Citations

Abstract Background Pregnancies complicated by gestational diabetes mellitus (GDM) are associated with increased risks of adverse perinatal outcomes, and with long-term metabolic and cardiovascular consequences for both mother and child. The original EMERGE randomized controlled trial (RCT) evaluated the effectiveness of early metformin in addition to usual care in women with GDM on glycaemic control and perinatal outcomes. The EMERGE Mothers and Kids study is a longitudinal follow-up of the EMERGE trial participants, designed to investigate the long-term metabolic, cardiovascular, and neurodevelopmental outcomes in mothers and their offspring. Methods This is a prospective, observational cohort study of participants and their children from the EMERGE trial (NCT06327191). A single follow-up visit will be conducted up to 6 years after the index pregnancy. Maternal assessments include anthropometric data, glucose tolerance, and metabolic parameters. Child assessments include growth metrics, adiposity measured via skinfold thickness, and neurodevelopmental status assessed through validated questionnaires. Additional data on quality of life, mental health, breastfeeding, and health economics will also be collected. Discussion This study aims to provide insights into the long-term safety and efficacy of metformin use during pregnancy and its potential impact on the long term maternal and child health outcomes, contributing to evidence-based management of GDM. Trial registration: ClinicalTrials.gov; Identifier: NCT06327191

Abstract Background Tau‐PET neuroimaging is increasingly applied to diagnose and stage, track progression, and assess response to putative disease‐modifying treatments in individuals with Alzheimer disease. However, it remains to be seen whether findings established in predominantly non‐Hispanic White (nHW) cohorts will generalize to Black and Latino participants who are underrepresented in dementia research. Method Community‐dwelling Black ( n = 83) and Latino participants ( n = 27) completed MRI (with quantification of white matter hyperintensity volumes), and amyloid‐ (PiB or florbetapir) and tau‐ (flortaucipir) PET brain imaging as part of a longitudinal study of memory and aging at Mayo Clinic in Florida. Global and regional tau‐PET standardized uptake value ratios (normalized to the cerebellar crus) were determined in Black and Latino participants and compared with findings from an independent cohort of nHW participants ( n = 110), 1:1‐matched for age, sex, education, and global Clinical Dementia Rating®. Conditional logistic modeling compared 47 regions of interest, adjusted for false discovery rate. Relevant associations between flortaucipir retention and clinical outcomes were assessed using Spearman rank correlations. Result Eighty‐three Black (mean 72±10.8‐years‐old, 63% female, 33% cognitively impaired) and 27 Latino participants (mean 65.8‐years‐old, 56% female, 11% cognitively impaired) completed neuroimaging. Data were compared with findings in 110 matched nHW individuals. Global tau‐PET burden was similar between matched cohorts (Black and nHW participants, mean SUVR: 1.34±0.39 vs 1.36±0.37, p = 0.71; Latino and nHW participants, mean SUVR: 1.17±0.09 vs 1.20±0.11, p = 0.66). Lower flortaucipir uptake was noted in the caudate ( p = 0.005) and putamen ( p = 0.022) of Black/Latino participants (vs nHW), although differences attenuated following adjustment for white matter hyperintensity volume. Global flortaucipir retention increased with age (Black: Rho=0.31; Latino: Rho=0.46; nHW: Rho=0.27; p <0.05), amyloid Centiloids (Black: Rho=0.65; Latino: Rho=0.41; nHW: Rho=0.58; p <0.05), and cognitive impairment (i.e., Clinical Dementia Rating® Sum‐of‐Box scores, Black/Latino: Rho=0.31, p = 0.07; nHW: 0.76, p <0.001). Conclusion Tau‐PET patterns were similar across ethnoracial groups after adjusting for white matter hyperintensity volumes—a biomarker of small vessel disease. Flortaucipir retention increased with age, amyloid accumulation, and cognitive impairment across all cohorts. These findings affirm the clinical and research applications of tau PET in diverse cohorts. Acknowledgements : Flortaucipir precursor and technology was supported by Avid Radiopharmaceuticals.

Abstract Background Black and Latino Americans experience a disparate dementia burden yet remain underrepresented in dementia research, including clinical trials designed to slow or prevent symptomatic Alzheimer's disease (AD). Accessible and non‐invasive AD blood biomarkers may improve identification and recruitment of underrepresented participants into AD clinical trials. There is a clear need to assess the performance of emergent plasma AD biomarkers for the detection of AD neuropathology in cognitively normal Black and Latino Americans. Method Cognitively normal Black and Latino participants underwent cognitive evaluations and PET (amyloid‐PiB, tau‐flortaucipir) imaging at Mayo Clinic in Florida. Plasma p ‐tau217 was measured using Fujirebio Lumipulse assays. We evaluated the diagnostic performance of a p ‐tau217 threshold (≥0.186 pg/mL) known to identify non‐Hispanic White participants with cognitive impairment and “positive” amyloid PET scans (>25 Centiloids). Next, we derived an optimized threshold to identify participants with “positive” amyloid PET using Youden's method. Result The cohort included 58 Black (55%) and 47 Latino‐White (45%) well‐educated (mean 16.1±2.3 years) individuals, with mean age 64.7±8.8 years, and slight female bias (63%). Plasma p ‐tau217 concentrations increased with age (rho=0.269, p = 0.004) and declined with MoCA scores (rho=‐0.225, p = 0.027). Sixty‐nine participants completed amyloid‐ and tau‐PET imaging. Plasma p ‐tau217 concentrations increased with amyloid‐ (rho=0.254, p = 0.044) but not with tau‐PET standardized uptake value ratio (rho=0.127; p = 0.334). p ‐tau217 concentrations were ≥0.186 pg/mL in 10/69 participants (14%), including 3/3 amyloid‐ and tau‐PET positive (A+T+) participants, 3/8 A+T‐ participants (sensitivity: 55%), and 4/58 A‐T‐ participants (specificity 93%). An optimized p ‐tau217 threshold of ≥0.118 pg/mL identified 10/11 A+T± participants (sensitivity 91%), and 16/58 A‐T‐ participants (specificity 73%). In A‐T‐ participants, estimated glomerular filtration rate was lower in participants with ‘false positive’ elevations in plasma p ‐tau217 (mean difference: 67 vs 81 ml/min/1.73m 2 , p = 0.004), emphasizing the need for caution when interpreting plasma p ‐tau217 concentrations in patients with decreased kidney function. Conclusion Plasma p ‐tau217 thresholds validated in participants with symptomatic AD (≥0.186 pg/mL) failed to identify early AD neuropathology in 5/8 cognitively normal Black and Latino participants. Optimized thresholds are required to improve detection of preclinical AD in Black/Latino individuals.

Abstract Background Bedside cognitive screening tools intend to reliably and efficiently detect cognitive impairment in research, clinical, and community settings. Black American (BA) and Hispanic/Latino (H/L) adults obtain lower performance on widely used screeners, largely driven by demographics and structural and social determinants of health (SSDoH). This study characterized the performance of the Montreal Cognitive Assessment (MoCA) performance in a cohort of cognitively normal ethnoracially diverse adults while considering cohort‐specific factors that contributed to misclassification of impairment. Method Cognitively normal BA and H/L participants completed a comprehensive neurological assessment, neuropsychological testing, and MRI and amyloid‐ and tau‐PET imaging as part of a longitudinal study of memory and aging at Mayo Clinic in Florida. Demographically adjusted MoCA cutoffs were applied to BA (MoCA ≤ 22) and WH/L (MoCA ≤ 24) subgroups. Hierarchical binary logistic regression assessed whether amyloid burden (Centiloid value) improved prediction of scoring below demographically adjusted MoCA cutoffs beyond demographic/SSDoH factors, including age, education, and Area Deprivation Index (ADI). Result Participants included 105 (47 WH/L, 58 BA/AA) cognitively normal adults (mean age = 64.71 years, SD = 8.91; 62.9% female) with average of 16.07 years of education (SD=2.35) and mild‐to‐moderate neighborhood disadvantage (mean ADI=47.60, SD=23.77). 40% of H/L participants (MoCA (≤ 24) and 17% of BA participants (MoCa ≤22) scored below demographically adjusted MoCA cut‐offs. For the H/L subgroup, the best fitting model included age, education, ADI, and amyloid burden ( R 2 = 0 .43, χ 2 = 10.98, p = 0.03). Age (OR=1.21, 95% CI: 0.986 – 1.487) and amyloid burden (OR = 0.83, 95% CI: 0.67 – 1.03) approached statistical significance as individual predictors ( p = 0.06, p = 0.09). In the BA/AA subgroup, the best fitting model included age, education and ADI only ( R 2 = 0.47, χ 2 = 9.06, p = 0.02), with education approaching significance as an individual predictor (OR=0.46, 95% CI: 0.21 – 1.01, p = 0.05). Conclusion Sociodemographic factors continued to drive low MoCA performance in cognitively normal individuals despite applying demographically adjusted cut‐off scores by subgroup. These factors differentially impacted performance among BA/AA and WH/L participants. Careful consideration of these factors is warranted to mitigate risk of overdiagnosing impairment based on cognitive screening across clinical and research settings.

Abstract Background The rare APOE3 ‐Christchurch ( APOE3Ch ) variant is associated with remarkable protective effects, delaying the age at onset of PSEN1 ‐E280A driven autosomal dominant Alzheimer's disease (AD). While much of the research on APOE3C h has focused on its role in AD, little is known about how this variant impacts APOE biology under non‐disease conditions. Using cortical organoids as a model system, we aim to investigate the fundamental mechanisms by which APOE3Ch alters APOE biology, including its effects on metabolism and cellular interactions, to better understand its unique properties and potential implications for broader applications. Method Cortical organoids were derived from the isogenic neurodegeneration iPSC line series, with either the APOE3 or APOE3Ch genotype. Single‐cell RNA sequencing (scRNA‐seq) was performed on three independent batches of 6‐month‐old cerebral organoids to identify pathways differentially regulated by APOE3Ch. To further investigate APOE lipidation and its effects on lipid metabolism, lipidomics analysis was conducted on 8‐month‐old cerebral organoids, offering additional insights into APOE3Ch ‐specific biological mechanisms. Validation was also carried out using iPSC‐derived astrocytes and neurons to confirm key findings. Result ScRNA‐seq revealed differences in cell populations and astrocyte subtypes between APOE3 and APOE3Ch organoids, with mitochondrial‐related pathways differentially regulated in APOE3Ch cerebral organoids. These findings were validated in iPSC‐derived astrocytes. APOE3Ch iPSC‐derived astrocytes exhibited increased APOE secretion compared to APOE3 . They also demonstrated enhanced mitochondrial function, as evidenced by increased spare respiratory capacity measured by Seahorse stress assays. Furthermore, APOE3Ch astrocytes showed reduced lipid droplet formation following oleic acid treatment. Lipidomics analysis of APOE3Ch cerebral organoids revealed decreased cholesterol ester levels, suggesting alterations in lipid metabolism. Conclusion Our findings provide novel insights into how the APOE3Ch variant alters APOE biology, revealing differences in mitochondrial function and lipid metabolism. The differential regulation of mitochondrial pathways in APOE3Ch cerebral organoids, along with the enhanced mitochondrial capacity and altered lipid metabolism observed in APOE3Ch astrocytes, highlights the unique properties of this variant. These results offer valuable mechanistic understanding that may inform future therapeutic strategies targeting APOE biology, particularly in the context of AD.

Abstract Background Self‐administered and remote digital cognitive assessments provide a scalable method for screening and longitudinal cognitive monitoring. Mayo Test Drive (MTD) is one such assessment with previously demonstrated usability, reliability, validity and multi‐device compatibility. MTD includes a computer‐adaptive word list memory test (Stricker Learning Span) and a measure of processing speed/executive functioning (Symbols Test) that combine to provide an MTD Composite. This study aimed to develop a conditional normative model predicting longitudinal cognitive change for MTD, and to validate the model in two independent samples of cognitively unimpaired (CU) and mild cognitive impairment (MCI)/dementia (DEM) participants. Method 1355 CU participants at initial MTD assessment with 2‐4 consecutive MTD assessments every 7.5 months comprised the development dataset. Linear mixed effects models were used to construct a conditional normative model for MTD assessments 2‐4. The baseline model was chosen a priori , consisting of age, sex, education, baseline score, number of assessments, and time. Device type, race, and baseline score by time interactions were also considered. Variables were only added if a >1% increment in r‐squared was observed. The models were externally validated in 113 CU and 51 MCI/DEM patients. Following model development, the data were updated and additional follow‐up MTD assessments were added for many participants, including the addition of additional CU validation data at test 3 ( N = 126) and 4 ( N = 279). T‐tests compared observed and predicted differences and residual z‐scores between development and validation at each follow‐up assessment. Result Table 1 presents demographic variables. No additional variables increased the r‐squared by >1%. The final models are presented in Table 2. Age, baseline score, sex, and education were significant. Residual z‐scores were not significantly different between CU development and CU validation cohorts, indicating observed scores were in line with model predicted scores. Residual z‐scores were significantly worse among MCI/DEM compared to CU development in 11/12 comparisons (Figure 1), indicating observed scores were below model predicted expectations and implying sensitivity to longitudinal cognitive decline. Conclusion These longitudinal normative models can be used to identify individuals with follow‐up scores outside of expected predicted ranges, signifying abnormal longitudinal cognitive decline.

Abstract Background Disparities in structural and social determinants of health in Latino and Black communities may increase the burden of Alzheimer disease and related dementias (ADRD). Identifying dementia risk factors, which may account for up to 45% of ADRD risk, is crucial to implement effective risk‐reduction strategies. This study aimed to assess ADRD risk factors in community‐dwelling, cognitively normal, Latino and Black Americans by measuring the frequency of modifiable dementia risk factors through subjective and objective measures. Method Community‐dwelling, cognitively normal, Latino and Black adults (≥45‐years‐old) were enrolled in a longitudinal study of memory and aging at Mayo Clinic in Jacksonville, Florida. Baseline assessments conducted between Mach 2022 and November 2024 included demographics, self‐reported race/ethnicity, and history of dementia risk factors. Socioeconomic deprivation [Area Deprivation Index (ADI) State scores] and modifiable dementia risk factors were reported by participants and directly measured, including hypertension (BP >130/80 mmHg), obesity (BMI≥30), hyperlipidemia (LDL>100 mg/dL), hyperglycemia (HbA1C >5.6%), low vitamin B12 (B12<350 pg/mL), hearing loss (bedside assessment), vision loss (bedside assessment), and depression (Geriatric Depression Scale ≥5). Result 105 participants (47 Latino, 55 Black), 64.7 (±8.8) years‐old, female 66 (63%), with 16 (±2.3) years of education were assessed. Black participants experienced higher socioeconomic deprivation than Latino participants (median ADI 7 vs 3; p <0.001). Dementia risk factors were common in Latino and Black participants. These included, hypertension (55.3%, 70.3%; p = 0.291), hyperlipidemia (58.7%, 55.8%; p = 0.908), obesity (29.8%, 45.5%; p = 0.263), hyperglycemia (51.1%, 49.1%; p = 0.834), low vitamin B12 (23.9%, 28.0%; p = 0.270), hearing loss (19.1%, 7.3%; p = 0.111), vision loss (85.1%, 85.2%; p = 0.771), and depression (6.4%, 5.5%; p = 0.168). Objective measures revealed a higher frequency of risk factors compared with participant‐provided history, highlighting a substantial proportion of unrecognized or inadequately treated risk factors: hypertension (62.3%, 45.1%; p = 0.067), hyperlipidemia (57.6%, 47.5%; p = 0.004), hyperglycemia (49%, 20%; p = <0.001), vitamin B12 deficiency (27.8%, 9.3%; p = 0.170), and depression (6.9%, 11.9%; p = 0.009). Conclusion Modifiable dementia risk factors were detected in most cognitively normal Latino and Black adults engaged in a longitudinal study of memory and aging. Objective measures highlighted unrecognized and undertreated risk factors. Active surveillance programs are needed to detect and treat modifiable ADRD risk factors in underrepresented populations.

Traumatic brain injury (TBI) is one of the leading causes of death and neurological disability worldwide. The search for biomarkers that indicate TBI severity and prognosis with greater accuracy is ongoing. This study aimed to evaluate the significance of several neuroinflammatory cytokines and chemokines, assessing their potential as biomarkers in pediatric TBI (pTBI). This was an exploratory analysis of inflammatory cytokines and chemokines measured in a subset of 26 children aged 0–18 years with TBI and 21 controls. TBI severity was determined by GCS. The functional outcome was measured via the GOS-E score at 6 weeks and 3, 6, 9, and 12 months post-injury. Serum samples were analyzed for ICAM-1, VCAM-1, SAA, CRP, IFN-g, IL-10, IL-12p70, IL-13, IL-1b, IL-2, IL-4, IL-6, IL-8, TNF-a, TNF-b, eotaxin, eotaxin-3, IP-10, MCP-1, MCP-4, MDC, MIP-1a, MIP-1b and TARC. Levels of IL-6, IL-10, IL-13, IL-16, MDC, and GM-CSF were increased, and IFN-γ, IL-5, IL-8, and eotaxin-3 were decreased at enrollment when compared with controls. Elevated IL-6 and IL-10 at enrollment were associated with severe TBI (AUC of 1, p = 0.0002 and p = <0.0001, respectively). IL-6, IL-10, IL-16, and TNF-β at enrollment and IL-5 at 24 h were elevated in children with unfavorable outcomes, with an AUC > 0.8, suggesting biomarker potential. Our data indicate that several cytokines and chemokines measured after TBI may aid in the assessment of pTBI severity and prognosis. IL-6, IL-10, and IL-16 may show potential as biomarkers for pTBI severity and outcomes.

Importance The choice of induction agent during rapid sequence intubation (RSI) of critically ill adults may affect clinical outcomes. Although ketamine and etomidate are frequently used for RSI, their comparative effectiveness remains controversial. Objective To compare the safety of etomidate vs ketamine for emergency RSI in critically ill adults. Design, Setting, and Participants This cohort study used a target trial emulation with observational data collected between March 1, 2022, and April 30, 2024, from 18 emergency departments across Brazil, with data from the Brazilian Airway Registry Cooperation. Adults who underwent RSI and received either etomidate or ketamine as a sole hypnotic agent were included; those with preintubation cardiac arrest or immediate postintubation transfer were excluded. Exposure Administration of etomidate or ketamine as the induction agent for RSI. Main Outcomes and Measures The primary outcome was 28-day in-hospital mortality. Secondary outcomes included 7-day in-hospital mortality, first-attempt intubation success, and major adverse events (new hemodynamic instability, severe hypoxemia, and cardiac arrest) within 30 minutes after intubation. Inverse probability of treatment weighting was used to adjust for confounding. Risk ratios (RRs) and risk differences (RDs) with 95% CIs were used to compare outcomes between groups. Results Among 1810 patients (median age, 64 years [IQR, 50-74 years]; 1048 men [57.9%]), 514 received ketamine and 1296 received etomidate. The median shock index was higher in the ketamine group than the etomidate group (0.81 [IQR, 0.65-1.01] vs 0.76 [IQR, 0.59-0.99]), and preintubation vasopressor use was more common in the ketamine group than the etomidate group (191 of 514 [37.2%] vs 391 of 1296 [30.2%]). Weighted 28-day mortality was higher with etomidate than ketamine (60.5% [95% CI, 57.2%-63.8%] vs 54.4% [95% CI, 45.0%-63.9%]; RR, 1.14 [95% CI, 1.03-1.27]; RD, 7.6% [95% CI, 2.0%-13.3%]). Seven-day mortality was also higher with etomidate than ketamine (35.2% [95% CI, 32.0%-38.3%] vs 30.1% [95% CI, 23.5%-36.7%]; RR, 1.19 [95% CI, 1.04-1.35]). New hemodynamic instability within 30 minutes after intubation was more frequent with ketamine (24.2% [95% CI, 20.4%-28.0%] vs 18.9% [95% CI, 16.7%-21.0%]; RR, 0.78 [0.64-0.95]). There were no statistically significant differences in the other secondary outcomes. Conclusions and Relevance In this cohort study of critically ill adults undergoing RSI, etomidate use was associated with higher in-hospital mortality at 7 and 28 days compared with ketamine. These findings highlight the need for definitive randomized clinical trials to compare both agents.