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Introduction Women residing in rural areas or belonging to lower socioeconomic status (SES) strata experience disproportionately low rates of breast cancer screening, contributing to delayed diagnoses and poorer prognoses. In addition, their participation in clinical trials remains markedly limited, reducing opportunities to access preventive and screening interventions. Promoting research preparedness among women before disease onset may empower them to make informed decisions regarding their health and willingness to participate in clinical research with fewer emotional and logistical barriers. Methods and analysis This project applies a community-based participatory research approach to develop and refine the WeCARE (Women’s Engagement for Cancer Awareness, Resources and Education) intervention for women aged 50–74 years who have either never undergone breast cancer screening or have not received screening in the past 5 years and who reside in rural areas or belong to low SES groups. The intervention consists of two components. Component 1 is a single-day, in-person community forum that includes (a) an educational seminar led by an oncologist to address breast cancer risk and screening guidelines, (b) survivor storytelling to enhance emotional engagement and cultural resonance and (c) facilitated navigation to breast cancer screening and future research participation. Component 2 involves structured post-forum follow-up through multiple touchpoints (phone calls and mailed boosters) to reinforce knowledge, address barriers and support screening completion and research enrolment. Quantitative data (eg, screening completion, satisfaction and follow-up engagement) will be summarised using descriptive statistics to assess feasibility and reach on 50 participants. Qualitative feedback from participants will undergo thematic analysis to identify barriers, facilitators and perceived cultural relevance. Integrated mixed-method interpretation will inform iterative refinement of the WeCARE intervention and guide design of subsequent larger trials. Ethics and dissemination Approved by the Mayo Clinic Institutional Review Board (IRB #25–008934). All participants will provide informed consent. Procedures ensure confidentiality, cultural sensitivity and participant safety. Data will be stored in REDCap and disseminated through publications, conferences, local town halls and community reports.

Abstract INTRODUCTION The tau positron emission tomography (PET) overlap index (OI) has shown promise in maximizing signal‐to‐noise for longitudinal tau PET imaging, particularly for early tau pathology, but requires validation against neuropathology. METHODS Fifty‐seven participants who underwent serial tau PET imaging (flortaucipir) and subsequent autopsy were included. Tau PET OI and standardized uptake value ratios (SUVRs) were compared across neuropathological diagnoses. RESULTS Tau PET OI showed greater concordance with neurofibrillary tangle (NFT) severity in the entorhinal cortex (a key region for Alzheimer's disease [AD] tauopathy) than SUVR, particularly in early Braak tangle stages (positivity: 52.2% for OI vs. 13.0% for SUVR). OI detected overlapping tau voxels that exhibited spatial correspondence with immunohistochemical and autoradiography measures of tau deposition across both AD and non‐AD tauopathies. DISCUSSION These findings demonstrate the enhanced capacity of OI in serial tau PET to robustly detect early and spatially localized tau pathology, supporting its application as a sensitive imaging metric in AD and select non‐AD tauopathies.

Abstract INTRODUCTION Globular glial tauopathy (GGT) is a rare type of frontotemporal lobar degeneration (FTLD) characterized by deposition of 4‐repeat tau. Detecting GGT with tau positron emission tomography (tau‐PET) is challenging. We aim to determine the associations between tau‐PET, autoradiography, and neuropathology methods in GGT. METHODS We identified three patients with GGT who had completed antemortem tau‐PET. Healthy control and two patients with Alzheimer's disease (AD) were also included for comparison. We analyzed gray matter (GM) and white matter (WM) from the superior/middle frontal gyrus (S/M‐FG) and the superior/middle temporal gyrus (S/M‐TG). Immunohistochemical staining was performed with antibodies against phospho‐tau (AT8, PHF‐1, RD4), glial fibrillary acidic protein (GFAP), and resting microglia (ionized calcium‐binding adaptor molecule 1; Iba1). Immunofluorescence with a fluorescent tau‐PET analog (T726) was performed. Regional tau‐PET standardized uptake value ratios (SUVRs) were calculated for comparative GM and WM regions. Autoradiographic studies with 18F‐AV1451 were also conducted. RESULTS Tau‐PET showed increased uptake in the WM regions of the S/M‐FG and S/M‐TG in GGT, and the GM regions in AD. Co‐localization was observed between T726 and PHF‐1, RD4, and GFAP in the WM in the patients with GGT, whereas co‐localization was observed with PHF‐1 predominantly in the GM in AD. Little co‐localization was observed with Iba1. In vitro 18F‐AV1451 autoradiography studies demonstrated minimal binding in GGT. Tau‐PET differentiated underlying GGT from AD based on the relative involvement of the WM and GM. CONCLUSION Histopathologic findings suggest that some flortaucipir uptake in GGT may represent underlying 4R tau, whereas autoradiographic analysis suggests that uptake is likely due to off‐target binding. Further studies with larger cohorts are needed to determine the pathological basis of flortaucipir uptake in GGT.

Introduction Burnout among healthcare professionals remains a critical public health issue linked to impaired cognition, emotional exhaustion and diminished clinical performance. Structured breathing practices have demonstrated promise in improving autonomic regulation and cerebral oxygenation, yet their feasibility, acceptability and implementation in real-world healthcare settings remain underexplored. Objectives This single-arm pilot feasibility trial aims to evaluate the feasibility, acceptability and implementation appropriateness of a structured breathing-based intervention for healthcare professionals across community-based Mayo Clinic Health System (MCHS) sites. Secondary objectives include assessing usability and engagement with the mobile breathing platform, while exploratory analyses will describe magnitude of variability and feasibility of collecting psychological and cerebral haemodynamic measures. This study will commence in November 2025 and is expected to be completed by June 2026. Methods and analysis A total of 40 clinicians (MD/DO/MBBS/PA) and nurses reporting moderate or greater burnout will be enrolled across four MCHS sites. Participants will complete a 4-month structured breathing programme delivered primarily online, supported by a mobile application for practice tracking. Assessments will occur at baseline, 2 months and 4 months, with functional near-infrared spectroscopy (fNIRS) measures of cerebral oxygenation collected at baseline and 4 months in a population subset. Primary outcomes include (1) recruitment yield, retention and adherence rates; (2) acceptability and participant satisfaction (survey and qualitative feedback); and (3) implementation appropriateness measured by the Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM) and Feasibility of Intervention Measure (FIM). Secondary outcomes include digital engagement and usability through mobile analytics and the System Usability Scale. Exploratory outcomes are psychological indicators (burnout, depression, anxiety, perceived stress, sleep, fatigue, professional fulfilment and resilience) and physiological endpoints (fNIRS). Analyses will be descriptive, summarising feasibility metrics with 95% CIs. Progression criteria (recruitment≥75%, retention≥80%, adherence≥70%, AIM/IAM/FIM≥4.0) will determine readiness for a definitive hybrid effectiveness–implementation trial. Ethics and dissemination The study is approved by the Mayo Clinic Institutional Review Board (IRB # 25-009320). All participants will provide informed consent. Study procedures ensure confidentiality, cultural sensitivity and participant safety. Data will be securely stored in REDCap and disseminated through peer-reviewed publications and scientific conference Trial registration number NCT07218458 .

Abstract INTRODUCTION Associations of short‐term use of menopausal hormone therapy (mHT) with Alzheimer's disease (AD) and structural magnetic resonance imaging (MRI) biomarkers were investigated 10 years after an mHT trial. METHODS Recently menopausal women with good cardiovascular health were randomized to oral conjugated equine estrogens (oCEE) or transdermal 17β‐estradiol (tE2) and micronized progesterone, or placebo for 4 years. Amyloid beta (Aβ) on positron emission tomography, hippocampal atrophy, and dorsolateral prefrontal cortex thickness on MRI were assessed 10 years after completion of the mHT trial ( n = 266). RESULTS Aβ and structural MRI biomarkers were not different in the oCEE and tE2 groups compared to placebo. Apolipoprotein E ε4 status did not modify the findings. DISCUSSION There was no evidence of adverse effects or benefits associated with 4 years of use of oral or transdermal mHT on Aβ and structural MRI biomarkers in relatively healthy women, 10 years after mHT. Findings support the long‐term safety of short‐term use of mHT on brain health. CLINICAL TRIALS REGISTRATION NCT00154180 Kronos Early Estrogen Prevention Study (KEEPS) Highlights There were no menopausal hormone therapy–related adverse effects or benefits on amyloid beta and magnetic resonance imaging biomarkers in the long term. Apolipoprotein E ε4 carrier status did not modify these findings. Findings align with neutral cognitive and cerebrovascular outcomes in this cohort.

Abstract INTRODUCTION Understanding neuroinflammation across the Alzheimer's disease (AD) spectrum is essential to elucidate disease mechanisms and individualize therapy. METHODS Human microglial translocator protein (TSPO) expression under inflammatory stimuli was assessed by immunoblot experiments. Ninety‐six participants were enrolled across four groups: cognitively unimpaired amyloid (CU A) + and −, mild cognitive impaired (MCI) A+, and Alzheimer's disease dementia (ADD) A+. Neuroinflammation using 11 C‐ER176 TSPO positron emission tomography (PET) was compared to amyloid and tau PET. Correlations between neuroinflammation, amyloid, and tau pathology were examined across disease stages. RESULTS TSPO was upregulated in human microglia under AD‐like inflammatory conditions. Neuroinflammation, defined by PET TSPO, increased in CU A+ participants and became more widespread with increasing disease severity, aligning with worsening amyloid and tau pathology. Associations with tau were particularly extensive in temporal and parietal regions. DISCUSSION These findings suggest probable amyloid association with early microglial activation, while tau pathology is closely tied to wider distribution of neuroinflammation. Highlights TSPO expression increases in human microglia under AD‐like inflammation. 11 C‐ER176 PET shows stage‐dependent neuroinflammation across the AD spectrum. Neuroinflammation overlaps with tau and is more widespread in amyloid‐positive individuals. Activity peaks in MCI, stabilizes later, and relates to vascular and neurodegenerative changes.

Abstract Background The overlap index (OI), previously introduced by Lee et al. (2022), has proven to be a reliable method for detecting tau accumulation via tau‐PET imaging with flortaucipir ([ 18 F]AV‐1451). This technique identifies voxel‐wise increases in standardized uptake value ratio (SUVr) across serial scans. However, the relationship between tau‐PET measurements obtained with [ 18 F]MK‐6240 and [ 18 F]AV‐1451 using the OI remains unclear. This study aims to investigate the relationship between [ 18 F]MK‐6240 and [ 18 F]AV‐1451 tau‐PET using the tau‐PET OI. Method The study included 27 participants from the HEAD project, all of whom underwent two serial tau‐PET scans (each [ 18 F]MK‐6240 and [ 18 F]AV‐1451) along with 3T T1‐weighted MRI, acquired within an average interval of 18 months. SUVr maps for each tau‐PET tracer were normalized to the cerebellar crus grey matter, and MR images were co‐registered to the MCALT T1 template. Tau‐PET images were spatially resampled to the template space, and OI was computed within a predefined META‐ROI using an intensity threshold of 1.3 and a cutoff of 0.5. Clusters containing fewer than 20 contiguous voxels were excluded from analysis. The META‐ROI SUVr was calculated as the average SUVr across the selected region's SUVr. Additionally, a visual comparison was performed to assess the spatial overlap of OI‐identified voxels between the two tau‐PET tracers. Result OI values within the META‐ROI exhibited a broad distribution between [ 18 F]MK‐6240 and [ 18 F]AV‐1451 tau‐PET, particularly in cognitively unimpaired (CU) and younger individuals (Figure 1A). Unlike the OI distribution, the relationship between META‐ROI SUVr values of both tracers followed an exponential trend (Figure 1B). Visual inspection revealed that OI‐detected voxels in [ 18 F]MK‐6240 tau‐PET were frequently localized to the meninges, an established site of off‐target binding, which was not observed in [ 18 F]AV‐1451 tau‐PET (Figure 2). Conclusion The association between [ 18 F]MK‐6240 and [ 18 F]AV‐1451 tau‐PET, as assessed using the OI, exhibited considerable variability in CU and younger participants. Additionally, the presence of overlapping voxels in the meninges in [ 18 F]MK‐6240 tau‐PET highlights the need to account for and potentially exclude off‐target binding effects in these populations. The influence of meningeal signal and other off‐target binding on the OI in the temporal META‐ROI needs to be further evaluated.

Abstract Background The tau PET imaging with 18F‐flortacipir (18F‐FTP) has focused interest in accurately tracking longitudinal tau changes in Alzheimer's disease [1]. Thus, minimizing variability is critical. Off‐target signal has the potential to complicate interpretation of tau‐PET imaging due to potential spillover or bleed‐in effects, with increased effects seen in later stages of Alzheimer's due to cerebral atrophy and proximity of off‐target areas to relevant cortical areas[2]. Previously, we demonstrated the effect of uptake period activity on 18F‐FTP signal. With increasing recent interest in demographic factors that may affect off‐target binding, we investigated the effect of age in extra‐cerebral off‐target signal in 18F‐FTP PET imaging. Method Standard 18F‐FTP PET protocol was performed in 330 participants. Two independent readers measured tau uptake in predetermined off‐target regions, including extraocular muscle, meninges, and occipital bone among others. Linear regression models assessed the relationship between participants’ age, sex, and tau uptake values (SUV and SUVr) (SUV = (Tissue radioactivity concentration / Injected dose) / Body weight & SUVr = SUV of target region/ SUV of reference region.) Result Sex had a significant effect on off‐target signal in most brain regions, with variable positive or negative correlation based on area. Notably, SUV in the eyeball‐retina, occipital bone, upper skull meninges all showed significant positive correlation with sex, with ‘male’ status generally associated with lower SUV. The greatest effect of sex was observed in superior skull meninges, occipital bone, and internal carotid artery ( p <0.001). Age showed minimally affected SUV and SUVr in off‐target regions. SUVr values show a significant correlation with SUV values of upper skull meninges in sex. Cognitive status did not significantly affect off‐target SUV. Conclusion We observed that sex significantly affected extra‐brain off‐target signal in 18F‐FTP PET imaging, while age has minimal effect, adding to previous evidence of off‐target binding within brain regions. Further evaluation is necessary to understand the age‐related effects on off‐target regions. As a result, the variability introduced by sex may pose challenges to studying tau accumulation.

Abstract Background An intense search is underway for tau PET tracers with enhanced capability to visualize tau aggregates. Research indicates that [18F] AV1451 and [18F]MK 6240 exhibit comparable binding properties in terms of spatial distribution and severity of tau aggregates, as observed both in‐vivo and in‐vitro. This study focused on head‐to‐head pathological comparison of both the tracers binding specificity to tangle maturity levels (pretangles, mature tangles and ghost tangles) of tau aggregates as seen on autoradiography as compared to CP‐13 (early tangle maturity marker) and PHF‐1(middling tangle maturity marker) immunohistochemical (IHC) stains in Alzheimer's disease (AD) and non‐AD tauopathies. Method Study participants included included those with AD and non‐AD tauopathies. Analyses were performed on serial 5um formalin fixed paraffin embedded postmortem human brain sections acquired from Mayo clinic brain bank. Visual assessment of colocalization with IHC as well as quantitative analyses were used. IHC sections were incubated with antibodies CP‐13 (recognizing early tangle maturity) and PHF‐1 (recognizing middling tangle maturity). Result A total of 38 participants were examined. The participants included a spectrum from normal to AD, including mild cognitive impairment (MCI) and atypical AD. Participants with N279K (4R), P301L (4R), and R406W MAPT mutations (3R+4R) were included as well. Both the tracers showed strong binding to AD tau aggregates and no or minimal binding to non‐AD tauopathies. Generally, early tangle maturity tau accumulation participants had more tau demonstrated with CP‐13 than PHF‐1 and both the tracers [18F]MK 6240 and [18F]AV 1451 binding are well correlated with the PHF‐1 staining suggesting the preference for middling tangle level and minimal to early tangles. Conclusion The emergence and validation of these new tau PET tracers have opened new opportunities for the development of more accurate diagnostic and management tools for AD. In our study on post‐mortem sections, [ 18 F]MK‐6240 and [ 18 F]Flortaucipir showed similar binding profiles with preference to middling tangle maturity levels.

Abstract Background Dementia with Lewy Bodies (DLB) has been overlooked or misdiagnosed as Alzheimer's disease (AD) dementia due to its frequent concomitant AD pathology with Lewy Body Disease (LBD) pathology. Although autopsy confirmation has been the gold standard for the precise diagnosis of DLB, time‐course 123 I‐FP‐CIT SPECT (DaT‐SPECT) findings in autopsy‐confirmed DLB are not well characterized. We previously reported that the DaTQUANT z‐score of the more affected side of the putamen has the best discriminatory power in detecting LBD pathology and nigrostriatal degeneration in dementia patients and demonstrated z‐score of −1 as the cutoff value. We sought to examine how DaT‐SPECT findings change over time in autopsy confirmed LBD patients in preparation for its use in LBD targeted clinical trials. Method Eight autopsy confirmed neocortical or limbic LBD patients who underwent two or more DaT‐SPECT were included. Nigrostriatal dopamine transporter (DaT) binding and age‐adjusted z‐scores were analyzed using the DaTQUANT 2.0 software (GE Healthcare). Result Six patients (75%) were male. The patients had 2.5±0.7 longitudinal DaT‐SPECT scans. Clinical diagnosis at initial scan was: DLB (75%), mild cognitive impairment (MCI) with REM sleep behavior disorder (RBD) (13%), and isolated RBD (iRBD) (13%). Clinical diagnosis at last scan was: DLB (88%) and iRBD (12%). All patients developed dementia during life. Mean age at initial scan/last scan/autopsy were 71.1±7.0/73.4±6.9/75.1±7.3 years old. Time from initial and last scan to autopsy were 4.0±1.9 and 1.8±1.9 years respectively. Seven patients (88%) had neocortical LBD and one (12%) had limbic LBD. Concomitant AD pathology was observed in four patients (two males (33%), two females (100%)). All patients had DaTQUANT putamen z‐score <‐1.0 at their initial scan including in MCI+RBD (‐1.76) and iRBD (‐1.53) patients. In the DLB patients at their initial scans, five (83%) had DaTQUANT putamen z‐score <‐2.0 and one (17%) had z‐score of ‐1.55. All patients (100%) showed DaTQUANT putamen z‐score <‐2.0 at their last scans. Conclusion DaTQUANT using cut‐off putamen z‐score of ‐1 was associated with underlying LBD pathology including at their iRBD and MCI stages. Nigrostriatal DaT binding tends to decline over time with DaTQUANT z‐score <‐2 at their last scans.