Proteomic Indicators of Health Predict Alzheimer's Disease Biomarker Levels and Dementia Risk.

OBJECTIVE: Few studies have comprehensively examined how health and disease risk influence Alzheimer's disease (AD) biomarkers. The present study examined the association of 14 protein-based health indicators with plasma and neuroimaging biomarkers of AD and neurodegeneration. METHODS: In 706 cognitively normal adults, we examined whether 14 protein-based health indices (ie, SomaSignal® tests) were associated with concurrently measured plasma-based biomarkers of AD pathology (amyloid-ß [Aß]42/40 , tau phosphorylated at threonine-181 [pTau-181]), neuronal injury (neurofilament light chain [NfL]), and reactive astrogliosis (glial fibrillary acidic protein [GFAP]), brain volume, and cortical Aß and tau. In a separate cohort (n = 11,285), we examined whether protein-based health indicators associated with neurodegeneration also predict 25-year dementia risk. RESULTS: Greater protein-based risk for cardiovascular disease, heart failure mortality, and kidney disease was associated with lower Aß42/40 and higher pTau-181, NfL, and GFAP levels, even in individuals without cardiovascular or kidney disease. Proteomic indicators of body fat percentage, lean body mass, and visceral fat were associated with pTau-181, NfL, and GFAP, whereas resting energy rate was negatively associated with NfL and GFAP. Together, these health indicators predicted 12, 31, 50, and 33% of plasma Aß42/40 , pTau-181, NfL, and GFAP levels, respectively. Only protein-based measures of cardiovascular risk were associated with reduced regional brain volumes; these measures predicted 25-year dementia risk, even among those without clinically defined cardiovascular disease. INTERPRETATION: Subclinical peripheral health may influence AD and neurodegenerative disease processes and relevant biomarker levels, particularly NfL. Cardiovascular health, even in the absence of clinically defined disease, plays a central role in brain aging and dementia. ANN NEUROL 2024;95:260-273.

Prediction of internalizing and externalizing symptoms in late childhood from attention-deficit/hyperactivity disorder symptoms in early childhood.

Limited analyses based on national samples have assessed whether early attention-deficit/hyperactivity disorder (ADHD) symptoms predict later internalizing and externalizing symptoms in youth and the influence of sex and pubertal timing on subsequent psychiatric symptoms. This study analyzed data (n = 2818) from the Environmental influences on Child Health Outcomes Program national cohort. Analyses used data from early childhood (mean age = 5.3 years) utilizing parent-reported ADHD symptoms to predict rates of internalizing and externalizing symptoms from late childhood/adolescence (mean age = 11.9 years). Within a subsample age at peak height velocity (APHV) acted as a proxy to assess pubertal timing from early childhood (mean age = 5.4 years) to adolescence (mean age = 12.3 years). Early-childhood ADHD symptoms predicted later psychiatric symptoms, including anxiety, depression, aggressive behavior, conduct problems, oppositional defiant disorder, and rule-breaking behavior. Earlier APHV was associated with increased Conduct Disorder symptoms from late childhood to adolescence for females only. A stronger relation between ADHD symptoms and later aggression was observed in females with earlier APHV, whereas this same pattern with aggression, conduct problems and depression was observed in males with later APHV. Clinicians should consider that both young girls and boys with elevated ADHD symptoms, particularly with off-set pubertal timing, may be at risk for later psychiatric symptoms.

Maternal Diet Quality During Pregnancy and Offspring Hepatic Fat in Early Childhood: The Healthy Start Study.

BACKGROUND: Overnutrition in utero may increase offspring risk of nonalcoholic fatty liver disease (NAFLD), but the specific contribution of maternal diet quality during pregnancy to this association remains understudied in humans. OBJECTIVES: This study aimed to examine the associations of maternal diet quality during pregnancy with offspring hepatic fat in early childhood (median: 5 y old, range: 4-8 y old). METHODS: Data were from 278 mother-child pairs in the longitudinal, Colorado-based Healthy Start Study. Multiple 24-h recalls were collected from mothers during pregnancy on a monthly basis (median: 3 recalls, range: 1-8 recalls starting after enrollment), and used to estimate maternal usual nutrient intakes and dietary pattern scores [Healthy Eating Index-2010 (HEI-2010), Dietary Inflammatory Index (DII), and Relative Mediterranean Diet Score (rMED)]. Offspring hepatic fat was measured in early childhood by MRI. Associations of maternal dietary predictors during pregnancy with offspring log-transformed hepatic fat were assessed using linear regression models adjusted for offspring demographics, maternal/perinatal confounders, and maternal total energy intake. RESULTS: Higher maternal fiber intake and rMED scores during pregnancy were associated with lower offspring hepatic fat in early childhood in fully adjusted models [Back-transformed ß (95% CI): 0.82 (0.72, 0.94) per 5 g/1000 kcal fiber; 0.93 (0.88, 0.99) per 1 SD for rMED]. In contrast, higher maternal total sugar and added sugar intakes, and DII scores were associated with higher offspring hepatic fat [Back-transformed ß (95% CI): 1.18 (1.05, 1.32) per 5% kcal/d added sugar; 1.08 (0.99, 1.18) per 1 SD for DII]. Analyses of dietary pattern subcomponents also revealed that lower maternal intakes of green vegetables and legumes and higher intake of "empty calories" were associated with higher offspring hepatic fat in early childhood. CONCLUSIONS: Poorer maternal diet quality during pregnancy was associated with greater offspring susceptibility to hepatic fat in early childhood. Our findings provide insights into potential perinatal targets for the primordial prevention of pediatric NAFLD.

Diabetes complications and cognitive function in young adults with youth-onset type 1 or type 2 diabetes: the SEARCH for Diabetes in Youth Study.

Aims/hypotheses: People with type 1 (T1D) or type 2 diabetes (T2D) who also have diabetes complications can have pronounced cognitive deficits. It remains unknown, however, whether and how multiple diabetes complications co-occur with cognitive dysfunction, particularly in youth-onset diabetes. Methods: Using data from the SEARCH for Diabetes in Youth study cohort, a prospective longitudinal cohort, we examined clustering of complications and their underlying clinical factors with performance on cognitive tests in young adults with youth-onset T1D or T2D. Cognition was assessed via the NIH Toolbox Cognition Battery. The main cognitive variables were age-corrected scores for composite fluid cognition and associated cognitive subdomains. Diabetes complications included retinopathy, microalbuminuria, and peripheral neuropathy (PN). Lipids, systolic blood pressure (SBP), hemoglobin A1c, and other clinical factors were included in the analyses. Clustering was applied separately to each group (T1D=646; T2D=165). A three-cluster(C) solution was identified for each diabetes type. Mean values and frequencies of all factors were compared between resulting clusters. Results: The average age-corrected score for composite fluid cognition differed significantly across clusters for each group (p<0.001). People with T1D and the lowest average fluid cognition scores had the highest frequency of self-reporting at least one episode of hypoglycemia in the year preceding cognitive testing and the highest prevalence of PN. Persons with T2D and the lowest average fluid cognition scores had the highest SBP, the highest central systolic and diastolic blood pressures, and highest prevalence of PN. Conclusions/interpretations: These findings highlight shared (PN) and unique factors (hypoglycemia in T1D; SBP in T2D) that could be targeted to potentially mitigate cognitive issues in young people with youth-onset diabetes.

Household Food Insecurity and Cognition in Youth and Young Adults with Youth-Onset Diabetes.

Objective: We evaluated the association of household food insecurity (FI) with cognition in youth and young adults with type 1 diabetes (T1D) or type 2 diabetes (T2D). Design: In this cross-sectional study, age-adjusted scores for composite Fluid Cognition, and sub-domain scores for Receptive Language and Inhibitory Control and Attention, were modeled stratified by diabetes-type using linear regression, with FI in the past year as the predictor, controlling for covariates. Tests for processing speed, inhibitory control/attention, working memory, episodic memory, and cognitive flexibility were administered to measure composite Fluid Cognition score. The NIHT-CB Picture Vocabulary Test was used to assess Crystallized Cognition score and rapid identification of congruent versus noncongruent items were used to assess Inhibitory Control and Attention score. Setting: The SEARCH for Diabetes in Youth study, representative of 5 U.S. states. Participants: Included 1574 youth and young adults with T1D or T2D, mean age of 21 years, mean diabetes duration of 11 years, 51% non-Hispanic white, and 47% had higher HbA1c levels (>9% HbA1c). Results: Approximately 18% of the 1,240 participants with T1D and 31% of the 334 with T2D experienced FI. The food-insecure group with T1D had a lower composite Fluid Cognition score (ß= -2.5, 95% confidence interval (CI)= -4.8, -0.1) and a lower Crystallized Cognition score (ß= -3.4, CI= -5.6, -1.3) than food-secure peers. Findings were attenuated to non-significance after adjustment for demographics. Among T2D participants, no associations were observed. In participants with T1D effect modification by glycemic levels were found in the association between FI and composite Fluid Cognition score but adjustment for socioeconomic characteristics attenuated the interaction (p=0.0531). Conclusions: Food-insecure youth and young adults with T1D or T2D did not have different cognition compared to those who were food-secure after adjustment for confounders. Longitudinal research is needed to further understand relations amongst these factors.

Characterization of Influenza-Like Illness Burden Using Commercial Wearable Sensor Data and Patient-Reported Outcomes: Mixed Methods Cohort Study.

BACKGROUND: The burden of influenza-like illness (ILI) is typically estimated via hospitalizations and deaths. However, ILI-associated morbidity that does not require hospitalization remains poorly characterized. OBJECTIVE: The main objective of this study was to characterize ILI burden using commercial wearable sensor data and investigate the extent to which these data correlate with self-reported illness severity and duration. Furthermore, we aimed to determine whether ILI-associated changes in wearable sensor data differed between care-seeking and non-care-seeking populations as well as between those with confirmed influenza infection and those with ILI symptoms only. METHODS: This study comprised participants enrolled in either the FluStudy2020 or the Home Testing of Respiratory Illness (HTRI) study; both studies were similar in design and conducted between December 2019 and October 2020 in the United States. The participants self-reported ILI-related symptoms and health care-seeking behaviors via daily, biweekly, and monthly surveys. Wearable sensor data were recorded for 120 and 150 days for FluStudy2020 and HTRI, respectively. The following features were assessed: total daily steps, active time (time spent with >50 steps per minute), sleep duration, sleep efficiency, and resting heart rate. ILI-related changes in wearable sensor data were compared between the participants who sought health care and those who did not and between the participants who tested positive for influenza and those with symptoms only. Correlative analyses were performed between wearable sensor data and patient-reported outcomes. RESULTS: After combining the FluStudy2020 and HTRI data sets, the final ILI population comprised 2435 participants. Compared with healthy days (baseline), the participants with ILI exhibited significantly reduced total daily steps, active time, and sleep efficiency as well as increased sleep duration and resting heart rate. Deviations from baseline typically began before symptom onset and were greater in the participants who sought health care than in those who did not and greater in the participants who tested positive for influenza than in those with symptoms only. During an ILI event, changes in wearable sensor data consistently varied with those in patient-reported outcomes. CONCLUSIONS: Our results underscore the potential of wearable sensors to discriminate not only between individuals with and without influenza infections but also between care-seeking and non-care-seeking populations, which may have future application in health care resource planning. TRIAL REGISTRATION: Clinicaltrials.gov NCT04245800; https://clinicaltrials.gov/ct2/show/NCT04245800.

Early microvascular complications in type 1 and type 2 diabetes: recent developments and updates.

The prevalence of youth-onset diabetes is progressing rapidly worldwide, and poor glycemic control, in combination with prolonged diabetes duration and comorbidities including hypertension, has led to the early development of microvascular complications including diabetic kidney disease, retinopathy, and neuropathy. Pediatric populations with type 1 (T1D) and type 2 (T2D) diabetes are classically underdiagnosed with microvascular complications, and this leads to both undertreatment and insufficient attention to the mitigation of risk factors that could help attenuate further progression of complications and decrease the likelihood for long-term morbidity and mortality. This narrative review aims to present a comprehensive summary of the epidemiology, risk factors, symptoms, screening practices, and treatment options, including future opportunities for treatment advancement, for microvascular complications in youth with T1D and T2D. We seek to uniquely focus on the inherent challenges of managing pediatric populations with diabetes and discuss the similarities and differences between microvascular complications in T1D and T2D, while presenting a strong emphasis on the importance of early identification of at-risk youth. Further investigation of possible treatment mechanisms for microvascular complications in youth with T1D and T2D through dedicated pediatric outcome trials is necessary to target the brief window where early pathological vascular changes may be significantly attenuated.

Infant and Toddler Consumption of Sweetened and Unsweetened Lipid Nutrient Supplements After 2-Week Home Repeated Exposures.

BACKGROUND: Small-quantity lipid-based nutrient supplements (SQ-LNS) are designed to address undernutrition during the complementary feeding period. SQ-LNS contains added sugars, but limited research has assessed whether infants' acceptance varies between versions with and without sugars. OBJECTIVES: Our objective was to examine the effects of repeated exposure on children's acceptance of sweetened and unsweetened SQ-LNS. We aimed to understand caregivers' perceptions of children's liking of the 2 SQ-LNS versions and their influences on infant acceptance of SQ-LNS. METHODS: Caregivers (86% non-Hispanic White) and children (7-24 mo), participated in a randomized, 2-week home-exposure study and baseline and post-home exposure assessments. Children were randomized to receive sweetened or unsweetened SQ-LNS versions, mixed with infant oatmeal. At in-person visits, caregivers fed both SQ-LNS versions to children and rated their child's liking for each. Caregivers fed the SQ-LNS version to which their child was randomized until the child refused to eat more. Acceptance was measured as total grams consumed. Mixed-effects linear models tested the change in SQ-LNS consumed between baseline and postexposure by the SQ-LNS version and number of home exposures. Covariates included the amount of SQ-LNS consumed at baseline, child BMI z-score, child age, and breastfeeding experience. RESULTS: Children's acceptance of both SQ-LNS versions increased from baseline to postexposure (ß, 0.71 g; 95% CI: 0.54-0.89 g; P = 0.04), regardless of SQ-LNS version (P = 0.88) or number of home exposures (P = 0.55). Caregivers rated children's liking of unsweetened SQ-LNS higher at baseline (P = 0.02). Children with lower liking ratings at baseline showed the greatest increases in acceptance between baseline and postexposure (P = 0.01). CONCLUSIONS: Children's acceptance of SQ-LNS increased with repeated exposure, whether offered the sweetened or unsweetened version, providing preliminary support that adding sugar to SQ-LNS may not improve acceptance in young children. Children who initially like the supplement less may need repeated experience to learn to accept SQ-LNS. This trial was registered at clinicaltrials.gov as NCT04544332.

Prenatal Exposure to Tobacco and Offspring Neurocognitive Development in the Healthy Start Study.

OBJECTIVE: To explore the associations between prenatal exposure to tobacco and neurocognitive development, in the absence of prematurity or low birth weight. STUDY DESIGN: We followed mother-child pairs within Healthy Start through 6 years of age. Children were born at ≥37 weeks of gestation with a birth weight of ≥2500 g. Parents completed the Third Edition Ages and Stages Questionnaire (n = 246) and children completed a subset of the National Institutes of Health Toolbox Cognition Battery (n = 200). The Ages and Stages Questionnaire domains were dichotomized as fail/monitor and pass. Maternal urinary cotinine was measured at approximately 27 weeks of gestation. Separate logistic regression models estimated associations between prenatal exposure to tobacco (cotinine below vs above the limit of detection) and the Ages and Stages Questionnaire domains. Separate linear regression models estimated associations between prenatal exposure to tobacco and fully corrected T-scores for inhibitory control, cognitive flexibility, and receptive language, as assessed by the National Institutes of Health Toolbox. A priori covariates included sex, maternal age, maternal education, daily caloric intake during pregnancy, race/ethnicity, household income, maternal psychiatric disorders, and, in secondary models, postnatal exposure to tobacco. RESULTS: Compared with unexposed offspring, exposed offspring were more likely to receive a fail/monitor score for fine motor skills (OR, 3.9; 95% CI, 1.5-10.3) and decreased inhibitory control (B: -3.0; 95% CI, -6.1 to -0.7). After adjusting for postnatal exposure, only the association with fine motor skills persisted. CONCLUSIONS: Prenatal and postnatal exposures to tobacco may influence neurocognitive development, in the absence of preterm delivery or low birth weight. Increased developmental screening may be warranted for exposed children.

Childhood Metabolic Biomarkers Are Associated with Performance on Cognitive Tasks in Young Children.

OBJECTIVE: To evaluate the hypothesis that metabolic measures (fasting glucose, insulin, and Homeostatic Model of Assessment for Insulin Resistance [HOMA-IR] levels) are inversely associated with performance on cognitive tasks using data from young (4- to 6-year-old), typically developing, healthy children. STUDY DESIGN: Data were obtained from children participating in the Healthy Start study, a pre-birth cohort in Colorado. HOMA-IR, glucose, and insulin values were centered and scaled using the study sample means and SD. Thus, they are reported in number of SD units from the mean. Fully corrected T scores for inhibitory control (Flanker task), cognitive flexibility (Dimensional Change Card Sort test), and receptive language (Picture Vocabulary test) were obtained via the National Institutes of Health Toolbox cognition battery. RESULTS: Children included in this analysis (n = 137) were 4.6 years old, on average. Per 1-SD unit, fasting glucose (B = -2.0, 95% CI -3.5, -0.5), insulin (B = -1.7, 95% CI -3.0, -0.4), and HOMA-IR values (B = -1.8, 95% CI -3.1, -0.5) were each significantly and inversely associated with inhibitory control (P < .05 for all, respectively). Fasting glucose levels were also inversely associated with cognitive flexibility (B = -2.0, 95% CI -3.7, -0.2, P = .03). CONCLUSIONS: Our data suggest that metabolic health may impact fluid cognitive function in healthy, young children.

Maternal Dietary Patterns during Pregnancy Are Associated with Newborn Body Composition.

Background: Maternal dietary intake during pregnancy may influence offspring growth and adiposity. Specific dietary patterns associated with newborn adiposity have not been identified.Objective: We aimed to identify patterns of maternal dietary intake associated with gestational weight gain (GWG) and fasting glucose during pregnancy and to evaluate whether adherence to these patterns is associated with newborn adiposity.Methods: In the Healthy Start prospective cohort, dietary intake during pregnancy was assessed via 24-h recalls. Reduced-rank regression identified dietary patterns predictive of GWG and fasting glucose. Associations between dietary patterns and newborn fat mass, fat-free mass, and adiposity were estimated by using linear regression models among 764 ethnically diverse mother-infant pairs.Results: Two dietary patterns were identified. Pattern 1, correlated with greater GWG (r = 0.22, P < 0.01), was characterized by a higher consumption of poultry, nuts, cheese, fruits, whole grains, added sugars, and solid fats. Greater adherence to pattern 1 (upper compared with lower tertile) predicted a greater newborn fat-free mass (61 g; 95% CI: 12, 110 g) but no difference in fat mass or adiposity. Pattern 2, correlated with greater maternal fasting glucose (r = 0.16, P < 0.01), was characterized by a higher consumption of eggs, starchy vegetables, solid fats, fruits, and nonwhole grains and a lower consumption of dairy foods, dark-green vegetables, and whole grains. Greater adherence to pattern 2 was associated with a greater newborn birth weight (80 g; 95% CI: 15, 145 g), fat mass (33 g; 95% CI: 8, 59 g), and adiposity (0.9%; 95% CI: 0.3%, 1.6%).Conclusions: Among pregnant women, adherence to a dietary pattern characterized by an intake of poultry, nuts, cheese, and whole grains was associated with greater GWG but not maternal fasting glucose or newborn adiposity. Adherence to a pattern characterized by an intake of eggs, starchy vegetables, and nonwhole grains was associated with higher maternal fasting glucose and greater newborn adiposity. Maternal dietary patterns during pregnancy may influence newborn body composition.

Exposure to maternal diabetes in utero and offspring eating behavior: The EPOCH study.

The risk of becoming overweight among offspring exposed to gestational diabetes (GDM) in utero is two-fold higher than in the general population. The responsible mechanisms are likely multifactorial, with some evidence that GDM exposure alters brain satiety signaling, which may impact eating behavior. To better understand these effects, we investigated the relationship between GDM exposure, eating behavior, and total energy intake in 268 adolescents from the Exploring Perinatal Outcomes among Children cohort, who were exposed (n = 50) or not exposed (n = 217) to GDM in utero. Eating behavior was measured by the Eating in the Absence of Hunger in Children and Adolescents (EAH-C) questionnaire, which included subscale scores for Negative Affect, External Stimuli, and Fatigue/Boredom. Total energy intake (kcal/day) was derived from the Block Kid's Food Questionnaire. The associations between GDM exposure and the outcomes of total score and each EAH-C subscale were evaluated in separate multivariable models. In addition to the main predictor, GDM, the models included a GDM-by-sex interaction term and were adjusted for important covariates. The associations between EAH-C total and subscale scores and the outcome of total energy intake were also tested in separate multivariable models. Female offspring exposed to GDM in utero (vs unexposed males and females) were more likely to continue eating beyond satiation due to feelings of boredom and fatigue (ß = 0.47, 95% CI: 0.11, 0.83), and in general (EAH-C total score; ß = 4.20, 95% CI: 0.56, 7.86) compared to unexposed males. All EAH-C subscale and total scores were significantly, positively associated with higher energy intake (p < 0.05 for all, respectively). Our findings highlight the need for further investigation into the possible early life programming of eating behaviors by GDM exposure in utero.

Infant Adiposity is Independently Associated with a Maternal High Fat Diet but not Related to Niacin Intake: The Healthy Start Study.

Objectives Over-nutrition during pregnancy resulting from maternal obesity or an unhealthy diet can lead to excess infant adiposity at birth. Specific dietary macro- and micronutrients have been shown to increase fat cell development in both in-vitro and in-vivo models and may therefore link maternal diet to increased infant adiposity. We hypothesized that high maternal dietary niacin intake during pregnancy, especially in combination with a high-fat diet (HFD) would increase infant adiposity. Methods We included 1040 participants from a pre-birth cohort of mother-infant pairs. Maternal diet was assessed using multiple 24-hour dietary recalls. HFD was defined as ≥30% of calories from fat and ≥12% of fat calories from saturated fat. Neonatal body composition (% fat mass [%FM], fat mass [FM], fat-free mass [FFM]) was measured by PEAPOD. We used multivariate regression to assess the joint effect of maternal dietary niacin and maternal HFD on neonatal body composition. Results Dietary niacin was not associated with neonatal body composition, and maternal HFD did not modify this finding. However, maternal HFD was independently associated with %FM (ß = 0.8 [0.1, 1.4]%, p < 0.01] and FM (ß = 32.4 [6.7, 58.0] g, p < 0.01). Conclusions for Practice Our results suggest that a HFD during pregnancy may increase infant adiposity, therefore supporting the need for improved diet counseling of pregnant women at both the clinical and community levels.

Maternal dietary intake during pregnancy and offspring body composition: The Healthy Start Study.

BACKGROUND: Consistent evidence of an influence of maternal dietary intake during pregnancy on infant body size and composition in human populations is lacking, despite robust evidence in animal models. OBJECTIVE: We sought to evaluate the influence of maternal macronutrient intake and balance during pregnancy on neonatal body size and composition, including fat mass and fat-free mass. STUDY DESIGN: The analysis was conducted among 1040 mother-offspring pairs enrolled in the prospective prebirth observational cohort: the Healthy Start Study. Diet during pregnancy was collected using repeated 24-hour dietary recalls (up to 8). Direct measures of body composition were obtained using air displacement plethysmography. The National Cancer Institute measurement error model was used to estimate usual dietary intake during pregnancy. Multivariable partition (nonisocaloric) and nutrient density (isocaloric) linear regression models were used to test the associations between maternal dietary intake and neonatal body composition. RESULTS: The median macronutrient composition during pregnancy was 32.2% from fat, 15.0% from protein, and 47.8% from carbohydrates. In the partition multivariate regression model, individual macronutrient intake values were not associated with birthweight or fat-free mass, but were associated with fat mass. Respectively, 418 kJ increases in total fat, saturated fat, unsaturated fat, and total carbohydrates were associated with 4.2-g (P = .03), 11.1-g (P = .003), 5.9-g (P = .04), and 2.9-g (P = .02) increases in neonatal fat mass, independent of prepregnancy body mass index. In the nutrient density multivariate regression model, macronutrient balance was not associated with fat mass, fat-free mass, or birthweight after adjustment for prepregnancy body mass index. CONCLUSION: Neonatal adiposity, but not birthweight, is independently associated with increased maternal intake of total fat, saturated fat, unsaturated fat, and total carbohydrates, but not protein, suggesting that most forms of increased caloric intake contribute to fetal fat accretion.

Testing the fuel-mediated hypothesis: maternal insulin resistance and glucose mediate the association between maternal and neonatal adiposity, the Healthy Start study.

AIMS/HYPOTHESIS: In women who are overweight or obese before or during pregnancy there is an associated risk of increased fetal growth and higher birthweight. The metabolic phenotype of the overweight/obese pregnant woman, characterised by higher than normal insulin resistance (IR) and increased circulating fuels, suggests a mechanism resulting in fetal overnutrition and subsequent increased adiposity. We tested the fuel-mediated hypothesis in an observational pre-birth cohort of 951 mother-offspring pairs, the Healthy Start study. METHODS: We conducted a path analysis to estimate the simultaneous effects of maternal IR and maternal fuels (fasting glucose, triacylglycerol [TG] and NEFA levels) in late pregnancy in mediating the relationship between maternal pre-pregnancy BMI and neonatal adiposity (per cent fat mass [%FM]). RESULTS: The total effect of maternal BMI on neonatal %FM was significant (total effect 0.16, 95% CI 0.08, 0.22, p < 0.001). The mediated path including maternal IR and glucose levels together accounted for 21% (p < 0.01) of the total effect of maternal BMI on neonatal %FM while the mediating effects of all other fuels were non-significant. CONCLUSIONS/INTERPRETATION: Using a novel application of path analysis our data implicate maternal IR and glucose levels as important mediators of the association between maternal and infant adiposity.

Critical brain regions for tool-related and imitative actions: a componential analysis.

Numerous functional neuroimaging studies suggest that widespread bilateral parietal, temporal, and frontal regions are involved in tool-related and pantomimed gesture performance, but the role of these regions in specific aspects of gestural tasks remains unclear. In the largest prospective study of apraxia-related lesions to date, we performed voxel-based lesion-symptom mapping with data from 71 left hemisphere stroke participants to assess the critical neural substrates of three types of actions: gestures produced in response to viewed tools, imitation of tool-specific gestures demonstrated by the examiner, and imitation of meaningless gestures. Thus, two of the three gesture types were tool-related, and two of the three were imitative, enabling pairwise comparisons designed to highlight commonalities and differences. Gestures were scored separately for postural (hand/arm positioning) and kinematic (amplitude/timing) accuracy. Lesioned voxels in the left posterior temporal gyrus were significantly associated with lower scores on the posture component for both of the tool-related gesture tasks. Poor performance on the kinematic component of all three gesture tasks was significantly associated with lesions in left inferior parietal and frontal regions. These data enable us to propose a componential neuroanatomic model of action that delineates the specific components required for different gestural action tasks. Thus, visual posture information and kinematic capacities are differentially critical to the three types of actions studied here: the kinematic aspect is particularly critical for imitation of meaningless movement, capacity for tool-action posture representations are particularly necessary for pantomimed gestures to the sight of tools, and both capacities inform imitation of tool-related movements. These distinctions enable us to advance traditional accounts of apraxia.

Complementary food exposure and children's early understanding of food words: the approaching eating through language (APPEAL) study.

Introduction: Language skills, such as the ability to understand words (receptive language), develop during infancy and are built through interactions with the environment, including eating. Exposure to complementary foods also begins in infancy and may play a significant role in language development, especially in understanding of food-related words. However, the relationship between the complementary foods to which a child is exposed and early language acquisition has not been previously studied. We hypothesized that young children's food-related receptive language (FRL) would reflect the complementary foods to which they were frequently offered by caregivers. Methods: Caregivers of young children (4-26 months; n = 408) in the Approaching Eating through Language (APPEAL) Study in the US were surveyed via Qualtrics. FRL was assessed by caregiver-report via a modified MacArthur-Bates Communicative Development Inventory. Complementary foods offered (CFO) by caregivers were assessed using a modified Food Frequency Questionnaire. Latent Class Analysis (LCA) was implemented to identify, 1) groupings of foods frequently offered (>1x/week) and 2) groupings of food-related words understood by the young children. Results: A 5-class best fit LCA model was identified for CFO (-log likelihood [-llik]=-8727) and for FRL (-llik=-5476). Cross-classification of the CFO and FRL derived classes revealed that children with higher exposure to complementary foods were perceived by caregivers to be most likely to also understand a greater number of food-related words (Probability=0.48). As expected, children having been offered a greater number of complementary foods and who understood a greater number of food-related words were older, compared to those with less complementary food exposure and food-related language acquisition (p < 0.001). Discussion: These findings support the potential role of introduction to complementary foods in development of food-related language.

The association of insulin responses and insulin sensitivity with cognition in adults with pre-diabetes: The Diabetes Prevention Program Outcomes Study.

OBJECTIVE: Dysglycemia is a significant risk factor for cognitive impairment. However, which pathophysiologic determinant(s) of dysglycemia, impaired insulin sensitivity (ISens) or the islet ß-cell's response (IResp), contribute to poorer cognitive function, independent of dysglycemia is not established. Among 1052 adults with pre-diabetes from the Diabetes Prevention Program Outcomes Study (DPPOS), we investigated the relationship between IResp, ISens and cognitive function. RESEARCH DESIGN AND METHODS: IResp was estimated by the insulinogenic index (IGI; pmol/mmol) and ISens as 1/fasting insulin from repeated annual oral glucose tolerance tests. The mean IResp and mean ISens were calculated over approximately 12 years of follow-up. Verbal learning (Spanish-English Verbal Learning Test [SEVLT]) and executive function (Digital Symbol Substitution Test [DSST]) were assessed at the end of the follow-up period. Linear regression models were run for each cognitive outcome and were adjusted for dysglycemia and other factors. RESULTS: Higher IResp was associated with poorer performance on the DSST (-0.69 points per 100 unit increase in IGI, 95 % CI: -1.37, -0.01). ISens was not associated with DSST, nor were IResp or ISens associated with performance on the SEVLT. CONCLUSIONS: These results suggest that a greater ß-cell response in people at high risk for type 2 diabetes is associated with poorer executive function, independent of dysglycemia and ISens.

Biomarkers of Neurodegeneration and Alzheimer's Disease Neuropathology in Adolescents and Young Adults with Youth-Onset Type 1 or Type 2 Diabetes: A Proof-of-Concept Study.

Adult-onset diabetes increases one's risk of neurodegenerative disease including Alzheimer's disease (AD); however, the risk associated with youth-onset diabetes (Y-DM) remains underexplored. We quantified plasma biomarkers of neurodegeneration and AD in participants with Y-DM from the SEARCH cohort at adolescence and young adulthood (Type 1, n = 25; Type 2, n = 25; 59% female; adolescence, age = 15 y/o [2.6]; adulthood, age = 27.4 y/o [2.2]), comparing them with controls (adolescence, n = 25, age = 14.8 y/o [2.7]; adulthood, n = 21, age = 24.9 y/o [2.8]). Plasma biomarkers, including glial fibrillary acidic protein (GFAP), neurofilament light chain protein (NfL), phosphorylated tau-181 (pTau181), and amyloid beta (Aß40, Aß42), were measured via Simoa. A subset of participants (n = 7; age = 27.5 y/o [5.7]) and six controls (age = 25.1 y/o [4.5]) underwent PET scans to quantify brain amyloid and tau densities in AD sensitive brain regions. Y-DM adolescents exhibited lower plasma levels of Aß40, Aß42, and GFAP, and higher pTau181 compared to controls (p < 0.05), a pattern persisting into adulthood (p < 0.001). All biomarkers showed significant increases from adolescence to adulthood in Y-DM (p < 0.01), though no significant differences in brain amyloid or tau were noted between Y-DM and controls in adulthood. Preliminary evidence suggests that preclinical AD neuropathology is present in young people with Y-DM, indicating a potential increased risk of neurodegenerative diseases.

Synergistic effects of GFAP and Aß42: Implications for white matter integrity and verbal memory across the cognitive spectrum.

Background: Plasma glial fibrillary acidic protein (GFAP), an astrocytic biomarker, has previously been linked with Alzheimer's disease (AD) status, amyloid levels, and memory performance in older adults. The neuroanatomical pathways by which astrogliosis/astrocyte reactivity might impact cognitive outcomes remains unclear. We evaluated whether plasma GFAP and amyloid levels had a synergistic effect on fornix structure, which is critically involved in AD-associated cholinergic pathways. We also examined whether fornix structure mediates associations between GFAP and verbal memory. Methods: In a cohort of both asymptomatic and symptomatic older adults (total n = 99), we assessed plasma GFAP, amyloid-ß42 (Aß42), other AD-related proteins, and vascular markers, and we conducted comprehensive memory testing. Tractography-based methods were used to assess fornix structure with whole brain diffusion metrics to control for diffuse alterations in brain white matter. Results: In individuals in the low plasma amyloid-ß42 (Aß42) group, higher plasma GFAP was associated with lower fractional anisotropy (FA; p = 0.007), higher mean diffusivity (MD; p < 0.001), higher radial diffusivity (RD; p < 0.001), and higher axial diffusivity (DA; p = 0.001) in the left fornix. These associations were independent of APOE gene status, plasma levels of total tau and neurofilament light, plasma vascular biomarkers, and whole brain diffusion metrics. In a sub-analysis of participants in the low plasma Aß42 group (n = 33), fornix structure mediated the association between higher plasma GFAP levels and lower verbal memory performance. Discussion: Higher plasma GFAP was associated with altered fornix microstructure in the setting of greater amyloid deposition. We also expanded on our prior GFAP-verbal memory findings by demonstrating that in the low plasma Aß42 group, left fornix integrity may be a primary white matter conduit for the negative associations between GFAP and verbal memory performance. Overall, these findings suggest that astrogliosis/astrocyte reactivity may play an early, pivotal role in AD pathogenesis, and further demonstrate that high GFAP and low Aß42 in plasma may reflect a particularly detrimental synergistic role in forniceal-memory pathways.