Citations

Abstract Introduction To investigate the effect of empagliflozin on right ventricular (RV) function in patients with heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve outcomes and reverse left ventricular (LV) remodelling in HFrEF. The impact on RV function remains uncertain. Methods The Empire HF trial was an investigator-initiated, double-blind, randomized, placebo-controlled trial of 190 participants with a left ventricular ejection fraction (LVEF) of 40% or lower, with New York Heart Association (NYHA) Class I−III symptoms. Participants were randomized to receive either empagliflozin (at a dose of 10 mg once daily) or placebo, on top of recommended therapy for 12 weeks. The primary endpoint of this exploratory substudy was changes in RV free wall strain (RVFWS) across the whole cohort. RVFWS was also stratified into tertiles based on baseline RVFWS. Secondary endpoints included changes in tricuspid annular plane systolic excursion (TAPSE) and RV S’ velocity. Results Between June 2017 and September 2019, a total of 190 patients were enrolled, of whom 160 were included in this substudy. Baseline characteristics were balanced between the groups (mean age of 64 ± 11 years, 86% male, mean LVEF: 29 ± 8%, 79% in NYHA Class II, 83 patients (52%) had an implanted cardiac device, and tricuspid valve regurgitation was absent/trace in 136 (85%) and mild in 24 (15%)). A high proportion of the population were on optimal medical treatment for HFrEF, and device therapy remained unchanged during follow-up. The overall mean RVFWS was −16.7 ± 6.1%, with the empagliflozin group at −16.4 ± 6.2% and the placebo group at −16.9 ± 5.9%. No differences were observed in RVFWS between the groups. When stratified by baseline RVFWS into tertiles, patients in the lowest tertile demonstrated a significant improvement with empagliflozin (treatment effect: −2.9% [95% CI: −5.0 to −0.3]; P = .027). This finding was independent of LVEF, plasma volume, and weight loss, and remained unchanged after additional adjustment for LV remodelling and the presence of resynchronization therapy. No significant treatment effect was observed in the middle or highest tertiles of RVFWS, nor in the overall or lowest tertiles of TAPSE or RV S’. Conclusion This exploratory substudy of the Empire HF, treatment with empagliflozin exerted no overall effect on RV function in stable HFrEF patients, but significantly improved RVFWS in patients in the lowest tertile of RVFWS after 12 weeks of treatment. Trial Registration ClinicalTrials.gov, Unique Identifier: NCT03198585

Abstract Ferritin, consisting of ferritin heavy chain (FTH1) and light chain (FTL) subunits, is an essential intracellular iron storage protein fundamental for cellular function. However, the source and the biological role of extracellular ferritin (ex-ferritin) are less understood. Recent studies have linked elevated serum ex-ferritin with adverse outcomes in individuals with acute respiratory distress syndrome (ARDS). In this study, we demonstrate that both FTH1 and FTL are significantly enriched in the serum, blood monocytes, and alveolar macrophages (AMs) of individuals with ARDS, a phenomenon we successfully replicate in a murine hyperoxia-induced acute lung injury (HALI) model. We show that FTH1 is consistently upregulated in macrophages during lung injury development, and mice with a targeted deletion of FTH1 in myeloid (LysMcre) or resident lung macrophage (Cd11ccre) populations exhibit attenuated HALI. This reduced injury is linked to macrophage resistance to ferroptotic cell death, ferritinophagy, altered airway inflammatory responses, and lower lung extracellular iron and higher levels of FTL-ex-ferritin. Transplantation of FTL-ex-ferritin-enriched bronchoalveolar lavage fluid to wild-type mice protected against HALI. The ratio of FTL-ex-ferritin to FTH1 in the serum of individuals with ARDS who died was higher than that of those that survived, suggesting that the balance between FTH1 and FTL may play a role in injury modulation. Our findings highlight macrophage ferritin as a key regulator of macrophage survival and the response of the lung to injury, presenting a potentially targetable pathway for ARDS treatment.

Abstract Background Tau‐PET tracers have been used to monitor the progression of Alzheimer's disease (AD). However, different tracers present distinct patterns of binding throughout the brain, challenging the harmonization of their findings. Leveraging the HEAD Study, the largest head‐to‐head study of tau‐PET tracers, we recently developed the Uniτ scale, which cross‐sectionally harmonizes Flortaucipir and MK6240 onto a universal tau‐PET measurement. Here, we provide a preliminary evaluation of the Uniτ scale's longitudinal performance in HEAD and two independent cohorts. Methods We assessed 422 individuals across the AD spectrum with longitudinal tau‐PET from three cohorts: HEAD [13 cognitively unimpaired (CU), 9 cognitively impaired (CI) individuals, scanned head‐to‐head with Flortaucipir and MK6240], ADNI [74 CU, 208 CI, tracer: Flortaucipir], and TRIAD [72 CU, 46 CI, tracer: MK6240]. Standardized uptake ratios (SUVRs) were harmonized to Uniτ using the Uniτ Ecosystem ( unitau.app ). Braak I‐II and the Meta‐Temporal regions were used as regions of interest. Annual tau‐PET uptake change was calculated, and the effect size was defined as the mean annual change divided by its standard deviation. Results In HEAD, annual change in tau‐PET uptake in Braak I‐II across CU and CI was only detectable in MK6240 (Figure 1A). However, both tracers detected significant annual changes in the Meta‐Temporal ROI for CI (Figure 1B). In both ADNI (Flortaucipir) and TRIAD (MK6240), changes in tau‐PET uptake in Braak I‐II regions were not significant (Figures 2‐3A). However, across all cohorts, the Meta‐Temporal ROI consistently showed detectable annual tau‐PET increases—most pronounced among CI—leading to larger effect sizes than in Braak I‐II (Figures 1‐3B). The Uniτ harmonization did not fundamentally alter the pattern of the findings. However, in ADNI (Flortaucipir), Uniτ yielded a slightly higher effect size than SUVR in CU for both Braak I‐II and Meta‐Temporal regions. Conclusion In this large longitudinal sample, our findings confirm that Flortaucipir and MK6240 can detect tau PET changes over time likely associated with the progression of tau tangle pathology. While MK6240 appears to show greater progression in CU, both tracers progress similarly in CI. Our data also suggested that Uniτ harmonized tau PET measurements maintain the longitudinal characteristics of each tau PET tracer for use in clinical trials.

Abstract Background T2*‐weighted imaging is of paramount importance for patient treatment eligibility and safety monitoring in anti‐amyloid pharmaceutical clinical trials and clinical care. Recently with the adoption of multi‐echo GRE (GRE) sequences, susceptibility weighted imaging (SWI), and quantitative susceptibility mapping (QSM) can be obtained in the same acquisition. In 2024, the QSM Consensus Organization Committee released a white paper recommending at least 1 mm isotropic voxel size for QSM. In clinical workflows microbleed detection is performed with higher in‐plane resolution (0.5x0.5mm 2 ), and large out‐of‐plane resolution (∼1.8mm), which was used in the ADNI4 protocol. In the CLARiTI protocol, a 1mm isotropic resolution was adopted. The objective of this work was to compare susceptibility estimates between the ADNI4 (0.5x0.5x1.8mm 3 ) and CLARiTI (1mm 3 ) protocols. Method The ADNI4 and CLARiTI QSM protocols were acquired on forty‐seven subjects (33 cognitively unimpaired (CU), 14 cognitively impaired (CI), in the same scan session. The groups were defined by their Clinical Demential Rating (CDR) global score (CDR global = 0 for CU, and CDR global >= 0.5 for CI subjects). QSM images were generated using publically available software (STI Suite, UC Berkeley). Mean susceptibility values in atlas regions were compared. Result Significant group differences (CU vs. CI) were observed in the fusiform and middle occipital gyrus with the ADNI4 protocol, only in the rectus with the CLARiTI protocol (Figure 1). These three regions are small in size and closer to surface‐air interfaces, which may have impacted estimation accuracy. However, in the substantia nigra and its sub‐regions (pars compacta and pars reticulata), which shows increased susceptibility in Lewy body disease, the ADNI4 and CLARiTI protocols were in good agreement (r 2 > 0.9) (Figure 2). Conclusion Group differences were observed between the ADNI4 and CLARiTI QSM only in 3 small regions close to surface‐air interfaces in this small dataset. The two techniques showed highly correlated (r 2 = 0.93) estimates in the substantia nigra, a region with high susceptibility due to iron deposition. Strong correlations between the two protocols are encouraging. Radiologists have historically preferred submillimeter in‐plane resolution for microbleed detection, which is more time manageable with anisotropic imaging.

Abstract Background We showed that astrocyte reactivity, as measured by plasma GFAP levels, influences Aβ mediated tau PET pathology in cognitively unimpaired (CU) Aβ‐positive individuals. However, the link between GFAP and tau PET in individuals without detectable Aβ pathology remains elusive. The aim of the current study is to investigate the association between plasma GFAP and tau PET in CU Aβ PET‐negative individuals. Method We studied 147 CU Aβ PET‐negative participants from the HEAD cohort with plasma GFAP and p ‐tau217, as well as tau PET Flortaucipir and MK6240 data. Aβ positivity was determined by Aβ PET visual reading and Centiloid 12. Voxel‐wise linear regression models adjusted for age and sex tested the association of plasma GFAP and p ‐tau217 with tau PET. Further, the associations of plasma GFAP with peak tau PET SUVR values extracted from voxel‐wise association were fitted with a linear regression model adjusted for age and sex. Result Voxel‐wise analysis showed that plasma GFAP levels, but not plasma p ‐tau217 levels, were associated with tau PET in the medial temporal lobe (e.g., amygdala, entorhinal cortex, hippocampus) predominantly for Flortaucipir tau PET [Figure 1A, B, C, D]. The association between plasma p ‐tau217 and tau PET was weak in Aβ‐negative individuals. These results were similar when Aβ positivity was defined based on Centiloid 12. Furthermore, plasma GFAP and peak tau PET SUVR of Flortaucipir showed stronger association than that of MK6240 [Flortaucipir: β=0.4017, p <0.0001; MK6240: β=0.194, p = 0.0424; Figure 2A, B]. Conclusion We found an association between GFAP levels and tau PET uptake in individuals not expected to exhibit high levels of tau tangle‐related tracer uptake. Further analysis will be designed to elucidate the underpinning of this association, which could represent low levels of tau pathology, astrogliosis, or other factors.

Abstract Background Quantifying tau aggregates in the human brain can be achieved using Positron Emission Tomography (PET) techniques, which can potentially be affected by binding competition due to medication use. Patients with dementia often have high rates of comorbidities and polypharmacy. Therefore, this study aims to investigate the potential influence of multiple medications on the uptake of the tau tracers MK6240 (MK) and Flortaucipir (FTP). Method Five classes of medications were evaluated: Anti‐Hypertensives, Statins, Anti‐Diabetics, Psychoactive drugs, and NSAIDs (Table 1). We included 292 individuals [170 cognitively unimpaired (CU) Aβ‐negative and 122 cognitively impaired (CI) Aβ‐positive] from the HEAD study (Table 2). We compared MK and FTP SUVR in the Medial Temporal Lobe (MTL) and Neotemporal Cortex (NTC) in individuals on and off medications. The linear regressions that tested associations were corrected for confounding factors, including age, sex, education, and MoCA score. Correction for multiple comparisons was applied using the Bonferroni method (adjusted p ‐value at 0.00125). Result Among CI Aβ‐positive individuals, Anti‐Diabetics were associated with lower SUVR in the NTC for both FTP and MK. However, these associations did not remain significant after correction for multiple comparisons. (Table 3). Conclusion Our findings indicate that there are no significant associations between the use of the medications studied and MK or FTP uptake when accounting for covariates and applying multiple comparison corrections.

Abstract Background Plasma p ‐tau217 represents a promising alternative to PET‐ and CSF‐based biomarkers of AD in well‐characterized research cohorts. However, the performance of this accessible biomarker in outpatient clinics comprised of patients with multiple causes of cognitive impairment has yet to be established. Method Plasma Aβ42/40 and p ‐tau217 concentrations were measured using Fujirebio Lumipulse assays in patients evaluated within a subspecialty memory clinic at Mayo Clinic in Florida. Syndromic and etiologic diagnoses were established by consensus, integrating clinical data and findings from MRI ( n = 484), FDG‐PET ( n = 117), and CSF AD biomarkers ( n = 440). Plasma biomarker performance was evaluated using established diagnostic cutpoints to identify patients with “positive/elevated”, “intermediate”, or “negligible” levels of cerebral amyloid pathology on amyloid‐PET. Result Plasma AD biomarkers were measured in 509 patients (mean 68.6±9.3 years; 47% female; 91.3% non‐Hispanic White), including patients with typical amnestic AD ( n = 237, 46.6%), non‐amnestic presentations of AD ( n = 48, 9.4%), and non‐AD causes of cognitive concerns ( n = 224, 44.0%). “Intermediate” plasma p ‐tau217 and p ‐tau217/Aβ42 concentrations were reported in <15% of patients (43% of patients with Aβ42/40), implying the need for further testing to inform the likelihood of AD neuropathologic change in these patients. After excluding these patients, plasma p ‐tau217 reliably distinguished patients with symptomatic AD with 95% sensitivity and 82% specificity. Integration of Aβ42 measures (ptau217/Aβ42) incrementally improved specificity (86%). Diagnostic performance was unaffected by age (> vs < 65‐years). Plasma p ‐tau217 (AUC: 0.94; 95%CI: 0.91‐0.96) and p ‐tau217/Aβ42 performance (AUC: 0.96; 95%CI: 0.94‐0.98) were closely aligned with results of established CSF AD biomarkers ( p ‐tau181/Aβ42), outperforming Aβ42/40 (AUC: 0.78; 95%CI: 0.74‐0.83). Reduced kidney function was associated with elevated plasma p ‐tau217 and p ‐tau217/Aβ42 concentrations in patients without AD (referencing CSF AD biomarkers). Conclusion Concentrations of plasma p ‐tau217, but not Aβ42/40, strongly associated with clinical diagnoses of symptomatic AD and CSF AD biomarker results. Integration of Aβ42 measures yielded marginal improvements in performance, with increased complexity and cost. These findings support the use of plasma p ‐tau217 in heterogeneous clinical cohorts, including patients with multiple causes of cognitive impairment. Caution is advised when interpreting p ‐tau217 concentrations in patients with decreased kidney function, due to potential elevations in plasma biomarker concentrations.

Abstract Background Black and Latino Americans experience a disparate dementia burden yet remain underrepresented in dementia research, including clinical trials designed to slow or prevent symptomatic Alzheimer's disease (AD). Accessible and non‐invasive AD blood biomarkers may improve identification and recruitment of underrepresented participants into AD clinical trials. There is a clear need to assess the performance of emergent plasma AD biomarkers for the detection of AD neuropathology in cognitively normal Black and Latino Americans. Method Cognitively normal Black and Latino participants underwent cognitive evaluations and PET (amyloid‐PiB, tau‐flortaucipir) imaging at Mayo Clinic in Florida. Plasma p ‐tau217 was measured using Fujirebio Lumipulse assays. We evaluated the diagnostic performance of a p ‐tau217 threshold (≥0.186 pg/mL) known to identify non‐Hispanic White participants with cognitive impairment and “positive” amyloid PET scans (>25 Centiloids). Next, we derived an optimized threshold to identify participants with “positive” amyloid PET using Youden's method. Result The cohort included 58 Black (55%) and 47 Latino‐White (45%) well‐educated (mean 16.1±2.3 years) individuals, with mean age 64.7±8.8 years, and slight female bias (63%). Plasma p ‐tau217 concentrations increased with age (rho=0.269, p = 0.004) and declined with MoCA scores (rho=‐0.225, p = 0.027). Sixty‐nine participants completed amyloid‐ and tau‐PET imaging. Plasma p ‐tau217 concentrations increased with amyloid‐ (rho=0.254, p = 0.044) but not with tau‐PET standardized uptake value ratio (rho=0.127; p = 0.334). p ‐tau217 concentrations were ≥0.186 pg/mL in 10/69 participants (14%), including 3/3 amyloid‐ and tau‐PET positive (A+T+) participants, 3/8 A+T‐ participants (sensitivity: 55%), and 4/58 A‐T‐ participants (specificity 93%). An optimized p ‐tau217 threshold of ≥0.118 pg/mL identified 10/11 A+T± participants (sensitivity 91%), and 16/58 A‐T‐ participants (specificity 73%). In A‐T‐ participants, estimated glomerular filtration rate was lower in participants with ‘false positive’ elevations in plasma p ‐tau217 (mean difference: 67 vs 81 ml/min/1.73m 2 , p = 0.004), emphasizing the need for caution when interpreting plasma p ‐tau217 concentrations in patients with decreased kidney function. Conclusion Plasma p ‐tau217 thresholds validated in participants with symptomatic AD (≥0.186 pg/mL) failed to identify early AD neuropathology in 5/8 cognitively normal Black and Latino participants. Optimized thresholds are required to improve detection of preclinical AD in Black/Latino individuals.

Abstract Colorectal cancer incidence and mortality have declined over time, due in part to high-quality screening and surveillance colonoscopy. Nevertheless, postcolonoscopy colorectal cancer (PCCRC) occurs in up to 7% of cases and is inversely related to examination quality. Artificial intelligence-assisted colonoscopy aims to improve performance metrics and, ultimately, patient outcomes. Multiple randomized trials show that computer-aided polyp detection (CADe) increases adenoma detection, predominantly for diminutive lesions (≤5 mm). Computer-aided polyp characterization (CADx) enables real-time optical diagnosis, potentially shifting management of diminutive polyps by supporting resect-and-discard and diagnose-and-leave in situ strategies. Computer-aided quality assessment (CAQ) systems monitor key metrics—including cecal intubation rate, withdrawal time, speed, and mucosal exposure. Whether CADe alone leads to a reduction in PCCRC or cancer-related mortality remains to be determined; in the near term, a combined approach using CADe, CADx, and CAQ is most likely to deliver the greatest improvements in patient outcomes.

Abstract Background Plasma phosphorylated‐tau217 (pTau217) is a blood‐based biomarker of Alzheimer's Disease (AD) pathology. Cognitive resilience describes the presence of neurodegenerative pathology and preserved cognition. Cognitive resistance describes avoidance of neurodegeneration. This post hoc analysis of the Post‐Operative Delirium Belfast (PODB) cohort aimed to define cognitive resilience using plasma pTau217 and Mini Mental State Examination (MMSE) measures. Methods PODB was an observational cohort study, investigating people aged 65 and over, without a diagnosis of dementia, undergoing elective hip and knee replacement between 2012‐2014 with subsequent long‐term follow‐up. In this analysis, pre‐operative plasma pTau217 was used as a marker of neuropathology. A cutoff of 0.42 pg/mL was used (Ashton NJ et al. 2024). Pre‐operative and 8‐year follow‐up MMSE scores were used as a marker of cognition. A score of ≥24 was considered preserved. Definitions used were: Cognitive resilience = pTau217 ≥0.42 pg/mL plus MMSE ≥24. Cognitive resistance = pTau217 <0.42pg/mL plus MMSE ≥24. Affected = pTau217 ≥0.42 pg/mL plus MMSE <24. Those with normal markers plus poor cognition were defined as pTau217 <0.42pg/mL plus MMSE <24. These four groups were identified at baseline and follow‐up, respectively. In this analysis, 231 participants were included at baseline, 104 at follow‐up. Results Of the n = 231 participants included at baseline, n = 147/231 (64%) were cognitively resilient, n = 65/231 (28%) resistant, n = 17/231 (7%) affected, and n = 2/231 (<1%) had normal markers and MMSE <24. Of the n = 104 participants with follow‐up information included in this analysis, n = 61/104 (59%) were cognitively resilient, n = 33/104 (32%) were resistant, n = 8/104 (8%) affected, and n = 2/104 (<1%) had normal markers and MMSE <24. Cognitively resilient participants at baseline were younger ( p = 0.011) and tended to be female ( p = 0.977) compared to affected participants. At follow‐up, those who were cognitively resilient tended to be younger ( p = 0.196) and female ( p = 0.212) compared to affected participants (Table 1). Of those cognitively resilient at follow up, n = 59/61 (97%) of these participants were also cognitively resilient at baseline. Conclusions Using pTAu217, at the cut‐off quoted, we found a high incidence of cognitive resilience in an older elective surgical cohort.