Citations

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

Abstract Autoinflammatory syndromes are increasingly recognized as heterogeneous disorders of innate immune dysregulation, often overlapping in clinical and genetic features. Although pulmonary manifestations are uncommon, several autoinflammatory conditions such as VEXAS syndrome, juvenile rheumatoid arthritis, adult-onset Still’s disease, and Familial Mediterranean Fever can produce inflammatory pulmonary nodules that mimic metastatic malignancy. Recognition of these presentations is critical, as they can respond dramatically to immunosuppressive therapy once the correct diagnosis is established. We describe a diagnostically challenging case of a young adult male initially suspected to have metastatic lung cancer, whose evaluation ultimately suggested a previously uncharacterized autoinflammatory process. We present a 26-year-old previously healthy male with progressive dry cough, exertional dyspnea, diffuse myalgias, small joint arthritis involving the fingers, wrists, and ankles, tendonitis, a Gottron-like rash on the hands and lower extremities, low-grade fevers, and occasional bloody stools. Initial external workup revealed a right infrahilar mass, right lower lobe pleural thickening, small pleural effusion, and mediastinal and hilar lymphadenopathy on CT chest, with corresponding PET activity. Initially suspected to have metastatic lung cancer, he was informed his prognosis was poor. However, transbronchial, EBUS, and mediastinal lymph node biopsies showed only active inflammation without malignancy. On presentation to our facility, a broad differential was pursued, with suspicion for an autoinflammatory or autoimmune etiology. Pulmonary function testing was normal. Laboratory evaluation revealed ESR >100, elevated CRP, positive ANA (1:160), negative HLA-B27, normal ferritin, and negative S100 staining. Cytokine analysis showed elevated TNF, IL-6, MCP-1, IL-2, and IL-18. Targeted variant testing identified a UBA1 gene variant, c.123G>T p.(M41L), with low-level mosaicism (0.004%), and a heterozygous MEFV mutation. Although his ethnicity made Familial Mediterranean Fever unlikely, these findings raised the possibility of overlapping somatic and germline contributions to innate immune activation. He was treated empirically with immunosuppression for a presumed multisystem inflammatory disorder, resulting in resolution of symptoms and marked radiologic improvement. This case highlights the expanding spectrum of adult-onset autoinflammatory diseases that may present with pulmonary findings mimicking malignancy. The coexistence of low-level UBA1 mosaicism and MEFV mutation suggests a potential interaction between somatic and inherited variants in triggering inflammation. Similar to the recent discovery of VEXAS syndrome, this case may represent a novel subtype of autoinflammatory disease. Continued genomic and immunologic investigation is warranted, as timely recognition and immunosuppressive therapy can lead to dramatic recovery. This abstract is funded by: None

Invasive lobular breast carcinoma (ILC), the most common special histological subtype of breast cancer, is characterized by nearly universal expression of estrogen receptor alpha (ER) and unique sites of metastases, neither of which is fully recapitulated by genetically engineered mouse models. Using reporter-labeled ILC mouse xenografts, herein we used mammary fat pad, tail vein and intracardiac orthotopic growth to analyze spontaneous and experimental metastasis and gene expression. We observed ER-positive primary tumors with single-file histology and collagen deposition, and spontaneous metastasis from the mammary fat pad to bones, ovaries, and brain including the leptomeninges, thereby closely mirroring the growth and metastatic spread of human ILC. Brain metastases showed strong ER staining, confirmed by sequencing analyses which identified estrogen signaling as top activated pathway, and the lesions exhibited robust response to endocrine therapy. In summary, we report endocrine responsive mammary fat pad, tail vein and intracardiac xenografts that faithfully demonstrate unique ILC features and can serve as invaluable pre-clinical translational platforms for validating candidate ILC genetic drivers and testing novel therapeutics.

ABSTRACT Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive sarcomas with poor prognosis and a strong tendency for metastasis and relapse. Surgical removal remains the mainstay of treatment but is frequently ineffective or impractical. Currently, no effective targeted therapy exists for this type of malignancy. PRMT5 has recently emerged as a promising therapeutic target in various human cancers with MTAP loss, which results in cancer cell dependency on PRMT5 activity. The frequent loss of MTAP in MPNSTs suggests that PRMT5 inhibition is a promising therapeutic option and enables the stratification of cancer patients with few treatment options. We first examined human nerve sheath tumor samples and found that increased PRMT5 expression and activity correlated with MTAP loss in 86.8% (33/38) of MPNSTs and in atypical neurofibromatous neoplasm with uncertain biologic potential (ANNUBP) (5/5). When PRMT5 activity was inhibited genetically and chemically, the cell growth of MTAP-deficient MPNST cell lines was suppressed, but not that of MTAP-proficient MPNST cell lines. Moreover, in the PRMT5-inhibited MTAP-deficient MPNST cell lines, spontaneous DNA damage accumulation was observed following G2/M cell cycle arrest. The DNA replication stress marker RPA32 decreased, and CHK1 was activated early after PRMT5 knockdown, likely contributing to the accumulation of DNA damage. In addition, we combined PRMT5 inhibition with the DNA-damaging agents doxorubicin and gemcitabine, resulting in synergistic effects and increased cancer cell death in MTAP-deficient MPNST cell lines. Together, these findings identify PRMT5 as a compelling therapeutic target in MTAP-deficient MPNSTs. This PRMT5 inhibition strategy has strong translational potential for MPNSTs. GRAPHICAL ABSTRACT

Abstract INTRODUCTION The Centiloid scale is the standard for amyloid (Aβ) PET quantification in research and clinical settings. However, variability between tracers and scanners remains a challenge. METHODS This study introduces DeepSUVR, a deep learning method to correct Centiloid quantification, by penalizing implausible longitudinal trajectories during training. The model was trained using data from 2,129 participants (7,149 Aβ positron emission tomography [PET] scans) in the Australian Imaging, Biomarkers and Lifestyle Study of ageing (AIBL)/Alzheimer's Disease Neuroimaging Initiative (ADNI) and validated using 15,807 Aβ PET scans from 10,543 participants across 10 external datasets. RESULTS DeepSUVR increased correlation between tracers, and reduced variability in the Aß‐negatives. It showed significantly stronger association with cognition, visual reads, neuropathology, and increased longitudinal consistency between studies. DeepSUVR also increased the effect size for detecting small treatment related slowing of amyloid accumulation in the A4 study. DISCUSSION DeepSUVR substantially advances Aβ PET quantification, outperforming all standard approaches, which is particularly important for clinical decision making and to detect subtle or early changes in Aβ. Highlights Novel artificial intelligence (AI)‐method that penalizes biologically implausible longitudinal trajectories, enabling the model to learn standardized uptake value ratios (SUVR) correction factors without requiring longitudinal data at inference time. Improves Centiloid consistency across tracers and studies, significantly enhancing cross‐sectional and longitudinal amyloid positron emission tomography (PET) quantification. DeepSUVR‐derived Centiloids show stronger associations with cognition, visual reads, and neuropathology. Longitudinal variability is reduced three‐ to five‐fold, enabling more reliable tracking of amyloid accumulation and better detection of treatment effects. Novel reference and target masks derived from DeepSUVR replicate most of the model's performance, offering a practical alternative for integration into existing pipelines.

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.

Importance Advances in Alzheimer disease (AD) have shifted research focus to earlier disease stages, necessitating more scalable approaches to identify cognitively unimpaired individuals with amyloid β (Aβ) pathology. Objective To assess the utility of plasma phosphorylated tau 217 (p-tau217) for classifying Aβ status in cognitively unimpaired individuals, both as a stand-alone test and in a 2-step approach where positive plasma results were confirmed using a second modality (Aβ positron emission tomography [PET] or cerebrospinal fluid [CSF]). Design, Setting, and Participants This cross-sectional cohort study used data collected between June 2009 and March 2024. We included 2916 cognitively unimpaired participants from 12 international independent observational cohorts in the US, Europe, Australia, and Canada with available plasma p-tau217 levels and CSF or PET Aβ biomarkers. Performance comparisons between mass spectrometry and immunoassay-based p-tau217 measurements were also performed (n = 964). Exposures Plasma p-tau217 levels measured by immunoassay. Main Outcome and Measures Aβ status, determined by CSF or Aβ PET biomarkers. Results Participants had a mean (SD) age of 66.9 (9.9) years; 971 (33.3%) were Aβ positive by either CSF or PET, 1667 (57.2%) were women, and 1108 (38.1%) carried at least 1 APOE ε4 allele. As a stand-alone test, plasma p-tau217 achieved a positive predictive value (PPV) of 79% (95% CI, 74-84) and an overall accuracy of 81% (95% CI, 80-82). In a 2-step workflow, the PPV and accuracy significantly increased to 91% (95% CI, 86-95). While this approach required screening of 677 individuals with plasma p-tau217 to identify 100 Aβ-positive individuals, compared to 536 participants when using PET alone, it reduced the need for PET testing to 124. Immunoassays demonstrated comparable PPVs to mass spectrometry (80% [95% CI, 74-86] vs 85% [95% CI, 81-90]; P = .12) but significantly lower overall accuracy (82% [95% CI, 79-84]% vs 88 [95% CI, 86-90]; P &amp;lt; .001) and true Aβ-positive detection rate (49% [95% CI, 43-55] vs 69% [95% CI, 64-75]; P &amp;lt; .001). Conclusions and Relevance The findings highlight the potential of plasma p-tau217 as a stand-alone test—or when used in a sequential 2-step approach alongside PET or CSF testing—as a cost-effective, scalable, and minimally burdensome strategy for identifying preclinical AD. Tailored screening workflows that incorporate p-tau217 can improve efficiency in participant selection for preclinical AD trials and, in the future, help guide access to disease-modifying treatments.

Abstract Background Methylation class pleomorphic xanthoastrocytoma (mcPXA) comprises tumors with the DNA methylation signature of classical PXA but with a wider histologic spectrum, including overlap with glioblastoma (GBM). Methods To clarify the histologic and molecular scope of mcPXA and characterize its clinical behavior, a cohort of 469 tumor samples from 458 patients matching to mcPXA by the DKFZ classifier (v12.6 score ≥0.85) was interrogated. Results Patient median age was 23 years (range 1-73 years) with a female predominance (259 female/199 male). CDKN2A/B homozygous deletion was observed in 406 of 469 (87%) samples. In samples tested for BRAF p.V600E mutations (n = 279), 240 (86%) harbored the mutation. A chr7+/chr10− pattern was observed in 103 of 469 (22%) samples. Among samples tested for TERT promoter mutations (n = 143), 32 (22%) harbored the mutation. Progression-free and overall survival of patients with mcPXA were comparable to patients with methylation class IDH-mutant astrocytoma, low grade, but a GBM-like subset (ie, cases with a pre-methylation working diagnosis of GBM) showed shorter survival. Histologic features of high grade, including palisading necrosis and microvascular proliferation, were prognostic in mcPXA. Compared to patients with BRAF p.V600E-altered GBM, patients with mcPXA were younger and had a lower frequency of TERT promoter mutations. Conclusion Tumors in mcPXA share molecular characteristics with histologically defined PXA, and high-grade histologic features can help predict their clinical behavior. The use of an epigenetic classification of PXA reveals that this group of tumors is more common than previously appreciated and warrants in-depth study to identify efficacious therapeutic options.

Abstract The Centiloid scale is the standard for Amyloid (Aβ) PET quantification, widely used in research, clinical settings, and trial stratification. However, variability between tracers and scanners remains a challenge. This study introduces DeepSUVR, a deep learning method to correct Centiloid quantification, by penalising implausible longitudinal trajectories during training. The model was trained using data from 2,098 participants (6,762 Aβ PET scans) in AIBL/ADNI and validated using 15,806 Aβ PET scans from 10,543 participants across 10 external datasets. DeepSUVR increased correlation between tracers, and reduced variability in the Aβ-negatives. It showed the strongest association with cognition, highest AUC against visual reads and best longitudinal consistency between studies. DeepSUVR also increased the effect size for detecting lower Centiloid increase per year in the A4 study. DeepSUVR advances Aβ PET quantification, outperforming standard approaches, which is particularly important for consistent decision making and to detect subtle and early changes in clinical interventions.