Air pollution and age-dependent changes in emotional behavior across early adolescence in the U.S.

Recent studies have linked air pollution to increased risk for behavioral problems during development, albeit with inconsistent findings. Additional longitudinal studies are needed that consider how emotional behaviors may be affected when exposure coincides with the transition to adolescence - a vulnerable time for developing mental health difficulties. This study investigates if annual average PM2.5 and NO2 exposure at ages 9-10 years moderates age-related changes in internalizing and externalizing behaviors over a 2-year follow-up period in a large, nationwide U.S. sample of participants from the Adolescent Brain Cognitive Development (ABCD) Study®. Air pollution exposure was estimated based on the residential address of each participant using an ensemble-based modeling approach. Caregivers answered questions from the Child Behavior Checklist (CBCL) at the baseline, 1-year follow-up, and 2-year follow-up visits, for a total of 3 waves of data; from the CBCL we obtained scores on internalizing and externalizing problems plus 5 syndrome scales (anxious/depressed, withdrawn/depressed, rule-breaking behavior, aggressive behavior, and attention problems). Zero-inflated negative binomial models were used to examine both the main effect of age as well as the interaction of age with each pollutant on behavior while adjusting for various socioeconomic and demographic characteristics. Against our hypothesis, there was no evidence that greater air pollution exposure was related to more behavioral problems with age over time.

Worth the Wait: Delayed Recall after 1 Week Predicts Cognitive and Medial Temporal Lobe Trajectories in Older Adults.

METHOD: Clinically normal older adults (52-92 years old) were followed longitudinally for up to 8 years after completing a memory paradigm at baseline [Story Recall Test (SRT)] that assessed delayed recall at 30 min and 1 week. Subsets of the cohort underwent neuroimaging (N = 134, mean age = 75) and neuropsychological testing (N = 178-207, mean ages = 74-76) at annual study visits occurring approximately 15-18 months apart. Mixed-effects regression models evaluated if baseline SRT performance predicted longitudinal changes in gray matter volumes and cognitive composite scores, controlling for demographics. RESULTS: Worse SRT 1-week recall was associated with more precipitous rates of longitudinal decline in medial temporal lobe volumes (p = .037), episodic memory (p = .003), and executive functioning (p = .011), but not occipital lobe or total gray matter volumes (demonstrating neuroanatomical specificity; p > .58). By contrast, SRT 30-min recall was only associated with longitudinal decline in executive functioning (p = .044). CONCLUSIONS: Memory paradigms that capture longer-term recall may be particularly sensitive to age-related medial temporal lobe changes and neurodegenerative disease trajectories. (JINS, 2020, xx, xx-xx).

Aging and Positive Mood: Longitudinal Neurobiological and Cognitive Correlates.

OBJECTIVE: Despite the losses commonly associated with aging, older adults seem to possess particularly preserved emotional regulation. To further understand this phenomenon, the authors examined longitudinal trajectories between age, depressive symptoms, brain structure, and cognition. METHODS: Seven hundred and sixteen functionally intact older adults (age M = 67.9, 56.8% female), followed longitudinally (visit range: 1-13, M = 2.5), completed cognitive testing and the Geriatric Depression Scale (GDS). A subset (N = 327) underwent 3T brain MRI. Mixed-effects linear regression models were conducted controlling for sex, education, and total intracranial volume. RESULTS: There was a significant interaction between age and time on GDS, such that GDS improved with increasing age over time, but attenuated around age 71 (age*time b = 0.10, p <0.001). Fractional anisotropy (FA) and mean diffusivity interacted with age to predict longitudinal changes in GDS (FA: b = -0.02, p = 0.01; MD: b = 0.03, p = 0.007), such that age-related benefits on GDS were attenuated in those with declining FA. Executive function (EF) and processing speed also interacted with age to predict longitudinal changes in GDS (EF: b = -0.04, p = 0.03; speed: b = 0.04, p = 0.04). Again, the positive effect of age on GDS attenuated in those with worsening EF and speed. There were no associations with memory, semantic fluency, or gray matter (p values >0.05). CONCLUSION: EF, processing speed, and white matter integrity moderated the longitudinal relationship between age and mood. Previous studies demonstrate the link between positivity and better cognitive control, leading to improved mood in older adults. Our results are not only consistent, but establish a potential neurobiological correlate. Future research further exploring biological mechanisms driving psychological processes may have important therapeutic implications.

Outdoor air pollution and brain development in childhood and adolescence.

Exposure to outdoor air pollution has been linked to adverse health effects, including potential widespread impacts on the CNS. Ongoing brain development may render children and adolescents especially vulnerable to neurotoxic effects of air pollution. While mechanisms remain unclear, promising advances in human neuroimaging can help elucidate both sensitive periods and neurobiological consequences of exposure to air pollution. Herein we review the potential influences of air pollution exposure on neurodevelopment, drawing from animal toxicology and human neuroimaging studies. Due to ongoing cellular and system-level changes during childhood and adolescence, the developing brain may be more sensitive to pollutants' neurotoxic effects, as a function of both timing and duration, with relevance to cognition and mental health. Building on these foundations, the emerging field of environmental neuroscience is poised to further decipher which air toxicants are most harmful and to whom.

A Systematic Review of Air Pollution Exposure and Brain Structure and Function during Development.

Objectives: Air pollutants are known neurotoxicants. In this updated systematic review, we evaluate new evidence since our 2019 systematic review on the effect of outdoor air pollution exposure on childhood and adolescent brain structure and function as measured by magnetic resonance imaging (MRI). Methods: Using PubMed and Web of Science, we conducted an updated literature search and systematic review of articles published through March 2024, using key terms for air pollution and functional and/or structural MRI. Two raters independently screened all articles using Covidence and implemented the risk of bias instrument for systematic reviews informing the World Health Organization Global Air Quality Guidelines. Results: We identified 222 relevant papers, and 14 new studies met our inclusion criteria. Including six studies from our 2019 review, the 20 publications to date include study populations from the United States, Netherlands, Spain, and United Kingdom. Studies investigated exposure periods spanning pregnancy through early adolescence, and estimated air pollutant exposure levels via personal monitoring, geospatial residential estimates, or school courtyard monitors. Brain MRI occurred when children were on average 6-14.7 years old; however, one study assessed newborns. Several MRI modalities were leveraged, including structural morphology, diffusion tensor imaging, restriction spectrum imaging, arterial spin labeling, magnetic resonance spectroscopy, as well as resting-state and task-based functional MRI. Air pollutants were associated with widespread brain differences, although the magnitude and direction of findings are largely inconsistent, making it difficult to draw strong conclusions. Conclusion: Prenatal and childhood exposure to outdoor air pollution is associated with structural and functional brain variations. Compared to our initial 2019 review, publications doubled-an increase that testifies to the importance of this public health issue. Further research is needed to clarify the effects of developmental timing, along with the downstream implications of outdoor air pollution exposure on children's cognitive and mental health.

Prenatal and childhood air pollution exposure, cellular immune biomarkers, and brain connectivity in early adolescents.

Introduction: Ambient air pollution is a neurotoxicant with hypothesized immune-related mechanisms. Adolescent brain structural and functional connectivity may be especially vulnerable to ambient pollution due to the refinement of large-scale brain networks during this period, which vary by sex and have important implications for cognitive, behavioral, and emotional functioning. In the current study we explored associations between air pollutants, immune markers, and structural and functional connectivity in early adolescence by leveraging cross-sectional sex-stratified data from the Adolescent Brain Cognitive Development℠ Study®. Methods: Pollutant concentrations of fine particulate matter, nitrogen dioxide, and ozone were assigned to each child's primary residential address during the prenatal period and childhood (9-10 years-old) using an ensemble-based modeling approach. Data collected at 11-13 years-old included resting-state functional connectivity of the default mode, frontoparietal, and salience networks and limbic regions of interest, intracellular directional and isotropic diffusion of available white matter tracts, and markers of cellular immune activation. Using partial least squares correlation, a multivariate data-driven method that identifies important variables within latent dimensions, we investigated associations between 1) pollutants and structural and functional connectivity, 2) pollutants and immune markers, and 3) immune markers and structural and functional connectivity, in each sex separately. Results: Air pollution exposure was related to white matter intracellular directional and isotropic diffusion at ages 11-13 years, but the direction of associations varied by sex. There were no associations between pollutants and resting-state functional connectivity at ages 11-13 years. Childhood exposure to nitrogen dioxide was negatively correlated with white blood cell count in males. Immune biomarkers were positively correlated with white matter intracellular directional diffusion in females and both white matter intracellular directional and isotropic diffusion in males. Lastly, there was a reliable negative correlation between lymphocyte-to-monocyte ratio and default mode network resting-state functional connectivity in females, as well as a compromised immune marker profile associated with lower resting-state functional connectivity between the salience network and the left hippocampus in males. In post-hoc exploratory analyses, we found that the PLSC-identified white matter tracts and resting-state networks related to processing speed and cognitive control performance from the NIH Toolbox. Conclusions: We identified novel links between childhood nitrogen dioxide and cellular immune activation in males, and brain network connectivity and immune markers in both sexes. Future research should explore the potentially mediating role of immune activity in how pollutants affect neurological outcomes as well as the potential consequences of immune-related patterns of brain connectivity in service of improved brain health for all.

Neural Correlates of Obesity and Inflammation in Children and Adolescents with Congenital Adrenal Hyperplasia.

INTRODUCTION: Patients with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency exhibit an increased prevalence of obesity from childhood including central adiposity and inflammation. There is also an emerging affected brain phenotype in CAH, with decreased cortico-limbic gray matter volumes and white matter abnormalities. We aimed to study the relationship between brain structure, obesity, and inflammation in children and adolescents with CAH compared to controls. METHODS: 27 CAH (12.6±3.4y, 16 females) and 35 controls (13.0±2.8y, 20 females) had MRI of gray matter regions of interest [prefrontal cortex (PFC), amygdala, hippocampus] and white matter microstructure [fornix, stria terminalis (ST)]. Anthropometric measures and lab analytes were obtained. Relaimpo analyses (relative importance for linear regression; percent variance) identified which brain structures were most different between groups. Subsequent regressions further quantified the magnitude and direction of these relationships. Correlations analyzed relationships between brain structure, obesity, and inflammation in the context of CAH status. RESULTS: PFC (13.3% variance) and its superior frontal (SF) subregion (14%) were most different between CAH and controls for gray matter; ST (16%) for white matter. Patients with CAH had lower caudal middle frontal [ß = -0.56, (-0.96, -0.15)] and superior frontal [ß = -0.58 (-0.92, -0.25)] subregion volumes, increased orientation dispersion index in the fornix [ß = 0.56 (0.01, 1.10)] and ST [ß = 0.85 (0.34, 1.36)], and decreased fractional anisotropy in the fornix [ß = -0.91 (-1.42, -0.42)] and ST [ß = -0.83 (-1.34, -0.33)] (all p's <0.05) indicating axonal disorganization, reduced myelin content, and/or higher microglial density within the affected white matter tracts. For the full cohort, SF was correlated with MCP-1 (r=-0.41), visceral adipose tissue (r=-0.25), and waist-to-height ratio (r=-0.27, all p's <0.05); ST was correlated with MCP-1 (r=0.31) and TNF-α (r= 0.29, all p's <0.05); however, after adjusting for CAH status, almost all correlations were attenuated for significance. CONCLUSIONS: Relationships among key brain structures, body composition and inflammatory markers in pediatric patients with CAH could be largely driven by having CAH, with implications for obesity and neuroinflammation in this high-risk population.

Outdoor Air Pollution Relates to Amygdala Subregion Volume and Apportionment in Early Adolescents.

Background: Outdoor air pollution is associated with an increased risk for psychopathology. Although the neural mechanisms remain unclear, air pollutants may impact mental health by altering limbic brain regions, such as the amygdala. Here, we examine the association between ambient air pollution exposure and amygdala subregion volumes in 9-10-year-olds. Methods: Cross-sectional Adolescent Brain Cognitive DevelopmentSM (ABCD) Study® data from 4,473 participants (55.4% male) were leveraged. Air pollution was estimated for each participant's primary residential address. Using the probabilistic CIT168 atlas, we quantified total amygdala and 9 distinct subregion volumes from T1- and T2-weighted images. First, we examined how criteria pollutants (i.e., fine particulate matter [PM2.5], nitrogen dioxide, ground-level ozone) and 15 PM2.5 components related with total amygdala volumes using linear mixed-effect (LME) regression. Next, partial least squares correlation (PLSC) analyses were implemented to identify relationships between co-exposure to criteria pollutants as well as PM2.5 components and amygdala subregion volumes. We also conducted complementary analyses to assess subregion apportionment using amygdala relative volume fractions (RVFs). Results: No significant associations were detected between pollutants and total amygdala volumes. Using PLSC, one latent dimension (LD) (52% variance explained) captured a positive association between calcium and several basolateral subregions. LDs were also identified for amygdala RVFs (ranging from 30% to 82% variance explained), with PM2.5 and component co-exposure associated with increases in lateral, but decreases in medial and central, RVFs. Conclusions: Fine particulate and its components are linked with distinct amygdala differences, potentially playing a role in risk for adolescent mental health problems.

Exposure to multiple ambient air pollutants changes white matter microstructure during early adolescence with sex-specific differences.

BACKGROUND: Air pollution is ubiquitous, yet questions remain regarding its impact on the developing brain. Large changes occur in white matter microstructure across adolescence, with notable differences by sex. METHODS: We investigate sex-stratified effects of annual exposure to fine particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3) at ages 9-10 years on longitudinal patterns of white matter microstructure over a 2-year period. Diffusion-weighted imaging was collected on 3T MRI scanners for 8182 participants (1-2 scans per subject; 45% with two scans) from the Adolescent Brain Cognitive Development (ABCD) Study®. Restriction spectrum imaging was performed to quantify intracellular isotropic (RNI) and directional (RND) diffusion. Ensemble-based air pollution concentrations were assigned to each child's primary residential address. Multi-pollutant, sex-stratified linear mixed-effect models assessed associations between pollutants and RNI/RND with age over time, adjusting for sociodemographic factors. RESULTS: Here we show higher PM2.5 exposure is associated with higher RND at age 9 in both sexes, with no significant effects of PM2.5 on RNI/RND change over time. Higher NO2 exposure is associated with higher RNI at age 9 in both sexes, as well as attenuating RNI over time in females. Higher O3 exposure is associated with differences in RND and RNI at age 9, as well as changes in RND and RNI over time in both sexes. CONCLUSIONS: Criteria air pollutants influence patterns of white matter maturation between 9-13 years old, with some sex-specific differences in the magnitude and anatomical locations of affected tracts. This occurs at concentrations that are below current U.S. standards, suggesting exposure to low-level pollution during adolescence may have long-term consequences.

Air pollution is known to affect health, but it is unclear whether it affects the growing human brain. We investigated whether there were differences in the development of white matter connections, which allow for faster communication between different brain regions, in children aged 9-13 years living in areas with relatively low or high air pollution in the USA. In a large group of U.S. teens, we find that polluted air is linked to differences in white matter at ages 9-10 years old and over the next two years. In some cases, males and females showed differences in the part of the brain showing changes and the amount of white matter change. Our study suggests that air pollution levels that are deemed acceptable under current regulations in the USA could have long-term effects on how a child's brain grows. Further studies are needed to better understand the impact of these changes.

Predicting brain atrophy and cognitive aging trajectories with baseline subjective cognitive concerns in cognitively normal older adults.

Subjective cognitive concerns (SCC) are common even in cognitively normal older adults who lack objectively-detectable deficits on standard neuropsychological evaluation. The clinical relevance of these concerns, particularly considering the nature of concerns (e.g., memory versus non-memory), remains unclear. Thus, we examined whether baseline memory and non-memory SCC relate to longitudinal change in brain volume and neuropsychological test performance in 476 functionally-intact, objectively unimpaired older adults (Mage = 72y, 56 % female, follow-up time = 1 - 9 years). Mixed-effects models revealed that both higher baseline memory and non-memory SCC predicted greater atrophy in total gray matter and dorsolateral prefrontal cortex atrophy over time, while only memory SCC predicted steeper medial temporal lobe atrophy. Regarding neuropsychological performance, higher non-memory SCC predicted decline in processing speed performance, while memory SCC did not predict neuropsychological trajectories. SCC are a risk factor for more adverse brain and cognitive aging trajectories, even in functionally-intact, seemingly cognitively normal older adults.

Altered Emotion Perception Linked to Structural Brain Differences in Youth With Congenital Adrenal Hyperplasia.

CONTEXT: Congenital adrenal hyperplasia (CAH) is a genetic disorder that results in hormonal imbalances and decreased brain volumes in regions important for emotional processing. OBJECTIVE: To examine whether emotion perception differs between youth with CAH and control youth, and if these differences relate to brain volumes. METHODS: In this cross-sectional study of 27 youths with CAH (mean age = 12.63 years, 16 female) and 35 age- and sex-matched controls (mean age = 13.03 years, 20 female), each participant rated picture stimuli and completed a 3T structural brain scan. Valence and arousal ratings and reaction times of 61 affective images were assessed. Gray matter volumes were measured by MRI. RESULTS: Youth with CAH had lower valence ratings for negative (P = .007) and neutral (P = .019) images. Controls showed differences in reaction times and arousal ratings across stimuli conditions, but youth with CAH did not. Brain volumes of the right amygdala (P = .025) and left hippocampus (P = .002) were associated with valence ratings. Left rostral middle frontal (P < .001) and right medial orbitofrontal cortex (P = .002) volumes were negatively related to valence scores only in youth with CAH, whereas left medial orbitofrontal cortex (P < .001) volumes were associated with valence scores positively in youth with CAH and negatively in controls. CONCLUSION: Findings suggest that youth with CAH perceive emotive stimuli as more unpleasant. Decreased brain volumes in the amygdala, hippocampus, and prefrontal cortex are associated with these measures of altered emotion perception in youth with CAH.

Effects of ambient fine particulates, nitrogen dioxide, and ozone on maturation of functional brain networks across early adolescence.

BACKGROUND: Air pollution is linked to neurodevelopmental delays, but its association with longitudinal changes in brain network development has yet to be investigated. We aimed to characterize the effect of PM2.5, O3, and NO2 exposure at ages 9-10 years on changes in functional connectivity (FC) over a 2-year follow-up period, with a focus on the salience (SN), frontoparietal (FPN), and default-mode (DMN) brain networks as well as the amygdala and hippocampus given their importance in emotional and cognitive functioning. METHODS: A sample of children (N = 9,497; with 1-2 scans each for a total of 13,824 scans; 45.6% with two brain scans) from the Adolescent Brain Cognitive Development (ABCD) Study® were included. Annual averages of pollutant concentrations were assigned to the child's primary residential address using an ensemble-based exposure modeling approach. Resting-state functional MRI was collected on 3T MRI scanners. First, developmental linear mixed-effect models were performed to characterize typical FC development within our sample. Next, single- and multi-pollutant linear mixed-effect models were constructed to examine the association between exposure and intra-network, inter-network, and subcortical-to-network FC change over time, adjusting for sex, race/ethnicity, income, parental education, handedness, scanner type, and motion. RESULTS: Developmental profiles of FC over the 2-year follow-up included intra-network integration within the DMN and FPN as well as inter-network integration between the SN-FPN; along with intra-network segregation in the SN as well as subcortical-to-network segregation more broadly. Higher PM2.5 exposure resulted in greater inter-network and subcortical-to-network FC over time. In contrast, higher O3 concentrations resulted in greater intra-network, but less subcortical-to-network FC over time. Lastly, higher NO2 exposure led to less inter-network and subcortical-to-network FC over the 2-year follow-up period. CONCLUSION: Taken together, PM2.5, O3, and NO2 exposure in childhood relate to distinct changes in patterns of network maturation over time. This is the first study to show outdoor ambient air pollution during childhood is linked to longitudinal changes in brain network connectivity development.

Sex-specific effects in how childhood exposures to multiple ambient air pollutants affect white matter microstructure development across early adolescence.

Ambient air pollution is ubiquitous, yet questions remain as to how it might impact the developing brain. Large changes occur in the brain's white matter (WM) microstructure across adolescence, with noticeable differences in WM integrity in male and female youth. Here we report sex-stratified effects of fine particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3) on longitudinal patterns of WM microstructure from 9-13 years-old in 8,182 (49% female) participants using restriction spectrum imaging. After adjusting for key sociodemographic factors, multi-pollutant, sex-stratified models showed that one-year annual exposure to PM2.5 and NO2 was associated with higher, while O3 was associated with lower, intracellular diffusion at age 9. All three pollutants also affected trajectories of WM maturation from 9-13 years-old, with some sex-specific differences in the number and anatomical locations of tracts showing altered trajectories of intracellular diffusion. Concentrations were well-below current U.S. standards, suggesting exposure to these criteria pollutants during adolescence may have long-term consequences on brain development.

Air pollution and emotional behavior in adolescents across the U.S.

Recent studies have linked air pollution to increased risk for behavioral problems during development, albeit with inconsistent findings. Additional longitudinal studies are needed that consider how emotional behaviors may be affected when exposure coincides with the transition to adolescence - a vulnerable time for developing mental health difficulties. This study examines how annual average PM2.5 and NO2 exposure at ages 9-10 years relates to internalizing and externalizing behaviors over a 2-year follow-up period in a large, nationwide U.S. sample of participants from the Adolescent Brain Cognitive Development (ABCD) Study®. Air pollution exposure was estimated based on the residential address of each participant using an ensemble-based modeling approach. Caregivers answered questions from the Child Behavior Checklist (CBCL) at baseline and annually for two follow-up sessions for a total of 3 waves of data; from the CBCL we obtained scores on internalizing and externalizing problems plus 5 syndrome scales (anxious/depressed, withdrawn/depressed, rule-breaking behavior, aggressive behavior, and attention problems). Zero-inflated negative binomial models were used to examine both the main effect of age as well as the interaction of age with each pollutant on behavior while adjusting for various socioeconomic and demographic characteristics. Overall, the pollution effects moderated the main effects of age with higher levels of PM2.5 and NO2 leading to an even greater likelihood of having no behavioral problems (i.e., score of zero) with age over time, as well as fewer problems when problems are present as the child ages. Albeit this was on the order equal to or less than a 1-point change. Thus, one year of annual exposure at 9-10 years is linked with very small change in emotional behaviors in early adolescence, which may be of little clinical relevance.

Congenital Adrenal Hyperplasia and Brain Health: A Systematic Review of Structural, Functional, and Diffusion Magnetic Resonance Imaging (MRI) Investigations.

BACKGROUND: Congenital adrenal hyperplasia (CAH) is a group of genetic disorders that affects the adrenal glands and is the most common cause of primary adrenal insufficiency in children. In the past few decades, magnetic resonance imaging (MRI) has been implemented to investigate how the brain may be affected by CAH. A systematic review was conducted to evaluate and synthesize the reported evidence of brain findings related to CAH using structural, functional, and diffusion-weighted MRI. METHODS: We searched bibliographical databases through July 2021 for brain MRI studies in individuals with CAH. RESULTS: Twenty-eight studies were identified, including 13 case reports or series, 10 studies that recruited and studied CAH patients vs unaffected controls, and 5 studies without a matched control group. Eleven studies used structural MRI to identify structural abnormalities or quantify brain volumes, whereas 3 studies implemented functional MRI to investigate brain activity, and 3 reported diffusion MRI findings to assess white matter microstructure. Some commonly reported findings across studies included cortical atrophy and differences in gray matter volumes, as well as white matter hyperintensities, altered white matter microstructure, and distinct patterns of emotion and reward-related brain activity. CONCLUSIONS: These findings suggest differences in brain structure and function in patients with CAH. Limitations of these studies highlight the need for CAH neuroimaging studies to incorporate larger sample sizes and follow best study design and MRI analytic practices, as well as clarify potential neurologic effects seen across the lifespan and in relation to clinical and behavioral CAH phenotypes.

White Matter Microstructural Differences in Youth With Classical Congenital Adrenal Hyperplasia.

CONTEXT: Gray matter morphology in the prefrontal cortex and subcortical regions, including the hippocampus and amygdala, are affected in youth with classical congenital adrenal hyperplasia (CAH). It remains unclear if white matter connecting these aforementioned brain regions is compromised in youth with CAH. OBJECTIVE: To examine brain white matter microstructure in youth with CAH compared to controls. DESIGN: A cross-sectional sample of 23 youths with CAH due to 21-hydroxylase deficiency (12.9 ±â€…3.5 year; 61% female) and 33 healthy controls (13.1 ±â€…2.8 year; 61% female) with 3T multishell diffusion-weighted magnetic resonance brain scans. MAIN OUTCOME MEASURES: Complementary modeling approaches, including diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), to examine in vivo white matter microstructure in six white matter tracts that innervate the prefrontal and subcortical regions. RESULTS: DTI showed CAH youth had lower fractional anisotropy in both the fornix and stria terminalis and higher mean diffusivity in the fornix compared to controls. NODDI modeling revealed that CAH youth have a significantly higher orientation dispersion index in the stria terminalis compared to controls. White matter microstructural integrity was associated with smaller hippocampal and amygdala volumes in CAH youth. CONCLUSIONS: These patterns of microstructure reflect less restricted water diffusion likely due to less coherency in oriented microstructure. These results suggest that white matter microstructural integrity in the fornix and stria terminalis is compromised and may be an additional related brain phenotype alongside affected hippocampus and amygdala neurocircuitry in individuals with CAH.

Association of Outdoor Ambient Fine Particulate Matter With Intracellular White Matter Microstructural Properties Among Children.

Importance: Outdoor particulate matter 2.5 µm or less in diameter (PM2.5) is a ubiquitous environmental neurotoxicant that may affect the developing brain. Little is known about associations between PM2.5 and white matter connectivity. Objectives: To assess associations between annual residential PM2.5 exposure and white matter microstructure health in a US sample of children 9 to 10 years of age and to examine whether associations are specific to certain white matter pathways or vary across neuroimaging diffusion markers reflective of intracellular and extracellular microstructural processes. Design, Setting, and Participants: This cross-sectional study, the Adolescent Brain and Cognitive Development (ABCD) Study, was composed of 21 study sites across the US and used baseline data collected from children 9 to 10 years of age from September 1, 2016, to October 15, 2018. Data analysis was performed from September 15, 2020, to June 30, 2021. Exposures: Annual mean PM2.5 exposure estimated by ensemble-based models and assigned to the primary residential addresses at baseline. Main Outcomes and Measures: Diffusion-weighted imaging (DWI) and tractography were used to delineate white matter tracts. The biophysical modeling technique of restriction spectrum imaging (RSI) was implemented to examine total hindered diffusion and restricted isotropic and anisotropic intracellular diffusion in each tract. Hierarchical mixed-effects models with natural splines were used to analyze the associations between PM2.5 exposure and DWI. Results: In a study population of 7602 children (mean [SD] age, 119.1 [7.42] months; 3955 [52.0%] female; 160 [ 21.%] Asian, 1025 [13.5%] Black, 1616 [21.3%] Hispanic, 4025 [52.9%] White, and 774 [10.2%] other [identified by parents as American Indian/Native American or Alaska Native; Native Hawaiian, Guamanian, Samoan, other Pacific Islander; Asian Indian, Chinese, Filipino, Japanese, Korean, Vietnamese, or other Asian; or other race]), associations were seen between annual ambient PM2.5 and hemispheric differences in white matter microstructure. Hemisphere-stratified models revealed significant associations between PM2.5 exposure and restricted isotropic intracellular diffusion in the left cingulum, in the left superior longitudinal fasciculus, and bilaterally in the fornix and uncinate fasciculus. In tracts with strong positive associations, a PM2.5 increase from 8 to 12 µg/m3 was associated with increases of 2.16% (95% CI, 0.49%-3.84%) in the left cingulum, 1.95% (95% CI, 0.43%-3.47%) in the left uncinate, and 1.68% (95% CI, 0.01%-3.34%) in the right uncinate. Widespread negative associations were observed between PM2.5 and mean diffusivity. Conclusions and Relevance: The findings of this cross-sectional study suggest that annual mean PM2.5 exposure during childhood is associated with increased restricted isotropic diffusion and decreased mean diffusivity of specific white matter tracts, potentially reflecting differences in the composition of white matter microarchitecture.

REM sleep is associated with white matter integrity in cognitively healthy, older adults.

There is increasing awareness that self-reported sleep abnormalities are negatively associated with brain structure and function in older adults. Less is known, however, about how objectively measured sleep associates with brain structure. We objectively measured at-home sleep to investigate how sleep architecture and sleep quality related to white matter microstructure in older adults. 43 cognitively normal, older adults underwent diffusion tensor imaging (DTI) and a sleep assessment within a six-month period. Participants completed the PSQI, a subjective measure of sleep quality, and used an at-home sleep recorder (Zeo, Inc.) to measure total sleep time (TST), sleep efficiency (SE), and percent time in light sleep (LS), deep sleep (DS), and REM sleep (RS). Multiple regressions predicted fractional anisotropy (FA) and mean diffusivity (MD) of the corpus callosum as a function of total PSQI score, TST, SE, and percent of time spent in each sleep stage, controlling for age and sex. Greater percent time spent in RS was significantly associated with higher FA (ß = 0.41, p = 0.007) and lower MD (ß = -0.30, p = 0.03). Total PSQI score, TST, SE, and time spent in LS or DS were not significantly associated with FA or MD (p>0.13). Percent time spent in REM sleep, but not quantity of light and deep sleep or subjective/objective measures of sleep quality, positively predicted white matter microstructure integrity. Our results highlight an important link between REM sleep and brain health that has the potential to improve sleep interventions in the elderly.

An IL-18-centered inflammatory network as a biomarker for cerebral white matter injury.

Chronic systemic sterile inflammation is implicated in the pathogenesis of cerebrovascular disease and white matter injury. Non-invasive blood markers for risk stratification and dissection of inflammatory molecular substrates in vivo are lacking. We sought to identify whether an interconnected network of inflammatory biomarkers centered on IL-18 and all previously associated with white matter lesions could detect overt and antecedent white matter changes in two populations at risk for cerebral small vessel disease. In a cohort of 167 older adults (mean age: 76, SD 7.1, 83 females) that completed a cognitive battery, physical examination, and blood draw in parallel with MR imaging including DTI, we measured cerebral white matter hyperintensities (WMH) and free water (FW). Concurrently, serum levels of a biologic network of inflammation molecules including MPO, GDF-15, RAGE, ST2, IL-18, and MCP-1 were measured. The ability of a log-transformed population mean-adjusted inflammatory composite score (ICS) to associate with MR variables was demonstrated in an age and total intracranial volume adjusted model. In this cohort, ICS was significantly associated with WMH (ß = 0.222, p = 0.013), FW (ß = 0.3, p = 0.01), and with the number of vascular risk factor diagnoses (r = 0.36, p<0.001). In a second cohort of 131 subjects presenting for the evaluation of acute neurologic deficits concerning for stroke, we used serum levels of 11 inflammatory biomarkers in an unbiased principal component analysis which identified a single factor significantly associated with WMH. This single factor was strongly correlated with the six component ICS identified in the first cohort and was associated with WMH in a generalized linear regression model adjusted for age and gender (p = 0.027) but not acute stroke. A network of inflammatory molecules driven by IL-18 is associated with overt and antecedent white matter injury resulting from cerebrovascular disease and may be a promising peripheral biomarker for vascular white matter injury.