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Alzheimer's disease (AD) is a devastating neurodegenerative disease that affects millions of seniors in the United States. Resting-state functional magnetic resonance imaging (rs-fMRI) is widely used to study neurophysiology in AD and its prodromal condition, mild cognitive impairment (MCI). The intrinsic neural timescale (INT), which can be estimated through the magnitude of the autocorrelation of neural signals from rs-fMRI, is thought to quantify the duration that neural information is stored in a local circuit. Such heterogeneity of the timescales forms a basis of the brain functional hierarchy and captures an aspect of circuit dynamics relevant to excitation/inhibition balance, which is broadly relevant for cognitive functions. Given that, we applied rs-fMRI to test whether distinct changes of INT at different hierarchies are present in people with MCI, those progressing to AD (called Converter), and AD patients of both sexes. Linear mixed-effect model was implemented to detect altered hierarchical gradients across populations followed by pairwise comparisons to identify regional differences. High similarities between AD and Converter were observed. Specifically, the inferior temporal, caudate, and pallidum areas exhibit significant alterations in both AD and Converter. Distinct INT-related pathological changes in MCI and AD were found. For AD/Converter, neural information is stored for a longer time in lower hierarchical areas, while higher levels of hierarchy seem to be preferentially impaired in MCI leading to a less pronounced hierarchical gradient. These results inform that the INT holds great potential as an additional measure for AD prediction, even a stable biomarker for clinical diagnosis.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Imagen por Resonancia Magnética , Humanos , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/fisiopatología , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/diagnóstico por imagen , Masculino , Femenino , Anciano , Imagen por Resonancia Magnética/métodos , Encéfalo/fisiopatología , Encéfalo/diagnóstico por imagen , Anciano de 80 o más Años , Persona de Mediana Edad , Progresión de la Enfermedad , Mapeo Encefálico/métodosRESUMEN
Previous diffusion MRI studies have reported mixed findings on white matter microstructure alterations in obsessive-compulsive disorder (OCD), likely due to variation in demographic and clinical characteristics, scanning methods, and underpowered samples. The OCD global study was created across five international sites to overcome these challenges by harmonizing data collection to identify consistent brain signatures of OCD that are reproducible and generalizable. Single-shell diffusion measures (e.g., fractional anisotropy), multi-shell Neurite Orientation Dispersion and Density Imaging (NODDI) and fixel-based measures, were extracted from skeletonized white matter tracts in 260 medication-free adults with OCD and 252 healthy controls. We additionally performed structural connectome analysis. We compared cases with controls and cases with early (<18) versus late (18+) OCD onset using mixed-model and Bayesian multilevel analysis. Compared with healthy controls, adult OCD individuals showed higher fiber density in the sagittal stratum (B[SE] = 0.10[0.05], P = 0.04) and credible evidence for higher fiber density in several other tracts. When comparing early (n = 145) and late-onset (n = 114) cases, converging evidence showed lower integrity of the posterior thalamic radiation -particularly radial diffusivity (B[SE] = 0.28[0.12], P = 0.03)-and lower global efficiency of the structural connectome (B[SE] = 15.3[6.6], P = 0.03) in late-onset cases. Post-hoc analyses indicated divergent direction of effects of the two OCD groups compared to healthy controls. Age of OCD onset differentially affects the integrity of thalamo-parietal/occipital tracts and the efficiency of the structural brain network. These results lend further support for the role of the thalamus and its afferent fibers and visual attentional processes in the pathophysiology of OCD.
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Edad de Inicio , Encéfalo , Conectoma , Imagen de Difusión Tensora , Trastorno Obsesivo Compulsivo , Sustancia Blanca , Humanos , Trastorno Obsesivo Compulsivo/patología , Sustancia Blanca/patología , Adulto , Masculino , Femenino , Conectoma/métodos , Imagen de Difusión Tensora/métodos , Encéfalo/patología , Persona de Mediana Edad , Imagen de Difusión por Resonancia Magnética/métodos , Adulto Joven , Anisotropía , Teorema de Bayes , Estudios de Casos y Controles , AdolescenteRESUMEN
Cognitive reserve (CR) explains differential susceptibility of cognitive performance to neuropathology. However, as brain pathologies progress, cognitive decline occurs even in individuals with initially high CR. The interplay between the structural brain health (= level of brain reserve) and CR-related brain networks therefore requires further research. Our sample included 142 individuals aged 60-70 years. National Adult Reading Test intelligence quotient (NART-IQ) was our CR proxy. On an in-scanner Letter Sternberg task, we used ordinal trend (OrT) analysis to extract a task-related brain activation pattern (OrT slope) for each participant that captures increased expression with task load (one, three, and six letters). We assessed whether OrT slope represents a neural mechanism underlying CR by associating it with task performance and NART-IQ. Additionally, we investigated how the following brain reserve measures affect the association between NART-IQ and OrT slope: mean cortical thickness, total gray matter volume, and brain volumes proximal to the areas contained in the OrT patterns. We found that higher OrT slope was associated with better task performance and higher NART-IQ. Further, the brain reserve measures were not directly associated with OrT slope, but they affected the relationship between NART-IQ and OrT slope: NART-IQ was associated with OrT slope only in individuals with high brain reserve. The degree of brain reserve has an impact on how (and perhaps whether) CR can be implemented in brain networks in older individuals.
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Reserva Cognitiva , Adulto , Humanos , Anciano , Reserva Cognitiva/fisiología , Pruebas de Inteligencia , Encéfalo/diagnóstico por imagen , Escalas de Wechsler , Mapeo EncefálicoRESUMEN
Few human studies have assessed the association of prenatal maternal immune activation (MIA) with measures of brain development and psychiatric risk in newborn offspring. Our goal was to identify the effects of MIA during the 2nd and 3rd trimesters of pregnancy on newborn measures of brain metabolite concentrations, tissue microstructure, and motor development. This was a prospective longitudinal cohort study conducted with nulliparous pregnant women who were aged 14 to 19 years and recruited in their 2nd trimester, as well as their children who were followed through 14 months of age. MIA was indexed by maternal interleukin-6 (IL-6) and C-reactive protein (CRP) in both trimesters of pregnancy. Primary outcomes included: (1) newborn brain metabolite concentrations as ratios to creatine (N-acetylaspartate (NAA)/creatine (Cr) and choline (Cho)/Cr) measured using Magnetic Resonance Spectroscopy; (2) newborn fractional anisotropy and mean diffusivity, measured using Diffusion Tensor Imaging; and (3) indices of motor development, assessed prenatally and postnatally at ages 4- and 14-months. Maternal IL-6 and CRP levels associated significantly with both metabolites in the putamen, thalamus, insula, and the internal capsule. Maternal IL-6 associated significantly with fractional anisotropy in the putamen, caudate, thalamus, insula, and precuneus, and with mean diffusivity in the inferior parietal and middle temporal gyrus. CRP associated significantly with fractional anisotropy in the thalamus, insula, and putamen. Significant associations were found in common regions across imaging modalities, though the direction of associations differed by immune marker. In addition, both maternal IL-6 and CRP (in both trimesters) prenatally associated significantly with offspring motor development at 4- and 14-months of age. The left thalamus mediated effects of IL-6 on postnatal motor development. These findings demonstrate that levels of MIA in mid- to late pregnancy in a generally healthy sample associate with tissue characteristics in newborn brain regions that primarily support motor integration and coordination, as well as behavioral regulation. Those brain effects may contribute to differences in motor development.
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The need to select mediators from a high dimensional data source, such as neuroimaging data and genetic data, arises in much scientific research. In this work, we formulate a multiple-hypothesis testing framework for mediator selection from a high-dimensional candidate set, and propose a method, which extends the recent development in false discovery rate (FDR)-controlled variable selection with knockoff to select mediators with FDR control. We show that the proposed method and algorithm achieved finite sample FDR control. We present extensive simulation results to demonstrate the power and finite sample performance compared with the existing method. Lastly, we demonstrate the method for analyzing the Adolescent Brain Cognitive Development (ABCD) study, in which the proposed method selects several resting-state functional magnetic resonance imaging connectivity markers as mediators for the relationship between adverse childhood events and the crystallized composite score in the NIH toolbox.
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Algoritmos , Encéfalo , Simulación por Computador , Imagen por Resonancia Magnética , Humanos , Imagen por Resonancia Magnética/métodos , Imagen por Resonancia Magnética/estadística & datos numéricos , Adolescente , Encéfalo/diagnóstico por imagen , Neuroimagen/métodos , Neuroimagen/estadística & datos numéricos , Interpretación Estadística de Datos , Modelos Estadísticos , Reacciones Falso Positivas , Biometría/métodos , CogniciónRESUMEN
INTRODUCTION: Evidence suggests microglial activation precedes regional tau and neurodegeneration in Alzheimer's disease (AD). We characterized microglia with translocator protein (TSPO) positron emission tomography (PET) within an AD progression model where global amyloid beta (Aß) precedes local tau and neurodegeneration, resulting in cognitive impairment. METHODS: Florbetaben, PBR28, and MK-6240 PET, T1 magnetic resonance imaging, and cognitive measures were performed in 19 cognitively unimpaired older adults and 22 patients with mild cognitive impairment or mild AD to examine associations among microglia activation, Aß, tau, and cognition, adjusting for neurodegeneration. Mediation analyses evaluated the possible role of microglial activation along the AD progression model. RESULTS: Higher PBR28 uptake was associated with higher Aß, higher tau, and lower MMSE score, independent of neurodegeneration. PBR28 mediated associations between tau in early and middle Braak stages, between tau and neurodegeneration, and between neurodegeneration and cognition. DISCUSSION: Microglia are associated with AD pathology and cognition and may mediate relationships between subsequent steps in AD progression.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Microglía/metabolismo , Proteínas tau/metabolismo , Tomografía de Emisión de Positrones/métodos , Disfunción Cognitiva/metabolismo , Progresión de la Enfermedad , Receptores de GABA/metabolismoRESUMEN
INTRODUCTION: This study derived composite scores for two novel cognitive measures, the No Practice Effect (NPE) battery and the Miami Computerized Functional Skills Assessment and Training system for use in early-stage Alzheimer's disease (AD) clinical trials. Their psychometric properties and associations with AD risk markers were compared to those of well-established measures. METHODS: For 291 older adults with healthy cognition or early mild cognitive impairment, Exploratory factor analyses were used to identify the factor structure of the NPE. Factor and total scores were examined for their psychometric properties and associations with AD risk biomarkers. RESULTS: Composite scores from the novel cognitive and functional measures demonstrated better psychometric properties (distribution and test-retest reliability) and stronger associations with AD-related demographic, genetic, and brain risk markers than well-established measures, DISCUSSION: These novel measures have potential for use as primary cognitive and functional outcomes in early-stage AD clinical trials. HIGHLIGHTS: Well-established cognitive tests may not accurately detect subtle cognitive changes. No Practice Effect (NPE) and Computerized Functional Skills Assessment and Training are novel measures designed to have improved psychometric properties. NPE had Executive Function, Cognitive Control/Speed, and Episodic Memory domains. Novel measures had better psychometric properties compared to established measures. Significant associations with Alzheimer's disease biomarkers were found with novel measures.
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Esclerosis Amiotrófica Lateral , Progresión de la Enfermedad , Índice Glucémico , Riluzol , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Humanos , Riluzol/uso terapéutico , Riluzol/farmacología , Índice Glucémico/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/farmacología , Glucemia/efectos de los fármacos , Glucemia/metabolismoRESUMEN
In mediation analysis, the exposure often influences the mediating effect, i.e., there is an interaction between exposure and mediator on the dependent variable. When the mediator is high-dimensional, it is necessary to identify non-zero mediators M and exposure-by-mediator ( X -by- M ) interactions. Although several high-dimensional mediation methods can naturally handle X -by- M interactions, research is scarce in preserving the underlying hierarchical structure between the main effects and the interactions. To fill the knowledge gap, we develop the XMInt procedure to select M and X -by- M interactions in the high-dimensional mediators setting while preserving the hierarchical structure. Our proposed method employs a sequential regularization-based forward-selection approach to identify the mediators and their hierarchically preserved interaction with exposure. Our numerical experiments showed promising selection results. Further, we applied our method to ADNI morphological data and examined the role of cortical thickness and subcortical volumes on the effect of amyloid-beta accumulation on cognitive performance, which could be helpful in understanding the brain compensation mechanism.
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Cognitive reserve explains differential susceptibility of cognitive performance to neuropathology. We investigated whether certain personality traits underlie cognitive reserve and are accordingly associated with better cognition and less cognitive decline in the presence of age-related brain changes. We included healthy adults aged 19-80 years for cross-sectional (N=399) and longitudinal (N=273, mean follow-up time=5 years, SD=0.7 years) analyses. Assessment of the BIG5 personality traits openness, conscientiousness, extraversion, agreeableness, and neuroticism was questionnaire-based. Each cognitive domain (perceptual speed, memory, fluid reasoning, vocabulary) was measured with up to six tasks. Cognitive domain-specific brain status variables were obtained by combining 77 structural brain measures into single scores using elastic net regularization. These brain status variables explained up to 43.1% of the variance in cognitive performance. We found that higher openness was associated with higher fluid reasoning and better vocabulary after controlling for brain status, age, and sex. Further, lower brain status was associated with a greater decline in perceptual speed only in individuals with low openness. We conclude that high openness benefits cognitive reserve.
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Reserva Cognitiva , Humanos , Personalidad , Estudios Transversales , Cognición , EncéfaloRESUMEN
Background: Resting state Functional Magnetic Resonance Imaging fMRI (rs-fMRI) has been used extensively to study brain function in psychiatric disorders, yielding insights into brain organization. However, the high dimensionality of the rs-fMRI data presents significant challenges for data analysis. Variational autoencoders (VAEs), a type of neural network, have been instrumental in extracting low-dimensional latent representations of resting state functional connectivity (rsFC) patterns, thereby addressing the complex nonlinear structure of rs-fMRI data. Despite these advances, interpreting these latent representations remains a challenge. This paper aims to address this gap by developing explainable VAE models and testing their utility using rs-fMRI data in autism spectrum disorder (ASD). Methods: One-thousand one hundred and fifty participants (601 healthy controls [HC] and 549 patients with ASD) were included in the analysis. RsFC correlation matrices were extracted from the preprocessed rs-fMRI data using the Power atlas, which includes 264 regions of interest (ROIs). Then VAEs were trained in an unsupervised manner. Lastly, we introduce our latent contribution scores to explain the relationship between estimated representations and the original rs-fMRI brain measures. Results: We quantified the latent contribution scores for both the ASD and HC groups at the network level. We found that both ASD and HC groups share the top network connectivitives contributing to all estimated latent components. For example, latent 0 was driven by rsFC within ventral attention network (VAN) in both the ASD and HC. However, we found significant differences in the latent contribution scores between the ASD and HC groups within the VAN for latent 0 and the sensory/somatomotor network for latent 2. Conclusion: This study introduced latent contribution scores to interpret nonlinear patterns identified by VAEs. These scores effectively capture changes in each observed rsFC feature as the estimated latent representation changes, enabling an explainable deep learning model that better understands the underlying neural mechanisms of ASD.
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The relationship between tau deposition and cognitive decline in cognitively healthy older adults is still unclear. The tau PET tracer 18F-MK-6240 has shown favorable imaging characteristics to identify early tau deposition in aging. We evaluated the relationship between in vivo tau levels (18F-MK-6240) and retrospective cognitive change over 5 years in episodic memory, processing speed, and reasoning. For tau quantification, a set of regions of interest (ROIs) was selected a priori based on previous literature: (1) total-ROI comprising selected areas, (2) medial temporal lobe-ROI, and (3) lateral temporal lobe-ROI and cingulate/parietal lobe-ROI. Higher tau burden in most ROIs was associated with a steeper decline in memory and speed. There were no associations between tau and reasoning change. The novelty of this finding is that tau burden may affect not only episodic memory, a well-established finding but also processing speed. Our finding reinforces the notion that early tau deposition in areas related to Alzheimer's disease is associated with cognitive decline in cognitively unimpaired individuals, even in a sample with low amyloid-ß pathology.
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Enfermedad de Alzheimer , Velocidad de Procesamiento , Humanos , Anciano , Estudios Retrospectivos , Envejecimiento , Enfermedad de Alzheimer/diagnóstico por imagen , Péptidos beta-AmiloidesRESUMEN
Background: Our goal in this study was to identify paths from APOE e4 to neurobehaviors itemized on a neuropsychiatric inventory that involved neuropathologies associated with e4 (amyloid, tau, cerebral amyloid angiopathy, and Lewy bodies) or cognition mediators (memory or global cognitive status), as well as direct paths from e4 to cognition or neurobehaviors. Methods: A total of 1199 cases with available neurobehavioral, cognition and neuropathological data were included. We then conducted a series of causal mediation analyses in R in which e4 always served as the independent variable and Neuropsychiatric Inventory (NPI) neurobehavioral items, when included in the mediation, the outcome. Neuropathologies or cognition served as mediators. Results: Multiple significant indirect paths from e4 through neuropathologies to neurobehaviors were identified. More refined analyses indicated that neuritic plaques and Braak stage, but not extent of diffuse amyloid plaques, drove the findings. A significant direct effect of e4 to memory was also identified. Additionally, Lewy body disease, when treated as an exposure, had a direct effect on hallucinations in keeping with known features of the disease. Conclusions: We found strong evidence for partial mediation of NPI symptoms by cognition, suggesting that cognitive limitations that may have influenced understanding (or misunderstanding) the environment with impacts on maladaptive behavior. In addition, neuritic amyloid plaque levels and Braak stage, but not diffuse amyloid plaque extent, were key in NPI mediated associations suggesting the possibility that synaptic failure play an important role in multiple neurobehavioral symptoms in dementia, including psychosis. Last, we found strong evidence that e4 may have direct effects on cognition when we used verbal episodic memory as an outcome, suggesting that medial temporal regions that support memory may be sensitive to non-amyloidogenic and non-tau related pathophysiological processes.
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Importance: Adverse childhood experiences (ACEs), potentially traumatic experiences occurring before the age of 18 years, are associated with epigenetic aging later in life and may be transmitted across generations. Objective: To test evidence of the transmission of biological embedding of life experience across generations by analyzing maternal ACEs and epigenetic clocks measured in mothers during pregnancy and in their children at birth. Design, Setting, and Participants: For this cross-sectional study, data from the Accessible Resource for Integrated Epigenomic Studies (ARIES) substudy of the Avon Longitudinal Study of Parents and Children (ALSPAC) were analyzed. The ALSPAC study recruited 14â¯541 women who gave birth in the Avon Health District in the UK between April 1, 1991, and December 31, 1992. The ARIES substudy comprised 1018 mother-offspring dyads based on the availability of DNA samples profiled in 2014. Epigenetic age was estimated using DNA methylation-based epigenetic clocks (including Horvath, Hannum, GrimAge, PhenoAge, and DunedinPACE) in mothers during pregnancy and the Knight and Bohlin cord blood epigenetic clocks in newborns. Analyses were performed between October 1, 2022, and November 30, 2023. Exposures: A composite measure of maternal ACEs was the primary exposure in both maternal and offspring models; as a secondary analysis, individual ACEs were measured separately. The Edinburgh Postnatal Depression Scale (EPDS) was used to investigate depression during pregnancy as an exposure. Main Outcomes and Measures: Changes in epigenetic age acceleration (EAA) were investigated as the primary outcome in maternal models during pregnancy. Changes in epigenetic gestational age acceleration (GAA) were the primary outcome in offspring analyses. Linear regression analyses were used to determine the association between maternal ACEs and both outcomes. Results: This study included 883 mother-child dyads. The mean (SD) maternal age at delivery was 29.8 (4.3) years. Pregnant women with higher ACE scores exhibited higher GrimAge EAA (ß, 0.22 [95% CI, 0.12 to 0.33] years; P < .001). Maternal ACEs were not associated with GAA in newborns using P < .05 as a cutoff to determine statistical significance. Depression was associated with higher GrimAge EAA (ß, 0.06 [95% CI, 0.02 to 0.10] years; P = .01) in mothers during pregnancy, but not in newborns, and did not mediate the association between ACEs and EAA. Conclusions and Relevance: The findings of this study suggest that maternal ACEs may be associated with epigenetic aging later in life, including during pregnancy, supporting a role for maternal ACEs in offspring development and health later in life.
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Experiencias Adversas de la Infancia , Envejecimiento , Humanos , Femenino , Experiencias Adversas de la Infancia/estadística & datos numéricos , Embarazo , Adulto , Recién Nacido , Estudios Transversales , Envejecimiento/genética , Envejecimiento/fisiología , Envejecimiento/psicología , Epigénesis Genética , Estudios Longitudinales , Madres/psicología , Madres/estadística & datos numéricos , Efectos Tardíos de la Exposición Prenatal/epidemiología , Efectos Tardíos de la Exposición Prenatal/genética , Masculino , Metilación de ADN , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: In this study, we sought to identify paths from APOE ε4 to neurobehaviors itemized on a neuropsychiatric inventory (Neuropsychiatric Inventory-Questionnaire [NPI-Q]) that involved neuropathologies associated with APOE ε4 (amyloid, tau, cerebral amyloid angiopathy, and Lewy bodies) or cognition mediators (memory or global cognitive status) as well as direct paths from APOE ε4 to neurobehaviors. METHODS: A total of 1199 cases with available neurobehavioral, cognition, and neuropathological data were included. We conducted a series of causal mediation analyses in which APOE ε4 always served as the independent variable, and NPI-Q neurobehavioral items, when included in the mediation analysis, served as the outcome. Neuropathologies or cognition served as mediators. RESULTS: Multiple significant indirect paths from APOE ε4 through neuropathologies to neurobehaviors were identified. More refined analyses indicated that neuritic plaques and Braak stage drove the findings. A significant direct effect of APOE ε4 on memory was also identified. Additionally, Lewy body disease, when treated as an exposure, had a direct effect on hallucinations consistent with features of the disease. CONCLUSIONS: We found strong evidence for partial mediation of NPI-Q symptoms by cognition, suggesting that cognitive limitations may have promoted maladaptive behavior. In addition, neuritic amyloid plaque levels and Braak stage, but not diffuse amyloid plaque extent, were key in NPI-Q-mediated associations, suggesting the possibility that synaptic failure plays an important role in multiple neurobehavioral symptoms in dementia, including psychosis. Finally, we found strong evidence that APOE ε4 may have direct effects on cognition when we used verbal episodic memory but not global cognitive status as an outcome.
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Enfermedad de Alzheimer , Apolipoproteína E4 , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Apolipoproteína E4/genética , Encéfalo/patología , Bases de Datos Factuales , Análisis de Mediación , Pruebas NeuropsicológicasRESUMEN
Background: Sleep difficulties are common in pregnancy, yet poor prenatal sleep may be related to negative long-term outcomes for the offspring, including risk for attention-deficit/hyperactivity disorder (ADHD). Existing studies are few and have not examined timing of exposure effects or offspring sex moderation. We thus aimed to test the hypotheses that poor sleep health in pregnancy is associated with increased risk for ADHD symptoms and offspring sleep problems at approximately 4 years of age. Methods: Participants were 794 mother-child dyads enrolled in the NIH Environmental Influences on Child Health Outcomes Study (ECHO). Participants self-reported on sleep duration, quality, and disturbances during pregnancy and on children's ADHD symptoms and sleep problems on the Child Behaviour Checklist. Findings: Pregnant participants were 32.30 ± 5.50 years and children were 46% female. 44 percent of pregnant participants identified as Hispanic or Latine; 49% identified as White. Second-trimester sleep duration was associated with offspring ADHD symptoms (b = -0.35 [95% CI = -0.57, -0.13], p = 0.026), such that shorter duration was associated with greater symptomatology. Poorer sleep quality in the second trimester was also associated with increased ADHD symptomatology (b = 0.66 [95% CI = 0.18, 1.14], p = 0.037). Greater sleep disturbances in the first trimester were associated with offspring ADHD (b = 1.03 [95% CI = 0.32, 1.03], p = 0.037) and in the second trimester with sleep problems (b = 1.53 [95% CI = 0.42, 2.92], p = 0.026). We did not document substantial offspring sex moderation. Interpretation: Poor prenatal sleep health, particularly quality and duration in the second trimester, may be associated with offspring risk of neurodevelopmental disorders and sleep problems in early childhood. Further research is needed to understand mechanisms, yet our study suggests that prenatal maternal sleep may be a modifiable target for interventions aimed at optimizing early neurodevelopment. Funding: NIH grants U2COD023375, U24OD023382, U24OD023319, UH3OD023320, UH3OD023305, UH3OD023349, UH3OD023313, UH3OD023272, UH3OD023328, UH3OD023290, K08MH117452 and NARSAD Young Investigator Award 28545.