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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.

Abstract Background Dementia with Lewy Bodies (DLB) is often misdiagnosed or conflated with Alzheimer's Disease (AD) due to overlapping clinical presentations and neuropathological features. The presence of AD‐like features correlates with accelerated cognitive decline and a worse overall prognosis. Compared to AD, studies suggest that amyloid uptake in DLB may spare the occipital lobe. This project aims to investigate whether amyloid PET could be leveraged to differentiate between AD and DLB patients, with the goal of improving diagnostic accuracy and supporting patient stratification and safety in anti‐amyloid trials. Method This study involves collaboration across six centres (University of Geneva, BioFINDER, AMPLE, AMYPAD PNHS, MCSA, GEHC), each contributing amyloid PET imaging data from patients diagnosed with DLB based on clinical or neuropathological assessments. Moreover, each center provided an additional subset of AD and healthy controls, then matched to DLB samples based on age/sex/APOE genotype/education for comparison. A sub analysis will be performed on patients with evidence of both DLB and AD markers. Given the relatively small sample size, key aspect of the methodological approach is to reduce technical sources of variability. The processing workflow includes rigorous quality control, formatting, normalisation to MNI space, harmonisation (differential smoothing), and MRI‐based segmentation. Result The dataset currently includes amyloid PET scans (acquired using [ 11 C]PiB, [ 18 F]Flutemetamol or [ 18 F]Florbetapir) and MRI scans from ∼130 DLB patients, along with ∼150 AD patients and ∼150 controls. In addition, 99 patients positive for the CSF α‐Synuclein Seeding Amplification Assay were included. Patient data were anonymized, and a harmonised database was created, including demographic characteristics, clinical history, and results from neuropsychological assessments. Conclusion The creation of a standardized, multi‐centre amyloid PET dataset for DLB will enable the study of amyloid PET patterns at the global, regional and voxel level, in comparison with uptake in AD patients and controls. This dataset will serve as a valuable resource for investigating the neuropathological underpinnings of DLB, improving diagnostic accuracy, and potentially guiding patient stratification in anti‐amyloid trials. Efforts to integrate [ 18 F]Florbetaben and additional data are ongoing.

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 Prior studies of Alzheimer's disease (AD) biomarker disclosure have answered important questions about individuals’ experiences learning amyloid results. In comparison, the experiences of individuals performing AD biomarker disclosure have been under characterized. The present study examines the clinician experience disclosing amyloid positron emission tomography (PET) results within the Alzheimer's Disease Neuroimaging Initiative's ADNI‐4 study. Methods The ADNI‐4 longitudinal cohort study includes a pragmatic process for amyloid PET disclosure for participants across the cognitive spectrum. Disclosing clinicians complete a short questionnaire after each disclosure session, reporting on the visit length, the clinician's rating of participant and study partner understanding and emotional reactions, topics discussed, challenges, assessment of the visit overall, and any feedback about the process. Results Across the first 100 disclosures (48 cognitively normal, 35 Mild Cognitive Impairment (MCI), 17 dementia) in ADNI‐4, visits lasted an average of 29.4 minutes (SD 13.9, range 10‐90). Most cognitively impaired participants had a loved one present at the disclosure visit (dementia 94%, MCI 80%) but the majority of cognitively normal participants (73%) did not. Clinicians rated understanding of the result as adequate for all study partners and the vast majority (94%) of participants. Clinicians reported feeling “very confident” in their ability to assess readiness to receive result (70%), disclose (73%), and answer questions (77%). Clinicians rated all visits as “good” or better, with two‐thirds (65%) rated as “excellent.” Frequently discussed topics included meaning of result (99%), other risk factors (72%), and emotional impact of result (49%). Stigma and discrimination were rarely discussed, coming up in 12% and 3% of disclosure sessions, respectively. Challenges were infrequent (7%) and primarily included desire for additional information and challenges related to the participant's impairment. Clinicians provided the study team feedback about the disclosure process for 25% of disclosure visits. Comments included the desire for additional information or resources, positive feedback, and the importance of the study partner. Conclusions Clinicians disclosing amyloid PET results in ADNI‐4 report high confidence, adequate participant and study partner understanding, and few challenges. These data from clinicians, in combination with participant data, will inform future disclosure practices in both research and care.

Abstract Background Individuals living in socioeconomically disadvantaged areas are disproportionately affected by dementia. However, the pathway leading from neighbourhood deprivation to cognitive symptoms is not well understood. To test our hypothesis that this relationship is associated with cerebral small vessel disease (SVD), we examined (1) whether neighbourhood deprivation related to midlife SVD burden and cognition, and (2) whether these links can be explained by modifiable lifestyle risk factors. Method In this multi‐centre cross‐sectional study, 514 cognitively healthy midlife participants aged 40‐59 years (median 52 years, 64.6% female) underwent clinical assessment and 3T MRI. Postcode data were used to obtain national indices of neighbourhood deprivation. To quantify SVD, we assessed white matter hyperintensities (WMH), perivascular spaces, cerebral microbleeds, and lacunes. Cognition was assessed using the Computerized Assessment of Information Processing (COGNITO) battery. Lifestyle risk factors were evaluated based on clinical data. Using multivariate statistics like structural equation modelling (SEM) and canonical correlation analysis (CCA), we examined associations between these constructs both globally and at the item‐level (i.e., distinction between domains of cognition/deprivation), to shed light on specific domains that could inform targeted prevention strategies. Result Neighbourhood deprivation related to greater prevalence of lifestyle risk factors ( r = 0.36, p < .001), greater SVD burden (b=0.18, p = .01; Figure 1), and greater cognitive impairment ( r = 0.36, p < .001), independent of educational attainment, sex, and age. These links with neighbourhood deprivation were largely driven by lifestyle factors relating to vascular health (sleep, physical activity, obesity, hypertension) (Figure 2), and cognitive deficits consistent with SVD (processing speed, visuospatial) (Figure 3). Residents of deprived neighbourhoods displayed greater prevalence of lifestyle risk factors, except alcohol consumption. Lower cognitive scores were most closely associated with deprivation domains of Crime and Living Environment (Figure 3). The DEPRIVATION→SVD path was mediated by lifestyle risk factors (z=2.57, p = .010), and the DEPRIVATION→COGNITION path was mediated by SVD (z=‐2.14, p = .032) (global SVD & hypertensive subtype, but not CAA‐SVD). Conclusion The pathway linking neighbourhood disadvantage to cognitive impairment at midlife is influenced by vascular risk factors and cerebrovascular burden. Tailored strategies could promote resilience against dementia by promoting health behaviours aligned with the community's unique needs.

Abstract Background Dementia with Lewy Bodies (DLB) is often misdiagnosed or conflated with Alzheimer’s Disease (AD) due to overlapping clinical presentations and neuropathological features. The presence of AD‐like features correlates with accelerated cognitive decline and a worse overall prognosis. Compared to AD, studies suggest that amyloid uptake in DLB may spare the occipital lobe. This project aims to investigate whether amyloid PET could be leveraged to differentiate between AD and DLB patients, with the goal of improving diagnostic accuracy and supporting patient stratification and safety in anti‐amyloid trials. Method This study involves collaboration across six centres (University of Geneva, BioFINDER, AMPLE, AMYPAD PNHS, MCSA, GEHC), each contributing amyloid PET imaging data from patients diagnosed with DLB based on clinical or neuropathological assessments. Moreover, each center provided an additional subset of AD and healthy controls, then matched to DLB samples based on age/sex/APOE genotype/education for comparison. A sub analysis will be performed on patients with evidence of both DLB and AD markers. Given the relatively small sample size, key aspect of the methodological approach is to reduce technical sources of variability. The processing workflow includes rigorous quality control, formatting, normalisation to MNI space, harmonisation (differential smoothing), and MRI‐based segmentation. Result The dataset currently includes amyloid PET scans (acquired using [ 11 C]PiB, [ 18 F]Flutemetamol or [ 18 F]Florbetapir) and MRI scans from ∼130 DLB patients, along with ∼150 AD patients and ∼150 controls. In addition, 99 patients positive for the CSF α‐Synuclein Seeding Amplification Assay were included. Patient data were anonymized, and a harmonised database was created, including demographic characteristics, clinical history, and results from neuropsychological assessments. Conclusion The creation of a standardized, multi‐centre amyloid PET dataset for DLB will enable the study of amyloid PET patterns at the global, regional and voxel level, in comparison with uptake in AD patients and controls. This dataset will serve as a valuable resource for investigating the neuropathological underpinnings of DLB, improving diagnostic accuracy, and potentially guiding patient stratification in anti‐amyloid trials. Efforts to integrate [ 18 F]Florbetaben and additional data are ongoing.

Key points Staphylococcus aureus showed a significant increase in relative abundance in CRSwNP patients following endoscopic sinus surgery compared to pre‐surgery samples. Other Staphylococcus species were found to correlate positively with S. aureus in patients with nasal polyps; among those, S. caprae correlated strongly while being the most represented in samples. Patients with recurrent nasal polyp growth exhibited a substantially greater postoperative increase in the relative abundance of S. aureus .

Abstract Objectives The aim of this work was to develop an American Headache Society position statement addressing diagnostic screening for migraine among girls and women. Background Despite its high prevalence and substantial negative impacts, migraine is underdiagnosed and undertreated. Diagnostic screening for migraine enables more patients to receive timely, appropriate, and effective management. Methods Development of this position statement followed the rules established by the American Headache Society Guidelines Committee. The published literature was reviewed to determine if migraine meets criteria for when disease screening is justified, to guide recommendations for screening tools, and to determine subpopulation(s) for which migraine screening is indicated. After author consensus was reached, the position statement was reviewed and approved by the American Headache Society Board of Directors. Results Migraine fulfills established criteria for conditions in which screening is appropriate since it is highly prevalent, results in significant morbidity, and exerts substantial economic and social costs. Migraine incidence and prevalence are exceptionally high among girls and women during adolescence and through menopause. Furthermore, there are valid and reliable diagnostic screening methods (e.g., ID Migraine) and effective treatments that reduce migraine symptoms and disease impact. Conclusion Yearly diagnostic screening for migraine should be included as part of women's preventive healthcare services, particularly from adolescence to menopause.

Abstract Background Erdheim-Chester disease (ECD) is a very rare histiocytic/dendritic cell neoplasm driven by mutations in genes of the MAPK pathway, such as BRAFV600E. Its clinical presentation is highly heterogeneous, and data on its natural history and prognosis in large cohorts are limited. Here, we investigated the clinical features and outcomes of a very large international cohort of patients with ECD. Methods We included patients diagnosed with ECD between 1990 and 2024, followed at 13 referral centers in Europe and the Americas, who had available clinical and follow-up data (with a minimal follow-up duration of 6 months). We analyzed the clinical presentation, treatment, and outcomes, and sought to identify predictors of survival. The study was conceived and conducted within the ECD Global Alliance network. Results A total of 1044 patients with ECD were included. The median age at diagnosis was 57 years (IQR 46-66), and the male-to-female ratio was 2.2. The median age at the first ECD manifestation was 55 years (IQR 43-65). Bone pain (20%), kidney and urinary manifestations (18%), and diabetes insipidus (11%) were the most frequently reported initial features. The median number of involved sites was 4 (IQR 3-6), most frequently including the long bones (n=768, 74%), the retroperitoneum, (n=605, 58%), the periaortic space (n=449, 43%), the CNS (n=368, 35%), the facial/orbit area (n=347, 33%), and the heart (n=334, 32%). Among 955 tested patients, 572 (60%) harbored the BRAFV600E mutation, and 86 (9%) a MAP2K1 mutation. Clinical and/or pathology overlap with Langerhans cell histiocytosis and Rosai-Dorfman-Destombes disease was observed in 115 (11%) and 42 (4%) patients, respectively. Clonal hematopoiesis was identified in 217 of 556 tested patients (39%), and a history of second cancer was reported in 272 patients (26%), including both solid (14%) and hematologic (12%) neoplasms. First-line treatment mostly included interferon-alpha (n=342, 33%) and BRAFi/MEKi (n=314, 30%), while second- and third-line treatments mostly consisted of BRAFi/MEKi (55% and 63%, respectively). After a median follow-up of 51 months (IQR 20-89), 222 (21%) patients died; causes of death were related to ECD in almost half of the patients (n=101). A multivariate Cox regression model identified the following factors as significantly associated with increased mortality: older age (HR 1.058, 95%CI 1.033-1.083; p&lt;0.001), pseudo-neurodegenerative lesions (HR 2.280, 95%CI 1.337-3.891; p=0.022), elevated CRP at diagnosis (HR 2.574, 95%CI 1.024-6.467; p=0.044), and second hematologic cancer (HR 2.639, 95%CI 1.602-4.348; p&lt;0.001). Conclusions Despite advances in treatments over the last decade, ECD remains associated with substantial mortality. Age, neurodegenerative lesions, elevated CRP levels, and the presence of a second hematologic cancer are the main predictors of poor survival.

Abstract Introduction: Patients diagnosed with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) exhibit an elevated risk of developing other cancers (OC) relative to the general population. Historically, chemoimmunotherapy (CIT) represented the cornerstone of CLL/SLL management. A systematic review of clinical trials of CIT for CLL that included 28 studies reported 352/3297 (12.6%) patients developed OC (Csanadi 2022). The introduction of targeted agents beginning in the mid-2010's, including Bruton tyrosine kinase inhibitors (BTKi) and BCL2 inhibitors, has shifted the standard of care toward these novel therapies. In this study, we determined the risk of OC in newly diagnosed CLL/SLL patients cared for at the US Department of Veteran Affairs (VA), The University of Texas MD Anderson Cancer Center, and Mayo Clinic in Rochester, MN. Methods: We identified patients with newly diagnosed CLL/SLL after 1/1/2016 using the VA Central Cancer Registry, MD Anderson, and the Mayo Clinic CLL Databases. The baseline clinical characteristics, CLL treatments, and the occurrence of OC were abstracted by electronic health record (EHR) review. Receipt of CLL directed therapy was categorized into a) CIT only; b) targeted therapy only; c) CIT and targeted therapy; and d) other (including monotherapy with monoclonal antibody therapy). The occurrence of OC was modeled using CLL treatment as a time-dependent variable. Prior and concurrent OC diagnosed within 3 months of CLL/SLL were excluded from analyses, to reduce ascertainment bias. Results: We identified 6844 patients with CLL/SLL who met inclusion criteria. Median follow up was 3.6 years (interquartile range [IQR] 1.9-5.8). The median age at diagnosis of CLL/SLL was 71 years (range, 23 - 102); most patients were white (81%) and male (90%). Although many patients had missing values, among those with available information, IGHV genes were unmutated in 884 (51%), CLL FISH panel showed del17 in 213 (7%), del11q in 389 (13%), trisomy 12 in 674 (23%), and del13q in 1508 patients (50%). A total of 2344 patients received CLL directed therapy during follow-up: 278 (12%) received CIT only, 1809 (77%) received targeted therapy (+/- monoclonal antibody), only 99 (4%) received CIT and targeted therapy and 150 (6%) monoclonal antibody therapy only. Among patients treated with targeted therapies, 950 (50%) received ibrutinib, 381 (20%) received acalabrutinib, 164 (9%) received zanubrutinib, 4 (&lt;1%) received orelabrutinib, 280 (15%) received venetoclax, and 3 (&lt;1%) received sonrotoclax. Other treatments included combinations of a covalent BTKi (cBTKi) and BCL2i in 52 (3%) patients, among others. A total of 583 patients were diagnosed with OC during the study period. Types of OC observed included neoplasms of the prostate (n=129, 22%), lung (n=118, 20%), hematologic malignancies (n=91, 16%), gastrointestinal tract (n=68, 12%), melanoma (n=66, 11%), kidney and bladder (n=44, 8%), head and neck (n=19, 3%), and other/unknown (n=48, 8%). Estimated risk of occurrence of OC was 4.2% (95%CI 3.8-4.8%) at 24 months and 9.7% (95%CI 8.9-10.6%) at 60 months after a diagnosis of CLL/SLL. Multivariable analyses demonstrated that older age (HR: 1.013, 95%CI: 1.00-1.021), male sex (HR: 1.6, 95%CI: 1.1-2.3), and receipt of CLL directed therapy (HR: 1.4, 95%CI: 1.2-1.7) were associated with an increased risk of OC. When considering different types of CLL directed treatments, those who received CIT with or without targeted therapies had the highest risk of development of OC (HR: 1.6, 95%CI: 1.2-2.1). Risk of OC were also increased for those who received CIT only (HR: 1.41, 95%CI: 0.97-2.05) and those who received targeted treatments alone (HR: 1.27, 95%CI: 1.02-1.58). Conclusion: In this large dataset of newly diagnosed patients with CLL/SLL in the past ten years, approximately 10% patients developed OC at 5 years. Receipt of CLL directed therapy was associated with a 40% increased risk of development of OC compared to those patients who did not receive therapy. The risk was highest among patients who received CIT with or without targeted therapy and was still elevated in those who received CIT only or targeted therapy only.