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Background This study examines the geographic representativeness of people who smoke, among newly registered users of a free digital tobacco cessation program (‘EX’). Methods User-provided ZIP codes from EX® Program registrants were mapped to Rural Urban Continuum Codes (RUCC). Reach Ratios (ReRas) and 95% confidence intervals were used to determine the extent to which geographic representation in EX was proportionate to their representation in the national population of individuals who smoke, as obtained from the United States National Survey of Drug Use and Health (2018-2020). Under- and overrepresentation was demonstrated by ReRas <1 or >1, respectively. Joinpoint regression analyses were used to determine significant changes in trend for ReRas from 2013 to 2020. Results Individuals who reported smoking residing in nonmetro rural areas were significantly overrepresented in 2018 [ReRa = 1.18 (95% CI: 1.15, 1.23)], 2019 [ReRa = 1.10 (95% CI: 1.07, 1.13)], and 2020 [ReRa = 1.10 (95% CI: 1.06, 1.13)]. Individuals who reported smoking from small metro areas were also overrepresented from 2018 to 2020 [ReRas = 1.09 (95% CI: 1.06, 1.11); 1.06 (95% CI: 1.04, 1.08), and 1.05 (95% CI: 1.03, 1.08), respectively] and individuals who reported smoking from large metro areas were underrepresented during the same time frame [ReRas = 0.87 (95% CI: 0.85, 0.89); 0.92 (95% CI: 0.91, 0.94), and 0.93 (95% CI: 0.91, 0.94), respectively]. ReRas for large metro areas decreased from 2013 to 2018 (annual percentage change, APC = −3.26; 95% CI: −6.69, −1.91). ReRas for non-metro areas increased from 2013 to 2017 (APC = 7.35; 95% CI: 4.10, 17.63). Conclusions Results suggest that individuals that smoke residing in nonmetro rural areas and small metro areas are proportionally reached by a digital tobacco cessation program. However, there continues to be an underrepresentation of individuals who smoke from large metro areas, which warrants further study.

Abstract Background We have recently reported that wolframin‐1‐expressing (Wfs1 + ) pyramidal neurons in the entorhinal cortex layer II (ECII) that projects to the CA1 propagate phosphorylated tau (pTau) via the temporoammonic pathway, mimicking early stages of tau pathology in AD (ECII‐CA1 tau mice). We examined if amyloid pathology and human tau expression with this mouse model may change the character and distribution of tau transfer. Furthermore, using a chemogenetic approach, we aimed to determine the effect of neuronal excitability on tau transfer to the hippocampal regions in mouse brains. Method Cre‐inducible AAV expression P301L tau mutant (AAV‐Flex‐P301Ltau) was injected into the EC II region of APP NL‐G‐F human MAPT double knockin (APP NL‐G‐F : TAUKI) mice crossed with Wfs1‐Cre and Wfs1‐Cre mice at 7 months of age. Tau propagation was evaluated in the hippocampal and cortex regions by immunofluorescence using HT7 (human tau) and AT8 (pS 202 /pT 205 tau) mAbs at one‐ and 3‐months post‐injection. AAV‐Flex‐P301Ltau was co‐injected with Cre‐inducible AAV expressing hM3D(Gq) or hM4D(Gi) DREADD in the ECII in Wfs1‐Cre mice at 4 months of age, followed by subcutaneous infusion of clozapine N ‐oxide or saline via osmotic pumps for 28 days. Immunofluorescence against HT7 mAb was performed at one‐month post‐injection. Result We observed robust HT7 positivity in the CA1 and subiculum in Wfs1‐Cre mice after AAV‐Flex‐P301Ltau injection, although there was little AT8 staining at both one‐ and 3‐month. Interestingly, APP NL‐G‐F :TauKI:Wfs1‐Cre mice showed strong HT7 and AT8 positivity in the subiculum, but not in CA1 at 1‐month. Notably, p ‐tau further advanced into the visual cortex (VC) region at 3‐month in APP NL‐G‐F :TauKI:Wfs1‐Cre mice, while neither HT7 nor AT8 was positive in the VC in Wfs1‐Cre mice. Increased or suppressed neuronal excitability in the medial ECII pyramidal neurons by DREADD approach significantly induced or reduced tau propagation to the CA1 compared to the control group at one‐month post‐injection, respectively. Conclusion Our study demonstrates that APP NL‐G‐F :TAUKI:Wfs1‐Cre mice injected with P301L tau in the ECII recapitulates advanced‐stage AD pathology with amyloid beta navigating tau to the neocortical region and enhancing the maturity of tau pathology. Furthermore, ECII neuronal excitability regulates tau transfer efficiency from the ECII to CA1 region.

Abstract Background Cognitive resilience is the discrepancy in individuals with intermediate to high Alzheimer's disease neuropathologic change (ADNC) and normal cognition. Currently, the role of microglial activation in cognitive resilience is understudied. Method In the MCSA brain bank, high‐cognitively unimpaired (high‐CU) participants were defined as those performing in the upper quartile of their respective age groups based upon antemortem global cognition z‐scores, computed from memory, language, executive function, and visuospatial domain z‐scores. From the high‐CU group ( N = 118, global z‐scores from 1.55 to 1.78), cognitively resilient (CR) individuals were identified as those with intermediate to high ADNC upon neuropathologic evaluation. First, regression models were fit to evaluate global cognition as a function of age, sex, amyloid PET, and microglial‐specific genes of interest, including MS4A gene cluster SNPs. Second, a subset of CR participants was analyzed for postmortem ARM expression in the dorsolateral prefrontal cortex. Single immunohistochemistry was performed on formalin‐fixed, paraffin‐embedded sections using antibodies against beta‐amyloid (6F3D) and CD163 (10D6). Digital image analysis was performed on scanned sections (40x, Leica Aperio GT 450), and ARM (CD163%area) and beta‐amyloid (%area) measurements were obtained using QuPath. Cognitively impaired (CI) control group was matched on age, sex, ADNC level, and APOE4 status. Spearman correlations were performed between postmortem ARM and antemortem MRI, PET, plasma, and global cognition metrics. Result A third (39/118) of high‐CU cases showed intermediate/high ADNC (CR group). Furthermore, 28% of CR individuals harbored an MS4A6A SNP, which showed a protective effect on cognition via amyloid‐PET ( p = 0.043, Figure 1). Moreover, CR individuals harbored significantly higher ARM:amyloid than the CI group ( p <0.001, Figure 2) and fewer neuritic plaques ( p = 0.03, Figure 3). Antemortem white matter hyperintensities and global cognition were significantly correlated to ARM expression (r=0.556 [p=0.042] and r=0.648 [p=0.02], respectively). Conclusion Microglial specific MS4A6A SNP, which modulates microglial activation, was seen in a third of CR individuals. Postmortem analyses in CR individuals revealed increased ARM:amyloid, which was also associated with higher antemortem cognitive performance. These findings underscore the role of microglial activation in cognitive resilience. Future work is needed to investigate microglial protective mechanisms and links between vascular disease and microglial activation.

Abstract Background Hispanic individuals are at a 1.5‐times higher risk for Alzheimer's disease and related dementias yet remain underrepresented in research. Longitudinal Hispanic cohorts provide antemortem biospecimen, cognitive, and epidemiological data, and GWAS/admixture mapping analyses identify Hispanic ancestry as a modifier of Alzheimer's disease‐associated gene expression. Additionally, antemortem‐based studies suggest an altered pathological burden in Hispanic individuals, with neuropathological reports revealing a disproportional anatomy‐dependent burden of Alzheimer's pathologies in Hispanic decedents. Despite these advances, few analyses investigate differential gene expression in dementia from postmortem brain of Hispanic decedents. To address the current knowledge gap, we investigated neuroinflammatory gene expression in Hispanic decedents with single or mixed etiology dementia. Method To quantify gene expression, RNA was extracted from postmortem frontal cortex brain tissue of Hispanic and non‐Hispanic decedents with Alzheimer's disease (AD, n = 6), cerebrovascular disease (CVD, n = 6), or a mixture of the two etiologies (ADCVD, n = 6). Following quality control, extracted RNA was hybridized to the NanoString Human Neuroinflammation panel, and gene expression quantified via SPRINT nCounter. Analysis was completed with NanoString Advanced Analysis criteria via ROSALIND®. Low counts and low background genes were omitted from analysis. Result Comparison of Hispanic decedents with either AD or ADCVD to non‐Hispanic decedents reveals shared pathway enrichment of the Astrocyte Function gene set. Respective to non‐Hispanic decedents, we find two genes in Hispanic AD and seven genes in Hispanic ADCVD that are differentially expressed. Across all samples, gene expression analysis indicates P2RY12, NRP2, PRKACB , and seven other genes are increased at the transcript level in the frontal cortex of Hispanic decedents with CVD when compared to either Hispanic or non‐Hispanic decedents with other etiologies. Conclusion These preliminary findings suggest an ancestry‐ and etiology‐specific transcriptional profile in CVD, and point to few genes modified by ancestry in AD and ADCVD. Ongoing experiments aim to determine differential gene expression relative to pathology, and to develop functional genetic models for screening. Overall, we seek to identify Hispanic ancestry‐ and disease‐specific genes among dementia etiologies as an avenue for precision medicine dementia care among an at‐risk, underrepresented population.

Background and Aims: Hypothermic oxygenated machine perfusion (HOPE) improves outcomes in orthotopic liver transplantation (OLT), but reliance on University of Wisconsin machine perfusion solution (UW-MPS) increases costs and logistical burden. Histidine-tryptophan-ketoglutarate (HTK) has potential as a single-solution alternative for HOPE. This study evaluated the safety and efficacy of HTK versus UW-MPS during HOPE. Methods: A retrospective, propensity score-matched cohort study including 46 patients who received donation after brain death (DBD) grafts that were preserved with HOPE at the Medical University of Vienna between May 2018 and October 2024 was conducted. A total of 23 patients received grafts perfused with HTK; another 23 patients transplanted with organs perfused with UW-MPS were matched based on recipient age and sodium model of end-stage liver disease score, donor age and sex, cold ischemia time, and perfusion time. Postoperative outcomes, perfusion parameters, and cost differences were assessed. Results: The HTK and UW-MPS cohorts demonstrated comparable perfusion dynamics and vascular resistance. While arterial pressure and flow were higher in the UW-MPS group, clinical outcomes—including early allograft dysfunction (47.8% each), ICU stay, and comprehensive complication index—were statistically similar. A trend toward fewer biliary complications (13.0% vs. 30.4%) and reduced hemodialysis requirement (17.4% vs. 30.4%) was observed in the HTK group. Use of HTK reduced perfusion-related costs by approximately EUR 560 per procedure. Conclusion: HTK is a viable alternative to UW-MPS during HOPE in OLT of DBD grafts, offering comparable short-term outcomes and relevant cost savings. Prospective studies are warranted to validate these findings and explore broader applications of single-solution perfusion strategies.

Abstract Background Neuropathologic evaluation is essential for diagnosing and treating dementia, but definitive diagnoses is only available after post‐mortem brain autopsy. Positron emission tomography (PET) offers a potential in vivo proxy for predicting neuropathology. This study proposes a semi‐supervised learning (SSL) model using a single FDG‐PET image to predict underlying neuropathology. Method The SSL model leverages a self‐organized graph structure based on a patient similarity network (PSN) created from 1,495 FDG‐PET images across the aging and neurodegenerative spectrum. Each patient is represented by a node, with edges indicating image similarity derived from principal component analysis features and cosine similarity weights. The PSN structure connects 20 nearest neighbors. Neuropathologic labels were available for 204 autopsied patients. The Poisson Learning Method was employed to propagate labels from these annotated nodes to unlabeled nodes, guided by the PSN structure. FDG‐PET images were collected from clinical and research participants at the Mayo Clinic and processed using an MRI‐free pipeline. Neuropathologic labels were assigned based on widely accepted diagnostic criteria. Leave‐one‐out cross‐validation (LOOCV) was used to assess model performance. Results The confusion matrix demonstrated high accuracy in predicting Alzheimer's disease, frontotemporal lobar degeneration with tau inclusions, and Lewy body disease pathology. A Sankey diagram and label distribution analysis revealed strong correlations between clinical and predicted neuropathologic labels. Conclusion This study highlights the potential of a graph‐based SSL pipeline to predict neuropathological changes using FDG‐PET imaging data, despite limited pathology labels. The findings underscore the value of SSL in bridging the gap between abundant neuroimaging data and scarce neuropathologic labels, contributing to improved dementia diagnosis and understanding.

Abstract Background The locus coeruleus (LC) degenerates early in Alzheimer's disease (AD), with profound volume and neuronal loss. The loss of noradrenergic LC projection neurons results in alterations in attention, memory, and arousal, and constitutes the first site of neurofibrillary tangle accumulation preceding the onset of cognitive symptoms. We sought to investigate the relationship between LC neuronal density and clinical heterogeneity in a neuropathologically‐diagnosed series of AD cases. Methods The FLorida Autopsied Multi‐Ethnic (FLAME) cohort database was queried for neuropathologically‐diagnosed AD cases with a clinical diagnosis of AD dementia or an atypical, non‐amnestic clinical syndrome (e.g., corticobasal syndrome, posterior cortical atrophy). AD cases were selected based on high AD neuropathologic change (ADNC) and lack of frontotemporal lobar degeneration or hippocampal sclerosis, resulting in 591 AD cases and an additional 74 none‐low ADNC controls. Databased clinical diagnosis for AD cases was classified as amnestic or non‐amnestic. Hematoxylin & eosin‐stained slides were digitized and neuronal density was quantified using an in‐house developed macro on 900µmx900µm region of interest using Aperio technology (Leica Biosystems). LC level was classified using neuroanatomic landmarks as rostral, middle, or caudal. Results Control cases had greater neuronal density in the LC compared to AD cases at all three levels, p <0.05. In AD cases, we observed an association between age and neuronal density. Examining these differences along the rostrocaudal‐axis, we found that a younger age at symptomatic onset was associated with lower LC neuronal density in the rostral (correlation coefficient: 0.48; p <0.001) and middle LC (correlation coefficient: 0.28; p <0.001), no association between age at onset and neuronal density was observed at the caudal level. Stratifying our analysis by clinical syndrome, we found fewer neurons in the rostral and middle LC in non‐amnestic AD compared to amnestic AD ( p = 0.006 and 0.029 respectively, Table 1). No significant differences between amnestic and non‐amnestic cases were observed in the caudal LC. Conclusions The locus coeruleus, especially the rostral and middle levels, are especially vulnerable in young‐onset and atypical forms of AD. The loss of noradrenergic neuromodulation may contribute to the atypical symptomatology.

ABSTRACT Objective Aging alters mesenchymal stromal cell (MSC) function, leading to dysregulated adipogenesis across tissues through biased lineage commitment. Fat redistribution from adipose depots to skeletal muscle and bone marrow is common in aging, but the underlying mechanisms remain unclear. This study investigates how MSC senescence modulates adipogenesis. Methods Primary MSCs were isolated from mouse skeletal muscle (FAPs), adipose tissue (APCs), and bone marrow (BMSCs). Single‐cell RNA sequencing was performed to compare transcriptional profiles among these populations. In vitro adipogenic differentiation and DNA damage–induced senescence assays were conducted, and the effects of autologous conditioned media from senescent MSCs on adipogenesis were assessed. Results Transcriptional analyses revealed that FAPs and APCs share greater similarity with each other than with BMSCs. All MSC types exhibited adipogenic potential and developed a robust senescence‐associated secretory phenotype (SASP) upon senescence induction. Conditioned media from senescent MSCs enhanced adipogenesis in BMSCs but inhibited adipogenesis in FAPs and APCs, revealing tissue‐specific paracrine effects. Conclusions MSC senescence reprograms adipogenic bias in a tissue‐dependent, non–cell autonomous manner, contributing to age‐related fat redistribution among adipose tissue, skeletal muscle, and bone marrow. Understanding these mechanisms may provide new therapeutic approaches for improving tissue composition and function in the context of aging.