Citations

Abstract BACKGROUND Tau‐derived cerebrospinal fluid (CSF) biomarkers correlate with amyloid‐beta (Aβ) plaques or tau tangles in Alzheimer's disease (AD). This study assessed the effects of long‐term anti‐Aβ antibodies on amyloid plaques, tau tangles, and CSF tau species to determine the relationships between them. METHODS A post‐hoc analysis of the DIAN‐TU‐001 trial (NCT01760005) examined 142 participants at risk for dominantly inherited AD randomized to solanezumab ( n = 50), gantenerumab ( n = 52), or placebo ( n = 40). High‐resolution mass spectrometry quantified CSF tau species over four years. RESULTS Phosphorylated tau (p‐tau) species (153, 181, 217, 231) increased early in preclinical AD but were reduced with gantenerumab‐mediated Aβ plaque reduction. Nearly a decade later, MTBR‐tau243 and p‐tau205 increased, showing no association with Aβ reduction, aligning with tau tangle pathology progression. DISCUSSION Initially changing soluble p‐tau species track Aβ plaque reduction, while ptau205 and MTBR‐243 reflect tau tangle pathology, informing different pathways of therapeutic strategies. Highlights p‐tau217 and p‐tau231 correlate with Aβ‐PET and respond to Aβ‐plaque lowering therapies. Aβ immunotherapy trials support a direct link between p‐tau changes and Aβ plaques Gantenerumab reduces Aβ plaques but does not affect tau NFT‐related biomarkers. Blood‐based p‐tau217 assays may provide a non‐invasive tool to monitor Aβ therapies. MTBR‐tau243 strongly correlates with tau PET and tracks NFT pathology progression. Further studies are needed to validate tau biomarkers for tracking NFT‐targeting therapies.

The FAITH! (Fostering African-American Improvement in Total Health) Cardiovascular Health and Wellness Program is more than a decade-long community-based participatory research initiative aimed at addressing cardiovascular health disparities among African-Americans in Minnesota. Founded in 2013, the program employs a culturally tailored, community-driven approach by partnering with African-American faith communities to promote cardiovascular health through education, digital health tools, and multilevel interventions targeting the social determinants of health. Grounded in community-based participatory research principles, FAITH! prioritizes equitable academic-community partnerships, co-learning, community capacity building, and shared ownership in all aspects of research and implementation. The program’s exemplary innovations include the NIH-funded FAITH! Trial, a randomized clinical trial, testing a mobile health intervention (the FAITH! App) co-created with the African-American community, and the Techquity by FAITH! study. Techquity by FAITH! evaluates the effectiveness of a culturally relevant, community-informed mHealth intervention supported by a Digital Health Advocate network to improve overall cardiovascular health and digital health literacy. During its evolution, FAITH! has addressed emergent public health crises, including the COVID-19 pandemic, by adapting programming to provide emergency preparedness resources, health education, and vaccine outreach. Key outcomes include sustainable church-based health ministries, increased research participation, and successful translation of research into practice. The program has also contributed to research workforce development by mentoring and training diverse early-career scholars and community leaders in community-based participatory research and cardiovascular health equity research. Lessons learned highlight the transformative impact of community-based participatory research in building trust, facilitating culturally relevant dissemination, and sustaining health equity initiatives. The FAITH! model demonstrates a scalable, community-led strategy for advancing cardiovascular health in underserved populations and provides a blueprint for future initiatives aiming to reduce racial health disparities.

Objectives Directly compare the brain glucose patterns seen with [F‐18] fluorodeoxyglucose (FDG) positron emission tomography (PET) between 2 genetically determined forms of Alzheimer's disease: Down syndrome (DS) and autosomal dominant Alzheimer's disease (ADAD). Methods Cross‐sectional analyses of FDG were performed in individuals with DS (n = 76) from the Alzheimer Biomarker Consortium‐Down Syndrome (ABC‐DS), ADAD (n = 297), and neurotypical familial controls (n = 188) from the Dominantly Inherited Alzheimer Network (DIAN). Within‐group linear regression models and generalized additive models were performed for select regional FDG uptake measures (isthmus cingulate and inferior parietal, precuneus, middle temporal gyrus, and precentral gyrus). Age, sex, apolipoprotein (APOE) ε4 carrier status, and cortical amyloid burden were included within these analyses. Results Even 20 years before expected onset of clinical symptoms, FDG uptake was lower for DS compared to neurotypical familial controls ( p < 0.01). ADAD baseline FDG was similar to neurotypical familial controls until 7 years before expected symptom onset. Both symptomatic individuals with DS and ADAD had lower FDG compared to neurotypical familial controls ( p < 0.01). A higher amyloid burden was associated with lower FDG for both genetic forms, with similar rates of decline in FDG uptake for DS and ADAD who were amyloid positive. Interpretation Brain glucose metabolism is substantially lower for people with DS, even in individuals who are cognitively stable. The patterns of FDG decline are distinct in these 2 genetically determined forms of AD. The diagnostic utility of FDG‐PET is specific to the genetic form of AD. ANN NEUROL 2025;98:1237–1248

Objectives The ‘tumour, node, metastasis’ (TNM) classification of colorectal cancer (CRC) predicts prognosis and so is vital to consider in analyses of patterns and outcomes of care when using electronic health records. Unfortunately, it is often only available in free-text reports. This study aimed to develop regex-based text-processing algorithms that identify the reports describing CRC and extract the TNM staging at a low computational cost. Methods The CRC and TNM extraction algorithms were iteratively developed using 58 634 imaging and pathology reports of patients with CRC from the Oxford University Hospitals (OUH) and Royal Marsden (RMH) NHS Foundation Trusts (FT), with additional input from Imperial College Healthcare and Christie NHS FTs. The algorithms were evaluated on a stratified random sample of 400 OUH development data reports and 400 newer ‘unseen’ OUH reports. The reports were annotated with the help of two clinicians. Results The CRC algorithm achieved at least 93.0% positive predictive value (PPV), 72.1% sensitivity, 64.0% negative predictive value (NPV) and 90.1% specificity for primary CRC on pathology reports. On imaging reports, it demonstrated at least 78.0% PPV, 91.8% sensitivity, 93.0% NPV and 80.9% specificity. For the main T/N/M categories, the TNM algorithm achieved PPVs of at least 93.9% (T), 97.7% (N) and 97.2% (M), and sensitivities of 63.6% (T), 89.6% (N) and 64.8% (M). NPVs were at least 45.0% (T), 91.1% (N), 88.4% (M), and specificities 95.7% (T), 98.1% (N), 99.3% (M). Reductions in performance were mostly due to implicit staging. For extracting explicit TNM stages, current or historical, the algorithm made no errors on 400 pathology reports and six errors on 400 imaging reports. Conclusion The TNM algorithm accurately extracts explicit TNM staging, but other methods are needed for retrieving implicit stages. The CRC algorithm is accurate on non-supplementary reports, but outputs need additional review if higher precision is required.

BACKGROUND. We developed a prospective, multicenter “registry” to evaluate the effect of extracorporeal photopheresis for lung transplant recipients who develop chronic lung allograft dysfunction (CLAD) with the bronchiolitis obliterans syndrome (BOS) phenotype (CLAD/BOS) and who are refractory to conventional standard-of-care therapy. METHODS. Data from 258 lung transplant recipients enrolled in the Registry between April 2015 and April 2022 were included in this analysis. All recorded parameters (eg, demographics), including forced expiratory volume in 1 s (FEV1) measurements and indices (FEV1% baseline, FEV1 rate of decline) at several time periods, were included in multivariate linear/logistic and Kaplan-Meier analyses to evaluate potential associations with survival. RESULTS. Mortality at 6 and 12 mo after CLAD/BOS diagnosis was 5% and 14%, whereas mortality at 6 and 12 mo after enrollment was 15% and 26%, respectively. The primary cause of death in the cohort was respiratory failure or graft failure (74%). Rate of FEV1 decline (log) at enrollment was independently associated with survival (log days) from CLAD/BOS diagnosis and enrollment (r = 0.55 and r = 0.3, respectively). The rates of FEV1 decline among survivors were lower (–77 ± 89 mL/mo) compared with nonsurvivors (–148 ± 155 mL/mo) at 6 mo after enrollment (P = 0.0001). CONCLUSIONS. The rate of FEV1 decline quantified using at least 5 FEV1 measurements is a robust surrogate outcome. We plan to use these findings to revise our randomized controlled trial to facilitate risk adjustment using FEV1 rate of decline strata at enrollment and as a scientifically valid surrogate for outcome.

Background Endovascular thrombectomy (EVT) has transformed acute ischemic stroke (AIS) care, with onset-to-puncture (OTP) time widely recognized as a critical determinant of outcome. However, emerging evidence suggests that in-hospital procedure time (PT)—from arterial puncture to final recanalization—may have an equally or more significant impact. This study examines the relative contribution of PT versus OTP to functional outcomes in patients with AIS undergoing EVT. Methods A retrospective analysis was conducted of 6644 patients with AIS treated at 44 international stroke centers from the Stroke Thrombectomy and Aneurysm Registry (STAR; 2016–2023). Multivariable regression, time-equivalence analysis, and marginal effects modeling were used to assess associations between PT, OTP, and 90-day modified Rankin Scale (mRS) outcomes. Centers were stratified by procedural efficiency and compared using propensity score matching (PSM). Mediation analysis evaluated whether PT accounted for inter-center differences. Results PT and OTP were independently associated with functional outcomes; however, PT had a significantly stronger effect (adjusted OR for mRS 0–2: PT=0.56 vs OTP=0.96 per hour). Each 5 min increase in PT was equivalent to 78–100 min of additional OTP in outcome impact. Centers with faster average PT had higher rates of functional independence (number needed to treat (NNT)=10), fewer complications, and lower symptomatic intracranial hemorrhage rates. PT significantly mediated the relationship between center tier and outcomes (Sobel’s P<0.001). Conclusion While minimizing OTP remains important, PT exerts a greater influence on outcomes after EVT. Procedural efficiency should be emphasized in stroke systems of care and included in center performance metrics to improve patient outcomes.

Abstract Although follicular lymphoma (FL) typically follows an indolent course, patients with FL who experience early events, such as transformation or progression, have increased risk of death related to lymphoma. The FL24Cx is an algorithm based on a 45-target gene expression profiling (GEP) assay, which was developed and trained using 265 formalin-fixed, paraffin-embedded tissue samples on a reliable platform to predict, at the time of diagnosis, whether a patient will experience an event within 24 months. The modeling also confirmed and relied upon previously reported synergy between immune response (IR) gene expression signatures IR1 and IR2. Once locked, the 5-factor logistic regression FL24Cx model was independently validated in a retrospectively assessed cohort of 232 patients from 2 immunochemotherapy-treated arms of SWOG Cancer Research Network S0016 phase 3 clinical trial, in which it assigned 169 patients to the low-risk group with 29 events before 24 months (17.2%) and 63 patients to the high-risk group with 24 events before 24 months (38.1%). The relative risk of an event within 24 months after registration among patients who were classified into the high-risk group relative to patients who were classified into the low-risk group was 2.2 (95% confidence interval, 1.41 to 3.51). An up-front GEP biomarker, such as the FL24Cx, rigorously validated in a clinical laboratory and with a clinically relevant turnaround time, could identify and steer enrollment of patients at high risk for early events in clinical trials, thus enabling timely interpretation of such trials and increasing the pace of innovation.

Abstract Background Lung adenocarcinoma in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve lung adenocarcinoma risk prediction. Methods PRSs were developed using genome-wide association study summary statistics from East Asian (8002 cases; 20 782 controls) and European (2058 cases; 5575 controls) populations. Single-ancestry models included a PRS with 25 single nucleotide variants (PRS-25), PRS clumping and thresholding (CT), and LDpred2; multi-ancestry models included LDpred2 plus European PRS-128, PRS-CSx, and clumping and thresholding, super learning, empirical Bayes (CT-SLEB). Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium and externally validated in the Nanjing Lung Cancer Cohort. We assessed predictive accuracy via area under the curve operating procedure (AUC), with 10-year and (ages 30-80 years) absolute risks estimates. Results The best multi-ancestry PRS, using East Asian and European data via CT-SLEB, outperformed the best East Asian-only (LDpred2; AUC = 0.629, 95% confidence interval [CI] = 0.618 to 0.641), achieving an AUC of 0.640 (95% CI = 0.629 to 0.653) and odds ratio of 1.71 (95% CI = 1.61 to 1.82) per standard deviation increase. Nanjing Lung Cancer Cohort validation confirmed robust performance (AUC = 0.649, 95% CI = 0.623 to 0.676). The top 20% PRS group had a 3.92-fold higher lung adenocarcinoma risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year lung adenocarcinoma risk at age 50 years (0.42%) by age 41 years, 9 years earlier. Conclusions Multi-ancestry PRS approaches enhance lung adenocarcinoma risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

ABSTRACT Precision medicine approaches have gained attention for their potential to more effectively manage obesity by tailoring diagnosis and treatment strategies to individual characteristics, including genetic background, phenotypes, metabolic profiles, and environmental exposures. The current review evaluates the evidence for precision medicine in weight management by summarizing the proceedings of a Pennington Biomedical Scientific Symposium titled “Precision Prevention, Diagnostics, and Treatment of Obesity: Pipedream or Reality?” This review discusses the extent to which we can classify and predict obesity risk based on individual‐level factors; whether we have the diagnostic capability to prospectively identify people who will benefit most from specific interventions; whether prospective trials demonstrate superior prevention and treatment of obesity when precision approaches are applied; and whether evidence is sufficient to guide policy decisions. Expert opinions were presented on the current evidence of precision medicine for obesity to collectively evaluate key barriers and opportunities for implementation of precision approaches in clinical and public health settings.

ABSTRACT Objective The optimal treatment for neurosarcoidosis myelitis is uncertain. We characterize incident neurosarcoidosis myelitis and assess treatment response by MRI and clinical scales. Methods Incident probable or definite neurosarcoidosis myelitis in adults was retrospectively identified from 13 academic medical centers. Cases were analyzed by initial treatment. The primary outcome was T1 post‐contrast gadolinium enhancement resolution at 6 months post‐treatment. Secondary outcomes were changes in modified Rankin scale (mRS) and Expanded Disability Status Scale (EDSS) from nadir to final follow‐up. Results Two hundred two patients were identified (median diagnosis age: 47 years (IQR 39–55); male: female 1.3:1). Median nadir mRS and EDSS were 2 (IQR 2–3) and 4 (IQR 2.5–6). At initial treatment, 129 (63.9%) received prolonged corticosteroids ≥ 4 weeks (group A 1 ), 36 (17.8%) received corticosteroids < 4 weeks (B 1 ), 21 (10.4%) received corticosteroids plus sarcoidosis‐directed immunosuppressant (E), and 16 (7.9%) received corticosteroids plus non‐sarcoidosis‐directed agents (F). In 167 cases with sufficient imaging, there were no significant differences in contrast enhancement resolution at 6 months (A 1 27/106 (25.5%), B 1 9/28 (32.1%), E 5/19 (26.3%), F 5/14 (35.7%); Fisher's exact p = 0.76). There were no significant differences in changes in mRS or EDSS among treatment groups (Kruskal–Wallis p = 0.69 and 0.63, respectively) after median follow‐up of 46.5 months (IQR 18–91.3). Interpretation Different initial immunosuppression strategies did not correlate with MRI contrast enhancement resolution at 6 months or clinical scales (mRS, EDSS). However, conclusions are limited by retrospective design, imbalanced cohorts, and insensitivity of binary MRI outcomes and available clinical scales for treatment response in neurosarcoidosis.