United States

### Introduction
Accelerated brain aging can lead to cognitive decline, as morphological changes occur in the brain. We hypothesize that lower social engagement and higher geriatric depression in older adults pose a greater risk for accelerated brain aging and thus a higher brain age gap (BAG).

### Methods
Participants in the AGES study, aged 66 to 96, were surveyed on depression and social engagement at baseline and again after approximately five years. The Geriatric Depression Scale and monthly leisure activity participation were used as measures. Depression scores of 0–5 were categorized as normal/low risk, and scores of 6–15 as moderate/severe risk. For social engagement, each point on the leisure variable corresponded to four leisure activities per month; then categorized into four groups: None (0), Low (0–2), Medium (2–5), and High (5+). Each measure was analyzed using BAG as the dependent variable. 

### Results
Depression predicted higher BAG at baseline (P&lt; 0.013), follow up (P &lt;0.01) and longitudinally (P&lt; 0.005). Leisure was associated with higher BAG at baseline (P &lt; 0.002), however not at follow-up. A post hoc Tukey test confirmed individuals in the &quot;None&quot; category differed significantly from those in the other leisure groups (P &lt; 0.01). No significance was found longitudinally for leisure on BAG.

### Conclusion
Depression has a significant impact on BAG in healthy older adults. Social engagement significantly influences brain aging at baseline, though this effect is not sustained over time; suggesting early intervention may be protective.


AMA Research Challenge 2025 

Psychosocial Predictors of Accelerated Brain Aging: A Study of Depression and Social Engagement in Healthy Older Adults

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ACL 2022

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### Introduction
Accelerated brain aging can lead to cognitive decline, as morphological changes occur in the brain. We hypothesize that lower social engagement and higher geriatric depression in older adults pose a greater risk for accelerated brain aging and thus a higher brain age gap (BAG).

### Methods
Participants in the AGES study, aged 66 to 96, were surveyed on depression and social engagement at baseline and again after approximately five years. The Geriatric Depression Scale and monthly leisure activity participation were used as measures. Depression scores of 0–5 were categorized as normal/low risk, and scores of 6–15 as moderate/severe risk. For social engagement, each point on the leisure variable corresponded to four leisure activities per month; then categorized into four groups: None (0), Low (0–2), Medium (2–5), and High (5+). Each measure was analyzed using BAG as the dependent variable. 

### Results
Depression predicted higher BAG at baseline (P< 0.013), follow up (P <0.01) and longitudinally (P< 0.005). Leisure was associated with higher BAG at baseline (P < 0.002), however not at follow-up. A post hoc Tukey test confirmed individuals in the "None" category differed significantly from those in the other leisure groups (P < 0.01). No significance was found longitudinally for leisure on BAG.

### Conclusion
Depression has a significant impact on BAG in healthy older adults. Social engagement significantly influences brain aging at baseline, though this effect is not sustained over time; suggesting early intervention may be protective.


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### Background
Anxiety disorders affect one in three people worldwide, yet current treatments, centered on brain neurotransmitters, fail many patients and often cause undesirable side effects. While these therapies act centrally, growing evidence suggests that emotional states are also influenced by signals from peripheral organs. We identify asprosin, a fasting-induced hormone secreted by adipose tissue, as a direct endocrine driver of anxiety. Asprosin crosses the blood-brain barrier and binds protein tyrosine phosphatase receptor delta (PTPRD), a neuronal receptor enriched in hippocampal neurons and genetically linked to anxiety risk. This work defines the first hormone–receptor circuit linking energy state to emotional behavior, one that is peripheral, mechanistically distinct, and therapeutically actionable.

### Methods
We manipulated the asprosin-Ptprd signaling axis in mice using five approaches: (1) viral overexpression of asprosin (Ad5-FBN1 or AAV8-asprosin); (2) peripheral neutralization with an anti-asprosin monoclonal antibody (mAb); (3) genetic loss-of-function models, including Fbn1NPS/+ mice (asprosin-deficient) and Ptprd+/- mice; (4) pharmacologic inhibition using 7-butoxy-illudalic acid (7-BIA), a selective Ptprd inhibitor; and (5) stereotactic Cre-mediated deletion of Ptprd in specific brain regions. Anxiety-like behavior was quantified across well-validated assays: open field, light–dark, and elevated plus maze, under both basal conditions and chronic stress paradigms. Asprosin binding was assessed using alkaline phosphatase-tagged ligands, and whole-cell patch-clamp electrophysiology evaluated neuronal excitability.

### Results
Reducing asprosin signaling through - genetic asprosin deficiency, pharmacologic sequestration with a monoclonal antibody, partial Ptprd loss and pharmacologic Ptprd inhibition - reduced baseline anxiety-like behavior across multiple assays. Conversely, elevating asprosin with viral overexpression increased baseline anxiety. When anxiety was induced using chronic stress paradigms, circulating asprosin surged, found to be driven by catecholamine release. Mechanistically, recombinant asprosin depolarized ventral CA1 pyramidal neurons and doubled their firing rate via a Ptprd-dependent, synapse-independent process. Region-specific deletion studies confirmed that Ptprd in ventral CA1 was necessary for stress-induced anxiety, identifying this subregion as the key node mediating asprosin-driven emotional changes.

### Conclusion
This study reframes anxiety as a hormonally gated state regulated by a defined adipose-to-brain endocrine axis. The asprosin–Ptprd pathway operates independently of classical neurotransmission, offering dual therapeutic targets: a peripheral hormone and its central receptor. Our findings highlight the body’s peripheral pathways as an untapped source of insight and innovation in neuropsychiatric disease. It establishes the mechanistic foundation for the first hormone-based anxiolytic, a strategy that is translatable, safe, and designed to reach the millions of patients for whom current drugs fall short.


A hormone circuit from fat to hippocampus drives a novel, druggable anxiety pathway

Vaccination remains one of the most effective strategies of modern medicine in controlling infectious disease outbreaks. However, numerous case reports have described ocular adverse events following administration of COVID-19, influenza, and herpes zoster vaccines. These manifestations range from mild inflammation to vision-threatening complications, including Graves’ orbitopathy, uveitis, optic neuropathies, acute retinal necrosis, retinal vascular occlusions, corneal graft rejection, and cranial nerve palsies. This systematic review was conducted according to PRISMA 2020 guidelines and included 143 studies retrieved from PubMed in February 2025. Articles were screened and categorized by anatomical location and type of ocular manifestation. Many cases resolved with corticosteroids, antivirals, or conservative management; however, a subset of patients experienced persistent vision loss, structural damage, or recurrence. While most cases showed a temporal association rather than definitive causality, proposed mechanisms include molecular mimicry, bystander T-cell activation, and dysregulated cytokine responses in genetically predisposed individuals. Although rare, clinicians should remain aware of these pos-sible adverse effects and monitor high-risk patients accordingly.

A systematic review of vaccine-associated ocular adverse events: Patterns, Pathogenesis, and Public Health Considerations

Background
Hematopoietic stem cells (HSCs) sustain lifelong blood and immune cell supply through their ability to self-renew and generate diverse cell lineages, beginning with the HSCs and progressing through multipotent progenitors (MPPs) and increasingly lineage-restricted intermediates. These transitions remain incompletely understood, particularly the mechanism involved in lineage priming and the timing within a spectrum of MPPs. IKAROS (Ikzf1), a zinc-finger DNA binding factor, is first expressed in the HSC and increases with lymphoid lineage specification. IKAROS proteins interact with chromatin remodeling complexes during lymphoid lineage differentiation, yet their precise role at the onset of hematopoiesis is not defined. We investigated whether IKAROS alters chromatin structure and organization in the nuclear space and how it influences lineage potentials of the earliest progenitors. 

Methods
With IKAROS-knockout and wild-type mice, we used fluorescence-activated cell sorting (FACS) to obtain early progenitor subsets from the bone marrow, including the long- and short-term HSCs, MPPs (from LSK: lineage-/loSca1+c-Kit+), and erythro-myeloid restricted precursors (from LK: lineage-/loSca1+c-Kit-). We performed single-cell RNA sequencing (scRNAseq), single-cell Multiome (scRNAseq and scATACseq/Assay for Transposase-Accessible Chromatin), and Hi-C assays to assess gene expression, chromatin accessibility at regulatory sites (e.g. enhancers and promoters), and 3D genome organization, respectively. Novel bioinformatic approaches were developed to integrate transcriptomic and epigenetic data.

Results
In IKAROS-deficient LSK populations, lymphoid-primed progenitors (CD150-CD48+Flt3+IL7R+) were markedly reduced, while myeloid-primed subsets (CD150-CD48+CD16/32+) were increased. Meanwhile, heterozygous deletions demonstrated haploinsufficiency with similar but milder effects, providing a working model for IKAROS as a molecular regulator for hemo-lymphopoiesis.

With our scMultiome and scRNAseq datasets, integration of MPPs based solely on scATACseq data yielded clearer cell type segregation than scRNAseq or integrated analyses (scRNAseq and scATACseq), reflecting a greater significance of chromatin accessibility over gene expression at this cell stage. Loss of IKAROS led to decreased accessibility at lymphoid-associated transcription factor binding sites and increased accessibility at myeloid sites, suggesting a shift in lineage potential driven by chromatin-level regulation and potential antagonism with myeloid programs. Ongoing 3C (Hi-C) studies examine the influence of IKAROS on lineage-specific 3D organization that appears to precede lineage restrictions.

Conclusion
Our study shows that IKAROS, a key regulator of early hemo-lymphopoiesis, is required for chromatin access at lineage-specific regulatory sites and three-dimensional genome organization. These findings highlight the importance of epigenetic mechanisms in governing early blood cell fates and suggest a new model of blood cell differentiation through lineage-specific epigenetic programs operating prior to lineage specification.


IKAROS-based chromatin regulation on early hematopoietic lineage trajectories

### Background
Despite the success of antiviral treatment for HIV-1 infection, people living with HIV (PWH) have persistent gastrointestinal inflammation which contributes to continued comorbidity. HIV-1 associated gut pathogenesis includes both structural and immunological changes resulting in local inflammation and increased bacterial translocation. In our prior study we observed that in PWH, higher frequencies of a serine protease called Granzyme B (GZB) were associated with greater abundance of potentially inflammatory bacteria. Moreover, enteric bacteria were shown to induce higher frequencies of GZB expressing gut CD4+ T cells. GZB is classically utilized by cytotoxic T cells to induce apoptosis but has additional functions of interest including inflammatory cytokine activation. Currently, significant gaps remain in how GZB affects inflammatory cytokine profiles in the gut. Here we aim to assess how GZB produced in response to enteric bacteria exposure drives gut associated inflammatory cytokine production in a gastrointestinal in vitro model.

### Methods
We utilized our previously established human gut lamina propria mononuclear cell (LPMCs) in-vitro model. LPMCs were stimulated with commensal Escherichia coli (E. coli) lysate in the presence of a cell permeable GZB inhibitor or extracellular anti-GZB blocking antibody. Levels of TNFα, IL-1α, IL-18, and IL-1β, which have been previously shown to be produced in response to exposure to granzymes, were measured by ELISA. Measurement after 48 hours was determined to be the optimal observation time. 

### Results
Exposure of LPMC’s to E. coli for 48 hours induced significantly higher levels of secreted GZB with measurable activity compared to LPMCs that were not exposed to E. coli. Secreted TNFα, IL-1α, IL-18, and IL-1β, and cell associated IL-1α were also increased. In the presence of cell permeable GZB inhibitor, intracellular and extracellular GZB activity was significantly inhibited, and cytokine production decreased to levels similar to unstimulated conditions. In the presence of extracellular anti-GZB blocking antibody, only extracellular GZB activity was significantly inhibited, however E. coli stimulated cytokine production was not reduced.

### Conclusion
Simultaneously blocking of both extracellular and intracellular GZB activity in response to E. coli stimulation of LPMCs in-vitro resulted in decreased production of inflammatory cytokines while inhibition of exclusively extracellular GZB did not attenuate production. This suggests that intracellular GZB, either produced or taken up by immune cell populations is the primary driver for enhancing microbe-induced inflammatory cytokine production within gut LPMCs. Treatments targeting intracellular Granzyme B function could be used in the future to better prevent and control inflammatory gut conditions.


The Role of Granzyme B on Inflammatory Cytokine Production by Human Gut Lamina Propria Mononuclear Cells

### Background
Ulcerative colitis (UC) is a chronic, relapsing and remitting immune mediated condition requiring long-term therapy. Moderate to severe disease is managed using steroids, sulfasalazine, thiopurines, biologicals (anti-tumor necrosis factor, anti-integrins and anti-interleukin IL 12/23) and small molecules (Janus kinase inhibitors, sphingosine-1-receptor modulators). Ustekinumab (UST) is a IgG1 monoclonal antibody acting on IL 12/23 recently authorized to treat moderate to severe UC that is not responsive to other biologic medicines. There remains an unmet need in management of UC despite growing availability of therapeutic agents. Current treatment algorithms use a standard approach for all patients, but targeted therapies are required for better outcomes. This study's goal is to determine the safety and effectiveness of UST therapy in moderate to severe UC. We also noted the clinical and endoscopic improvement with maintenance of clinical and steroid free remission across multiple databases to strengthen reproducibility. 

### Methods
This systematic review followed the Preferred Reporting Items for Systematic Review and Meta Analysis (PRISMA) 2020 guidelines. Relevant literature was retrieved from PubMed, PubMed Central, Cochrane Library, Science Direct and Google Scholar. Articles published in English within the last 5 years (2020 to 2025) were included. Quality assessment tools were applied to ensure the quality of evidence-based medicine that will be utilized to develop a conclusion and direct future review. 

### Results
The studies analysed showed a superiority of UST in induction and maintenance of remission in active, difficult to treat UC. Our findings indicate that reduction in Mayo score with improvement in C-reactive protein (CRP) and fecal calprotectin (fCal) can be used to assess a reduction in inflammatory burden and response to treatment. Histo-endoscopic mucosal healing also provides a long-term clinical assessment of reduction in disease burden. All safety events which led to drug discontinuation and malignancy were similar for UST therapy and placebo. 

### Conclusion
UST as a treatment option for moderate to severe UC can provide an alternative avenue in development of patient centric targeted therapies. Further research targets should include formulation of a standard dosing regimen and evaluation of long-term safety profile of the drug. There also remains an unmet need in comparative analysis of UST treatment with other available therapeutic options, especially biologic agents and effect on extra-intestinal manifestations.

Efficacy and Safety of Ustekinumab in Treatment of Ulcerative Colitis: A Systematic Review

### Background
African American women experience higher breast cancer mortality and are more frequently diagnosed with aggressive tumor subtypes compared to other racial and ethnic groups. Despite advances in cancer genomics, the absence of population-specific diagnostic tools contributes to persistent disparities in clinical outcomes. Circular RNAs (circRNAs) are stable, non-coding RNAs with emerging potential as non-invasive biomarkers in cancer detection and profiling. This study aims to identify tumor-associated circRNAs in African American breast cancer patients using a circRNA analysis pipeline. Discovering circRNA biomarkers specific to African American patients is a key step toward advancing precision oncology and achieving equity in cancer diagnostics and treatment.

### Methods
Serum samples from 35 breast cancer patients and 15 healthy female controls were obtained from the Prisma Health Cancer Institute Biorepository. Following cell-free RNA isolation and circRNA enrichment, full-length circRNA libraries were prepared using the circFL-seq protocol and sequenced using Oxford Nanopore long-read technology. After basecalling and adapter trimming, reads were aligned to the GRCh38 human reference genome. Differential expression analysis using edgeR identified circRNAs associated with cancer status. Expression profiles were compared to public circRNA datasets from individuals of European ancestry to assess race-associated differences. 

### Results
Differential gene expression analysis identified 11 circRNAs associated with race, 27 with tumor status, and 4 showing a race-tumor interaction, revealing race-specific differences in breast tumor biology. Among these, circRNAs from REG3A, a secreted lectin involved in inflammatory signaling and epithelial-mesenchymal transition (EMT), were upregulated in African-American tumors. REG3A drives tumor progression through STAT3 and mTOR activation. Similarly, circRNAs from REG1A, a secreted lectin involved in immune modulation, were upregulated and are linked to tumor progression and resistance to immune surveillance. CircRNAs from CTNNA2, a cell adhesion gene, were upregulated, indicating altered adhesion signaling and a potential regulatory role in tumor progression. In addition, AC011754.1, a long noncoding RNA was also differentially expressed and may contribute to race-specific tumor regulation.

### Conclusion
This study identifies a race-specific gene expression profile in African-American breast cancer involving dysregulation of immune and epithelial pathways. CircRNAs from REG1A, REG3A, CTNNA2, and AC011754.1 may act as molecular drivers of aggressive tumor phenotypes and serve as race-conscious diagnostic and therapeutic biomarkers. CircRNAs regulate gene expression by blocking microRNAs, limiting their ability to suppress targets involved in proliferation, invasion, and immune response. These findings highlight a critical gap in cancer genomics and underscores the need to integrate race-informed molecular data into precision oncology to drive equitable biomarker discovery and improve outcomes in underrepresented populations.

Uncovering Race-Specific CircRNA Biomarkers in African American Breast Cancer Patients

### Background
Prior studies suggest that patient-reported allergies (PRAs) may correlate with poorer surgical outcomes, including greater psychological distress, increased postoperative pain, and reduced mobility in orthopedic populations. However, the relationship between PRAs and outcomes after lumbar interbody fusion (LIF) remains unclear. This study evaluates the association between PRAs and postoperative pain, mobility, and functional improvement following LIF. 

### Methods
A retrospective review was conducted for patients who underwent elective LIF for degenerative spine pathology between November 2019 and January 2023. Patients were grouped by the presence of PRAs (n=242) or no known drug allergies (NKDA; n=83). Baseline demographics, psychiatric history, preoperative opioid use, and reported allergies—categorized as medical or environmental—were recorded. Primary outcomes included one-year changes in Patient-Reported Outcomes Measurement Information System (PROMIS) overall and mental health scores, and Oswestry Disability Index (ODI). Secondary outcomes included postoperative visual analog scale (VAS) pain scores and Activity Measure for Post-Acute Care (AMPAC) scores. Associations were assessed using univariate and multivariate regression models. Receiver operating characteristic (ROC) analysis evaluated the predictive value of PRA count for achieving minimal clinically important difference (MCID) in PROMIS and ODI scores. 

### Results
Patients with PRAs were more likely to be female (57%, p=0.002) and have psychiatric histories (0.9 ± 1.1 vs. 0.7 ± 1.0, p=0.02). PRA patients had greater improvement in PROMIS overall (11.5 ± 12.8 vs. 6.7 ± 10.2, p=0.048) and mental health scores (13.5 ± 18.7 vs. 6.6 ± 14.6, p=0.026). ODI improvement did not differ significantly. PRA count was not associated with VAS, AMPAC, or MCID achievement in PROMIS or ODI. Increasing fusion levels negatively impacted AMPAC scores (-1.096 per level fused, p<0.05) but not VAS. Psychiatric history reduced odds of achieving MCID for PROMIS physical and ODI scores, while preoperative opioid use had no impact on pain, mobility, or MCID outcomes. ROC analysis showed poor predictive value of PRA count for MCID (AUC <0.600).

### Conclusion
PRAs were not associated with worse outcomes following LIF. Instead, patients with PRAs experienced greater improvements in PROMIS, particularly in mental health. PRA count did not affect postoperative pain, mobility, or MCID achievement. These findings suggest that the presence or quantity of PRAs should not deter clinicians from recommending lumbar fusion surgery.


The Influence of Patient-Reported Allergies on Postoperative Mobility, Pain, and Long-Term Outcomes following Lumbar Interbody Fusion

### Background
Deep vein thrombosis (DVT) is a major healthcare burden with significant morbidity and mortality. Anticoagulation therapy is the current treatment of choice. However, this approach can sometimes lead to only partial resolution, allowing for thrombus organization. This can result in the development of post-thrombotic syndrome (PTS), a sequela of chronic DVT that includes symptoms such as limb pain, cramping, edema, stasis dermatitis, or even venous ulceration. There is currently no effective treatment for PTS, and as a consequence, it can become a lifelong problem that significantly impairs a patient’s quality of life. Here, we examine whether the local delivery of non-thermal irreversible electroporation (IRE) can impede thrombus organization and fibrosis by achieving cellular ablation and allowing time for natural thrombus resolution to occur.

### Methods
In vitro and ex vivo methods were utilized to investigate the thermal and ablative effects of IRE. A microfluidics device was seeded with neutrophils and endothelial cells to determine voltage thresholds for selective, safe ablation. Rheological analysis was conducted to evaluate the impact of IRE on blood coagulation. Porcine blood clots, generated in a syringe model, were used to assess red blood cell and fibrin architecture following IRE treatment. These models guided the optimization of IRE parameters for subsequent in vivo studies. Calibrated pulsed electric fields were then delivered locally using a tweezer-style electrode system to target acute DVT lesions induced in the femoral veins of rat and swine models. Animals were monitored for three or seven days post-treatment. Histological, immunohistochemical, and molecular analyses were performed to assess thrombus organization, vessel integrity, luminal cellularity, cytokine expression, and inflammatory or fibrotic markers following IRE-treatment.

### Results
IRE-treated blood demonstrated preserved clotting kinetics and minimal hemolysis, supporting the safety and efficacy of blood cell ablation using IRE. Histologic analysis of IRE-treated animal femoral vein segments revealed significantly reduced cellular proliferation, collagen deposition, and angiogenesis. IRE-treated tissues also exhibited lower expression of pro-fibrotic, pro-thrombogenic, and pro-coagulant markers compared to controls. Across both models, vessel wall thickness and luminal architecture remained intact, confirming the non-destructive nature of IRE, with no evidence of structural wall damage or aneurysm formation.

### Conclusion
These findings suggest that IRE may serve as a promising adjunctive therapy to anticoagulation by preventing the organization of acute thrombi into chronic DVT. This could ultimately reduce the incidence of post-thrombotic syndrome and improve long-term patient outcomes.

Non-Thermal Pulsed Electric Field Ablation of Blood Clots Reduces Fibrosis

### Background
The dorsal nerve of the clitoris (DNC) and dorsal nerve of the penis (DNP) are vital to sexual sensation, erectile function, and reproduction; however, these nerves are frequently subject to injury from tumor resections, aesthetic procedures, and female genital mutilation (FGM). Concerning FGM alone, the World Health Organization notes that approximately 6.5 million females in Europe and North America, and over 230 million females worldwide, are living with FGM. Nerve coaptation or neurotization may be warranted to restore function after dorsal nerve injury. Accordingly, close nerve size-matching is necessary to minimize the risk of fascicle loss and neuroma formation. However, little is known about the diameter of the dorsal nerves. Therefore, this study aims to describe the diameter of the DNC and DNP through gross anatomical assessment.

### Methods
A total of 101 donor bodies (51 female, 50 male) were dissected to visualize the paired dorsal nerves as they traveled inferior to the pubic bone. Dorsal nerves were photographed, and images were screened for quality. A total of 199 dorsal nerves met criteria for measurement. Nerve diameter was measured via ImageJ software. Sexual dimorphism and asymmetry were assessed by unpaired and paired t-tests, respectively. Correlation between nerve diameter and age was evaluated via Pearson’s test.

### Results
Nerve diameters were normally distributed in both females and males. The DNC diameter averaged 2.9±0.6mm (mean ± SD) (min=1.5mm; max=4.9mm; range=3.4mm) and the DNP averaged 3.6±0.6mm (min=1.6mm; max=5.1mm; range=3.5mm). Significant differences were found between sexes (t=7.647; p<.00001); however, within-sex, no significant side-to-side difference was identified (females: t=0.6278; p=0.5332) (males: t=1.206; p=0.2337). Age was not correlated with nerve size (r=0.17; p=0.248). Although generally symmetrical, bilateral asymmetry of up to 1.7mm in females and 1.5mm in males was noted.

### Conclusion
This report details DNC and DNP size from the largest sample population to date. Surgeons should anticipate dorsal nerve size differences between sexes, wide size variation within-sex, and possible bilateral asymmetry. These results, assessed alongside other reports, suggest that commonly grafted nerves are generally more size-compatible with the DNC as compared to the relatively larger DNP. Regarding unilateral graft procedures, such as an ilioinguinal nerve coaptation, asymmetry may influence the side upon which the procedure is performed. The results of this study will improve genital reconstruction procedures and guide optimal nerve graft selection for dorsal nerve repair.

Dorsal Nerve of the Clitoris and Dorsal Nerve of the Penis Size: Implications for Reconstruction

### Background
Executive dysfunction in Alzheimer’s disease (AD)—often linked to early frontal lobe involvement—can impair real-world behavior even during the mildest stages, well before memory loss becomes disabling. Yet many clinicians delay supervision planning until patients reach moderate dementia, overlooking critical safety risks in earlier phases. High misdiagnosis rates in early dementia further delay appropriate intervention, especially when subtle but meaningful executive deficits go undetected. Although tools like the Mini-Mental State Examination and Trails B assess cognition, none directly evaluate whether a patient can live safely without supervision. The Test of Executive Functioning in an Emergency (TEFE), developed at UNT Health, addresses this gap. TEFE is a brief, performance-based tool that assesses whether patients can complete real-world safety tasks—such as dialing 911, stating their address, and contacting a family member. This study examined whether TEFE performance—particularly on the 911 task—can differentiate mild AD from vascular dementia (VD), mixed dementia, and mild cognitive impairment (MCI), while also identifying clinically meaningful patterns of executive dysfunction across diagnoses.

### Methods
We retrospectively reviewed records of 908 patients from a university-affiliated memory clinic. Diagnoses included mild AD, mild VD, mild mixed dementia, mild cognitive impairment (MCI), or normal cognition. TEFE includes six items total: three knowledge-based questions (e.g., “What number do you call in an emergency?”) and three behavioral tasks (e.g., dialing 911). Total TEFE scores were compared across diagnostic groups using Kruskal-Wallis and chi-square tests. We further analyzed failure rates on the 911 knowledge and behavioral items individually and used contingency tables to examine disconnects between knowing and performing the task (e.g., correctly identifying 911 but failing to dial it).

### Results
TEFE performance significantly differed by diagnosis (H = 215.73, p < 1×10−44). AD patients scored significantly lower than MCI or cognitively normal groups. Nearly one-quarter of AD patients failed the 911 knowledge (24.1%) and behavioral (27.0%) tasks. In contrast, 911 failure was rare in non-AD groups—under 6% in MCI and 0% in normal controls. Chi-square tests confirmed AD patients were significantly more likely to fail 911 tasks than VD or mixed dementia (p < 0.001). Only AD patients exhibited a disconnect of identifying 911 but failing to dial it.

### Conclusion
TEFE effectively detects executive dysfunction and emergency readiness deficits in mild AD, identifying safety risks not captured by traditional cognitive screens. By revealing real-world impairments before more obvious cognitive decline, TEFE offers actionable insight that help guide earlier interventions in dementia care.

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