Citations

Abstract INTRODUCTION Risk factors associated with sporadic non‐amnestic and early‐onset Alzheimer's disease (AD) remain underexamined. METHODS We investigated a large, clinically heterogeneous, AD cohort for frequencies of established risk factors (hypertension, hypercholesterolemia, diabetes mellitus) alongside novel factors (non–right‐handedness, learning disability, seizures, autoimmune disease). RESULTS Early‐onset AD possessed lower frequencies of established risk factors (hypertension, hypercholesterolemia, diabetes mellitus, all p < 0.001) and higher frequencies of novel factors (non–right‐handedness, learning disability, active seizure, all p < 0.001; remote seizure, p = 0.002; and autoimmune disease, p = 0.007). An age at onset < 70 maximally distinguished novel from typical factors. Principal component analysis loaded novel factors into two components, non–right‐handedness and learning disability versus seizure and autoimmune disease, which combined, resulted in an exponential decrease in age at onset from one factor alone. DISCUSSION Identifying novel factors enriched in early‐onset and non‐amnestic AD introduces new theories of AD susceptibility and phenotypic heterogeneity, with significant implications for disease prediction and treatment. Highlights We identified a suite of novel factors overrepresented in early‐onset and non‐amnestic AD. These factors can be broadly conceptualized as neurodevelopmental (non–right‐handedness and learning disability) and neural environmental (seizure and autoimmunity). The combination of these factors produced exponential decreases in AD age at onset, compared to each alone, supporting a new theoretical framework for understanding AD risk with implications for disease prediction, prevention, and therapeutic intervention.

ABSTRACT Objective Autosomal dominant progranulin ( GRN ) pathogenic variants are a genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN ‐related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that asymptomatic GRN variant carriers exhibit thalamocortical hyperconnectivity that increases with age, presumably as they are approaching symptom onset. Whether hyperconnectivity arises concomitantly with markers of neurodegeneration remains unclear. Methods Utilizing T1 and task‐free functional magnetic resonance imaging from 49 asymptomatic and 26 symptomatic GRN variant carriers, we determined the relationships between functional connectivity, as measured by voxelwise whole‐brain degree, and GRN ‐relevant markers of disease progression, including plasma neurofilament light chain concentrations, cerebrospinal fluid complement C1q and C3b protein levels, obsessive‐compulsive disorder symptom severity, and gray matter volume. Results Neurofilament light chain concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in asymptomatic GRN variant carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter volume, in symptomatic carriers. Obsessive‐compulsive disorder symptom severity was associated with hypoconnectivity across all GRN carriers. Asymptomatic carriers with thalamic hyperconnectivity tended to have lower gray matter volume in the bilateral insula and left lateral parietal cortex, early regions of atrophy in GRN ‐frontotemporal dementia. Interpretation In asymptomatic carriers, the co‐occurrence of hyperconnectivity, high neurofilament light chain, and low gray matter volume suggests that functional hyperconnectivity may portend the onset of clinical decline. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.

OBJECTIVE The Centers for Medicare & Medicaid Services (CMS) requires a low C-peptide level for insulin pump coverage unless the individual is β-cell autoantibody positive, which precludes coverage of automated insulin delivery (AID) systems for many people with type 2 diabetes. RESEARCH DESIGN AND METHODS In the Randomized Trial Evaluating the Efficacy and Safety of Control-IQ+ Technology in Adults With Type 2 Diabetes Using Basal-Bolus Insulin Therapy study evaluating the t:slim X2 insulin pump with Control-IQ+ technology, adults with insulin-treated type 2 diabetes were categorized into high C-peptide (n = 195) and low C-peptide (n = 59) groups based on CMS criteria. RESULTS In the AID group, mean HbA1c decreased from baseline by 0.8%, which was significantly greater than in the control group with both high (P &lt; 0.001) and low (P = 0.02) C-peptide levels. Results were similar in participants ≥65 years old. CONCLUSIONS The benefit of AID is present with high and low C-peptide levels. Thus, requiring a low C-peptide level as a prerequisite for AID therapy is not warranted.

Importance The Implantable Neurostimulator for the Treatment of Parkinson’s Disease (INTREPID) trial was a randomized, double-blind, sham-controlled study of subthalamic nucleus (STN) deep brain stimulation (DBS) for the treatment of Parkinson disease (PD). Objective To evaluate the long-term (5-year) outcomes and safety of STN-DBS for PD. Design, Setting, and Participants This was a prospective, randomized (3:1), 12-week double-blind sham-controlled study at 23 movement disorder centers across the US with an open-label 5-year follow-up. Patients were implanted and followed up with the Vercise DBS system from May 2013 to December 2022. Eligibility required diagnosis of bilateral idiopathic PD with more than 5 years of motor symptoms, more than 6 hours per day of poor motor function, modified Hoehn and Yahr Scale scores higher than 2, Unified Parkinson’s Disease Rating Scale (UPDRS-III) score of 30 or higher (medication-off state), and 33% or higher improvement in UPDRS-III medication-on score. Intervention Bilateral STN-DBS for moderate to advanced PD. Main Outcomes and Measures Primary outcomes included changes in UPDRS and dyskinesia scores, quality-of-life measures, and safety assessments. Exploratory analyses included medication reduction and DBS association with motor signs. Results A total of 313 patients were enrolled with 191 receiving the DBS system, and 137 participants (72%) completed the study. The study population had a mean (SD) age of 60 (7.9) years, with 139 (73%) male participants. Motor function without medication as measured by UPDRS-III improved from a mean (SD) of 42.8 (9.4) to 21.1 (10.6) at year 1 (51%; 95% CI, 49%-53%; P &amp;lt; .001) and 27.6 (11.6) at year 5 (36%; 95% CI, 33%-38%; P &amp;lt; .001). Activities of daily living without medication as measured by UPDRS-II improved from a mean (SD) of 20.6 (6.0) to 12.4 (6.1) at year 1 (41%; 95% CI, 38%-42%; P &amp;lt; .001) and 16.4 (6.5) at year 5 (22%; 95% CI, 18%-23%; P &amp;lt; .001). Dyskinesia scores decreased from 4.0 (5.1) to 1.0 (2.1) at year 1 (75%; 95% CI, 73%-75%; P &amp;lt; .001) and to 1.2 (2.1) at year 5 (70%; 95% CI, 63%-75%; P &amp;lt; .001). The levodopa equivalent dose was reduced by 28% at year 1, remaining stable at year 5 (28%; 95% CI, 26%-31%; P &amp;lt; .001). The most common serious adverse event was infection (9 participants). Ten deaths were reported, none related to the study. Conclusions and Relevance Although STN-DBS outcomes declined slightly, possibly due to the progressive nature of the disease, patients with PD sustained significant improvement in motor and activities of daily living scores, along with a stable reduction in anti-parkinsonian medication over the 5-year follow-up period.

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 Electronic portal imaging devices (EPIDs) have been in widespread clinical use for almost two decades due to favorable measurement characteristics such as fast image acquisition, high sensitivity and resolution, digital data format, long‐term stability, linear dose response, and large detection area. On‐board EPIDs are widely used as a quality assurance (QA) tool to monitor nearly every aspect of linear accelerator (linac) performance. In both the commercial QA equipment market and in clinical practice, there is a trend toward replacing conventional QA approaches with fully automated, EPID‐based QA tools. Despite widespread use, EPIDs are complex devices, and there has yet to be consensus or formal recommendations published by the AAPM for their use in routine linac QA. Task Group 330 (TG‐330) was, therefore, formed to provide guidelines and recommendations for physicists on the safe and appropriate use of EPIDs for linac QA. In particular, the report: (a) provides a comprehensive review of the characteristics and limitations of EPIDs as time‐resolved measurement devices and dosimeters; (b) summarizes the application of EPIDs for linac QA; (c) provides recommendations on efficient and effective implementations of EPID‐based QA techniques; (d) describes risks associated with the use of EPIDs for linac QA and provides examples of how risk analysis can be used to ensure the safe use of EPIDs for linac QA. Many of the guidelines in this report are drawn from the literature that is included in the references and from the collective experience of the task group members. This report does not provide recommendations on the implementation of EPID‐based patient‐specific IMRT or VMAT QA, which is the topic of AAPM's report from AAPM TG‐307.

Background Anti- N -methyl-D-aspartate receptor (anti-NMDAR) encephalitis was formally described in 2007 and includes a range of psychiatric and neurologic symptoms. Most patients with anti-NMDAR encephalitis initially present to psychiatrists for diagnosis and treatment. However, there is limited literature summarizing treatment strategies for psychiatric symptoms. In an effort to improve identification and treatment, this review article provides an overview of anti-NMDAR encephalitis, with a focus on psychopharmacologic treatment strategies. Two case reports provide a clinical context for the literature review. Methods The authors conducted a PubMed search. Results Prominent psychiatric symptoms of anti-NMDAR encephalitis include psychosis, agitation, insomnia, and catatonia. Neuroleptics may be helpful for managing psychosis and agitation, but may exacerbate movement abnormalities. Diphenhydramine and benzodiazepines are helpful for agitation and insomnia. In addition, the anticholinergic affinity of diphenhydramine can improve dystonia or rigidity attributable to anti-NMDAR encephalitis, while benzodiazepines and electroconvulsive therapy have been used for catatonia associated with this condition. Conclusions Psychiatrists play an important role in the diagnosis and treatment of anti-NMDAR encephalitis. Recognizing the typical clinical progression and closely monitoring for accompanying neurologic symptoms will facilitate diagnosis and timely treatment. Careful selection of psycho-pharmacological interventions may reduce suffering.

Abstract Jagim, AR, Horswill, CA, Dobbs, WC, Twohey, EE, Tinsley, GM, Fields, JB, and Jones, MT. Minimum wrestling weight for high school girls wrestling: Time to revisit minimal body fat percent. J Strength Cond Res 39(3): 332–339, 2025—The purpose of this study was to determine whether an alternative body fat percentage (BF%) could be established as a safer margin for minimal wrestling weight (MWW) determination by evaluating the distribution of BF% and MWW values naturally occurring for high school girls wrestling. Data from the 2022–2023 high school season were retrospectively analyzed. In total, 33,321 female wrestlers completed skinfold (SKF) assessments or bioelectrical impedance analysis (BIA) in accordance with sport governing body mandates for weight certification. Frequency statistics and descriptive analysis were performed to compute normative MWW and BF% profiles. Body fat percentage thresholds of 12% (12MWW) and the BF% value defining the lowest fifth percentile were used to determine the resulting MWW and minimum weight class for each method. The median ± interquartile range for BF% was 28.3 ± 9.2%. There was a difference ( p < 0.001) in BF% values between BIA (28.4 ± 6.8%) and SKF (29.4 ± 7.6%), but a trivial effect size (ES = 0.14). The fifth percentile for BF% was 19%, which was used for alternative MWW determination (19MWW). 12MWW and 19MWW were 11.2 ± 6.4 kg ( p < 0.001; ES = 1.8) and 8.6 ± 7.7 kg ( p < 0.001; ES = 1.1) lower than the body mass of the wrestlers at the time of weight certification. Nearly all BF% values were above the 12% threshold currently used to determine MWW. Current body weights were more than 9.1 kg above MWW values for both 12MWW and 19MWW. Increasing the minimum BF% threshold from 12 to 19% would affect a small percentage of wrestlers and improve the margin of safety for those intent on achieving a lower weight class.

Abstract Magee, MK, Fields, JB, Jagim, A, Lockard, B, Miller, A, Stroiney, D, and Jones, MT. Estimation of whole-body bone mineral density through air displacement plethysmography in a large sample of elite athletes. J Strength Cond Res 39(4): 427–432, 2025—Dual-energy x-ray absorptiometry (DXA) is used to determine bone mineral density (BMD) and body composition. Regulations and cost may limit DXA's utility in some athletic settings. Air displacement plethysmography (ADP), while able to measure body composition, does not measure BMD. The purpose was to evaluate the influence of body composition parameters obtained from ADP on BMD. Collegiate athletes (males, n = 153; females, n = 208) underwent ADP and DXA assessments. For ADP testing, the Brozek equation was used to estimate body fat percent (BF%) and fat-free mass (FFM) from body density. Dual-energy x-ray absorptiometry tests were completed to obtain BMD using the whole-body scan mode. Stepwise regression was conducted using age, body mass, height, sex, race, FFM (ADP), BF% (ADP), and sport type as independent variables. Total BMD (DXA) was the dependent variable. Accuracy and precision of the final equation were evaluated through Bland–Altman and linear regression. The final regression equation yielded an R 2 of 0.691 with race, mass, BF%, age, and sport type as significant predictors ( p < 0.05) of BMD. Bland–Altman and linear regression showed systematic {95% confidence interval [CI] (−0.619 to −0.360)} and proportional bias (95% CI [0.173–0.374]). Although an ADP-derived regression equation may not provide a precise prediction of BMD, it may be useful to establish risk for low BMD if DXA is unavailable. Dual-energy x-ray absorptiometry may not be feasible for some athletic programs; therefore, an estimation equation for BMD derived from ADP values is advantageous for practitioners. This equation may assist in screening athletes for risk of low BMD.