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INTRODUCTION: In trials of amyloid-lowering drugs for Alzheimers disease (AD), differential eligibility may contribute to under-inclusion of racial and ethnic underrepresented groups. We examined plasma amyloid beta 42/40 and positron emission tomography (PET) amyloid eligibility for the ongoing AHEAD Study preclinical AD program (NCT04468659). METHODS: Univariate logistic regression models were used to examine group differences in plasma and PET amyloid screening eligibility. RESULTS: Of 4905 participants screened at time of analysis, 1724 were plasma eligible to continue in screening: 13.3% Hispanic Black, 24.7% Hispanic White, 20.8% non-Hispanic (NH) Asian, 24.7% NH Black, and 38.9% NH White. Plasma eligibility differed across groups in models controlling for covariates (odds ratio from 1.9 to 4.0 compared to the NH White reference group, P

IntroductionTrialists need a thorough understanding of whether reactions to Alzheimer's disease (AD) biomarker information differ among racial and ethnic groups in preclinical AD trials.MethodsWe used data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease Study to analyze cognitively unimpaired participants' responses on the Impact of Event Scale (IES) 24 to 72 hours after amyloid disclosure. We fit a linear regression model to test whether mean IES scores differed among participants from specific racial and ethnic groups. We considered potential effect modification by amyloid status.ResultsReactions to disclosure did not significantly differ among participant groups based on self-reported race and ethnicity. Although the results were not significant when stratified by amyloid status, all racial and ethnic groups except for participants self-reporting Hispanic/Latino ethnicity were observed to have higher mean IES in the elevated amyloid group.DiscussionThese results support continued use of current disclosure methods in preclinical AD trials.

IntroductionThe number of American Indian and Alaska Native (AI/AN) elders is expected to double by 2060. Thus it is imperative to retain AI/AN participants in longitudinal research studies to identify novel risk factors and potential targets for intervention for Alzheimer's disease and related dementias in these communities.MethodsThe National Alzheimer's Coordinating Center houses uniformly collected longitudinal data from the network of National Institute on Aging (NIA)-funded Alzheimer's Disease Research Centers (ADRCs). We used logistic regression to quantify participant retention at 43 ADRCs, comparing self-identified AI/AN participants to non-Hispanic White (NHW) participants, adjusting for potential confounding factors including baseline diagnosis, age, sex, education, and smoking.ResultsThe odds of AI/AN participant retention at the first follow-up visit were significantly lower than those for NHW participants (adjusted odds ratio [aOR]: 0.599; 95%: 0.46-0.78; p

IntroductionWe elicited Vietnamese Americans' perspectives on culturally appropriate recruitment into a new research registry: Collaborative Approach for Asian Americans, Native Hawaiians, and Pacific Islanders (AANHPIs) Research and Education (CARE).MethodsThree focus groups were conducted with 21 Vietnamese Americans. Topics included knowledge about and experiences with research, outreach and recruitment methods for research participation and registry enrollment, and views about research incentives. Focus group transcripts were analyzed thematically.ResultsMean age of participants was 41 years (range 18-73), 57% were male, 86% were non-US born, and 81% had never participated in a research study. Themes that emerged included (1) motivations to participate in research to gain knowledge: for oneself, for family's benefit, and for the Vietnamese American community as a whole; (2) necessity of trustworthy and credible individuals/spokespersons to promote the research initiative; (3) recruitment strategies that are age-specific and culturally appropriate, and (4) importance of monetary incentives.ConclusionFindings from this study will be used to guide recruitment into and engagement with CARE among Vietnamese Americans but are also relevant for other registries aiming to diversify their participants.

BackgroundIn randomized clinical trials (RCTs), monitoring adverse events (AEs) and serious AEs (SAEs) is critical. All Alzheimer's disease (AD) RCTs require participants to enroll with a study partner.ObjectiveWe examined AE reporting rates in mild-to-moderate AD trials and their associations with study partner type.MethodsWe estimated AE reporting rates using placebo data from seven independent RCTs conducted by the Alzheimer's Disease Cooperative Study. We assessed the heterogeneity of reporting rates as a function of visits using generalized estimating equations. In the primary analysis, we tested the hypotheses that the rates of reporting differed by study partner type and time they spent with the participant weekly using Poisson regression with robust variance estimation. In all regression models, log-transformed total patient years was included.ResultsThe estimated reporting rates were 2.83 (95% CI: 2.66, 3.02), 1.18 (95% CI: 1.09, 1.28), 0.23 (95% CI: 0.19, 0.27), and 0.28 (95% CI: 0.24, 0.33) events per participant year for grade 1-3 AEs and SAEs, respectively. We estimated that greater number of visits per year was associated with increased reporting for grade 1-2 AEs and SAEs. We did not find evidence to suggest that AE reporting differed by study partner type or by time the study partner spent with the participant.ConclusionsStudy partner type and time the study partner spent with the participant did not appear to impact AE reporting. Estimated reporting rates may be useful to evaluate safety in future studies, particularly those with no control arm and similar visit frequencies.

BackgroundPrior studies of Alzheimer's disease (AD) biomarker disclosure have answered important questions about individuals' safety after learning and comprehending their amyloid PET results; however, these studies have typically employed highly structured disclosure protocols and focused on the psychological impact of disclosure (e.g., anxiety, depression, and suicidality) in homogeneous populations. More work is needed to develop flexible disclosure protocols and study outcomes in ethnoculturally representative samples.MethodsThe Alzheimer's Disease Neuroimaging Initiative (ADNI) is formally incorporating amyloid PET disclosure into the newest protocol (ADNI-4). Participants across the cognitive spectrum who wish to know their amyloid PET results may learn them. The pragmatic disclosure process spans four timepoints: (1) a pre-disclosure visit, (2) the PET scan and its read, (3) a disclosure visit, and (4) a post-disclosure check-in. This process applies to all participants, with slight modifications to account for their cognitive status. In designing this process, special emphasis was placed on utilizing investigator discretion. Participant measures include perceived risk of dementia, purpose in life, and disclosure satisfaction. Investigator assessment of the disclosure visit (e.g., challenges encountered, topics discussed, etc.) is also included.ResultsData collection is ongoing. Results will allow for more robust characterization of the impact of learning amyloid PET results on individuals and describe the perspectives of investigators.ConclusionThe pragmatic design of the disclosure process in ADNI-4 coupled with the novel participant and investigator data will inform future disclosure practices. This is especially important as disclosure of biomarker results expands in research and care.

Campus maps and architectural images from institutional websites were used to compare 45 collegiate institutions cited in prior literature as manifesting traits of either conventional or nonconformist student cultures. Based on person--environment interaction theory, it was anticipated that the physical traits of campuses associated with conventional student cultures would be more uniform than those of campuses associated with nonconformist student cultures. Nonparametric tests revealed significant differences in the anticipated direction on three of six aspects of architectural design (i.e., color, roofline, and ornamentation). Differences in uniformity of campus layout were in the anticipated direction but fell slightly short of statistical significance.

UNLABELLED: Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. SIGNIFICANCE: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293.

IntroductionAlzheimer's disease (AD) trials require enrollment with an informant.MethodsWe assessed relationships between informant replacement and Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scores across four AD trials. Using generalized estimating equations, we examined associations between replacement and change in ADCS-ADL between successive visits. We used analysis of covariance to estimate the association between replacement and 18-month change from baseline, and an F-test to compare the variance of this change.ResultsAmong 1336 participants, 63 (≈5%) experienced replacement. Between-visit mean change in ADCS-ADL was 2.44 points lower comparing replacement to stable informants (95% confidence interval [CI]: -3.91, -0.98). The difference in between-visit mean absolute change was 2.38 points (95% CI: 1.24, 3.52). Replacement was not significantly associated with an 18-month change from baseline. The ratio of variances (replacement/stable) was 1.80 (95% CI: 1.19, 2.99).DiscussionInformant replacement is associated with bias and increased variability between visits and increased variance for overall ADCS-ADL.

Abstract When multiple visual stimuli are presented simultaneously in the receptive field, the neural response is suppressed compared to presenting the same stimuli sequentially. The prevailing hypothesis suggests that this suppression is due to competition among multiple stimuli for limited resources within receptive fields, governed by task demands. However, it is unknown how stimulus-driven computations may give rise to simultaneous suppression. Using fMRI, we find simultaneous suppression in single voxels, which varies with both stimulus size and timing, and progressively increases up the visual hierarchy. Using population receptive field (pRF) models, we find that compressive spatiotemporal summation rather than compressive spatial summation predicts simultaneous suppression, and that increased simultaneous suppression is linked to larger pRF sizes and stronger compressive nonlinearities. These results necessitate a rethinking of simultaneous suppression as the outcome of stimulus-driven compressive spatiotemporal computations within pRFs, and open new opportunities to study visual processing capacity across space and time.

While deep brain stimulation (DBS) is widely employed for managing motor symptoms in Parkinson's disease (PD), its exact circuit mechanisms remain controversial. To identify the neural targets affected by therapeutic DBS in PD, we analyzed DBS-evoked whole brain activity in female hemi-parkinsonian rats using functional magnetic resonance imaging (fMRI). We delivered subthalamic nucleus (STN) DBS at various stimulation pulse repetition rates using optogenetics, allowing unbiased examination of cell-type specific STN feedforward neural activity. Unilateral optogenetic STN DBS elicited pulse repetition rate-dependent alterations of blood-oxygenation-level-dependent (BOLD) signals in SNr (substantia nigra pars reticulata), GP (globus pallidus), and CPu (caudate putamen). Notably, this modulation effectively ameliorated pathological circling behavior in animals expressing the kinetically faster Chronos opsin, but not in animals expressing ChR2. Furthermore, mediation analysis revealed that the pulse repetition rate-dependent behavioral rescue was significantly mediated by optogenetic DBS induced activity changes in GP and CPu, but not in SNr. This suggests that the activation of GP and CPu are critically involved in the therapeutic mechanisms of STN DBS.

Abstract Necessary diversification of battery chemistry and related cell design call for investigation of more exotic materials and configurations, such as solid-state potassium batteries. In the core of their development lies the necessity of discovering new and electrochemically more efficient inorganic solid-state electrolytes. This review focuses on suitable chemical structures, their fundamental properties and status of the materials synthesis, related electrochemical performance, contemporary characterization techniques and modeling efforts for inorganic solid-state potassium electrolytes.

High-temperature (470-1170 K) properties of CdTe:P single crystals, grown by Bridgman technique, with an initial concentration of impurities in the melt 1×1019 at/cm3, were investigated by measuring of the Hall effect. Experimental results indicate that up to the temperature of ~700 K samples had p-type conductivity and above ~940 K – n-type one. Character of isothermal dependences of Hall constant strongly differs from the dependence of the undoped material due to the influence of impurities. Acceptor effect of phosphorus is observed up to 1170 K, it shows a high content of acceptor impurity form (PTe). The low-temperature electric measurements data confirm the fact of phosphorus high solubility in CdTe. The results of IR microscopy indicate that the introduction of phosphorus into CdTe crystal resulted in almost complete elimination of second phase inclusions with size ≥1 μm, which are usually present in such material.