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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 < .001) and true Aβ-positive detection rate (49% [95% CI, 43-55] vs 69% [95% CI, 64-75]; P < .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 Repetitive head impacts are associated with structural brain changes and an increased risk for chronic traumatic encephalopathy, a progressive neurodegenerative disease that can only be diagnosed after death. Chronic traumatic encephalopathy is defined by the abnormal accumulation of phosphorylated tau protein, particularly at the depths of the superior frontal sulci, suggesting that sulcal morphology may serve as a relevant structural biomarker. Contact sport athletes, such as former football players, are at elevated risk due to their prolonged exposure to repetitive head impacts. Cortical atrophy linked to underlying tau accumulation may result in shallower and wider sulci, potentially making sulcal morphology an imaging marker for identifying individuals at risk for this disease. This study investigated sulcal morphological differences in former football players and examined associations with age, football-related exposure, clinical diagnosis of traumatic encephalopathy syndrome, levels of certainty for chronic traumatic encephalopathy pathology, neuropsychological performance, and positron emission tomography imaging using flortaucipir. We analysed structural magnetic resonance imaging data from 169 male former football players (mean age 57.2 (8.2) years, range 45–74) and 54 age-matched, unexposed asymptomatic male controls (mean age 59.4 (8.5) years, range 45–74). Sulcal depth and width were quantified using the CalcSulc, focusing on two regions in each hemisphere commonly affected by chronic traumatic encephalopathy pathology: the superior frontal and occipitotemporal sulci. Generalized least squares models were used to assess group differences and interactions with age and football exposure variables, including age of first exposure, total years played, and cumulative head impact exposure. An analysis of covariance evaluated relationships between sulcal morphology, clinical measures, and flortaucipir uptake, adjusting for age, race, body mass index, education, imaging site, apolipoprotein E4 status, and total intracranial volume. Former football players demonstrated significantly shallower sulcal depth in the left superior frontal sulcus compared to unexposed controls. Earlier age of first exposure and longer football careers were associated with greater widening of the left occipitotemporal sulcus. Higher cumulative head impact exposure was linked to reduced sulcal depth in the left superior frontal region. However, sulcal morphology was not associated with clinical diagnosis, levels of certainty, neuropsychological test performance, or flortaucipir imaging. These findings suggest that sulcal morphology may reflect cumulative exposure to repetitive head impacts, particularly in brain regions vulnerable to chronic traumatic encephalopathy pathology. Future ante- and post-mortem validation studies are needed to determine whether sulcal morphology can serve as a reliable in vivo biomarker of risk.

Objectives: The practice parameter was revised collaboratively by the American College of Radiology (ACR), the American Brachytherapy Society (ABS), the American College of Nuclear Medicine (ACNM), the American Radium Society (ARS), the Society of Interventional Radiology (SIR), and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). This document summarizes current evidence-based guidelines for the administration of Yttrium radioembolic therapy to the liver, including training requirements, evidence-based guidelines for administration, and safe practice for administration. Methods: This practice parameter was revised according to the process described under the heading The Process for Developing ACR Practice Parameters and Technical Standards on the ACR website (https://www.acr.org/ClinicalResources/Practice-Parameters-and-Technical-Standards) by the Committee on Practice Parameters—Interventional and Cardiovascular Radiology of the ACR Commission on Interventional and Cardiovascular, Committee on Practice Parameters and Technical Standards—Nuclear Medicine and Molecular Imaging of the ACR Commission on Nuclear Medicine and Molecular Imaging and the Committee on Practice Parameters—Radiation Oncology of the ACR Commission on Radiation Oncology in collaboration with the ABS, the ACNM, the ARS, the SIR, and the SNMMI. Results: This review seeks not to be a comprehensive discussion of radiotherapy to the liver, but rather, seeks to provide a parameter for safe and effective therapy. We discuss the qualifications of physicians involved in this therapy, basic indications, contraindications, procedural work-up, safe-handling, and regulatory requirement for the administration of selective internal radiation therapy to patients that are likely to benefit. The goal of this document is not to define which patients are best treated by these therapies, as this is best determined for individual patients after multidisciplinary review. A consistent and evidence-based approach to therapy, however, would benefit all patients who are offered this therapy. This document seeks to provide a framework for current best practices for the administration of the 2 currently available radioembolization devices. Conclusions: As Yttrium-90 radiotherapy to the liver occupies a growing role in the treatment of primary and metastatic liver cancer, this review seeks to assist clinicians of all involved specialties to optimize the efficacy and safety of these procedures.

Objective: To evaluate treatment trends and compare outcomes following fenestrated-branched endovascular aortic repair (FB-EVAR) versus open surgical repair (OSR) of thoracoabdominal aortic aneurysms (TAAA). Background: FB-EVAR has been increasingly utilized as a less invasive alternative to OSR for treatment of TAAAs. Methods: We studied patients who underwent elective FB-EVAR or OSR of TAAAs (2008-2020), since the initiation of an Advanced Endovascular Aortic Program. Primary endpoints were early major adverse events (MAE) and early and late all-cause mortality. Propensity score overlap weighting analysis was performed to adjust for measured confounders between groups. Results: There were 357 (70.8%) patients treated by FB-EVAR and 147 (29.2%) with OSR. The use of FB-EVAR increased from 16.7% in 2008 to >80% since 2017 ( P <0.001). Incidences of early MAEs were 25.8% and 49.0%, respectively; early mortality rates for FB-EVAR and OSR were 2.5% and 6.8%, respectively. In the weighted cohort, FB-EVAR patients had decreased early MAEs (weight-adjusted odds ratio [aOR], 0.28; 95% confidence interval [CI], 0.18-0.41; P <0.001) and mortality (aOR, 0.35; 95% CI, 0.17-0.73; P =0.005) versus OSR patients. Five-year survival estimates were 52.2% (95% CI, 45.2-60.4%) and 78.0% (95% CI, 70.6-86.2%), respectively. In the weighted cohort, there was no significant difference in late survival between groups (weight-adjusted hazard ratio, 1.33; 95% CI, 0.74-2.39; P =0.34). Conclusions: This study confirmed the change in practice from OSR to FB-EVAR for treatment of TAAAs over the past decade. Incidences of early MAEs and mortality were lower with FB-EVAR, with no significant difference in late survival in the weighted cohort.

Abstract Introduction While randomized clinical trials (RCT) confirmed superiority of Mepitel film (MF) in reducing acute radiation dermatitis (ARD) compared to standard-of-care (SoC), the incremental cost difference has limited its use. A cost-effectiveness analysis (CEA) was conducted from a Canadian healthcare payer’s perspective to guide policy decisions. Methods: A decision model was constructed to perform a CEA for MF compared to SoC (moisturisers) for prevention of grade 2 or higher ARD following adjuvant hypo-fractionated whole-breast radiotherapy (RT) based on a Canadian multicentre RCT. Direct and indirect cost data were collected from two oncology centres in Canada. Quality-of-life (QoL) utility values were derived from mapping Dermatology Life Quality Index (DLQI) scores for patients with grade 2 or higher ARD at week 6 of RT to EQ-5D. A willingness-to-pay (WTF) threshold of CAD 50,000 per quality-adjusted life years (QALY) gained was used. One-way sensitivity analysis was performed to account for uncertainty in decision model assumptions. Results: Base case analysis demonstrated that MF is cost-effective in preventing grade 2 or higher ARD as compared with SoC with an incremental cost-effectiveness ratio (ICER) of CAD 3,366 per QALY gained. When nursing costs were included, MF resulted in an ICER of CAD 2,823 per QALY gained. One-way sensitivity analysis showed that the results were most sensitive to the QoL utility value for ARD. All sensitivity variations remained well below the WTP threshold. Conclusions: MF is a cost-effective intervention for preventing high-grade ARD and should be recommended for patients with breast cancer undergoing adjuvant RT.

Abstract The lack of a molecular understanding of mood disorders has impeded progress in diagnosis and treatment. Glycosylation may provide insights into the complex mechanisms underlying these conditions. We conducted N-glycoproteomic analysis on dorsolateral prefrontal cortex samples from individuals with major depressive disorder (MDD) and bipolar disorder (BD), in depressive or manic states at death. Additionally, we examined depression prevalence in congenital disorders of glycosylation (CDG) through a literature review and assessment of 110 CDG patients. Glycoproteomic analysis revealed a significant increase in protein glycosylation in individuals with MDD relative to both controls and individuals with BD. Depression prevalence was lower in our pediatric and adult cohort of individuals with CDG. These results suggest brain glycosylation changes may play a role in mood disorder pathology and highlight the distinct biology of unipolar and bipolar depression. Our findings propose that impaired glycosylation may confer resilience to depression, offering potential therapeutic insights.

ABSTRACT Bipolar disorder’s (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD’s genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity beyond diagnostic subtypes.

Abstract INTRODUCTION Neurofilament light chain (NfL) quantification aids in diagnosing and predicting neurological disorders, but clinical and laboratory practices vary across centers. Differences in result interpretation and reporting further challenge test commutability. This study aimed to review the global analytical and post‐analytical methods used for NfL measurement in routine clinical practice across different contexts. METHODS We established an international working group (WG) and distributed a survey to its members to gather information on context of use (COU), (pre) analytical methods, cutoff usage, as well as the interpretation and reporting of NfL measurements. RESULTS Among the centers, 63% measured NfL in cerebrospinal fluid (CSF), 87% in blood, and 53% in both. COU was widespread, with 50% defining pathological cutoffs based on publications and 42% considering age. Reporting was primarily done through numeric results (95%). DISCUSSION Harmonizing cutoffs, reporting, and interpretation across various clinical contexts will facilitate the incorporation of this biomarker into routine clinical practice. Highlights Unique international overview of current analytical and post‐analytical methods for neurofilament light chain (NfL) measurement in routine clinical practice. Tailored sheets for each neurological application. Strategies to harmonize cutoffs, reporting, and interpretation of NfL's measurement.

Abstract Objective Myositis is a heterogeneous family of inflammatory myopathies. We sought to define the differential expression of cytokines, cytokine receptors and immune checkpoint genes in muscle biopsies from patients with different forms of myositis in order to characterize patterns of inflammation in each. Methods Bulk RNA-sequencing was performed on muscle biopsy samples from 669 patients, including 105 with DM, 80 with immune-mediated necrotizing myopathy (IMNM), 65 with anti-synthetase syndrome, 53 with IBM, 19 with anti-PM/Scl myositis, 310 with other inflammatory or genetic myopathies and 37 controls with normal tissue (NT). Myositis clinical groups and autoantibody subgroups were analysed separately. Expression data were analysed for 338 genes encoding cytokines, cytokine receptors and immune checkpoints. Myositis group-specific genes were identified from this list by finding genes that were specifically differentially expressed in one group compared with all samples and compared with NT (α &lt; 0.001). Results IBM patients had the most differentially overexpressed genes (71) among all clinical groups, including 37 that were IBM-specific. Among the top genes were several involved in type 1 inflammation, including CCL5, CXCR3, CCR5, CXCL9 and IFNG. Anti-Jo1 and anti-PM/Scl patients exhibited differential overexpression of a similar set of genes, while DM patients exhibited differential overexpression of a different set of genes involved in type 1 inflammation. IMNM patients had the least number of differentially overexpressed genes with no predominant inflammatory pattern. Conclusion Each myositis clinical group and autoantibody subgroup had differentially overexpressed inflammatory mediators, including a strong type 1 inflammatory gene signature in IBM.