Cortical Gray Matter Volume Research Articles

Developmental exposure to thyroid disruptors: misprogramming of the brain's stem cells in later life?

Developmental exposure to thyroid disruptors: misprogramming of the brain's stem cells in later life?

Detangling the Structural Neural Correlates Associated with Resting versus Dynamic Phantom Limb Pain Intensity Using a Voxel-based Morphometry Analysis.

The management of phantom limb pain (PLP) is still challenging due to a partial understanding of its neurophysiological mechanisms. Structural neuroimaging features are potential biomarkers. However, only a few studies assessed their correlations with clinical severity and treatment response. This study aims to explore the association between brain gray matter volume (GMV) with phantom limb manifestations severity and PLP improvement after neuromodulatory treatments (transcranial direct current stimulation and mirror therapy). Voxel-based morphometry analyses and functional decoding using a reverse inference term-based meta-analytic approach were used. We included 24 lower limb traumatic amputees with moderate to severe PLP. We found that alterations of cortical GMV were correlated with PLP severity but not with other clinical manifestations. Less PLP severity was associated with larger brain clusters GMV in the non-affected prefrontal, insula (non-affected mid-anterior region), and bilateral thalamus. However, only the insula cluster survived adjustments. Moreover, the reverse inference meta-analytic approach revealed that the found insula cluster is highly functionally connected to the contralateral insula and premotor cortices, and the decoded psychological processes related to this cluster were "rating," "sustained attention," "impulsivity, " and "suffering." Moreover, we found that responders to neuromodulatory treatment have higher GMV in somatosensory areas (total volume of S1 and S2) in the affected hemisphere at baseline, compared to non-responders, even after adjustments.

Association of daily physical activity with brain volumes and cervical spinal cord areas in multiple sclerosis

Background: Remote activity monitoring has the potential to evaluate real-world, motor function, and disability at home. The relationships of daily physical activity with spinal cord white matter and gray matter (GM) areas, multiple sclerosis (MS) disability and leg function, are unknown. Objective: Evaluate the association of structural central nervous system pathology with ambulatory disability. Methods: Fifty adults with progressive or relapsing MS with motor disability who could walk >2 minutes were assessed using clinician-evaluated, patient-reported outcomes, and quantitative brain and spinal cord magnetic resonance imaging (MRI) measures. Fitbit Flex2, worn on the non-dominant wrist, remotely assessed activity over 30 days. Univariate and multivariate analyses were performed to assess correlations between physical activity and other disability metrics. Results: Mean age was 53.3 years and median Expanded Disability Status Scale (EDSS) was 4.0. Average daily step counts (STEPS) were highly correlated with EDSS and walking measures. Greater STEPS were significantly correlated with greater C2-C3 spinal cord GM areas (ρ = 0.39, p = 0.04), total cord area (TCA; ρ = 0.35, p = 0.04), and cortical GM volume (ρ = 0.32, p = 0.04). Conclusion These results provide preliminary evidence that spinal cord GM area is a neuroanatomical substrate associated with STEPS. STEPS could serve as a proxy to alert clinicians and researchers to possible changes in structural nervous system pathology.

Deep Grey Matter Volume is Reduced in Amateur Boxers as Compared to Healthy Age-matched Controls

PurposeMild traumatic brain injuries (mTBI) sustained during contact sports like amateur boxing are found to have long-term sequelae, being linked to an increased risk of developing neurological conditions like Parkinson’s disease. The aim of this study was to assess differences in volume of anatomical brain structures between amateur boxers and control subjects with a special interest in the affection of deep grey matter structures.MethodsA total of 19 amateur boxers and 19 healthy controls (HC), matched for age and intelligence quotient (IQ), underwent 3T magnetic resonance imaging (MRI) as well as neuropsychological testing. Body mass index (BMI) was evaluated for every subject and data about years of boxing training and number of fights were collected for each boxer. The acquired 3D high resolution T1 weighted MR images were analyzed to measure the volumes of cortical grey matter (GM), white matter (WM), cerebrospinal fluid (CSF) and deep grey matter structures. Multivariate analysis was applied to reveal differences between groups referencing deep grey matter structures to normalized brain volume (NBV) to adjust for differences in head size and brain volume as well as adding BMI as cofactor.ResultsTotal intracranial volume (TIV), comprising GM, WM and CSF, was lower in boxers compared to controls (by 7.1%, P = 0.009). Accordingly, GM (by 5.5%, P = 0.038) and WM (by 8.4%, P = 0.009) were reduced in boxers. Deep grey matter showed statistically lower volumes of the thalamus (by 8.1%, P = 0.006), caudate nucleus (by 11.1%, P = 0.004), putamen (by 8.1%, P = 0.011), globus pallidus (by 9.6%, P = 0.017) and nucleus accumbens (by 13.9%, P = 0.007) but not the amygdala (by 5.5%, P = 0.221), in boxers compared to HC.ConclusionSeveral deep grey matter structures were reduced in volume in the amateur boxer group. Furthermore, longitudinal studies are needed to determine the damage pattern affecting deep grey matter structures and its neuropsychological relevance.

Early brain morphometrics from neonatal MRI predict motor and cognitive outcomes at 2-years corrected age in very preterm infants

Infants born very preterm face a range of neurodevelopmental challenges in cognitive, language, behavioural and/or motor domains. Early accurate identification of those at risk of adverse neurodevelopmental outcomes, through clinical assessment and Magnetic Resonance Imaging (MRI), enables prognostication of outcomes and the initiation of targeted early interventions. This study utilises a prospective cohort of 181 infants born <31 weeks gestation, who had 3T MRIs acquired at 29-35 weeks postmenstrual age and a comprehensive neurodevelopmental evaluation at 2 years corrected age (CA). Cognitive, language and motor outcomes were assessed using the Bayley Scales of Infant and Toddler Development – Third Edition and functional motor outcomes using the Neuro-sensory Motor Developmental Assessment. By leveraging advanced structural MRI pre-processing steps to standardise the data, and the state-of-the-art developing Human Connectome Pipeline, early MRI biomarkers of neurodevelopmental outcomes were identified. Using Least Absolute Shrinkage and Selection Operator (LASSO) regression, significant associations between brain structure on early MRIs with 2-year outcomes were obtained (r = 0.51 and 0.48 for motor and cognitive outcomes respectively) on an independent 25% of the data. Additionally, important brain biomarkers from early MRIs were identified, including cortical grey matter volumes, as well as cortical thickness and sulcal depth across the entire cortex. Adverse outcome on the Bayley-III motor and cognitive composite scores were accurately predicted, with an Area Under the Curve of 0.86 for both scores. These associations between 2-year outcomes and patient prognosis and early neonatal MRI measures demonstrate the utility of imaging prior to term equivalent age for providing earlier commencement of targeted interventions for infants born preterm.

Breast Milk Exposure is Associated With Cortical Maturation in Preterm Infants.

Breast milk exposure is associated with improved neurocognitive outcomes following preterm birth but the neural substrates linking breast milk with outcome are uncertain. We tested the hypothesis that high versus low breast milk exposure in preterm infants results in cortical morphology that more closely resembles that of term-born infants. We studied 135 preterm (<32 weeks' gestation) and 77 term infants. Feeding data were collected from birth until hospital discharge and brain magnetic resonance imaging (MRI) was performed at term-equivalent age. Cortical indices (volume, thickness, surface area, gyrification index, sulcal depth, and curvature) and diffusion parameters (fractional anisotropy [FA], mean diffusivity [MD], radial diffusivity [RD], axial diffusivity [AD], neurite density index [NDI], and orientation dispersion index [ODI]) were compared between preterm infants who received exclusive breast milk for <75% of inpatient days, preterm infants who received exclusive breast milk for ≥75% of inpatient days and term-born controls. To investigate a dose response effect, we performed linear regression using breast milk exposure quartile weighted by propensity scores. In preterm infants, high breast milk exposure was associated with reduced cortical gray matter volume (d=0.47, 95% confidence interval [CI]=0.14 to 0.94, p=0.014), thickness (d=0.42, 95% CI=0.08 to 0.84, p=0.039), and RD (d=0.38, 95% CI=0.002 to 0.77, p=0.039), and increased FA (d=-0.38, 95% CI=-0.74 to -0.01, p=0.037) after adjustment for age at MRI, which was similar to the cortical phenotype observed in term-born controls. Breast milk exposure quartile was associated with cortical volume (ß=-0.192, 95% CI=-0.342 to -0.042, p=0.017), FA (ß=0.223, 95% CI=0.075 to 0.372, p=0.007), and RD (ß=-0.225, 95% CI=-0.373 to -0.076, p=0.007) following adjustment for age at birth, age at MRI, and weighted by propensity scores, suggesting a dose effect. High breast milk exposure following preterm birth is associated with a cortical imaging phenotype that more closely resembles the brain morphology of term-born infants and effects appear to be dose-dependent. ANN NEUROL 2023;93:591-603.

Multiple sclerosis as a model to investigate SARS-CoV-2 effect on brain atrophy.

Data on structural brain changes after infection with SARS-CoV-2 is sparse. We postulate multiple sclerosis as a model to study the effects of SARS-CoV-2 on brain atrophy due to the unique availability of longitudinal imaging data in this patient group, enabling assessment of intraindividual brain atrophy rates. Global and regional cortical gray matter volumes were derived from structural MRIs using FreeSurfer. A linear model was fitted to the measures of the matching pre-SARS-CoV-2 images with age as an explanatory variable. The residuals were used to determine whether the post-SARS-CoV-2 volumes differed significantly from the baseline. Fourteen RRMS patients with a total of 113 longitudinal magnetic resonance images were retrospectively analyzed. We found no acceleration of brain atrophy after infection with SARS-CoV-2 for global gray matter volume (p= 0.17). However, on the regional level, parahippocampal gyri showed a tendency toward volume reduction (p= 0.0076), suggesting accelerated atrophy during or after infection. Our results illustrate the opportunity of using longitudinal MRIs from existing MS registries to study brain changes associated with SARS-CoV-2 infections. We would like to address the global MS community with a call for action to use the available cohorts, reproduce the proposed analysis, and pool the results.

Two progression patterns in Alzheimer's disease identified from structural MRI in a memory clinic‐based cohort

AbstractBackgroundAlzheimer’s disease (AD) is known to be heterogeneous in pathobiology and clinical manifestation. Most previous studies demarcating AD subtypes rely on data‐driven clustering methods that are likely confounded by interindividual differences in disease progression within samples. Addressing this problem, we aim to identify and characterize distinct AD atrophy progression patterns in a memory clinic‐based cohort.Method N = 914 subjects (296 cognitively unimpaired, 366 with subjective cognitive impairment, 153 with mild cognitive impairment, and 99 with AD dementia) from the multicenter observational DZNE Longitudinal Cognitive Impairment and Dementia Study (DELCODE) were included. The Subtype and Stage Inference algorithm (Young et al., 2018, Nat. Commun.) was applied to ROI‐based cortical thickness and gray matter volume data obtained from T1w and T2w 3T‐MRI using FreeSurfer. Subtypes were characterized in demographics, ApoE genotype, various fluid biomarkers, and cognition.ResultTwo atrophy subtypes were identified. A limbic‐predominant subtype exhibited initial volume loss in the amygdala and hippocampus, followed by cortical thinning in the medial temporal, temporal, frontal, parietal, and occipital lobes. Contrary, in a hippocampal‐sparing subtype, cortical thinning first occured in the frontal, parietal, and occipital lobes before the temporal and medial temporal lobes, hippocampus, and amygdala were affected. Compared to the hippocampal‐sparing subtype, the limbic‐predominant subtype included subjects who were older, reported fewer years of education, and tended to have more ApoE e4 alleles, higher risk of vascular pathology, and higher plasma neurofilament light levels. The subtypes differed in their CSF biomarker profiles indicating higher β‐amyloid and tau burden in the limbic‐predominant subtype. In the limbic‐predominant subtype, cognitive impairment was accentuated in the learning and memory as well as language domains. Belonging to the hippocampal‐sparing subtype was associated with an impairment in executive functions and processing speed, visuospatial functions, and working memory.ConclusionWe provide evidence on atrophy heterogeneity that is largely in line with previous theoretical and empirical contributions while overcoming key limitations that are commonly faced in earlier studies. Heterogeneity may have substantial impact even in cohort studies designed to primarily include “typical” amnestic AD which highlights the need for optimized and subtype‐specific measures of early detection and disease progression.

In vivo biomarkers of arteriolosclerosis are associated with ADRD biomarkers

AbstractBackgroundBrain arteriolosclerosis, which involves thickening of the vessel wall and stenosis of arterioles, is one of the main pathologies of cerebral small vessel disease, and often co‐occurs with other pathology indicative of Alzheimer’s disease and related disorders (ADRD). A novel classifier of arteriolosclerosis, ARTS, was recently developed by the MarkVCID consortium for in vivo studies of arteriolosclerosis. We hypothesized that higher levels of arteriolosclerosis are associated with worse ADRD biomarker levels.Method109 participants from the Wake Forest Alzheimer’s Disease Research Center’s Clinical Core underwent clinical and cognitive evaluation, 3T brain MRI, and PiB (amyloid) PET (n=92). Participants were adjudicated by NIA‐AA criteria as having normal cognition (n=69), mild cognitive impairment (n=25), or dementia (n=15). Raw T1, FLAIR, and TOPUP and Eddy Current Corrected DTI images along with age and sex were inputs to a machine learning based classifier generating ARTS scores; higher ARTS indicates higher likelihood of arteriolosclerosis. For variables of interest, T1 MRI were processed (FreeSurfer v5.3) to calculate cortical gray matter (GM), hippocampal, and intracranial (ICV) volumes, and temporal meta‐ROI cortical thickness. White matter hyperintensity (WMH) volumes were calculated on FLAIR with LST in SPM12. NODDI were processed using AMICO to generate mean Free Water (FW) in hippocampus and global GM and white matter (WM). A set of AD‐sensitive cortical ROIs were used to extract mean PET SUVr signal. Separate multivariable general linear models (GLM) examined relationships between ARTS and variables of interest adjusted initially for age and total ICV (Table 1), and then again after adjusting for additional covariates (sex, race, education, APOE‐e4 carrier status, and clinical diagnosis).ResultAmong 109 participants (71±7 years, 60% women), ARTS ranged from ‐.80 to .29 (mean±SD = ‐.37±.20), suggesting a low overall likelihood of arteriolosclerosis in our sample. Higher ARTS was significantly associated with lower cortical thickness, higher WMH, higher WM FW, and greater amyloid deposition (Table 1). When adjusting for additional covariates, only amyloid no longer significantly associated with ARTS (p=0.19).ConclusionHigher ARTS scores are cross‐sectionally associated with other abnormalities in ADRD biomarkers. Future directions will examine the relationship between ARTS and Flortaucipir (tau) uptake.

In vivo biomarkers of arteriolosclerosis are associated with ADRD biomarkers

AbstractBackgroundBrain arteriolosclerosis, which involves thickening of the vessel wall and stenosis of arterioles, is one of the main pathologies of cerebral small vessel disease, and often co‐occurs with other pathology indicative of Alzheimer’s disease and related disorders (ADRD). A novel classifier of arteriolosclerosis, ARTS, was recently developed by the MarkVCID consortium for in vivo studies of arteriolosclerosis. We hypothesized that higher levels of arteriolosclerosis are associated with worse ADRD biomarker levels.Method109 participants from the Wake Forest Alzheimer’s Disease Research Center’s Clinical Core underwent clinical and cognitive evaluation, 3T brain MRI, and PiB (amyloid) PET (n=92). Participants were adjudicated by NIA‐AA criteria as having normal cognition (n=69), mild cognitive impairment (n=25), or dementia (n=15). Raw T1, FLAIR, and TOPUP and Eddy Current Corrected DTI images along with age and sex were inputs to a machine learning based classifier generating ARTS scores; higher ARTS indicates higher likelihood of arteriolosclerosis. For variables of interest, T1 MRI were processed (FreeSurfer v5.3) to calculate cortical gray matter (GM), hippocampal, and intracranial (ICV) volumes, and temporal meta‐ROI cortical thickness. White matter hyperintensity (WMH) volumes were calculated on FLAIR with LST in SPM12. NODDI were processed using AMICO to generate mean Free Water (FW) in hippocampus and global GM and white matter (WM). A set of AD‐sensitive cortical ROIs were used to extract mean PET SUVr signal. Separate multivariable general linear models (GLM) examined relationships between ARTS and variables of interest adjusted initially for age and total ICV (Table 1), and then again after adjusting for additional covariates (sex, race, education, APOE‐e4 carrier status, and clinical diagnosis).ResultAmong 109 participants (71±7 years, 60% women), ARTS ranged from ‐.80 to .29 (mean±SD = ‐.37±.20), suggesting a low overall likelihood of arteriolosclerosis in our sample. Higher ARTS was significantly associated with lower cortical thickness, higher WMH, higher WM FW, and greater amyloid deposition (Table 1). When adjusting for additional covariates, only amyloid no longer significantly associated with ARTS (p=0.19).ConclusionHigher ARTS scores are cross‐sectionally associated with other abnormalities in ADRD biomarkers. Future directions will examine the relationship between ARTS and Flortaucipir (tau) uptake.

Childhood abuse and cortical gray matter volume in patients with major depressive disorder

Childhood abuse is associated with brain structural alterations; however, few studies have investigated the association between specific types of childhood abuse and cortical volume in patients with major depressive disorder (MDD). We aimed to investigate the association between specific types of childhood abuse and gray matter volumes in patients with MDD. Seventy-five participants with MDD and 97 healthy controls (HCs) aged 19–64 years were included. Cortical gray matter volumes were compared between MDD and HC groups, and also compared according to exposure to each type of specific childhood abuse. Emotional, sexual, and physical childhood abuse were assessed using the 28-item Childhood Trauma Questionnaire. Patients with MDD showed a significantly decreased gray matter volume in the right anterior cingulate gyrus (ACG). Childhood sexual abuse (CSA) was associated with significantly decreased gray matter volume in the right middle occipital gyrus (MOG). In the post-hoc comparison of volumes of the right ACG and MOG, MDD patients with CSA had significantly smaller volumes in the right MOG than did MDD patients without CSA or HCs. The right MOG volume decrease could be a neuroimaging marker associated with CSA and morphological changes in the brain may be involved in the pathophysiology of MDD.

Abstract 13520: Impaired Prenatal Brain Development Predicts Adverse Neurodevelopmental Outcomes in Infants With Congenital Heart Disease

Introduction: Fetuses with complex congenital heart disease (CHD) are at high risk for impaired brain development. However, the relationship between altered fetal brain development and infant neurobehavioral outcomes in CHD remains largely unknown. Hypothesis: We hypothesized that impaired fetal brain volumetric growth and cortical folding in CHD would predict impaired infant neurodevelopment. Methods: We prospectively recruited women with pregnancies complicated by a fetal CHD diagnosis. Women underwent a fetal MRI on a GE 1.5T scanner. Volumes of fetal total brain, cortical gray matter, white matter, deep gray matter, cerebellum, and brainstem were quantified. Cortical folding included local gyrification index, sulcal depth, and surface area. We completed Bayley Scales of Infant and Toddler Development III and Infant-Toddler Social and Emotional Assessment at 18 months. Generalized estimating equations were used to measure associations between fetal brain measures and infant neurodevelopment outcomes. Results: We enrolled 186 mother/baby dyads who underwent 250 MRIs between 20-39 gestational weeks. Seventy-seven had single-ventricle (SV) CHD and 109 had two-ventricle (2V) CHD. Forty-nine subjects died and 133 infants underwent neurodevelopment testing at a mean age of 19.6 months. Decreased fetal brain volumes and delayed cortical folding (all p&lt;0.05) were associated with poorer infant cognitive outcomes. Impairments in fetal cerebellum (p=0.004), cortical (p=0.05) and deep gray matter (p=0.03) volumes, and cortical folding measures (all p&lt;0.01) were associated with language delays. Reduced prenatal cortical gray matter volume (p=0.008), gyrification (p=0.02), and surface area (p=0.05) were associated with motor delays. Infants with SV CHD had lower competence scores compared to 2V CHD. Conclusions: We report that impairments in fetal brain growth and cortical folding predict adverse cognitive, language and motor outcomes in CHD. Infants with SV CHD showed greater susceptibility to social-emotional problems compared to those with 2V CHD. These data suggest that impaired prenatal regional brain growth disturbances and delayed cerebral cortical development are important biomarkers for later neurobehavioral dysfunction.

Impaired in vivo feto-placental development is associated with neonatal neurobehavioral outcomes.

Fetal growth restriction (FGR) is a risk factor for neurodevelopmental problems, yet remains poorly understood. We sought to examine the relationship between intrauterine development and neonatal neurobehavior in pregnancies diagnosed with antenatal FGR. We recruited women with singleton pregnancies diagnosed with FGR and measured placental and fetal brain volumes using MRI. NICU Network Neurobehavioral Scale (NNNS) assessments were performed at term equivalent age. Associations between intrauterine volumes and neurobehavioral outcomes were assessed using generalized estimating equation models. We enrolled 44 women diagnosed with FGR who underwent fetal MRI and 28 infants underwent NNNS assessments. Placental volumes were associated with increased self-regulation and decreased excitability; total brain, brainstem, cortical and subcortical gray matter (SCGM) volumes were positively associated with higher self-regulation; SCGM also was positively associated with higher quality of movement; increasing cerebellar volumes were positively associated with attention, decreased lethargy, non-optimal reflexes and need for special handling; brainstem volumes also were associated with decreased lethargy and non-optimal reflexes; cerebral and cortical white matter volumes were positively associated with hypotonicity. Disrupted intrauterine growth in pregnancies complicated by antenatally diagnosed FGR is associated with altered neonatal neurobehavior. Further work to determine long-term neurodevelopmental impacts is warranted. Fetal growth restriction is a risk factor for adverse neurodevelopment, but remains difficult to accurately identify. Intrauterine brain volumes are associated with infant neurobehavior. The antenatal diagnosis of fetal growth restriction is a risk factor for abnormal infant neurobehavior.

Brain cortical alterations in COVID-19 patients with neurological symptoms.

Growing evidence suggests that the central nervous system is affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), since infected patients suffer from acute and long-term neurological sequelae. Nevertheless, it is currently unknown whether the virus affects the brain cortex. The purpose of this study was to assess the cortical gray matter volume, the cortical thickness, and the cortical surface area in a group of SARS-CoV-2 infected patients with neurological symptoms compared to healthy control subjects. Additionally, we analyzed the cortical features and the association with inflammatory biomarkers in the cerebrospinal fluid (CSF) and plasma. Thirty-three patients were selected from a prospective cross-sectional study cohort during the ongoing pandemic (August 2020-April 2021) at the university hospitals of Basel and Zurich (Switzerland). The group included patients with different neurological symptom severity (Class I: nearly asymptomatic/mild symptoms, II: moderate symptoms, III: severe symptoms). Thirty-three healthy age and sex-matched subjects that underwent the same MRI protocol served as controls. For each anatomical T1w MPRAGE image, regional cortical gray matter volume, thickness, and surface area were computed with FreeSurfer. Using a linear regression model, cortical measures were compared between groups (patients vs. controls; Class I vs. II-III), with age, sex, MRI magnetic field strength, and total intracranial volume/mean thickness/total surface area as covariates. In a subgroup of patients, the association between cortical features and clinical parameters was assessed using partial correlation adjusting for the same covariates. P-values were corrected using a false discovery rate (FDR). Our findings revealed a lower cortical volume in COVID-19 patients' orbitofrontal, frontal, and cingulate regions than in controls (p < 0.05). Regional gray matter volume and thickness decreases were negatively associated with CSF total protein levels, the CSF/blood-albumin ratio, and CSF EN-RAGE levels. Our data suggest that viral-triggered inflammation leads to neurotoxic damage in some cortical areas during the acute phase of a COVID-19 infection in patients with neurological symptoms.

Air pollution exposure during pregnancy and childhood, APOE ε4 status and Alzheimer polygenic risk score, and brain structural morphology in preadolescents

BackgroundAir pollution exposure is associated with impaired neurodevelopment, altered structural brain morphology in children, and neurodegenerative disorders. Differential susceptibility to air pollution may be influenced by genetic features. ObjectivesTo evaluate whether the apolipoprotein E (APOE) genotype or the polygenic risk score (PRS) for Alzheimer's Disease (AD) modify the association between air pollution exposure during pregnancy and childhood and structural brain morphology in preadolescents. MethodsWe included 1186 children from the Generation R Study. Concentrations of fourteen air pollutants were calculated at participants’ home addresses during pregnancy and childhood using land-use-regression models. Structural brain images were collected at age 9–12 years to assess cortical and subcortical brain volumes. APOE status and PRS for AD were examined as genetic modifiers. Linear regression models were used to conduct single-pollutant and multi-pollutant (using the Deletion/Substitution/Addition algorithm) analyses with a two-way interaction between air pollution and each genetic modifier. ResultsHigher pregnancy coarse particulate matter (PMcoarse) and childhood polycyclic aromatic hydrocarbons exposure was differentially associated with larger cerebral white matter volume in APOE ε4 carriers compared to non-carriers (29,485 mm3 (95% CI 6,189; 52,781) and 18,663 mm3 (469; 36,856), respectively). Higher pregnancy PMcoarse exposure was differentially associated with larger cortical grey matter volume in children with higher compared to lower PRS for AD (19436 mm3 (825, 38,046)). DiscussionAPOE status and PRS for AD possibly modify the association between air pollution exposure and brain structural morphology in preadolescents. Higher air pollution exposure is associated with larger cortical volumes in APOE ε4 carriers and children with a high PRS for AD. This is in line with typical brain development, suggesting an antagonistic pleiotropic effect of these genetic features (i.e., protective effect in early-life, but neurodegenerative effect in adulthood). However, we cannot discard chance findings. Future studies should evaluate trajectorial brain development using a longitudinal design.

Brain structure in autoimmune Addison's disease.

Long-term disturbances in cortisol levels might affect brain structure in individuals with autoimmune Addison's disease (AAD). This study investigated gray and white matter brain structure in a cohort of young adults with AAD. T1- and diffusion-weighted images were acquired for 52 individuals with AAD and 70 healthy controls, aged 19-43years, using magnetic resonance imaging. Groups were compared on cortical thickness, surface area, cortical gray matter volume, subcortical volume (FreeSurfer), and white matter microstructure (FSL tract-based spatial statistics). Individuals with AAD had 4.3% smaller total brain volume. Correcting for head size, we did not find any regional structural differences, apart from reduced volume of the right superior parietal cortex in males with AAD. Within the patient group, a higher glucocorticoid (GC) replacement dose was associated with smaller total brain volume and smaller volume of the left lingual gyrus, left rostral anterior cingulate cortex, and right supramarginal gyrus. With the exception of smaller total brain volume and potential sensitivity of the parietal cortex to GC disturbances in men, brain structure seems relatively unaffected in young adults with AAD. However, the association between GC replacement dose and reduced brain volume may be reason for concern and requires follow-up study.

Sensorimotor network dynamics predict decline in upper and lower limb function in people with multiple sclerosis

Background: Upper and lower limb disabilities are hypothesized to have partially independent underlying (network) disturbances in multiple sclerosis (MS). Objective: This study investigated functional network predictors and longitudinal network changes related to upper and lower limb progression in MS. Methods: Two-hundred fourteen MS patients and 58 controls underwent functional magnetic resonance imaging (fMRI), dexterity (9-Hole Peg Test) and mobility (Timed 25-Foot Walk) measurements (baseline and 5 years). Patients were stratified into progressors (>20% decline) or non-progressors. Functional network efficiency was calculated using static (over entire scan) and dynamic (fluctuations during scan) approaches. Baseline measurements were used to predict progression; significant predictors were explored over time. Results: In both limbs, progression was related to supplementary motor area and caudate efficiency (dynamic and static, respectively). Upper limb progression showed additional specific predictors; cortical grey matter volume, putamen static efficiency and posterior associative sensory (PAS) cortex, putamen, primary somatosensory cortex and thalamus dynamic efficiency. Additional lower limb predictors included motor network grey matter volume, caudate (dynamic) and PAS (static). Only the caudate showed a decline in efficiency over time in one group (non-progressors). Conclusion: Disability progression can be predicted using sensorimotor network measures. Upper and lower limb progression showed unique predictors, possibly indicating different network disturbances underlying these types of progression in MS.

Structural brain changes in patients with persistent headache after COVID-19 resolution

Headache is among the most frequently reported symptoms after resolution of COVID-19. We assessed structural brain changes using T1- and diffusion-weighted MRI processed data from 167 subjects: 40 patients who recovered from COVID-19 but suffered from persistent headache without prior history of headache (COV), 41 healthy controls, 43 patients with episodic migraine and 43 patients with chronic migraine. To evaluate gray matter and white matter changes, morphometry parameters and diffusion tensor imaging-based measures were employed, respectively. COV patients showed significant lower cortical gray matter volume and cortical thickness than healthy subjects (p < 0.05, false discovery rate corrected) in the inferior frontal and the fusiform cortex. Lower fractional anisotropy and higher radial diffusivity (p < 0.05, family-wise error corrected) were observed in COV patients compared to controls, mainly in the corpus callosum and left hemisphere. COV patients showed higher cortical volume and thickness than migraine patients in the cingulate and frontal gyri, paracentral lobule and superior temporal sulcus, lower volume in subcortical regions and lower curvature in the precuneus and cuneus. Lower diffusion metric values in COV patients compared to migraine were identified prominently in the right hemisphere. COV patients present diverse changes in the white matter and gray matter structure. White matter changes seem to be associated with impairment of fiber bundles. Besides, the gray matter changes and other white matter modifications such as axonal integrity loss seemed subtle and less pronounced than those detected in migraine, showing that persistent headache after COVID-19 resolution could be an intermediate state between normality and migraine.

Subcortical structures associated with childhood trauma and perceived stress in schizophrenia.

Childhood trauma influences the clinical features of schizophrenia. In this study, we examined how childhood trauma and perceived stress are associated with clinical manifestations and subcortical gray matter volumes (GMVs) in patients with schizophrenia. We recruited 127 patients with schizophrenia and 83 healthy controls for assessment of early childhood trauma, perceived stress, and clinical symptoms. With structural brain imaging, we identified the GMVs of subcortical structures and examined the relationships between childhood trauma, perceived stress, clinical symptoms, and subcortical GMVs. Compared to controls, patients with schizophrenia showed higher levels of childhood trauma and perceived stress. Patients with schizophrenia showed significantly smaller amygdala and hippocampus GMVs as well as total cortical GMVs than age-matched controls. Childhood trauma score was significantly correlated with the severity of clinical symptoms, depression, perceived stress, and amygdala GMVs. Perceived stress was significantly correlated with clinical symptoms, depression, and hippocampus and amygdala GMVs. Further, the association between childhood trauma (emotional neglect) and stress coping ability was mediated by right amygdala GMV in patients with schizophrenia. Patients with schizophrenia had more exposure to early-life trauma and poorer stress coping. Both childhood trauma and perceived stress were associated with smaller amygdala volumes. The relationship between early-life trauma and perceived stress was mediated by right amygdala GMV in patients with schizophrenia. These findings together suggest the long-term effects of childhood trauma on perceived stress and the subcortical volumetric correlates of the effects in schizophrenia.

Air Pollution Exposure during Pregnancy and Childhood, APOE ε4 Status and Polygenic Risk Score for Alzheimer’s Disease, and Brain Structural Morphology in Preadolescents

Background and Aim. Air pollution exposure is associated with impaired neurodevelopment, altered structural brain morphology in children and neurodegenerative disorders. Differential susceptibility to air pollution may be influenced by genetic features. We aimed to evaluate whether the apolipoprotein E (APOE) genotype or the polygenic risk score (PRS) for Alzheimer’s Disease (AD), modify the association between air pollution exposure during pregnancy and childhood and structural brain morphology in preadolescents. Methods. We included 1186 children from the Generation R Study. Concentrations of 14 air pollutants were calculated at the participants’ home address during pregnancy and childhood using land-use-regression models. Structural brain images were collected at age 9–12 years to assess (sub)cortical brain volumes. APOE status and PRS for AD were examined as effect modifiers. We conducted single-pollutant analyses with a two-way interaction between air pollution and APOE status or PRS for AD and multi-pollutant analyses with the two-way interaction. Results. Higher pregnancy PMcoarse and childhood PAHs exposure was differentially associated with larger cerebral white matter volume in APOE ε4 carriers compared to non-carriers (29485 mm3 [95% CI 6189, 52781] and 18663 mm3 [469, 36856], respectively). Higher pregnancy PMcoarse exposure was differentially associated with larger cortical grey matter volume in children with higher compared to lower PRS for AD (19436 mm3 [825, 38046]). Conclusions. APOE status and PRS for AD have a possible modifying effect on the association between air pollution exposure and brain structural morphology in preadolescents. Both seem to modify the association towards the typical development of the brain, with increasing cortical volumes, highlighting the possibility of the antagonistic pleiotropic effect (i.e., protective effect in early life but altered neurodegenerative processes in adulthood). Future studies should research this antagonistic pleiotropic effect and study trajectorial brain development using a longitudinal design. Keywords. environmental pollution, neurodevelopment, neuroimaging, genetic modifiers