Sex differences in trajectories of cortical development in autistic children from 2-13 years of age.

Previous studies have reported alterations in cortical thickness in autism. However, few have included enough autistic females to determine if there are sex specific differences in cortical structure in autism. This longitudinal study aimed to investigate autistic sex differences in cortical thickness and trajectory of cortical thinning across childhood. Participants included 290 autistic (88 females) and 139 nonautistic (60 females) individuals assessed at up to 4 timepoints spanning ~2-13 years of age (918 total MRI timepoints). Estimates of cortical thickness in early and late childhood as well as the trajectory of cortical thinning were modeled using spatiotemporal linear mixed effects models of age-by-sex-by-diagnosis. Additionally, the spatial correspondence between cortical maps of sex-by-diagnosis differences and neurotypical sex differences were evaluated. Relative to their nonautistic peers, autistic females had more extensive cortical differences than autistic males. These differences involved multiple functional networks, and were mainly characterized by thicker cortex at ~3 years of age and faster cortical thinning in autistic females. Cortical regions in which autistic alterations were different between the sexes significantly overlapped with regions that differed by sex in neurotypical development. Autistic females and males demonstrated some shared differences in cortical thickness and rate of cortical thinning across childhood relative to their nonautistic peers, however these areas were relatively small compared to the widespread differences observed across the sexes. These results support evidence of sex-specific neurobiology in autism and suggest that processes that regulate sex differentiation in the neurotypical brain contribute to sex differences in the etiology of autism.

Altered behavior, brain structure, and neurometabolites in a rat model of autism-specific maternal autoantibody exposure.

Maternal immune dysregulation is a prenatal risk factor for autism spectrum disorder (ASD). Importantly, a clinically relevant connection exists between inflammation and metabolic stress that can result in aberrant cytokine signaling and autoimmunity. In this study we examined the potential for maternal autoantibodies (aAbs) to disrupt metabolic signaling and induce neuroanatomical changes in the brains of exposed offspring. To accomplish this, we developed a model of maternal aAb exposure in rats based on the clinical phenomenon of maternal autoantibody-related ASD (MAR-ASD). Following confirmation of aAb production in rat dams and antigen-specific immunoglobulin G (IgG) transfer to offspring, we assessed offspring behavior and brain structure longitudinally. MAR-ASD rat offspring displayed a reduction in pup ultrasonic vocalizations and a pronounced deficit in social play behavior when allowed to freely interact with a novel partner. Additionally, longitudinal in vivo structural magnetic resonance imaging (sMRI) at postnatal day 30 (PND30) and PND70, conducted in a separate cohort of animals, revealed sex-specific differences in total and regional brain volume. Treatment-specific effects by region appeared to converge on midbrain and cerebellar structures in MAR-ASD offspring. Simultaneously, in vivo 1H magnetic resonance spectroscopy (1H-MRS) data were collected to examine brain metabolite levels in the medial prefrontal cortex. Results showed that MAR-ASD offspring displayed decreased levels of choline-containing compounds and glutathione, accompanied by increased taurine compared to control animals. Overall, we found that rats exposed to MAR-ASD aAbs present with alterations in behavior, brain structure, and neurometabolites; reminiscent of findings observed in clinical ASD.

Caregivers of People With Mild Cognitive Impairment and Dementia: Characterizing Social and Psychological Outcomes.

OBJECTIVE: Little is known about caregiving across the spectrum of cognitive impairment [mild cognitive impairment (MCI) to dementia] and how early life and sociocultural factors affect caregiver health. In this study, we characterized differences between caregivers of those with MCI versus those with dementia. METHODS: A total of 158 caregivers were enrolled in this cross-sectional study, most of whom were dementia caregivers (65%). Caregivers completed questionnaires on depressive symptoms, self-rated health (SRH), perceived burden and stress, as well as psychosocial and demographic measures. RESULTS: Caregivers of those with MCI reported fewer depressive symptoms and lower stress and burden compared with dementia caregivers. In adjusted analyses caregivers with greater stress reported more depressive symptoms. For SRH, at lower stress levels, having a sibling die before age 18 (ie, early life adversity) was associated with poorer SRH; at higher stress levels, having early life adversity was associated with better SRH. At lower burden levels, more live births were associated with worse SRH; at higher burden levels, more live births were associated with better SRH. CONCLUSIONS: Early life factors are relevant for caregivers of those with cognitive impairment and targeted prevention and early intervention may be helpful in alleviating caregiver burden and stress.

Long-term characterization of cognitive phenotypes in children with seizures over 36 months.

RATIONALE: Children with new-onset epilepsies often exhibit co-morbidities including cognitive dysfunction, which adversely affects academic performance. Application of unsupervised machine learning techniques has demonstrated the presence of discrete cognitive phenotypes at or near the time of diagnosis, but there is limited knowledge of their longitudinal trajectories. Here we investigate longitudinally the presence and progression of cognitive phenotypes and academic status in youth with new-onset seizures as sibling controls. METHODS: 282 subjects (6-16 years) were recruited within 6 weeks of their first recognized seizure along with 167 unaffected siblings. Each child underwent a comprehensive neuropsychological assessment at baseline, 18 and 36 months later. Factor analysis of the neuropsychological tests revealed four underlying domains - language, processing speed, executive function, and verbal memory. Latent trajectory analysis of the mean factor scores over 36 months identified clusters with prototypical cognitive trajectories. RESULTS: Three unique phenotypic groups with distinct cognitive trajectories over the 36-month period were identified: Resilient, Average, and Impaired phenotypes. The Resilient phenotype exhibited the highest neuropsychological factor scores and academic performance that were all similar to controls; while the Impaired phenotype showed the polar opposite with the worst performances across all test metrics. These findings remained significant and stable over 36 months. Multivariate logistic regression indicated that age of onset, EEG, neurological examination, and sociodemographic disadvantage were associated with phenotype classification. CONCLUSIONS: This study demonstrates the presence of diverse latent cognitive trajectory phenotypes over 36 months in youth with new-onset seizures that are associated with a stable neuropsychological and academic performance longitudinally.

Standardized statistical framework for comparison of biomarkers: Techniques from ADNI.

INTRODUCTION: Well-chosen biomarkers have the potential to increase the efficiency of clinical trials and drug discovery and should show good precision as well as clinical validity. METHODS: We suggest measures that operationalize these criteria and describe a general approach that can be used for inference-based comparisons of biomarker performance. The methods are applied to measures obtained from structural magnetic resonance imaging (MRI) from individuals with mild dementia (n = 70) or mild cognitive impairment (MCI; n = 303) enrolled in the Alzheimer's Disease Neuroimaging Initiative. RESULTS: Ventricular volume and hippocampal volume showed the best precision in detecting change over time in both individuals with MCI and with dementia. Differences in clinical validity varied by group. DISCUSSION: The methodology presented provides a standardized framework for comparison of biomarkers across modalities and across different methods used to generate similar measures and will help in the search for the most promising biomarkers. HIGHLIGHTS: A framework for comparison of biomarkers on pre-defined criteria is presented. Criteria for comparison include precision in capturing change and clinical validity. Ventricular volume has high precision in change for both dementia and mild cognitive impairment (MCI) trials. Imaging measures' performance in clinical validity varies more for dementia than for MCI.

Contributions of the ADNI Biostatistics Core.

The goal of the Biostatistics Core of the Alzheimer's Disease Neuroimaging Initiative (ADNI) has been to ensure that sound study designs and statistical methods are used to meet the overall goals of ADNI. We have supported the creation of a well-validated and well-curated longitudinal database of clinical and biomarker information on ADNI participants and helped to make this accessible and usable for researchers. We have developed a statistical methodology for characterizing the trajectories of clinical and biomarker change for ADNI participants across the spectrum from cognitively normal to dementia, including multivariate patterns and evidence for heterogeneity in cognitive aging. We have applied these methods and adapted them to improve clinical trial design. ADNI-4 will offer us a chance to help extend these efforts to a more diverse cohort with an even richer panel of biomarker data to support better knowledge of and treatment for Alzheimer's disease and related dementias. HIGHLIGHTS: The Alzheimer's Disease Neuroimaging Initiative (ADNI) Biostatistics Core provides study design and analytic support to ADNI investigators. Core members develop and apply novel statistical methodology to work with ADNI data and support clinical trial design. The Core contributes to the standardization, validation, and harmonization of biomarker data. The Core serves as a resource to the wider research community to address questions related to the data and study as a whole.

Individuals with Alzheimer's disease and low tau burden: Characteristics and implications.

INTRODUCTION: Abnormal amyloid-beta (Aß) and tau deposition define Alzheimer's Disease (AD), but non-elevated tau is relatively frequent in patients on the AD pathway. METHODS: We examined characteristics and regional patterns of 397 Aß+ unimpaired and impaired individuals with low tau (A+T-) in relation to their higher tau counterparts (A+T+). RESULTS: Seventy-one percent of Aß+ unimpaired and 42% of impaired Aß+ individuals were categorized as A+T- based on global tau. In impaired individuals only, A+T- status was associated with older age, male sex, and greater cardiovascular risk. α-synuclein was linked to poorer cognition, particularly when tau was low. Tau burden was most frequently elevated in a common set of temporal regions regardless of T+/T- status. DISCUSSION: Low tau is relatively common in patients on the AD pathway and is linked to comorbidities that contribute to impairment. These findings have implications for the selection of individuals for Aß- and tau-modifying therapies.

The Alzheimer's Disease Neuroimaging Initiative in the era of Alzheimer's disease treatment: A review of ADNI studies from 2021 to 2022.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to improve Alzheimer's disease (AD) clinical trials. Since 2006, ADNI has shared clinical, neuroimaging, and cognitive data, and biofluid samples. We used conventional search methods to identify 1459 publications from 2021 to 2022 using ADNI data/samples and reviewed 291 impactful studies. This review details how ADNI studies improved disease progression understanding and clinical trial efficiency. Advances in subject selection, detection of treatment effects, harmonization, and modeling improved clinical trials and plasma biomarkers like phosphorylated tau showed promise for clinical use. Biomarkers of amyloid beta, tau, neurodegeneration, inflammation, and others were prognostic with individualized prediction algorithms available online. Studies supported the amyloid cascade, emphasized the importance of neuroinflammation, and detailed widespread heterogeneity in disease, linked to genetic and vascular risk, co-pathologies, sex, and resilience. Biological subtypes were consistently observed. Generalizability of ADNI results is limited by lack of cohort diversity, an issue ADNI-4 aims to address by enrolling a diverse cohort.

Overview of ADNI MRI.

The magnetic resonance imaging (MRI) Core has been operating since Alzheimer's Disease Neuroimaging Initiative's (ADNI) inception, providing 20 years of data including reliable, multi-platform standardized protocols, carefully curated image data, and quantitative measures provided by expert investigators. The overarching purposes of the MRI Core include: (1) optimizing and standardizing MRI acquisition methods, which have been adopted by many multicenter studies and trials worldwide and (2) providing curated images and numeric summary values from relevant MRI sequences/contrasts to the scientific community. Over time, ADNI MRI has become increasingly complex. To remain technically current, the ADNI MRI protocol has changed substantially over the past two decades. The ADNI 4 protocol contains nine different imaging types (e.g., three dimensional [3D] T1-weighted and fluid-attenuated inversion recovery [FLAIR]). Our view is that the ADNI MRI data are a greatly underutilized resource. The purpose of this paper is to educate the scientific community on ADNI MRI methods and content to promote greater awareness, accessibility, and use. HIGHLIGHTS: The MRI Core provides multi-platform standardized protocols, carefully curated image data, and quantitative analysis by expert groups. The ADNI MRI protocol has undergone major changes over the past two decades to remain technically current. As of April 25, 2024, the following numbers of image series are available: 17,141 3D T1w; 6877 FLAIR; 3140 T2/PD; 6623 GRE; 3237 dMRI; 2846 ASL; 2968 TF-fMRI; and 2861 HighResHippo (see Table 1 for abbreviations). As of April 25, 2024, the following numbers of quantitative analyses are available: FreeSurfer 10,997; BSI 6120; tensor based morphometry (TBM) and TBM-SYN 12,019; WMH 9944; dMRI 1913; ASL 925; TF-fMRI NFQ 2992; and medial temporal subregion volumes 2726 (see Table 4 for abbreviations). ADNI MRI is an underutilized resource that could be more useful to the research community.

Implementation and validation of face de-identification (de-facing) in ADNI4.

INTRODUCTION: Recent technological advances have increased the risk that de-identified brain images could be re-identified from face imagery. The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a leading source of publicly available de-identified brain imaging, who quickly acted to protect participants' privacy. METHODS: An independent expert committee evaluated 11 face-deidentification ("de-facing") methods and selected four for formal testing. RESULTS: Effects of de-facing on brain measurements were comparable across methods and sufficiently small to recommend de-facing in ADNI. The committee ultimately recommended mri_reface for advantages in reliability, and for some practical considerations. ADNI leadership approved the committee's recommendation, beginning in ADNI4. DISCUSSION: ADNI4 de-faces all applicable brain images before subsequent pre-processing, analyses, and public release. Trained analysts inspect de-faced images to confirm complete face removal and complete non-modification of brain. This paper details the history of the algorithm selection process and extensive validation, then describes the production workflows for de-facing in ADNI. HIGHLIGHTS: ADNI is implementing "de-facing" of MRI and PET beginning in ADNI4. "De-facing" alters face imagery in brain images to help protect privacy. Four algorithms were extensively compared for ADNI and mri_reface was chosen. Validation confirms mri_reface is robust and effective for ADNI sequences. Validation confirms mri_reface negligibly affects ADNI brain measurements.

The ADNI4 Digital Study: A novel approach to recruitment, screening, and assessment of participants for AD clinical research.

INTRODUCTION: We evaluated preliminary feasibility of a digital, culturally-informed approach to recruit and screen participants for the Alzheimer's Disease Neuroimaging Initiative (ADNI4). METHODS: Participants were recruited using digital advertising and completed digital surveys (e.g., demographics, medical exclusion criteria, 12-item Everyday Cognition Scale [ECog-12]), Novoic Storyteller speech-based cognitive test). Completion rates and assessment performance were compared between underrepresented populations (URPs: individuals from ethnoculturally minoritized or low education backgrounds) and non-URPs. RESULTS: Of 3099 participants who provided contact information, 654 enrolled in the cohort, and 595 completed at least one assessment. Two hundred forty-seven participants were from URPs. Of those enrolled, 465 met ADNI4 inclusion criteria and 237 evidenced possible cognitive impairment from ECog-12 or Storyteller performance. URPs had lower ECog and Storyteller completion rates. Scores varied by ethnocultural group and educational level. DISCUSSION: Preliminary results demonstrate digital recruitment and screening assessment of an older diverse cohort, including those with possible cognitive impairment, are feasible. Improving engagement and achieving educational diversity are key challenges. HIGHLIGHTS: A total of 654 participants enrolled in a digital cohort to facilitate ADNI4 recruitment. Culturally-informed digital ads aided enrollment of underrepresented populations. From those enrolled, 42% were from underrepresented ethnocultural and educational groups. Digital screening tools indicate > 50% of participants likely cognitively impaired. Completion rates and assessment performance vary by ethnocultural group and education.

Association of Breastfeeding Duration with Neurodevelopmental Outcomes in an Enriched Familial Likelihood Cohort for Autism Spectrum Disorder.

This study aimed to compare the breastfeeding (BF) duration of the younger siblings of children with ASD in an enriched-likelihood cohort for autism spectrum disorder (ASD), and to determine whether longer BF duration was associated with differences in neurodevelopmental outcomes in this cohort. Information on BF practices was collected via surveys in the MARBLES (Markers of Autism Risk in Babies-Learning Early Signs) study. Developmental evaluations, including the Mullen Scales of Early Learning and the Autism Diagnostic Observation Schedule, were conducted by expert clinicians. Participants' neurodevelopmental outcome was classified by an algorithm into three groups: typical development, ASD, and non-typical development. The median duration of BF was 10.70 months (interquartile range of 12.07 months). There were no significant differences in the distribution of duration of BF among the three neurodevelopmental outcome categories. Children in this enriched-likelihood cohort who were breastfed for > 12 months had significantly higher scores on cognitive testing compared to those who were breastfed for 0-3 months. There was no significant difference in ASD symptomatology or ASD risk based on BF duration.

Optimizing quantification of MK6240 tau PET in unimpaired older adults.

Accurate measurement of Alzheimer's disease (AD) pathology in older adults without significant clinical impairment is critical to assessing intervention strategies aimed at slowing AD-related cognitive decline. The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (POINTER) is a 2-year randomized controlled trial to evaluate the effect of multicomponent risk reduction strategies in older adults (60-79 years) who are cognitively unimpaired but at increased risk for cognitive decline/dementia due to factors such as cardiovascular disease and family history. The POINTER Imaging ancillary study is collecting tau-PET ([18F]MK6240), beta-amyloid (Aß)-PET ([18F]florbetaben [FBB]) and MRI data to evaluate neuroimaging biomarkers of AD and cerebrovascular pathophysiology in this at-risk sample. Here 481 participants (70.0±5.0; 66% F) with baseline MK6240, FBB and structural MRI scans were included. PET scans were coregistered to the structural MRI which was used to create FreeSurfer-defined reference regions and target regions of interest (ROIs). We also created off-target signal (OTS) ROIs to examine the magnitude and distribution of MK6240 OTS across the brain as well as relationships between OTS and age, sex, and race. OTS was unimodally distributed, highly correlated across OTS ROIs and related to younger age and sex but not race. Aiming to identify an optimal processing approach for MK6240 that would reduce the influence of OTS, we compared our previously validated MRI-guided standard PET processing and 6 alternative approaches. The alternate approaches included combinations of reference region erosion and meningeal OTS masking before spatial smoothing as well as partial volume correction. To compare processing approaches we examined relationships between target ROIs (entorhinal cortex (ERC), hippocampus or a temporal meta-ROI (MetaROI)) SUVR and age, sex, race, Aß and a general cognitive status measure, the Modified Telephone Interview for Cognitive Status (TICSm). Overall, the processing approaches performed similarly, and none showed a meaningful improvement over standard processing. Across processing approaches we observed previously reported relationships with MK6240 target ROIs including positive associations with age, an Aß+> Aß- effect and negative associations with cognition. In sum, we demonstrated that different methods for minimizing effects of OTS, which is highly correlated across the brain within subject, produced no substantive change in our performance metrics. This is likely because OTS contaminates both reference and target regions and this contamination largely cancels out in SUVR data. Caution should be used when efforts to reduce OTS focus on target or reference regions in isolation as this may exacerbate OTS contamination in SUVR data.

Time- and region-dependent blood-brain barrier impairment in a rat model of organophosphate-induced status epilepticus.

Acute organophosphate (OP) intoxication can trigger seizures that progress to status epilepticus (SE), and survivors often develop chronic morbidities, including spontaneous recurrent seizures (SRS). The pathogenic mechanisms underlying OP-induced SRS are unknown, but increased BBB permeability is hypothesized to be involved. Previous studies reported BBB leakage following OP-induced SE, but key information regarding time and regional distribution of BBB impairment during the epileptogenic period is missing. To address this data gap, we characterized the spatiotemporal progression of BBB impairment during the first week post-exposure in a rat model of diisopropylfluorophosphate-induced SE, using MRI and albumin immunohistochemistry. Increased BBB permeability, which was detected at 6 h and persisted up to 7 d post-exposure, was most severe and persistent in the piriform cortex and amygdala, moderate but persistent in the thalamus, and less severe and transient in the hippocampus and somatosensory cortex. The extent of BBB leakage was positively correlated with behavioral seizure severity, with the strongest association identified in the piriform cortex and amygdala. These findings provide evidence of the duration, magnitude and spatial breakdown of the BBB during the epileptogenic period following OP-induced SE and support BBB regulation as a viable therapeutic target for preventing SRS following acute OP intoxication.

Impact of sociodemographic disadvantage on neurobehavioral outcomes in children with newly diagnosed seizures and their unaffected siblings over 36 months.

OBJECTIVE: This study was undertaken to determine the short-term and longer term impact of sociodemographic disadvantage on the emotional-behavioral status of youths with new onset epilepsy and their unaffected siblings at the time of diagnosis and the subsequent 3 years. METHODS: Three hundred twelve youths with newly diagnosed epilepsies and 223 unaffected siblings, aged 6-16 years, were independently assessed regarding their emotional and behavioral status by their parents and teachers at baseline, and at 18 at 36 months later; youths with seizures also completed self-report measures of depression, anxiety, and hostility at those three time points. A sociodemographic disadvantage score was computed for each family (children with newly diagnosed seizures and their siblings), and families were separated into four categories from most disadvantaged to least disadvantaged. RESULTS: In both children and siblings, the least disadvantaged group exhibited the lowest level of neurobehavioral problems, whereas the most disadvantaged group showed a higher level of neurobehavioral problems across all the same behavior metrics. Findings remained stable and significant across all informants (parent, teacher, child) and across all time periods (throughout the 3-year period). Furthermore, both corrected and uncorrected linear regression analyses indicated that disadvantage was a more constant and stable predictor of behavioral and emotional problems over time compared to clinical seizure characteristics and abnormalities in magnetic resonance imaging and electroencephalographic testing. SIGNIFICANCE: Sociodemographic disadvantage bears a strong relationship to youths with emotional and behavioral problems both at the time of diagnosis as well as prospectively. The relationship is robust and reflected in reports from multiple informants (parent, teacher, child self-report), evident in siblings as well, and possibly more explanatory than traditional clinical seizure variables. Future studies will be needed to determine whether this disadvantage factor is modifiable with early intervention.

The impact of selected methodological factors on data collection outcomes in observational studies of device-measured physical behaviour in adults: A systematic review.

BACKGROUND: Accelerometer measures of physical behaviours (physical activity, sedentary behaviour and sleep) in observational studies offer detailed insight into associations with health and disease. Maximising recruitment and accelerometer wear, and minimising data loss remain key challenges. How varying methods used to collect accelerometer data influence data collection outcomes is poorly understood. We examined the influence of accelerometer placement and other methodological factors on participant recruitment, adherence and data loss in observational studies of adult physical behaviours. METHODS: The review was in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA). Observational studies of adults including accelerometer measurement of physical behaviours were identified using database (MEDLINE (Ovid), Embase, PsychINFO, Health Management Information Consortium, Web of Science, SPORTDiscus and Cumulative Index to Nursing & Allied Health Literature) and supplementary searches to May 2022. Information regarding study design, accelerometer data collection methods and outcomes were extracted for each accelerometer measurement (study wave). Random effects meta-analyses and narrative syntheses were used to examine associations of methodological factors with participant recruitment, adherence and data loss. RESULTS: 123 accelerometer data collection waves were identified from 95 studies (92.5% from high-income countries). In-person distribution of accelerometers was associated with a greater proportion of invited participants consenting to wear an accelerometer (+ 30% [95% CI 18%, 42%] compared to postal distribution), and adhering to minimum wear criteria (+ 15% [4%, 25%]). The proportion of participants meeting minimum wear criteria was higher when accelerometers were worn at the wrist (+ 14% [ 5%, 23%]) compared to waist. Daily wear-time tended to be higher in studies using wrist-worn accelerometers compared to other wear locations. Reporting of information regarding data collection was inconsistent. CONCLUSION: Methodological decisions including accelerometer wear-location and method of distribution may influence important data collection outcomes including recruitment and accelerometer wear-time. Consistent and comprehensive reporting of accelerometer data collection methods and outcomes is needed to support development of future studies and international consortia. Review supported by the British Heart Foundation (SP/F/20/150002) and registered (Prospero CRD42020213465).

Dietary inflammatory index and cardiovascular disease risk in Hispanic women from the Women's Health Initiative.

BACKGROUND: To evaluate the association between the dietary inflammatory index (DII®) and incident cardiovascular disease (CVD) in Hispanic women from the Women's Health Initiative (WHI), and to determine if body mass index (BMI) interacted with the DII scores. METHODS: Secondary analysis of baseline dietary data and long-term CVD outcomes among 3,469 postmenopausal women who self-identified as Hispanic enrolled in WHI. DII scores were calculated from self-administered food frequency questionnaires. The CVD outcomes included coronary heart disease (CHD) and stroke. Stratified Cox regression models were used to assess the relationship between DII scores and CVD in women with and without obesity. Models were adjusted for age, lifestyle risk factors, known risk factors, and neighborhood socioeconomic status. RESULTS: The incidence of CHD was 3.4 and 2.8% for stroke after a median follow-up of 12.9 years. None of the DIIs were associated with CVD risk in this sample of Hispanic women. BMI interacted with the DII (p < 0.20) and stratified models showed that the associations between the DII and CVD were only significant in women with overweight (p < 0.05). In this group, higher DII scores were associated with a higher risk of CHD (HR 1.27; 95% CI: 1.08, 1.51) and a higher risk of stroke (HR 1.32; 95% CI: 1.07, 1.64). CONCLUSION: Among postmenopausal Hispanic women with overweight, greater adherence to pro-inflammatory diets was associated with higher risk of CVD. Additional research is needed to understand how to promote long-term heart-healthy dietary habits to reduce inflammation and prevent CVD in at-risk Hispanic women.

Increasing participant diversity in AD research: Plans for digital screening, blood testing, and a community-engaged approach in the Alzheimer's Disease Neuroimaging Initiative 4.

INTRODUCTION: The Alzheimer's Disease Neuroimaging Initiative (ADNI) aims to validate biomarkers for Alzheimer's disease (AD) clinical trials. To improve generalizability, ADNI4 aims to enroll 50-60% of its new participants from underrepresented populations (URPs) using new biofluid and digital technologies. ADNI4 has received funding from the National Institute on Aging beginning September 2022. METHODS: ADNI4 will recruit URPs using community-engaged approaches. An online portal will screen 20,000 participants, 4000 of whom (50-60% URPs) will be tested for plasma biomarkers and APOE. From this, 500 new participants will undergo in-clinic assessment joining 500 ADNI3 rollover participants. Remaining participants (∼3500) will undergo longitudinal plasma and digital cognitive testing. ADNI4 will add MRI sequences and new PET tracers. Project 1 will optimize biomarkers in AD clinical trials. RESULTS AND DISCUSSION: ADNI4 will improve generalizability of results, use remote digital and blood screening, and continue providing longitudinal clinical, biomarker, and autopsy data to investigators.

Cholesterol, Amyloid Beta, Fructose, and LPS Influence ROS and ATP Concentrations and the Phagocytic Capacity of HMC3 Human Microglia Cell Line.

Research has found that genes specific to microglia are among the strongest risk factors for Alzheimer's disease (AD) and that microglia are critically involved in the etiology of AD. Thus, microglia are an important therapeutic target for novel approaches to the treatment of AD. High-throughput in vitro models to screen molecules for their effectiveness in reversing the pathogenic, pro-inflammatory microglia phenotype are needed. In this study, we used a multi-stimulant approach to test the usefulness of the human microglia cell 3 (HMC3) cell line, immortalized from a human fetal brain-derived primary microglia culture, in duplicating critical aspects of the dysfunctional microglia phenotype. HMC3 microglia were treated with cholesterol (Chol), amyloid beta oligomers (AßO), lipopolysaccharide (LPS), and fructose individually and in combination. HMC3 microglia demonstrated changes in morphology consistent with activation when treated with the combination of Chol + AßO + fructose + LPS. Multiple treatments increased the cellular content of Chol and cholesteryl esters (CE), but only the combination treatment of Chol + AßO + fructose + LPS increased mitochondrial Chol content. Microglia treated with combinations containing Chol + AßO had lower apolipoprotein E (ApoE) secretion, with the combination of Chol + AßO + fructose + LPS having the strongest effect. Combination treatment with Chol + AßO + fructose + LPS also induced APOE and TNF-α expression, reduced ATP production, increased reactive oxygen species (ROS) concentration, and reduced phagocytosis events. These findings suggest that HMC3 microglia treated with the combination of Chol + AßO + fructose + LPS may be a useful high-throughput screening model amenable to testing on 96-well plates to test potential therapeutics to improve microglial function in the context of AD.

Resources for Enhancing Alzheimer's Caregiver Health in Vietnam (REACH VN): Exploratory Analyses of Outcomes of a Cluster Randomized Controlled Trial to Test the Feasibility and Preliminary Efficacy of a Family Dementia Caregiver Intervention in Vietnam.

OBJECTIVE: Few support services and caregiving interventions exist to support family caregivers in low- and middle-income countries (LMIC). This paper presents exploratory analyses of outcomes of Resources for Enhancing Alzheimer's Caregiver Health in Vietnam (REACH VN). METHODS: A cluster randomized controlled trial (RCT) was conducted in Soc Son, a semi-rural area in Hanoi. Nine clusters with 60 caregivers were randomized to either an enhanced control group or REACH VN, an in-home, multicomponent, family caregiver support intervention delivered over two to three months. Outcomes were assessed at baseline and three months. RESULTS: Caregivers in the intervention group experienced a significantly greater reduction in frustration levels compared to those in the control group. There were differences in other outcomes (e.g., care recipient problem behaviors and associated caregiver bother) favoring the intervention condition that did not reach statistical significance. CONCLUSION: We found additional evidence that REACH VN is a promising intervention to improve family caregiver outcomes in Vietnam.