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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 (AβO), lipopolysaccharide (LPS), and fructose individually and in combination. HMC3 microglia demonstrated changes in morphology consistent with activation when treated with the combination of Chol + AβO + fructose + LPS. Multiple treatments increased the cellular content of Chol and cholesteryl esters (CE), but only the combination treatment of Chol + AβO + fructose + LPS increased mitochondrial Chol content. Microglia treated with combinations containing Chol + AβO had lower apolipoprotein E (ApoE) secretion, with the combination of Chol + AβO + fructose + LPS having the strongest effect. Combination treatment with Chol + AβO + 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 + AβO + 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.

Organophosphate (OP) nerve agents and pesticides are a class of neurotoxic compounds that can cause status epilepticus (SE), and death following acute high-dose exposures. While the standard of care for acute OP intoxication (atropine, oxime, and high-dose benzodiazepine) can prevent mortality, survivors of OP poisoning often experience long-term brain damage and cognitive deficits. Preclinical studies of acute OP intoxication have primarily used rat models to identify candidate medical countermeasures. However, the mouse offers the advantage of readily available knockout strains for mechanistic studies of acute and chronic consequences of OP-induced SE. Therefore, the main objective of this study was to determine whether a mouse model of acute diisopropylfluorophosphate (DFP) intoxication would produce acute and chronic neurotoxicity similar to that observed in rat models and humans following acute OP intoxication. Adult male C57BL/6J mice injected with DFP (9.5 mg/kg, s.c.) followed 1 min later with atropine sulfate (0.1 mg/kg, i.m.) and 2-pralidoxime (25 mg/kg, i.m.) developed behavioral and electrographic signs of SE within minutes that continued for at least 4 h. Acetylcholinesterase inhibition persisted for at least 3 d in the blood and 14 d in the brain of DFP mice relative to vehicle (VEH) controls. Immunohistochemical analyses revealed significant neurodegeneration and neuroinflammation in multiple brain regions at 1, 7, and 28 d post-exposure in the brains of DFP mice relative to VEH controls. Deficits in locomotor and home-cage behavior were observed in DFP mice at 28 d post-exposure. These findings demonstrate that this mouse model replicates many of the outcomes observed in rats and humans acutely intoxicated with OPs, suggesting the feasibility of using this model for mechanistic studies and therapeutic screening.

We aimed to evaluate the value of ATN biomarker classification system (amyloid beta [A], pathologic tau [T], and neurodegeneration [N]) for predicting conversion from mild cognitive impairment (MCI) to dementia. In a sample of people with MCI (n = 415) we assessed predictive performance of ATN classification using empirical knowledge-based cut-offs for each component of ATN and compared it to two data-driven approaches, logistic regression and RUSBoost machine learning classifiers, which used continuous clinical or biomarker scores. In data-driven approaches, we identified ATN features that distinguish normals from individuals with dementia and used them to classify persons with MCI into dementia-like and normal groups. Both data-driven classification methods performed better than the empirical cut-offs for ATN biomarkers in predicting conversion to dementia. Classifiers that used clinical features performed as well as classifiers that used ATN biomarkers for prediction of progression to dementia. We discuss that data-driven modeling approaches can improve our ability to predict disease progression and might have implications in future clinical trials.

In planning randomized clinical trials (RCTs) for diseases such as Alzheimer's disease (AD), researchers frequently rely on the use of existing data obtained from only two time points to estimate sample size via the subtraction of baseline from follow-up measurements in each subject. However, the inadequacy of this method has not been reported. The aim of this study is to discuss the limitation of sample size estimation based on the subtraction of available data from only two time points for RCTs. Mathematical equations are derived to demonstrate the condition under which the obtained data pairs with variable time intervals could be used to adequately estimate sample size. The MRI-based hippocampal volume measurements from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Monte Carlo simulations (MCS) were used to illustrate the existing bias and variability of estimates. MCS results support the theoretically derived condition under which the subtraction approach may work. MCS also show the systematically under- or over-estimated sample sizes by up to 32.27 % bias. Not used properly, such subtraction approach outputs the same sample size regardless of trial durations partly due to the way measurement errors are handled. Estimating sample size by subtracting two measurements should be treated with caution. Such estimates can be biased, the magnitude of which depends on the planned RCT duration. To estimate sample sizes, we recommend using more than two measurements and more comprehensive approaches such as linear mixed effect models.

Objectives: Increasingly diverse caregiver populations have prompted studies examining culture and caregiver outcomes. Still, little is known about the influence of sociocultural factors and how they interact with caregiving context variables to influence psychological health. We explored the role of caregiving and acculturation factors on psychological distress among a diverse sample of adults. Design: Secondary data analysis of the California Health Interview Survey (CHIS). Participants: The 2009 CHIS surveyed 47,613 adults representative of the population of California. This study included Latino and Asian American Pacific Islander (AAPI) caregivers and non-caregivers (n = 13,161). Measurements: Multivariate weighted regression analyses examined caregiver status and acculturation variables (generational status, language of interview, and English language proficiency) and their associations with psychological distress (Kessler-6 scale). Covariates included caregiving context (e.g., support and neighborhood factors) and demographic variables. Results: First generation caregivers had more distress than first-generation non-caregivers (β=0.92, 95% CI: (0.18, 1.65)); the difference in distress between caregivers and non-caregivers was smaller in the third than first generation (β=-1.21, 95% CI: (-2.24, -0.17)). Among those who did not interview in English (β=1.17, 95% CI: (0.13, 2.22)) and with low English proficiency (β=2.60, 95% CI: (1.21, 3.98)), caregivers reported more distress than non-caregivers. Conclusions: Non-caregivers exhibited the "healthy immigrant effect," where less acculturated individuals reported less distress. In contrast, caregivers who were less acculturated reported more distress.

INTRODUCTION The Alzheimer's Disease Neuroimaging Initiative (ADNI) has accumulated 15 years of clinical, neuroimaging, cognitive, biofluid biomarker and genetic data, and biofluid samples available to researchers, resulting in more than 3500 publications. This review covers studies from 2018 to 2020. METHODS We identified 1442 publications using ADNI data by conventional search methods and selected impactful studies for inclusion. RESULTS Disease progression studies supported pivotal roles for regional amyloid beta (Aβ) and tau deposition, and identified underlying genetic contributions to Alzheimer's disease (AD). Vascular disease, immune response, inflammation, resilience, and sex modulated disease course. Biologically coherent subgroups were identified at all clinical stages. Practical algorithms and methodological changes improved determination of Aβ status. Plasma Aβ, phosphorylated tau181, and neurofilament light were promising noninvasive biomarkers. Prognostic and diagnostic models were externally validated in ADNI but studies are limited by lack of ethnocultural cohort diversity. DISCUSSION ADNI has had a profound impact in improving clinical trials for AD.

This study examined the effectiveness of a 10-week cognitive rehabilitation and lifestyle modifying intervention that integrated compensation strategies, engagement in brain activities, and improving everyday function. The trial was registered with ClinicalTrials.gov (NCT03549078). Older adults with subjective cognitive concerns and normal performance on a cognitive screener were randomized into the intervention (n = 28) or waitlist control (n = 29) groups. The total sample comprised 57 individuals (age, mean = 74.8, SD = 6.5), mostly female (80.4% of the total sample), and well educated (education years: mean = 15.9, SD = 2.1). Outcome measures were completed at baseline, and immediately and 3- and 6-months post-intervention. Intervention participants reported significant improvements in aspects of everyday functioning and select compensation strategies and brain health activities. Increased compensation strategy use was maintained at 6-month follow up. This intervention has benefits for improving everyday functioning and increasing engagement with compensation strategies and brain health activities.

Introduction The Everyday Cognition scale (ECog), a measure of everyday functioning developed in 2008, is sensitive to early detection and progression of neurodegenerative disease. The goal was to update ECog item content to ensure relevancy to contemporary older adults from diverse backgrounds. Methods Participants included 44 culturally diverse older adults (18 with normal cognition, 11 with mild cognitive impairment) and their study partners. Item understandability and relevance was evaluated using iterative interviewing methods that were analyzed using standard qualitative methods. On the basis of this information, items were modified, deleted, or developed as needed. Results Of the 39 original items, 19 were revised, 3 new items were added (primarily to cover contemporary activities such as the use of technology), and 1 was deleted. The revised version (ECog-II) includes 41 items. Discussion To ensure strong psychometric properties, and to facilitate harmonization of previously collected data, we preserved well over half of the items. Future work will validate the revised ECog by measuring associations with neuropsychological performance, external measures of disease, and other functional measures. Overall, the revised ECog will continue to be a useful tool for measuring cognitively relevant everyday abilities in clinical settings and intervention clinical trials.

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 ([

Alzheimer's disease (AD) is a progressive and incurable brain disorder that has been associated with structural changes in brain phospholipids (PLs), including diacyl species and ether-linked PLs known as plasmalogens. Most studies have characterized total changes in brain PL pools (e.g., choline plasmalogens), particularly in prefrontal cortex, but detailed and quantitative information on the molecular PL species impacted by the disease is limited. In this study, we used a comprehensive mass-spectrometry method to quantify diacyl and plasmalogen species, alkyl synthetic precursors of plasmalogens, and lysophospholipid degradation products of diacyl and plasmalogen PLs, in postmortem samples of prefrontal cortex from 21 AD patients and 20 age-matched controls. Total PLs were also quantified with gas-chromatography analysis of bound fatty acids following thin layer chromatography isolation. There was a significant 27% reduction in the concentration (nmol/g wet weight) of choline plasmalogen containing stearic acid (alkenyl group) and docosahexaenoic acid in AD compared to controls. Stearic acid concentration in total PLs was reduced by 26%. Our findings suggest specific changes in PLs containing stearic acid and docosahexaenoic acid in AD prefrontal cortex, highlighting structural and turnover PL pathways that could be targeted.

BackgroundIt is well known that individuals with Down syndrome (DS) or fragile X syndrome (FXS) demonstrate expressive language difficulties beginning early in childhood. It is less clear, however, whether expressive language skills change during the adolescent period in these individuals, and if any of these changes are syndrome specific. Studying this, as well as the role of maternal and family-related factors in expressive language development, may provide the foundation for efficacious interventions for adolescents with DS or FXS.MethodsIn this study, we examined expressive language trajectories, assessed through conversation and narration, in 57 adolescent males with intellectual disability (ID) (20 DS and 37 FXS) in relation to the diagnostic group (DS vs. FXS) and family-related factors (maternal IQ, maternal psychological distress, closeness in the mother–child relationship, family income, and maternal and paternal education) after adjusting for chronological age (CA) and nonverbal cognition.ResultsChanges over repeated annual assessments for males with DS or FXS were observed only during conversation, such as an increase in talkativeness, but a decrease in syntax complexity and lexical diversity. We found a diagnosis-related effect in the change over time in conversational talkativeness favoring those with FXS. Finally, a closer mother–child relationship predicted less decrease over time in lexical diversity during conversation, and participants of mothers who graduated college showed a greater increase in conversational talkativeness over time compared to those of mothers with a high school education.ConclusionsOur results suggest that, during the adolescent period for males with DS or FXS, there is an increase in the amount of talk produced in conversational contexts, but also a decrease in the quality of the language produced. In addition, our results indicate syndrome-specificity for aspects of expressive language development and reinforce the protective role of family-related factors.

Introduction We investigated plasma proteomic markers of astrocytopathy, brain degeneration, plasticity, and inflammation in sporadic early-onset versus late-onset Alzheimer's disease (EOAD and LOAD). Methods Plasma was analyzed using ultra-sensitive immuno-based assays from 33 EOAD, 30 LOAD, and 36 functionally normal older adults. Results Principle component analyses identified 3 factors: trophic (BDNF, VEGF, TGFβ), degenerative (GFAP, NfL), and inflammatory (TNFα, IL-6, IP-10, IL-10). Trophic factor was elevated in both AD groups and associated with cognition and gray matter volumes. Degenerative factor was elevated in EOAD, with higher levels associated with worse functioning in this group. Biomarkers of inflammation were not significantly different between groups and were only associated with age. Disucssion Plasma proteomic biomarkers provide novel means of investigating molecular processes in vivo and their contributions to clinical outcomes. We present initial investigations of several of these fluid biomarkers, capturing aspects of astrocytopathy, neuronal injury, cellular plasticity, and inflammation in EOAD versus LOAD.

Lyme disease (LD), caused by the bacterium Borrelia burgdorferi, is transmitted to humans in California through the bite of infected blacklegged ticks (Ixodes pacificus). Overall, the incidence of LD in California is low: approximately 0.2 confirmed cases per 100,000 population. However, California’s unique ecological diversity results in wide variation in local risk, including regions with local foci at elevated risk of human disease. The diagnosis of LD can be challenging in California because the prior probability of infection for individual patients is generally low. Combined with nonspecific symptoms and complicated laboratory testing, California physicians need a high level of awareness of LD in California to recognize and diagnose LD efficiently. This research addresses an under-studied area of physicians’ knowledge and practice of the testing and treatment of LD in a low-incidence state. We assessed knowledge and practices related to LD diagnosis using an electronic survey distributed to physicians practicing in California through mixed sampling methods. Overall, responding physicians in California had a general awareness of Lyme disease and were knowledgeable regarding diagnosis and treatment. However, we found that physicians in California could benefit from further education to improve test-ordering practices, test interpretation, and awareness of California’s disease ecology with elevated levels of focal endemicity, to improve recognition, diagnosis, and treatment of LD in California patients.

BackgroundHispanics are a heterogeneous population with differences in the prevalence of cardiovascular disease (CVD) and its related risk factors among ethnic sub-groups. This study evaluated the association of genetic admixture and CVD in self-identified Hispanic women from the Women's Health Initiative (WHI).MethodsData came from the WHI Observational Study and the Clinical Trial Components conducted among postmenopausal women. The CVD outcomes included coronary heart disease (CHD) and stroke. The proportions of European (EUR), sub-Saharan African (AFR), and Amerindian (AMI) admixture were estimated using 92 ancestry-informative markers. Cox regression models were used to assess the relationship between genetic admixture and CVD adjusting for age, lifestyle risk factors, known risk factors, and neighborhood socioeconomic status.ResultsAmong 5195 participants EUR ancestry was associated with a lower CHD risk after adjusting for age (HR 0.41, p=0.02), and in the fully adjusted model (HR 0.40, p=0.03). AFR ancestry was associated with a higher CHD risk after adjusting for age (HR 2.91, p=0.03), but it only showed a trend in in the fully adjusted model (HR 2.46, p=0.10). AMI ancestry was not statistically significantly associated with CHD and none of the genetic admixture proportions were statistically significantly associated with stroke (p>0.05).ConclusionEUR ancestry was associated with a lower risk of CHD in Hispanic women. This highlights the need to account for genetic admixture in future CVD studies to consider different heritage groups to understand the role that genetic, neighborhood socioeconomic status, and environmental factors contribute to CVD health disparities in Hispanic women.

Epidemiological studies have demonstrated that air pollution is a significant risk factor for age-related dementia, including Alzheimer’s disease (AD). It has been posited that traffic-related air pollution (TRAP) promotes AD neuropathology by exacerbating neuroinflammation. To test this hypothesis, serum and hippocampal cytokines were quantified in male and female TgF344-AD rats and wildtype (WT) Fischer 344 littermates exposed to TRAP or filtered air (FA) from 1 to 15 months of age. Luminex™ rat 23-cytokine panel assays were used to measure the levels of hippocampal and serum cytokines in 3-, 6-, 10-, and 15-month-old rats (corresponding to 2, 5, 9, and 14 months of exposure, respectively). Age had a pronounced effect on both serum and hippocampal cytokines; however, age-related changes in hippocampus were not mirrored in the serum and vice versa. Age-related changes in serum cytokine levels were not influenced by sex, genotype, or TRAP exposure. However, in the hippocampus, in 3-month-old TgF344-AD and WT animals, TRAP increased IL-1ß in females while increasing TNF ɑin males. In 6-month-old animals, TRAP increased hippocampal levels of M-CSF in TgF344-AD and WT females but had no significant effect in males. At 10 and 15 months of age, there were minimal effects of TRAP, genotype or sex on hippocampal cytokines. These observations demonstrate that TRAP triggers an early inflammatory response in the hippocampus that differs with sex and age and is not reflected in the serum cytokine profile. The relationship of TRAP effects on cytokines to disease progression remains to be determined.

BackgroundIndividuals with fragile X syndrome (FXS) have significant delays in cognition and language, as well as anxiety, symptoms of autism spectrum disorder, and challenging behaviors such as hyperactivity and aggression. Biological mothers of children with FXS, who are themselves FMR1 premutation or full mutation carriers, are at elevated risk for mental health challenges in addition to experiencing stress associated with parenting a child with significant disabilities. However, little is known about fathers in these families, including the ways in which parental well-being influences the mother-father relationship and the impact of child characteristics on paternal and couple functioning.MethodThe current study examined features of, and relationships between, parental well-being, couple well-being, and child functioning in 23 families of young boys with FXS. Mothers and fathers independently completed multiple questionnaires about their individual well-being, couple functioning, and child behavior. One parent per family also completed an interview about the child’s adaptive skills.ResultsResults suggest that both mothers and fathers in these families experience clinically significant levels of mental health challenges and elevated rates of parenting stress relative to the general population. Findings also indicate that the couples’ relationship may be a source of strength that potentially buffers against some of the daily stressors faced by these families. Additionally, parents who reported less parenting stress had higher couples satisfaction and dyadic coping. Finally, parents of children with less severe challenging behaviors exhibited fewer mental health challenges, less parenting stress, and higher levels of both couples satisfaction and dyadic coping. Parents of children with higher levels of adaptive behavior also reported less parenting stress and higher couples satisfaction.ConclusionOverall, this study provides evidence that families of children with FXS need access to services that not only target improvements in the child’s functioning, but also ameliorate parental stress. Family-based services that include both mothers and fathers would lead to better outcomes for all family members.