United States

### Background
Prostate-specific membrane antigen positron emission tomography/computerized tomography (PSMA PET/CT) has demonstrated high sensitivity for prostate cancer (PCa) metastases, changing the manner in which PCa is managed. This study aims to report PSMA PET/CT data alongside multiparametric mRI workup and pathological reports from ultrasound/MRI biopsy (fBx) as a gold standard in patients cared for in the VCU Health System. 

### Methods
A retrospective analysis of 765 records of patients who received fBx from January 2022 through December 2024 was conducted. Inclusion criteria involved patients who underwent PSMA PET/CT in initial planning (newly diagnosed cases). Exclusion criteria involved patients who received prior prostate treatment, including surgery or radiation. Data recorded from chart review included age, PSA, Prostate Imaging Reporting &amp; Data System (PI-RADS) scores, fBx Gleason Score (GS), and prostate volume. Additionally, the presence of metastasis and how this altered their treatment plan as evidenced by PSMA PET/CT was also distinguished. There were 177 patients with complete data available for analysis. Statistical analysis was performed with GraphPad.

### Results
PSMA PET/CT found 36 patients to be positive for metastatic disease, while 141 were negative. Of those that presented with evidence of metastasis, 27 patients changed their initial treatment plan based on their PSMA PET/CT (75%), compared to 69 patients that presented without metastatic lesions (48.9%). Meanwhile, 9 patients with metastatic involvement as evidenced by PSMA PET/CT did not change their initial treatment regimen (25%), while 72 patients without evidence of metastasis did not (51.1%) The average age of patients included in this study was 68.9 (± 8.61) years. Other descriptive statistics showed an average fBx GS of 7.84 (± 0.97), average PI-RADS of 4.75 (± 0.56), and average prostate volume of 44.65 mL (± 23.49). Lastly, average PSA at time of diagnosis for those with metastasis was 97.13 ng/mL (± 224.53) compared to 23.002 ng/mL (± 52.67) for those without metastasis (p &lt; 0.0406).

### Conclusion
PSMA PET/CT is a valuable imaging modality that not only helps to visualize possible metastatic lesions within patients with prostate cancer, but also alters clinical management in a large proportion of patients in our hospital. Further studies and investigation into the broader utilization of PSMA PET/CT nationwide would prove beneficial.

2025 AMA Research Challenge – Member Premier Access

Characterizing the impact of PSMA PET/CT in the detection and treatment of prostate cancer in the VCU Health System

### Background
Prostate-specific membrane antigen positron emission tomography/computerized tomography (PSMA PET/CT) has demonstrated high sensitivity for prostate cancer (PCa) metastases, changing the manner in which PCa is managed. This study aims to report PSMA PET/CT data alongside multiparametric mRI workup and pathological reports from ultrasound/MRI biopsy (fBx) as a gold standard in patients cared for in the VCU Health System. 

### Methods
A retrospective analysis of 765 records of patients who received fBx from January 2022 through December 2024 was conducted. Inclusion criteria involved patients who underwent PSMA PET/CT in initial planning (newly diagnosed cases). Exclusion criteria involved patients who received prior prostate treatment, including surgery or radiation. Data recorded from chart review included age, PSA, Prostate Imaging Reporting & Data System (PI-RADS) scores, fBx Gleason Score (GS), and prostate volume. Additionally, the presence of metastasis and how this altered their treatment plan as evidenced by PSMA PET/CT was also distinguished. There were 177 patients with complete data available for analysis. Statistical analysis was performed with GraphPad.

### Results
PSMA PET/CT found 36 patients to be positive for metastatic disease, while 141 were negative. Of those that presented with evidence of metastasis, 27 patients changed their initial treatment plan based on their PSMA PET/CT (75%), compared to 69 patients that presented without metastatic lesions (48.9%). Meanwhile, 9 patients with metastatic involvement as evidenced by PSMA PET/CT did not change their initial treatment regimen (25%), while 72 patients without evidence of metastasis did not (51.1%) The average age of patients included in this study was 68.9 (± 8.61) years. Other descriptive statistics showed an average fBx GS of 7.84 (± 0.97), average PI-RADS of 4.75 (± 0.56), and average prostate volume of 44.65 mL (± 23.49). Lastly, average PSA at time of diagnosis for those with metastasis was 97.13 ng/mL (± 224.53) compared to 23.002 ng/mL (± 52.67) for those without metastasis (p < 0.0406).

### Conclusion
PSMA PET/CT is a valuable imaging modality that not only helps to visualize possible metastatic lesions within patients with prostate cancer, but also alters clinical management in a large proportion of patients in our hospital. Further studies and investigation into the broader utilization of PSMA PET/CT nationwide would prove beneficial.

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### Background
Lyme arthritis (LA) is a late-stage manifestation of Lyme disease characterized by joint swelling and pain. LA’s clinical presentation mimics other pathologies such as septic arthritis (SA) and toxic synovitis (TS). Despite their similar presentations, the necessary treatments vary. LA is treated medically, septic arthritis surgically, and TS resolves with conservative therapy. The similar clinical presentations of these pathologies can lead to misdiagnosis, subjecting patients to unnecessary interventions, and prolonged hospitalizations. 
The state of West Virginia has suffered an exponential increase in Lyme disease (LD) over the last decade. The CDC defines high-incidence states as those having an annual incidence of ≥10 confirmed LD cases per 100,000 for three reporting years. Over the span of this study, West Virginia averaged 40.3 cases per 100,000. 
The purpose of this study was to conduct a retrospective review of pediatric patients that presented to our health system with concern for joint infection/inflammation to identify physical examination and laboratory findings that may differentiate between LA, SA, and TS.

### Methods
Pediatric patients were selected for the study based on ICD-9/10 codes suggestive of an infectious/inflammatory/Lyme-related process. The initial group was filtered down to patients who had undergone testing for an infectious process. This group was then manually reviewed, and each patient was assigned to a diagnostic category. Relevant patient information was extracted from their charts. Continuous data were summarized with simple numerical summaries and categorical data as counts and proportions.

### Results
506 patients were analyzed in this study. Subgroup analysis focused on LA, SA, and TS. Patients with LA had the highest proportion of joint swelling, followed by SA. Pain with short arc motion was most prevalent in the SA group and they were least likely to bear weight. LA favored the knee, TS the hip and SA the knee and hip however other joints were also involved. SA presented with the highest CRP, ESR, WBC, %neutrophils, and cell count values. TS had the lowest elevation in CRP, ESR, %neutrophils, and cell count. TS had the highest %lymphocyte and LA the highest platelet count.

### Conclusion
As Lyme disease continues to spread, clinicians will increasingly encounter patients with LA. Clinicians must differentiate between LA and similar pathologies to ensure appropriate treatment and avoid unnecessary interventions. Key differentiating variables, such as anatomic location, CRP, and ESR, can aid in diagnosis, though there are limitations. Clinicians can use this
information to guide treatment decisions for these patients.


Differentiating the Clinical & Laboratory Presentations of Lyme Arthritis, Septic Arthritis, & Toxic Synovitis

South Korea’s healthcare system is internationally recognized for its accessibility and efficiency; however, beneath this success lies an emergency care crisis marked by widespread hospital refusals of critical patients—a phenomenon known as “ER ping-pong.” Patients, particularly in rural regions, are often transferred between multiple facilities before receiving care, with fatal consequences. Recognizing the absence of national data and clear policy guidance, this study sought to quantify provincial emergency admission refusal rates and evaluate structural reforms to improve equitable access to emergency care.

A PRISMA-guided systematic review was conducted using Covidence to assess 46 peer-reviewed studies on emergency access policies across OECD nations. This was combined with quantitative analysis of South Korea’s 2023–2024 national emergency transfer data, made available through the Ministry of Health and Welfare (MOHW) and the Korean Society of Emergency Medicine (KSEM). Provincial refusal rates were estimated and compared with policy frameworks from the United States (Emergency Medical Treatment and Labor Act, EMTALA) and Germany (Sozialgesetzbuch V and Leitstelle dispatch systems).

Findings reveal that refusal rates range from 30% in Seoul to nearly 98% in North Gyeongsang, with rural provinces experiencing rates more than double those of urban centers. Most refusals cited limited ICU capacity or specialist coverage as primary causes. Comparative analysis demonstrated that regions with integrated referral databases, legal stabilization mandates, and regionalized workforce incentives experience significantly lower refusal rates.

This research proposes a multi-tiered reform model for South Korea, including a Standardized Emergency Referral and Triage Protocol (SERTP), expansion of tele-emergency consultation hubs, and a national integrated emergency operations platform, to reduce refusals by an estimated 60% within a decade. These policy addendums provide an actionable blueprint for improving emergency equity and sustainability within South Korea’s universal health system.

Policy Addendums to Resolve South Korea’s Emergency Room Admission Crisis

### Background
As the first applied motor task to develop, assessment of head and trunk control in infants may provide valuable insight into potential developmental delays. While electromyography (EMG) is the gold standard for assessing neuromuscular function, its use in infants is limited due to their size, difficulty establishing normative values, and lack of standard protocols. Existing research in infants largely focuses on discrete tasks in advanced postures, with few studying spontaneous movements or proximal muscle activity. This study aimed to assess the feasibility of using surface EMG during prone play and to identify potential movement biomarkers associated with delayed postural control in young infants. 

### Methods
This pilot study involved five infants aged 3-6 months (mean age = 4.61 months). Subjects played in the prone position while wearing wireless surface EMG sensors (Delsys) based on SENIAM guidelines. Bilateral recordings were taken from muscles involved in proximal control: upper trapezius, lower trapezius, and triceps. Functional motor performance was assessed using the Alberta Infant Motor Scale (AIMS) percentiles. Raw EMG signals were processed in MATLAB®. The metrics analyzed were mean RMS amplitudes (mV), bilateral symmetry index ratios (> or < 1 indicating asymmetry), and onset of activation (s). Association between EMG metrics and AIMS percentile was analyzed using Spearman correlations.

### Results
EMG data was successfully collected for all five infants. There was no significant correlation between AIMS percentile and EMG metrics collected, but interesting trends were observed. Infants in lower percentiles showed greater upper (r= -0.7) and lower trapezius (r= -0.7) activation and overall unbalanced recruitment between muscle groups compared to infants in higher percentiles. Average muscle onset times across all subjects were: lower trapezius (1.3s), upper trapezius (1.6s), and triceps (3.9s). Symmetry indices varied across participants, with the lower trapezius showing the most consistent symmetry (0.88), compared to upper trapezius (1.22) and triceps (1.56). Lower AIMS percentiles were generally associated with greater asymmetry.

### Conclusion
Surface EMG is feasible during prone play. We identified movement biomarkers that may offer early insight into atypical postural control strategies in at-risk infants. Infants with lower motor performance demonstrated more proximal motor unit recruitment, indicating less stability. These infants may be more likely to have asymmetrical recruitment than higher performing infants. Larger sampled studies are needed to further develop the baseline of expected muscle activation patterns. Increased knowledge in this understudied area could aid in identifying potential developmental delays at an earlier age.

Assessment of Proximal Postural Control Biomarkers During Spontaneous Play in Infants Using Surface EMG

### Background
Neurologic illnesses often involve high symptom burden, complex prognostication, and emotionally charged decision-making, making palliative care (PC) skills essential for neurologists. Despite national recommendations, formal training in neuropalliative care remains limited in neurology residencies and fellowships. A prior needs assessment revealed that only 4.5% of U.S. neurocritical care (NCC) fellowship programs had faculty with formal PC training, and many fellows felt underprepared in communication, prognostication, and discussions surrounding life-sustaining treatments. The objective of this study was to develop a novel, scalable palliative care curriculum for neurocritical care fellows that is being expanded across neurology residency and subspecialty fellowship training programs. We aimed to assess feasibility, learner engagement, and changes in self-reported preparedness in serious illness communication using pre/post surveys, performance-based simulation assessments, and qualitative interviews.

### Methods
We piloted a novel, interdisciplinary neuropalliative care curriculum for NCC fellows over three academic years (2022–2025), combining asynchronous didactics from the Education in Palliative and End-of-Life Care for Neurology (EPEC-N) curriculum with in-person, simulation-based training using VitalTalk techniques. Simulation scenarios were collaboratively developed and vetted by neurocritical care and palliative care faculty to reflect realistic, frequently encountered clinical experiences. Building on the success of this pilot, we are expanding the curriculum to neurology residency and fellowship training across subspecialties. Using Kern’s Six-Step Curriculum Development framework and situated learning theory, we created subspecialty-specific simulation scenarios (e.g., stroke, epilepsy, movement disorders), integrated into an academic neurology curriculum. A prospective, mixed-methods study was used to evaluate the program’s feasibility, effectiveness, and impact.

### Results
Preliminary results from the pilot program demonstrate high learner engagement and improved self-reported preparedness in serious illness communication. Fellows reported increased confidence in delivering bad news, discussing prognosis and code status, and managing emotional conversations with families. Program directors identified key competencies, including prognostication (95%), delivering bad news (85%), and discussions on withdrawal of care (80%), as educational priorities. Evaluation tools included pre/post surveys, simulation performance assessments, and qualitative interviews. Data collection and analysis are ongoing.

### Conclusion
This curriculum represents a novel approach to neuropalliative care education by integrating simulation-based training into neurology and subspecialty education for interdisciplinary teams. Grounded in evidence-based communication frameworks and tailored to subspecialty practice, the program addresses a critical training gap in neurology education. Preliminary outcomes support its feasibility and impact on learner confidence and skill development. Future directions include national expansion and integration across neurology subspecialties to establish a sustainable, standardized model for neuropalliative care education.


Development, Implementation and Evaluation of a Novel Neuropalliative Care Education Curriculum

### Background
The majority of people living with HIV globally are women and girls. Although combined antiretroviral therapy (cART) can drastically improve prognosis and prevent vertical transmission, its off-target metabolic and systemic effects in pregnant women and women of childbearing age remain understudied. Concurrent exposure to ubiquitous environmental pollutants, such as per and polyfluoroalkyl substances (PFAS), may interact with cART to impact maternal health, given their shared potential for mitochondrial and cardiotoxicity. Our broader project investigates the combined structural, functional, and molecular impact of cART and a legacy PFAS compound, perfluorooctanesulfonic acid (PFOS), on cardiometabolic outcomes in a rat model. Here, we present findings from non-pregnant animals, which will later be compared to pregnant counterparts.

### Methods
Female Sprague-Dawley rats were treated with cART (abacavir/dolutegravir/lamivudine; Triumeq at 300/25/150 mg/kg/day) or vehicle (aqueous methylcellulose/Tween 80). Animals also received either PFOS-contaminated water, directly mimicking concentrations measured in a North Carolina community, or vehicle (reverse osmosis-filtered water). They received echocardiography and electrocardiography immediately prior to tissue harvest at study day (SD) 27 or SD 49. Tissue and plasma samples underwent PFAS quantification, pathological evaluation, qPCR, and mitochondrial function analysis.

### Results
The non-pregnant cohort demonstrated perturbations in several structural and functional parameters by exposure group. Echocardiography revealed shortened ejection times at SD 26 in the cART group compared to controls, indicating early systolic dysfunction. Rats in the PFOS + cART group showed slower isovolumetric relaxation times and increased ejection fractions at SD 26. Structural changes included increased interventricular septal thickness, posterior wall thickness, and left ventricular (LV) mass in the cART group. At SD 48, persistent hypertrophy was demonstrated by increased LV mass and heart weight:tibia length ratios for the cART-exposed rats. Surprisingly, cART alone did not impact mitochondrial copy number. However, both the PFOS and PFOS + cART groups showed reduced mitochondrial copy numbers and increased deletions, indicating alterations to the mitochondrial genome.

### Conclusion
These findings suggest that cART exposure, particularly in combination with PFOS, alters cardiac structure and function, with early systolic impairment followed by compensatory adaptations. Despite partial recovery over time, persistent hypertrophy suggests cardiac remodeling. Ongoing analysis of pregnant animals will determine whether the added physiologic strain of pregnancy sensitizes the cardiovascular system of the animals. This work highlights a need to evaluate the cardiovascular safety of cART in the context of common environmental exposures, particularly in women of reproductive age.

Cardiac Phenotype and Mitochondrial Effects of Antiretroviral Therapy and PFAS Exposures

### Background
Glioblastoma (GBM) is a highly aggressive malignancy with limited therapeutic advancements despite extensive research. Receptor tyrosine kinase (RTK) amplification, a common feature in glioblastoma (GBM), drives tumor growth/recurrence, therapeutic resistance, and invasion, making RTKs attractive therapeutic targets. Currently, Bevacizumab, the only FDA-approved RTK inhibitor in GBM, improves progression-free survival in patients through vascular normalization. This study evaluates the efficacy of cabozantinib (XL184), a multi-kinase inhibitor targeting various RTKs such as VEGFR2, MET, and AXL, in GBM cancer stem cells (CSCs) and patient-derived xenograft (PDX) models, with a focus on uncovering resistance mechanisms and identifying opportunities for combination therapies. 

### Methods
Nine genomically diverse GBM CSCs were treated with XL184 to assess drug sensitivity. Reverse Phase Protein Array (RPPA) Proteomics at 24h and 72h was used to evaluate changes in key signaling pathways along with a focused analysis of RTK signaling changes. CSC-derived PDX from two proneural (HF2587, HF3016) and one classical (HF2927) GBM were treated with XL184 monotherapy and in combination with TMZ. Tumor growth and survival were monitored. Immunohistochemical (IHC) analysis of CD31 expression to assess angiogenesis was performed with high-resolution microscopy. 

### Results
GBM CSCs exhibited a wide range of sensitivity to XL184 (IC50: 2μM - 34μM). Proteomics showed XL184-mediated inhibition of phospho-VEGFR2, AKT, and ERK, while sub-lethal XL184 doses upregulated phospho-MET and STAT3, suggesting adaptive resistance mechanisms. In vivo, HF2587 (p=0.00022, n>18) and HF2927 (p=0.1847, n>12) xenografts responded to XL184 monotherapy, and in combination with TMZ, with reduced tumor growth and improved survival while HF3016 (p=0.061, n>16) was resistant to monotherapy. HF2587 and HF2927 demonstrated a reduction in vessel density, measured by CD31 expression, compared to normal brain. The non-responsive HF3016 exhibited increased angiogenesis following therapy, a potential indicator of treatment resistance. 

### Conclusion
Insights into CSC signaling and tumor-specific dependencies provide a foundation for biomarker-driven, personalized therapeutic approaches in GBM. The vasculature results, assessed through CD31 immunohistochemistry, demonstrate the modulation of angiogenesis and tumor blood supply by XL184, which is crucial for understanding its therapeutic effects on GBM and the tumor microenvironment. These findings highlight the heterogeneity of XL184 response in GBM and the potential for combination strategies to overcome resistance. Moreover, this work builds on limitations of existing RTK therapies (bevacizumab), offering multi-targeted inhibition with microenvironmental modulation. Additionally, it contributes valuable preclinical evidence supporting a rational framework for designing more targeted, effective interventions in a highly treatment-refractory cancer.

Testing the Efficacy of Cabozantinib (XL-184) to Treat Glioblastoma (GBM)

### Background
Frequent drought has heightened nutritional concerns in Ethiopia. This study assesses the prevalence and risk factors of severe food insecurity and poor food consumption in Productive Safety Net Programme households in drought-prone East Hararghe, Ethiopia.

### Methods
Data was from the USAID-funded Resilience Food Security Activity baseline survey in East Hararghe, Ethiopia. Severe food insecurity (n=4628; multivariate n=4335) was defined as Food Insecurity Experience Scale (>7) and poor food consumption (n=4554; multivariate n=4268) was defined as Food Consumption Score (<21). Logistic regression identified adjusted odds ratio and 95% confidence interval of risk and protective factors.

### Results
Severe food insecurity prevalence was 77.79% and poor food consumption was 69.74%. Risk factors for severe food insecurity included women/girls aged 15-19 (1.79; 1.36-2.34), current pregnancy (1.52; 1.17-1.96), history of pregnancy (3.46; 2.76-4.33), cash-earning work (1.35; 1.12-1.61), daily-per-capita food consumption <1.61USD (2.98; 1.91-4.66), crop-planting (1.67; 1.31-2.13), and handwashing facilities (3.83; 1.92-7.63); protective factors included two or more children-under-5 (0.72; 0.60-0.88), raising livestock/crops to sell (0.50; 0.42-0.60), and raising oxen (0.34; 0.26-0.45). Risk factors for poor food consumption included woman/girl (1.44; 1.15-1.81) and household-head no education (1.46; 1.18-1.79), daily-per-capita food consumption <1.61USD (4.01; 2.58-6.21), and financial services (2.10; 1.69-2.59); protective factors included women/girls aged 15-19 (0.59; 0.46-0.76) and 30-49 (0.76; 0.63-0.91), two or more children-under-5 (0.77; 0.64-0.91), current pregnancy (0.57; 0.47-0.70), history of pregnancy (0.70; 0.55-0.89), crop-planting (0.57; 0.44-0.75), raising livestock/crops to sell (0.40; 0.34-0.48) and raising oxen (0.68; 0.52-0.90). 

### Conclusion
With high severe food insecurity and poor food consumption prevalence, we identified vulnerable households in drought emergencies as those with pregnant/lactating women, mothers, adolescent girls/women, no education and/or livestock. Notably, households where the WRA respondent was pregnant, had been pregnant, was 15-19 years old, and/or planted crops were more likely to experience severe food insecurity, yet less likely to have poor food consumption. Our findings highlight a conceptual distinction, that women/girls’ pregnancy and/or age status may influence household perception and/or definitions of food security despite adequate consumption. The strongest predictor of severe food insecurity and poor food consumption was daily-per-capita food consumption costs <1.61 USD, and the strongest protectors were households that raised livestock/crops to sell and/or raised oxen. Although crop production appeared insufficient to maintain food security, this may improve food consumption score by increased diversity of nutrient intake. The dual burden of food insecurity and poor consumption threatens current and future generations, and data-driven action can help progress towards the goal of zero hunger in Ethiopia.

Prevalence and risk factors for severe food insecurity and poor food consumption during a drought emergency in Ethiopia

### Background
Preadipocytes play a central role in skin immune defense. In response to Staphylococcus aureus infection, they rapidly proliferate, leading to dermal fat expansion. When adipogenesis is impaired, susceptibility to infection increases. During differentiation, preadipocytes and adipocytes produce cathelicidin (CRAMP in mice, CAMP in humans), a vital antimicrobial peptide whose expression is further upregulated by S. aureus exposure. CRAMP accumulates through both neutrophil recruitment and de novo synthesis by preadipocytes, strengthening the skin’s antimicrobial response.

### Methods
C57BL/6 mice were intradermally injected with S. aureus USA300. Preadipocytes were isolated from digested dorsal skin, cultured, and induced to differentiate. Oil Red O staining confirmed adipogenesis. Skin sections underwent H&E and immunofluorescence staining for Pref-1, CRAMP, and Ly6G. Gene expression (Camp, Adipoq, inflammatory markers) was measured by qPCR; protein levels were assessed via Western blotting. CRAMP function was evaluated using neutralizing
antibodies in vitro and in vivo. Bacterial burden was determined through CFU counts. Data were analyzed using unpaired t-tests or ANOVA (p < 0.05).

### Results
In vivo, infection triggered visible skin lesions and dermal fat layer expansion within 24–72 hours. Histology and immunofluorescence confirmed increased Pref-1⁺ preadipocytes in infected dermis. Isolated preadipocytes differentiated into lipid-rich adipocytes in vitro. qPCR showed significant upregulation of Camp and Adipoq in infected tissue; Western blotting confirmed increased CRAMP protein levels. CRAMP localized to both Pref-1⁺ cells and Ly6G⁺ neutrophils, indicating dual
sources. Neutralizing CRAMP resulted in larger lesions and higher bacterial burden (p < 0.01), while in vitro inhibition reduced bactericidal activity. Mice with stronger preadipocyte responses exhibited lower CFUs, linking preadipocyte activation to bacterial clearance.

### Conclusion
Preadipocytes play a critical role in the skin’s immune defense against S. aureus. Beyond serving as adipocyte precursors, they actively contribute to antimicrobial defense through CRAMP production and support of neutrophil recruitment. Their activation and differentiation are essential for limiting infection and promoting bacterial clearance. These findings position preadipocytes as immunologically active cells and potential therapeutic targets to enhance host resistance to bacterial skin infections.


Preadipocytes as Key Players in Skin Immune Defense Against Staphylococcus aureus Infection

### Background
Racial disparities in Alzheimer’s disease and related dementias (ADRD) are well-documented, yet the contribution of neighborhood socioeconomic context to these disparities among breast cancer survivors remains unclear. The Index of Concentration at the Extremes (ICE) captures neighborhood-level deprivation and affluence, potentially mediating racial differences in ADRD diagnosis. Understanding the role of neighborhood-level factors may explain mechanisms behind these disparities.

### Objective
To assess whether neighborhood-level socioeconomic conditions, measured by ICE, mediate the racial disparity in ADRD diagnosis among older female breast cancer survivors.

### Methods
We analyzed SEER-Medicare linked data from 17,741 women aged 65 and older diagnosed with breast cancer (2007–2009) with up to 10 years of follow-up. ADRD diagnosis was identified through diagnostic codes. We conducted causal mediation analysis to estimate the average causal mediation effect (ACME), total effect, and proportion mediated by ICE on the association between race (Black vs. White) and ADRD diagnosis, adjusting for age, comorbidities using the Charlson Comorbidity Index (CCI), treatment type, and neighborhood -level poverty indicator.

### Results
Race was significantly associated with ADRD diagnosis (total effect estimate = 0.052, 95% CI 0.028–0.077, p < 0.001). ICE significantly mediated this association, with an ACME of 0.049 (95% CI 0.035–0.063, p < 0.001), explaining approximately 93% of the total effect. This strongly suggests that neighborhood-level deprivation/advantage (ICE) explains most of the racial disparity in ADRD diagnoses in the dataset, after adjusting for age, neighborhood-level poverty indicator, treatment type, and CCI. The mediation findings remained robust in sensitivity analyses adjusting for additional covariates.

### Conclusion
Neighborhood-level deprivation, as captured by ICE, substantially mediates racial disparities in ADRD diagnosis among breast cancer survivors, highlighting the critical role of social
determinants and structural inequities on cognitive health outcomes. These findings suggest that beyond biological factors, such as hormone-modulating therapy-related cognitive effects, social context profoundly shapes racial disparities in cognitive health outcomes. This study shows the importance of neighborhood socioeconomic context in understanding racial disparities in ADRD diagnosis among breast cancer survivors. Further analyses incorporating additional covariates and stratified mediation will clarify the pathways influencing these disparities. Targeted interventions addressing neighborhood disadvantage may be essential for advancing equity in dementia prevention and care.

Neighborhood Socioeconomic Status and Racial Disparities in ADRD in Breast Cancer Survivors

### Background 
Aging confers the most significant risk for dementia, yet the underlying mechanisms remain poorly understood. While the amyloid cascade hypothesis has dominated the field for decades, a large proportion of variance in cognitive impairment remains unexplained by classical proteinopathies. Thromboinflammation—a vascular and immune signaling axis involving brain barrier dysfunction and protein extravasation—may represent an upstream initiator of neuronal vulnerability that precedes amyloid pathology. Recent work by our colleague shows fibrinogen, a peripheral coagulation protein, to exhibit one of the earliest age-related increases in cerebrospinal fluid, yet its role as a driver of brain degeneration in living humans remains unexplored. 

### Methods 
We present the most comprehensive investigation of thromboinflammation as a driver of degenerative brain changes in aging living humans. We integrated high-dimensional cerebrospinal fluid proteomics (~7,000 proteins) across 1,655 individuals from three independent cohorts with single-cell transcriptomics, brain imaging, and cognitive data. Using CSF fibrinogen levels as a quantifiable marker of brain barrier dysfunction, we employed systematic mediation analysis to identify molecular pathways linking vascular compromise to synaptic vulnerability in amyloid-negative, cognitively typical older adults, with validation across independent cohorts and testing in amyloid-positive states. 

### Results
We identified a reproducible molecular network linking brain barrier dysfunction to white matter degeneration, synaptic loss, and cognitive slowing—well before amyloid pathology appears. Fibrinogen emerged as a central hub of brain aging biology, with higher CSF levels significantly associating with elevated markers of synaptic dysfunction (pTau181, neurogranin, GAP43, SNAP25) and cognitive slowing in amyloid-negative adults. We identified 53 validated molecular mediators of fibrinogen's neurotoxic effects, enriched in neurovascular unit cells and demonstrating coordinated dysregulation of angiogenesis, fibrosis, and immune signaling. These mediator signatures correlated with compromised white matter integrity in tracts critical for cognitive processing speed. Critically, fibrinogen associated with tauopathy independent of amyloid buildup, and these associations persisted robustly in amyloid-positive individuals while remaining independent of amyloid burden, demonstrating relevance across the neurodegeneration spectrum. 

### Conclusion 
Our findings offer a paradigm-shifting answer to why aging confers powerful dementia risk by positioning thromboinflammation as an upstream initiator of neuronal vulnerability that challenges the prevailing temporal hierarchy of neurodegeneration. This work reframes vascular disease from comorbidity to causality, introducing a vascular-centered model of brain aging that bypasses classical proteinopathy models. The identified molecular mediators provide an upstream, druggable axis with immediate implications for biomarker development, clinical trial stratification, and brain healthspan-preserving interventions across the aging spectrum. "

A proteomic signature of vascular disease is associated with the aging brain's vulnerability to degeneration preceding accumulation of amyloid pathology

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