The H-2Db class I restricted CD8 T cell response is critical for clearance of neurotropic Theiler’s virus encephalomyelitis virus (TMEV) infection. However, the key central nervous system cell types required to present H-2Db for CD8 T cell trafficking and expansion in the brain are not known. Mural cells are a critical cellular component of the neurovascular unit for maintaining vascular integrity which also express MHC class I molecules. However, the importance of mural cell antigen-restricted engagement by CD8 T cells has not been investigated. Methods To determine the function of mural cell MHC Class I antigen presentation, we crossed the Pdgfrβ-creERT2 mouse to our novel H-2Db LoxP mouse developed by our laboratory. This transgenic mouse approach enabled us to target mural cells during neuroinflammation. Results We observed robust knockdown of H-2Db on mural cells during acute TMEV infection. Conditional H-2Db knockdown in mural cells resulted in increased brain infiltration of CD8 T cells specific to the immunodominant Db:VP2 121-130 epitope of TMEV, demonstrating an important role of mural cells for immune cell recruitment. Conclusion To our knowledge, this is the first study demonstrating MHC class I antigen presentation by mural cells impacts CD8 T cell recruitment during neuroinflammation. Funding Source R01-NS103212, T32-AI170478 Topic Categories Neuroimmunology (NEUR)