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Abstract Background Ten years after the original publication, the Centiloid framework is now broadly used to harmonize amyloid‐PET quantification, facilitate data sharing and comparison across cohorts, and even assist visual interpretation in clinical settings. We evaluated the global implementation of Centiloids by comparing their distribution and corresponding positivity thresholds across cohorts. Methods We gathered data from publicly available cohorts and reached out to investigators across the world to collect cross‐sectional Centiloids, demographic and clinical information, and visual read data. Gaussian mixture models (GMM, k=2) were fitted to Centiloid values for each cohort and cutoffs were calculated as mean + 2SD of the lower Gaussian. When visual reads were available, we determined Centiloid cutoffs that maximized correspondence with visual reads (Cohen's kappa). Data was combined across cohorts using random effects meta‐analyses. Results As of January 2025, we included 37 cohorts ( n = 41,678 participants) with heterogeneous pipelines, radiotracers, and clinical and demographic characteristics (Table‐1). The low Gaussian peaks ranged from ‐9 to 10CL; the meta‐analysis identified a common peak at 1CL. The second peaks were more heterogeneous (range=38‐102CL; meta‐analysis outcome=64CL). Across cohorts, the proportion of cognitively unimpaired versus impaired participants impacted the position of both peaks, with better separation in cohorts enriched in impaired individuals (Figure 1C). The meta‐analysis indicated a GMM‐based cutoff of 19CL (95%CI: 16‐21CL, Figure 1B); subgroup analyses showed no evidence of significant effect between single versus multicenter settings (17 versus 20CL, p = 0.30), MRI‐based or PET‐only processing (18 versus 19CL, p = 0.88), and no evidence of difference across radiotracers (Flutemetamol: 16CL; PIB: 17CL, Flutafuranol: 18CL, Florbetaben: 19CL, Florbetapir: 20CL, p = 0.78). In a subset of 29,496 participants with visual reads available, binary visual reads corresponded well to Centiloids (common kappa=0.86, Figure 2A). The visual read‐based cutoff of 24CL (95%CI: 21‐27CL, Figure 2B) maximized correspondence between visual read and quantification and was slightly higher than the GMM‐based cutoff. All meta‐analysis models showed high non‐random heterogeneity (I 2 >80%) across studies, suggesting non‐random differences in peaks and cutoffs. Conclusions Meta‐analysis‐based cutoffs align well with thresholds from the existing literature. High heterogeneity among studies underscores the need to investigate contributing factors, raising concerns about applying common cutoffs.

Abstract Background Sex, education and race/ethnicity are all associated with risk of Alzheimer's disease dementia. Here, we assess the effects of self‐reported sex, educational attainment and race/ethnicity on amyloid‐positivity, and tau‐PET‐positivity in 12,048 (7,394 cognitively unimpaired [CU], 2,177 MCI, and 2,477 dementia) individuals from 42 cohorts worldwide. Method Logistic generalized estimating equations were used to estimate frequency of amyloid‐positivity (using cohort‐specific thresholds for amyloid‐PET [84%] or CSF) and tau‐PET‐positivity (cohort‐specific thresholds of 2SD above mean temporal uptake in amyloid‐negative controls). We assessed: i) sex and APOEε4 ( N = 10,098) associations, to complement earlier findings of a higher frequency of tau‐positivity in females, ii) effects of lower/higher education ( N = 10,970; cohort‐specific median‐split), and iii) effects of race/ethnicity (non‐Hispanic White [hereafter: White], N = 4880; Asian, N = 116; Black or African‐American [hereafter: Black], N = 353; Hispanic, N = 356, only from Northern‐American cohorts). Outcomes were frequency of amyloid‐positivity in CU individuals only, and tau‐PET‐positivity in both amyloid‐positive (AB+) CU and cognitively impaired (CI, i.e. MCI and dementia) individuals. Interaction effects on the relationship between age and amyloid/tau‐positivity were assessed and only retained in the models when significant. Result Female sex was associated with an APOEε4 ‐independent increased frequency of amyloid‐positivity (β=0.51[0.22], p = 0.02) in CU and increase of tau‐positivity in both AB+CU (β=0.27[0.08]) and AB+CI (β=0.37[0.08], both p <0.01). Remarkably, tau‐positivity frequencies of female APOEε4 non‐carriers were equivalent to male APOEε4 carriers in AB+CI (Figure 1). No significant sex* APOE interactions were observed. In CU, higher education was associated with lower amyloid‐positivity frequency (β=‐0.12[0.05], p = 0.02). In contrast, among AB+CU, there was an age*education interaction effect that indicated more pronounced age effects on tau‐positivity in individuals with higher education (age*education:β interaction =0.03[0.01], p <0.01). There were no education effects in AB+CI (Figure 2). In CU, an age*race/ethnicity interaction effect was observed across all non‐White groups compared to White (Hispanic:β interaction =‐0.05[0.01], p <0.01; Black:‐0.04[0.01], p <0.01; Asian:‐0.02[0.01], p = 0.04). This suggests that the impact of age on amyloid‐positivity was less pronounced in non‐White groups. Furthermore, in AB+CI, Hispanic ethnicity was related to higher tau‐positivity frequency than White (β=0.51[0.22], p = 0.02; Figure 3). Conclusion In this multi‐center initiative comprised of clinical and community‐based cohorts, we observed that self‐reported sex, educational attainment and race/ethnicity were related to positivity‐frequencies of Alzheimer's disease pathology.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Small Cell Lung Cancer provide recommendations for diagnostic workup, staging, and treatment. These NCCN Guidelines Insights highlight recent updates, with a particular focus on changes to systemic therapies and radiation treatment in the NCCN Guidelines for Small Cell Lung Cancer.

Abstract Background The Overlap Index (OI) as previously published (Lee et al., 2022) is a reliable method for detecting tau accumulation using tau‐PET imaging (flortaucipir; AV1451). It identifies voxel‐wise standardized uptake value ratio (SUVr) elevations across serial scans. Although OI showed more sensitivity to tau signal elevation and longitudinal change than standard ROI measures, to our knowledge, the relationship of the tau PET overlap index to neuropathologic findings is still unclear. This study aims to investigate the potential of OI to detect NFTs of the neuropathologic Braak tangle stage, especially the early Braak tangle stage (I–IV). Method This study included 57 participants from the Mayo Clinic Study of Aging or Mayo Alzheimer's Disease Research Center, all of whom underwent autopsy and at least two serial AV1451 tau‐PET scans and 3T T1‐weighted MRI within an average of 16 months. Tau‐PET SUVr images were normalized to cerebellar crus grey matter, and MR images were co‐registered to a single‐subject MRI mean. Tau‐PET scans were resampled into MRI space, and OI was calculated by applying intensity thresholds 1.3. Clusters with fewer than 20 contiguous voxels were excluded. An OI cutoff of 0.5 was used and an SUVr cutoff of 1.29. Postmortem immunohistochemistry (IHC) using phospho‐tau antibodies (AT8, PHF‐1) was performed on the amygdala, temporal cortex (middle and superior), and anterior/posterior hippocampus. Neuropathological Braak staging was determined based on AT8‐stained sections. We conducted visual comparison of tau‐PET overlap signal in these regions with IHC‐confirmed tau pathology across Braak tangle stages. Result OI‐detected voxels corresponded to NFT distribution across Braak stages. In early Braak stages, standard SUVr‐based META‐ROI values remained negative, whereas OI showed positive signals, indicating greater sensitivity to early tau pathology (Figure 1). The spatial distribution of OI‐derived overlap regions aligned with high NFT burden, suggesting that OI captures early‐stage tau pathology more effectively than conventional SUVr methods. Conclusion OI in serial tau‐PET imaging demonstrated better detection of early‐stage tau pathology than standard ROI‐based SUVr measures. The alignment between OI‐detected voxels and neuropathological tau burden supports its potential as an in vivo biomarker for detecting early neurofibrillary tangles.

Abstract Background The link between regional tau load and clinical manifestation of Alzheimer's disease (AD) highlights the importance of characterizing spatial tau distribution. In typical (memory‐predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicenters. However, atypical (non‐amnestic‐predominant) AD variants with heterogeneous tau patterns provide a key opportunity to assess the universality of connectivity as a scaffold for tau progression. Method We included tau‐PET data from 320 subjects with atypical AD, characterized by highly heterogeneous tau patterns ( n = 139 posterior cortical atrophy/PCA‐AD; n = 103 logopenic variant primary progressive aphasia/lvPPA‐AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS‐AD) from 14 sites, with a subset of patients ( n = 78) having longitudinal tau‐PET data. As an independent sample, we further included regional post‐mortem tau stainings from 93 atypical AD patients from two sites ( n = 19 PCA‐AD, n = 32 lvPPA‐AD, n = 23 bvAD, n = 19 CBS‐AD). Gaussian mixture modeling was used to harmonize different tau‐PET tracers by transforming tau‐PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether 1) brain regions with stronger functional connectivity showed greater covariance in cross‐sectional and longitudinal tau‐PET and post‐mortem tau pathology, and 2) functional connectivity of tau‐PET epicenters and tau‐PET accumulation epicenters was associated with cross‐sectional and longitudinal tau patterns. Result Tau‐PET epicenters—defined as the 5% brain regions with the highest tau load—aligned with clinical variants, e.g. a posterior pattern in PCA‐AD (“visual AD”) and left‐hemispheric temporal predominance in lvPPA‐AD (“language AD”) (Figure 1). More strongly functionally connected regions showed correlated concurrent tau‐PET levels, which was confirmed with post‐mortem data (Figure 2). Moreover, the connectivity profile of tau‐PET epicenters and accumulation epicenters corresponded to tau‐PET progression patterns (Figure 3). Conclusion Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicenters, across all AD clinical variants. Since tau proteinopathy is a key driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant‐specific endpoints in clinical trials.

Abstract Background Despite advancements in care, pregnant individuals with congenital heart disease (CHD) face disproportionately high risks. Objectives To address these challenges, a national consortium was established to improve maternal outcomes in CHD through multidisciplinary collaboration and patient engagement. Study design As part of a 2.5‐year multi‐phase consortium initiative, an in‐person research summit followed by three virtual focus groups (Project PHASE 3) was conducted with patients, clinicians, researchers, advocates, and policy representatives. Qualitative data were collected, and reflexive thematic analysis was performed to identify shared priorities. Results A total of 48 individuals participated in the in‐person meeting, including 18 patients (83% female; 11% Black/African American, 17% Asian, 11% Hispanic, 61% White) and 30 clinicians/researchers. An additional 19 patients (100% female; 32% rural/non‐urban; 16% Black/African American, 10% Hispanic, 74% White) participated in virtual focus groups. Key priorities identified included improved patient–healthcare provider communication, expanded access to multidisciplinary and adult CHD‐specialized care, and greater inclusion of patient voices in reproductive planning and research. Focus groups underscored racial disparities in care, limited CHD education for patients of color, and the need for culturally tailored resources. Participants emphasized the importance of representative research cohorts, integration of genetic counseling, and dissemination of research in accessible, plain‐language formats. Conclusions Findings demonstrate the value of integrating patient expertise and partnership in shaping cardio‐obstetric research, care models, and education. Addressing maternal health concerns in CHD research requires both structural changes and community‐driven, inclusive research strategies.