Citations

Abstract Approximately 17% of people aged 65 years and older are anemic, and 10% of death certificates report anemia as a secondary cause of death in the United States. Nonetheless, anemia remains unexplained in 30%-50% of older adults. This unexplained anemia of aging (UAA) is a diagnosis of exclusion. The mechanism, impact, and progression of UAA remain unknown. At older ages, anemia adds to pre-existing co-morbidities with significant adverse health consequences, representing a compelling unmet clinical concern. The National Institute on Aging held a workshop in 2024 to discuss current knowledge and research opportunities. Topics included the epidemiology of anemia at older age and its clinical implications; probable mechanism(s) underlying UAA, that is, low-grade inflammation’s effects on erythropoiesis; the role of microbiota in iron regulation in bone marrow; the importance of ruling out a diagnosis of leukemic clonal hematopoiesis (CH), which is more prevalent in older age; the role of senescence and aging governing hematopoiesis; and the effects of sex hormones on hematopoietic stem cell aging. Understanding the roles of these factors could reduce the proportion of the older anemic population whose anemia remains unexplained and offer insights into new potential diagnostic and intervention strategies. Speakers reviewed previous clinical trials in patients with UAA and CH. They discussed lessons learned and future research priorities, including efforts to develop new diagnostic algorithms and potential uses of machine learning.

Abstract Repetitive head impacts are common in contact and collision sports and are linked to structural brain changes and an elevated risk of neurodegenerative diseases such as Chronic Traumatic Encephalopathy. Identifying early in vivo structural markers remains challenging. Although diagnosis currently requires post-mortem confirmation, clinical symptoms, including cognitive impairment and behavioural changes, are reflected in the diagnosis of Traumatic Encephalopathy Syndrome. These symptoms align with dysfunction in key brain regions—amygdala, hippocampus and thalamus—which support memory, emotion and behaviour and commonly show tau pathology in Chronic Traumatic Encephalopathy. This study uses shape analysis to examine structural differences in these regions between former American football players and unexposed asymptomatic controls and evaluates the influence of age, head impact exposure and clinical diagnosis on brain structure. We analyzed brain morphology in former American football players (n = 163) and unexposed, asymptomatic controls (n = 53). Structural segmentation was performed with FreeSurfer 7.1, and the shape analysis pipeline was used to generate subregional reconstructions. Vertex-level morphometry, based on the logarithm of the Jacobian determinant and radial distance, quantified local surface area dilation and thickness. Group differences were examined with covariate-adjusted linear regression models contrasting football players and controls, as well as participants with and without a Traumatic Encephalopathy Syndrome diagnosis. Partial correlations examined the influence of age, age of first football exposure and cumulative head impact index metrics, including frequency, linear acceleration and rotational force. Models were adjusted accordingly for age, body mass index, education, race, imaging site, apolipoprotein ϵ4 status and total intracranial volume. Former football players exhibited bilateral surface area contractions in the hippocampus and amygdala, along with reduced amygdala thickness, compared to controls. Older age was associated with widespread surface contractions and thinning across all regions, except for preserved thickness in the left hippocampus. An earlier age of first exposure to football correlated with surface contractions in the thalamus and left hippocampus. Greater cumulative linear acceleration was linked to bilateral hippocampal surface contractions and reduced thickness in the left thalamus, while greater rotational force exposure was associated with hippocampal thinning. No significant structural differences were found between players with and without a diagnosis of Traumatic Encephalopathy Syndrome. These findings extend volume-based research by revealing localized alterations in surface area dilation and thickness and emphasize the roles of age and repetitive head impact exposure in long-term brain changes.

Background: Age is the strongest factor determining disease expression in multiple sclerosis (MS). We previously demonstrated biological age acceleration in pediatric-onset MS (POMS) compared to controls with both epigenetic clocks (DNAm) and telomere length (TL). It is unknown whether these markers report overlapping or distinct aging-related processes. Objectives: To determine the correlation between DNAm and TL aging markers. Methods: We conducted a cross-sectional case–control study within the US Network of Pediatric MS Centers. We calculated age acceleration residuals for the Horvath, Hannum, PhenoAge, and GrimAge epigenetic clocks and measured TL from whole blood samples to estimate telomere to somatic DNA ratios (T/S ratio). We employed multivariable analysis of covariance to assess the correlation between DNAm estimates and TL. Results: We analyzed biological ages in 270 participants (125 POMS, mean 15.7 years; 145 controls, mean 15.3 years). There were moderate correlations among the different DNAm clocks, but no correlations between DNAm clocks and TL in pooled analyses. In a stratified analysis, only the control group showed a modest correlation between TL and PhenoAge clock ( r = 0.2, p = 0.06). Conclusions: DNAm did not correlate with TL in this sample of POMS and controls, suggesting that these biomarkers may capture complementary and non-overlapping elements of aging-related biology.

Objective To assess real‐world effectiveness of switching disease‐modifying therapy (DMT) in pediatric multiple sclerosis (MS) and clinically isolated syndrome (CIS) initially treated with platform injectables on disease activity. Methods Of 2615 pediatric‐onset demyelinating disease patients at 12 clinics in the United States (US) Network of Pediatric MS Centers, those with MS/CIS on initial therapy with a platform injectable who switched to another class of platform injectable, oral or infusion DMT were analyzed. Relapse rate was modeled with negative binomial regression, adjusted for preidentified confounders. Results A total of 212 children switched DMT before age 18 (67% female, 95% MS). Ninety‐three switched from injectable to injectable, 76 injectable to oral, and 43 injectable to infusion. Switchers to oral or infusion were older at onset (injectable 12.3 years, oral 13.5 years, and infusion 14.2 years) and switch (injectable 14.6 years, oral 16.0 years, and infusion 15.7 years). Switchers to infusion DMT were more likely to have enhancing lesions (injectable 45%, oral 28%, and infusion 67%). Compared to injectable (annualized relapse rate [ARR] = 0.88, 95% confidence interval [CI] = 0.52–1.48), relapse rates were lower for injectable to oral (ARR = 0.34, 95% CI = 0.20–0.57; rate ratio: 0.38, 95% CI = 0.21–0.69) and injectable to infusion (ARR = 0.18, 95% CI = 0.09–0.37; rate ratio: 0.21, 95% CI = 0.10–0.44) ( p < 0.001). Adjusted number needed to treat in person‐years to prevent 1 relapse with oral over injectable was 1.84 (95% CI = 1.03–8.69) and infusion over injectable 1.43 (95% CI = 1.00–3.88). Interpretation Switching from platform injectable to oral or infusion compared to other platform injectable DMT led to better disease control in pediatric MS. Long‐term safety data are required. ANN NEUROL 2026;99:715–729

Background: Breast cancer polygenic risk scores (PRS) and traditional risk models (e.g., the Gail model [Gail]) are known to contribute largely independent information, but it is unclear how the overlap varies by ancestry, age, disease type (invasive breast cancer, DCIS), and risk threshold. Methods: In a retrospective case–control study, we evaluated risk prediction performance in 180,398 women (161,849 of European ancestry; 18,549 of Asian ancestry). Odds ratios (ORs) from logistic regression models and the area under the receiver operating characteristic curve (AUC) were estimated. Results: PRS for invasive disease showed a stronger association in younger (<50 years) women (OR = 2.51, AUC = 0.622) than in women ≥ 50 years (OR = 2.06, AUC = 0.653) of European ancestry. PRS performance in Asians was lower (OR range = 1.62–1.64, AUC = 0.551–0.600). Gail performance was modest across groups and poor in younger Asian women (OR = 0.94–0.99, AUC = 0.523–0.533). Age interactions were observed for both PRS (p < 0.001) and Gail (p < 0.001) in Europeans, whereas in Asians, age interaction was observed only for Gail (invasive: p < 0.001; DCIS: p = 0.002). PRS identified more high-risk individuals than Gail in Asian populations, especially ≥50 years, while Gail identified more in Europeans. Overlap between PRS, Gail, and family history was limited at higher thresholds. Calibration analysis, comparing empirical and model-based ROC curves, showed divergence for both PRS and Gail (p < 0.001), which indicates miscalibration. In Europeans, family history and prior biopsies drove Gail discrimination. In younger Asians, age at first live birth was influential. Conclusions: PRS adds value to risk stratification beyond traditional tools, especially in younger women and Asian ancestry populations.

Background/Objectives: Erythromelalgia is a rare condition characterized by burning pain, redness, and warmth primarily in the extremities, usually worsened by heat and alleviated by cold. The objective of this study was to identify the top 10 priorities in pediatric erythromelalgia from multiple perspectives, including clinicians, people with lived experience of childhood-onset erythromelalgia, and their family members. Methods: A modified James Lind Alliance Priority-Setting Process was conducted. The top priorities were identified through four phases: (1) an international online survey to gather priorities, (2) data processing, (3) an interim prioritization online survey, and (4) a virtual workshop to set the final priorities. Results: In phase 1, 185 potential priorities were submitted by 74 respondents (53% patients, 24% family members, and 23% clinicians) that were developed into 68 unique research questions (phase 2). In phase 3, of the 68 questions, 50 were rated for importance by 58 participants (38% patients, 36% family members, and 26% clinicians), reducing the list to 25 questions. In phase 4, the top 10 was reached through consensus by 12 participants (33% patients, 25% family members, and 42% clinicians) across Canada, South Africa, the United States of America, and the United Kingdom. Conclusions: The final priorities focused on the treatment of erythromelalgia, understanding underlying mechanisms, the association of erythromelalgia with various body systems, and generating awareness. This list is the first international patient-centered research agenda for childhood-onset erythromelalgia and a call to action from key partners to improve future research and care.

Background: Spontaneous Coronary Artery Dissection (SCAD) is a cause of acute coronary syndrome, particularly among women, and is associated with psychological distress, including depression, anxiety, and post-traumatic stress (PTSD) symptoms. Fibromuscular dysplasia (FMD), a vascular condition that alters the arteries, is often found in patients with SCAD, adding complexity and uncertainty with a second serious diagnosis. This study examined the differences in mental health symptoms between SCAD survivors with and without FMD to better understand their unique psychosocial needs and inform interventions to enhance patient outcomes. Methods: Patients diagnosed with SCAD within the past 3 years were recruited from 6 Canadian cardiac hospitals. Participants completed questionnaires assessing socio-demographics, comorbidities, and validated psychological measures, including Patient Health Questionnaire-9 (PHQ-9) for depression, Generalized Anxiety Disorder-7 (GAD-7) for generalized anxiety, Cardiac Anxiety Questionnaire (CAQ) for cardiac-related anxiety, and PTSD Checklist (PCL-5) for PTSD symptoms. Differences in mental health outcomes between SCAD survivors with and without FMD were analyzed using t-tests for continuous variables and chi-square tests for categorical variables. Results: The study included 326 participants (92.9% female; mean age 53.3 years), with 67 participants (20.6%) having a confirmed diagnosis of FMD at the time of questionnaire completion (39.3% FMD at study completion). Post-SCAD, patients with FMD reported significantly higher scores than patients without FMD on the GAD-7 (6.4±5.9 vs. 4.7±4.9, p = .028), CAQ (29.9±13.1 vs. 26.0±12.3, p = .023), and PCL-5 (17.2±15.4 vs. 13.3± 14.0, p = .048). The proportion of SCAD survivors with FMD scoring in the clinically diagnostic range was significantly higher than those in patients without FMD: 32.8% vs. 20.8% for depression, 31.3% vs. 17.4% for anxiety, 64.2% vs. 49.2% for cardiac anxiety, and 25.4% vs. 11.6% for PTSD (all p < .05). Conclusions: Our findings suggest that SCAD survivors with comorbid FMD experience significantly higher distress —depression, generalized anxiety, cardiac-related anxiety, and PTSD symptoms—compared to those without FMD. Longitudinal research is needed to explore the role of these mental health concerns in long-term mental health and cardiac outcomes. Enhanced psychological interventions for those with FMD may be required.

Background: The progression of CHF after MI has been traditionally evaluated by serial changes in EF. However, mechanical parameters can provide a greater insight into cardiac function. Wall strain measures myocardial deformation, and reflects contractile function as a percentage change in length. Wall stress represents the force per unit area on the myocardium, as an evaluation of LV afterload. The relationship between wall stress and wall strain is termed Young’s modulus, and it represents cardiac elasticity. This study leverages in-vivo Young’s modulus analysis derived from cardiac MRI, which has the potential to quantify the extent of myocardial remodeling, and aid in early detection of heart failure progression. Hypothesis: We hypothesize that Young’s modulus offers a more detailed assessment of regional wall motion abnormality than conventional imaging measures alone. Methods: Male Yucatan mini-swine underwent 90-minute balloon occlusion-reperfusion of the left anterior descending coronary artery to induce MI (N=13). Cardiac MRIs were obtained at baseline and 1-month post-MI. Cardiac wall stress and wall strain were calculated separately in the anteroseptal (infarcted) and inferolateral (non-infarcted) regions, and in the longitudinal and circumferential fiber orientations. These measurements were correlated to determine the Young’s modulus of the LV. Results: Anteroseptal and inferolateral longitudinal Young’s modulus increased from 28.01±8.14 to 67.14±15.08 kPa (p < 0.05) from 13.88±1.92 to 38.80±7.29 kPa (p < 0.001), respectively. Anteroseptal and inferolateral circumferential Young’s modulus increased from 34.61±10.33 to 119.17±30.94 kPa (p < 0.05) and from 16.77±1.32 to 58.76±18.98 kPa (p < 0.001), respectively. The regional changes were accompanied by a decrease in EF from 60.6±1.5 to 50.9±3.3% (p < 0.01). Discussion: Our findings show that Young’s modulus is a valuable parameter in quantifying regional changes that occur with LV systolic dysfunction after ischemic insult; specifically that regional abnormalities occur in the non-infarcted area as well as the infarcted area––a change that would not be picked up by global LV EF. Thus, quantifying regional and directional cardiac elasticity non-invasively is a novel parameter that warrants further study. Prior research has explored the in-vitro characteristics of cardiac elasticity, but there is limited research that details the in-vivo changes within any disease affecting myocardial fiber contractility.