Distinct Longitudinal Brain White Matter Microstructure Changes and Associated Polygenic Risk of Common Psychiatric Disorders and Alzheimer's Disease in the UK Biobank.

Background: During the course of adulthood and aging, white matter (WM) structure and organization are characterized by slow degradation processes such as demyelination and shrinkage. An acceleration of such aging processes has been linked to the development of a range of diseases. Thus, an accurate description of healthy brain maturation, particularly in terms of WM features, is fundamental to the understanding of aging. Methods: We used longitudinal diffusion magnetic resonance imaging to provide an overview of WM changes at different spatial and temporal scales in the UK Biobank (UKB) (n = 2678; agescan 1 = 62.38 ± 7.23 years; agescan 2 = 64.81 ± 7.1 years). To examine the genetic overlap between WM structure and common clinical conditions, we tested the associations between WM structure and polygenic risk scores for the most common neurodegenerative disorder, Alzheimer's disease, and common psychiatric disorders (unipolar and bipolar depression, anxiety, obsessive-compulsive disorder, autism, schizophrenia, attention-deficit/hyperactivity disorder) in longitudinal (n = 2329) and cross-sectional (n = 31,056) UKB validation data. Results: Our findings indicate spatially distributed WM changes across the brain, as well as distributed associations of polygenic risk scores with WM. Importantly, brain longitudinal changes reflected genetic risk for disorder development better than the utilized cross-sectional measures, with regional differences giving more specific insights into gene-brain change associations than global averages. Conclusions: We extend recent findings by providing a detailed overview of WM microstructure degeneration on different spatial levels, helping to understand fundamental brain aging processes. Further longitudinal research is warranted to examine aging-related gene-brain associations.

In their study, Korbmacher et al. benchmark healthy aging processes in the brain's white matter. Findings of degrading white matter at higher ages were consistent with recent cross-sectional and longitudinal findings, particularly outlining changes in ventricle-near and cerebellar white matter. Degenerative processes were also found to accelerate at a higher age. Finally, the polygenic risk to develop psychiatric and neurodegenerative disorders was weakly associated with the white matter change in the otherwise healthily aging participants.

The role of functional emotion circuits in distinct dimensions of psychopathology in youth.

Several mental disorders emerge during childhood or adolescence and are often characterized by socioemotional difficulties, including alterations in emotion perception. Emotional facial expressions are processed in discrete functional brain modules whose connectivity patterns encode emotion categories, but the involvement of these neural circuits in psychopathology in youth is poorly understood. This study examined the associations between activation and functional connectivity patterns in emotion circuits and psychopathology during development. We used task-based fMRI data from the Philadelphia Neurodevelopmental Cohort (PNC, N = 1221, 8-23 years) and conducted generalized psycho-physiological interaction (gPPI) analyses. Measures of psychopathology were derived from an independent component analysis of questionnaire data. The results showed positive associations between identifying fearful, sad, and angry faces and depressive symptoms, and a negative relationship between sadness recognition and positive psychosis symptoms. We found a positive main effect of depressive symptoms on BOLD activation in regions overlapping with the default mode network, while individuals reporting higher levels of norm-violating behavior exhibited emotion-specific lower functional connectivity within regions of the salience network and between modules that overlapped with the salience and default mode network. Our findings illustrate the relevance of functional connectivity patterns underlying emotion processing for behavioral problems in children and adolescents.

Current Auditory Hallucinations Are Not Associated With Specific White Matter Diffusion Alterations in Schizophrenia.

Background and Hypothesis: Studies have linked auditory hallucinations (AH) in schizophrenia spectrum disorders (SCZ) to altered cerebral white matter microstructure within the language and auditory processing circuitry (LAPC). However, the specificity to the LAPC remains unclear. Here, we investigated the relationship between AH and DTI among patients with SCZ using diffusion tensor imaging (DTI). Study Design: We included patients with SCZ with (AH+; n = 59) and without (AH-; n = 81) current AH, and 140 age- and sex-matched controls. Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) were extracted from 39 fiber tracts. We used principal component analysis (PCA) to identify general factors of variation across fiber tracts and DTI metrics. Regression models adjusted for sex, age, and age2 were used to compare tract-wise DTI metrics and PCA factors between AH+, AH-, and healthy controls and to assess associations with clinical characteristics. Study Results: Widespread differences relative to controls were observed for MD and RD in patients without current AH. Only limited differences in 2 fiber tracts were observed between AH+ and controls. Unimodal PCA factors based on MD, RD, and AD, as well as multimodal PCA factors, differed significantly relative to controls for AH-, but not AH+. We did not find any significant associations between PCA factors and clinical characteristics. Conclusions: Contrary to previous studies, DTI metrics differed mainly in patients without current AH compared to controls, indicating a widespread neuroanatomical distribution. This challenges the notion that altered DTI metrics within the LAPC is a specific feature underlying AH.

Dimensions of early life adversity are differentially associated with patterns of delayed and accelerated brain maturation.

BACKGROUND: Different types of early-life adversity have been associated with children's brain structure and function. However, understanding the disparate influence of distinct adversity exposures on the developing brain remains a major challenge. METHODS: This study investigates the neural correlates of 10 robust dimensions of early-life adversity identified through exploratory factor analysis in a large community sample of youth from the Adolescent Brain Cognitive Development (ABCD) Study. Brain age models were trained, validated, and tested separately on T1-weighted (T1; N = 9524), diffusion tensor (DTI; N = 8834), and resting-state functional (rs-fMRI; N = 8233) magnetic resonance imaging (MRI) data from two time points (mean age = 10.7 years, SD = 1.2, range = 8.9-13.8 years). RESULTS: Bayesian multilevel modelling supported distinct associations between different types of early-life adversity exposures and younger- and older-looking brains. Dimensions generally related to emotional neglect, such as lack of primary and secondary caregiver support, and lack of caregiver supervision, were associated with lower brain age gaps (BAGs), i.e., younger-looking brains. In contrast, dimensions generally related to caregiver psychopathology, trauma exposure, family aggression, substance use and separation from biological parent, and socio-economic disadvantage and neighbourhood safety were associated with higher BAGs, i.e., older-looking brains. CONCLUSIONS: The findings suggest that dimensions of early-life adversity are differentially associated with distinct neurodevelopmental patterns, indicative of dimension-specific delayed and accelerated brain maturation.

Dissecting unique and common variance across body and brain health indicators using age prediction.

Ageing is a heterogeneous multisystem process involving different rates of decline in physiological integrity across biological systems. The current study dissects the unique and common variance across body and brain health indicators and parses inter-individual heterogeneity in the multisystem ageing process. Using machine-learning regression models on the UK Biobank data set (N = 32,593, age range 44.6-82.3, mean age 64.1 years), we first estimated tissue-specific brain age for white and gray matter based on diffusion and T1-weighted magnetic resonance imaging (MRI) data, respectively. Next, bodily health traits, including cardiometabolic, anthropometric, and body composition measures of adipose and muscle tissue from bioimpedance and body MRI, were combined to predict 'body age'. The results showed that the body age model demonstrated comparable age prediction accuracy to models trained solely on brain MRI data. The correlation between body age and brain age predictions was 0.62 for the T1 and 0.64 for the diffusion-based model, indicating a degree of unique variance in brain and bodily ageing processes. Bayesian multilevel modelling carried out to quantify the associations between health traits and predicted age discrepancies showed that higher systolic blood pressure and higher muscle-fat infiltration were related to older-appearing body age compared to brain age. Conversely, higher hand-grip strength and muscle volume were related to a younger-appearing body age. Our findings corroborate the common notion of a close connection between somatic and brain health. However, they also suggest that health traits may differentially influence age predictions beyond what is captured by the brain imaging data, potentially contributing to heterogeneous ageing rates across biological systems and individuals.

Parental education and income are linked to offspring cortical brain structure and psychopathology at 9-11 years.

Background: A child's socioeconomic environment can shape central aspects of their life, including vulnerability to mental disorders. Negative environmental influences in youth may interfere with the extensive and dynamic brain development occurring at this time. Indeed, there are numerous yet diverging reports of associations between parental socioeconomic status (SES) and child cortical brain morphometry. Most of these studies have used single metric- or unimodal analyses of standard cortical morphometry that downplay the probable scenario where numerous biological pathways in sum account for SES-related cortical differences in youth. Methods: To comprehensively capture such variability, using data from 9758 children aged 8.9-11.1 years from the ABCD Study®, we employed linked independent component analysis (LICA) and fused vertex-wise cortical thickness, surface area, curvature and grey-/white-matter contrast (GWC). LICA revealed 70 uni- and multimodal components. We then assessed the linear relationships between parental education, parental income and each of the cortical components, controlling for age, sex, genetic ancestry, and family relatedness. We also assessed whether cortical structure moderated the negative relationships between parental SES and child general psychopathology. Results: Parental education and income were both associated with larger surface area and higher GWC globally, in addition to local increases in surface area and to a lesser extent bidirectional GWC and cortical thickness patterns. The negative relation between parental income and child psychopathology were attenuated in children with a multimodal pattern of larger frontal- and smaller occipital surface area, and lower medial occipital thickness and GWC. Conclusion: Structural brain MRI is sensitive to SES diversity in childhood, with GWC emerging as a particularly relevant marker together with surface area. In low-income families, having a more developed cortex across MRI metrics, appears beneficial for mental health.

Recommendations for a Better Understanding of Sex and Gender in the Neuroscience of Mental Health.

There are prominent sex/gender differences in the prevalence, expression, and life span course of mental health and neurodiverse conditions. However, the underlying sex- and gender-related mechanisms and their interactions are still not fully understood. This lack of knowledge has harmful consequences for those with mental health problems. Therefore, we set up a cocreation session in a 1-week workshop with a multidisciplinary team of 25 researchers, clinicians, and policy makers to identify the main barriers in sex and gender research in the neuroscience of mental health. Based on this work, here we provide recommendations for methodologies, translational research, and stakeholder involvement. These include guidelines for recording, reporting, analysis beyond binary groups, and open science. Improved understanding of sex- and gender-related mechanisms in neuroscience may benefit public health because this is an important step toward precision medicine and may function as an archetype for studying diversity.

Brain asymmetries from mid- to late life and hemispheric brain age.

The human brain demonstrates structural and functional asymmetries which have implications for ageing and mental and neurological disease development. We used a set of magnetic resonance imaging (MRI) metrics derived from structural and diffusion MRI data in N=48,040 UK Biobank participants to evaluate age-related differences in brain asymmetry. Most regional grey and white matter metrics presented asymmetry, which were higher later in life. Informed by these results, we conducted hemispheric brain age (HBA) predictions from left/right multimodal MRI metrics. HBA was concordant to conventional brain age predictions, using metrics from both hemispheres, but offers a supplemental general marker of brain asymmetry when setting left/right HBA into relationship with each other. In contrast to WM brain asymmetries, left/right discrepancies in HBA are lower at higher ages. Our findings outline various sex-specific differences, particularly important for brain age estimates, and the value of further investigating the role of brain asymmetries in brain ageing and disease development.

Assessing the Longitudinal Associations Between Decision-Making Processes and Attention Problems in Early Adolescence.

Cognitive functions and psychopathology develop in parallel in childhood and adolescence, but the temporal dynamics of their associations are poorly understood. The present study sought to elucidate the intertwined development of decision-making processes and attention problems using longitudinal data from late childhood (9-10 years) to mid-adolescence (11-13 years) from the Adolescent Brain Cognitive Development (ABCD) Study (n = 8918). We utilised hierarchical drift-diffusion modelling of behavioural data from the stop-signal task, parent-reported attention problems from the Child Behavior Checklist (CBCL), and multigroup univariate and bivariate latent change score models. The results showed faster drift rate was associated with lower levels of inattention at baseline, as well as a greater reduction of inattention over time. Moreover, baseline drift rate negatively predicted change in attention problems in females, and baseline attention problems negatively predicted change in drift rate. Neither response caution (decision threshold) nor encoding- and responding processes (non-decision time) were significantly associated with attention problems. There were no significant sex differences in the associations between decision-making processes and attention problems. The study supports previous findings of reduced evidence accumulation in attention problems and additionally shows that development of this aspect of decision-making plays a role in developmental changes in attention problems in youth.

Spherical means-based free-water volume fraction from diffusion MRI increases non-linearly with age in the white matter of the healthy human brain.

The term free-water volume fraction (FWVF) refers to the signal fraction that could be found as the cerebrospinal fluid of the brain, which has been demonstrated as a sensitive measure that correlates with cognitive performance and various neuropathological processes. It can be quantified by properly fitting the isotropic component of the magnetic resonance (MR) signal in diffusion-sensitized sequences. Using N=287 healthy subjects (178F/109M) aged 25-94, this study examines in detail the evolution of the FWVF obtained with the spherical means technique from multi-shell acquisitions in the human brain white matter across the adult lifespan, which has been previously reported to exhibit a positive trend when estimated from single-shell data using the bi-tensor signal representation. We found evidence of a noticeably non-linear gain after the sixth decade of life, with a region-specific variate and varying change rate of the spherical means-based multi-shell FWVF parameter with age, at the same time, a heteroskedastic pattern across the adult lifespan is suggested. On the other hand, the FW corrected diffusion tensor imaging (DTI) leads to a region-dependent flattened age-related evolution of the mean diffusivity (MD) and fractional anisotropy (FA), along with a considerable reduction in their variability, as compared to the studies conducted over the standard (single-component) DTI. This way, our study provides a new perspective on the trajectory-based assessment of the brain and explains the conceivable reason for the variations observed in FA and MD parameters across the lifespan with previous studies under the standard diffusion tensor imaging.

Bio-psycho-social factors' associations with brain age: a large-scale UK Biobank diffusion study of 35,749 participants.

Brain age refers to age predicted by brain features. Brain age has previously been associated with various health and disease outcomes and suggested as a potential biomarker of general health. Few previous studies have systematically assessed brain age variability derived from single and multi-shell diffusion magnetic resonance imaging data. Here, we present multivariate models of brain age derived from various diffusion approaches and how they relate to bio-psycho-social variables within the domains of sociodemographic, cognitive, life-satisfaction, as well as health and lifestyle factors in midlife to old age (N = 35,749, 44.6-82.8 years of age). Bio-psycho-social factors could uniquely explain a small proportion of the brain age variance, in a similar pattern across diffusion approaches: cognitive scores, life satisfaction, health and lifestyle factors adding to the variance explained, but not socio-demographics. Consistent brain age associations across models were found for waist-to-hip ratio, diabetes, hypertension, smoking, matrix puzzles solving, and job and health satisfaction and perception. Furthermore, we found large variability in sex and ethnicity group differences in brain age. Our results show that brain age cannot be sufficiently explained by bio-psycho-social variables alone. However, the observed associations suggest to adjust for sex, ethnicity, cognitive factors, as well as health and lifestyle factors, and to observe bio-psycho-social factor interactions' influence on brain age in future studies.

Puberty differentially predicts brain maturation in male and female youth: A longitudinal ABCD Study.

Research has demonstrated associations between pubertal development and brain maturation. However, existing studies have been limited by small samples, cross-sectional designs, and inconclusive findings regarding directionality of effects and sex differences. We examined the longitudinal temporal coupling of puberty status assessed using the Pubertal Development Scale (PDS) and magnetic resonance imaging (MRI)-based grey and white matter brain structure. Our sample consisted of 8896 children and adolescents at baseline (mean age = 9.9) and 6099 at follow-up (mean age = 11.9) from the Adolescent Brain and Cognitive Development (ABCD) Study cohort. Applying multigroup Bivariate Latent Change Score (BLCS) models, we found that baseline PDS predicted the rate of change in cortical thickness among females and rate of change in cortical surface area for both males and females. We also found a correlation between baseline PDS and surface area and co-occurring changes over time in males. Diffusion tensor imaging (DTI) analyses revealed correlated change between PDS and fractional anisotropy (FA) for both males and females, but no significant associations for mean diffusivity (MD). Our results suggest that pubertal status predicts cortical maturation, and that the strength of the associations differ between sex. Further research spanning the entire duration of puberty is needed to understand the extent and contribution of pubertal development on the youth brain.

Brain-wide associations between white matter and age highlight the role of fornix microstructure in brain ageing.

Unveiling the details of white matter (WM) maturation throughout ageing is a fundamental question for understanding the ageing brain. In an extensive comparison of brain age predictions and age-associations of WM features from different diffusion approaches, we analyzed UK Biobank diffusion magnetic resonance imaging (dMRI) data across midlife and older age (N = 35,749, 44.6-82.8 years of age). Conventional and advanced dMRI approaches were consistent in predicting brain age. WM-age associations indicate a steady microstructure degeneration with increasing age from midlife to older ages. Brain age was estimated best when combining diffusion approaches, showing different aspects of WM contributing to brain age. Fornix was found as the central region for brain age predictions across diffusion approaches in complement to forceps minor as another important region. These regions exhibited a general pattern of positive associations with age for intra axonal water fractions, axial, radial diffusivities, and negative relationships with age for mean diffusivities, fractional anisotropy, kurtosis. We encourage the application of multiple dMRI approaches for detailed insights into WM, and the further investigation of fornix and forceps as potential biomarkers of brain age and ageing.

Relationship between function and structure in the visual cortex in healthy individuals and in patients with severe mental disorders.

Patients with schizophrenia spectrum disorders (SCZspect) and bipolar disorders (BD) show impaired function in the primary visual cortex (V1), indicated by altered visual evoked potential (VEP). While the neural substrate for altered VEP in these patients remains elusive, altered V1 structure may play a role. One previous study found a positive relationship between the amplitude of the P100 component of the VEP and V1 surface area, but not V1 thickness, in a small sample of healthy individuals. Here, we aimed to replicate these findings in a larger healthy control (HC) sample (n = 307) and to examine the same relationship in patients with SCZspect (n = 30) or BD (n = 45). We also compared the mean P100 amplitude, V1 surface area and V1 thickness between controls and patients and found no significant group differences. In HC only, we found a significant positive P100-V1 surface area association, while there were no significant P100-V1 thickness relationships in HC, SCZspect or BD. Together, our results confirm previous findings of a positive P100-V1 surface area association in HC, whereas larger patient samples are needed to further clarify the function-structure relationship in V1 in SCZspect and BD.

Reaction Time Variability in Children Is Specifically Associated With Attention Problems and Regional White Matter Microstructure.

BACKGROUND: Increased intraindividual variability (IIV) in reaction times (RTs) has been suggested as a key cognitive and behavioral marker of attention problems, but findings for other dimensions of psychopathology are less consistent. Moreover, while studies have linked IIV to brain white matter microstructure, large studies testing the robustness of these associations are needed. METHODS: We used data from the Adolescent Brain Cognitive Development (ABCD) Study baseline assessment to test the associations between IIV and psychopathology (n = 8622, age = 8.9-11.1 years) and IIV and white matter microstructure (n = 7958, age = 8.9-11.1 years). IIV was investigated using an ex-Gaussian distribution analysis of RTs in correct response go trials in the stop signal task. Psychopathology was measured by the Child Behavior Checklist and a bifactor structural equation model was performed to extract a general p factor and specific factors reflecting internalizing, externalizing, and attention problems. To investigate white matter microstructure, fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity were examined in 23 atlas-based tracts. RESULTS: Increased IIV in both short and long RTs was positively associated with the specific attention problems factor (Cohen's d = 0.13 and d = 0.15, respectively). Increased IIV in long RTs was also positively associated with radial diffusivity in the left and right corticospinal tract (both tracts, d = 0.12). CONCLUSIONS: Using a large sample and a data-driven dimensional approach to psychopathology, the results provide novel evidence for a small but specific association between IIV and attention problems in children and support previous findings on the relevance of white matter microstructure for IIV.

Associations between everyday activities and arterial spin labeling-derived cerebral blood flow: A longitudinal study in community-dwelling elderly volunteers.

Cerebral blood flow (CBF) is critical for brain metabolism and function. Age-related changes in CBF are associated with increased risk of neurocognitive disorders and vascular events such as stroke. Identifying correlates and positive modifiers of age-related changes in CBF before the emergence of incipient clinical decline may inform public health advice and clinical practice. Former research has been inconclusive regarding the association between regular physical activity and CBF, and there is a lack of studies on the association between level of everyday activities and CBF, in older adults. To investigate these relationships, 118 healthy community-dwelling adults (65-89 years) underwent pseudo-continuous arterial spin labeling (ASL) MRI, neurocognitive, physical, and activity assessments at baseline. Eighty-six participants completed a follow-up ASL MRI, on average 506 (SD = 113) days after the baseline scan. Cross-sectional analysis revealed credible evidence for positive associations between time spent on low intensity physical activity and CBF in multiple cortical and subcortical regions, time spent on moderate to vigorous intensity physical activity and accumbens CBF, participation in social activity and CBF in multiple cortical regions, and between reading and thalamic CBF, indicating higher regional CBF in more active adults. Longitudinal analysis revealed anecdotal evidence for an interaction between time and baseline level of gardening on occipital and parietal CBF, and baseline reading on pallidum CBF, indicating more change in CBF in adults with lower level of activity. The findings support that malleable lifestyle factors contribute to healthy brain aging, with relevance for public health guidelines.

Linking brain maturation and puberty during early adolescence using longitudinal brain age prediction in the ABCD cohort.

The temporal characteristics of adolescent neurodevelopment are shaped by a complex interplay of genetic, biological, and environmental factors. Using a large longitudinal dataset of children aged 9-13 from the Adolescent Brain Cognitive Development (ABCD) study we tested the associations between pubertal status and brain maturation. Brain maturation was assessed using brain age prediction based on convolutional neural networks and minimally processed T1-weighted structural MRI data. Brain age prediction provided highly accurate and reliable estimates of individual age, with an overall mean absolute error of 0.7 and 1.4 years at the two timepoints respectively, and an intraclass correlation of 0.65. Linear mixed effects (LME) models accounting for age and sex showed that on average, a one unit increase in pubertal maturational level was associated with a 2.22 months higher brain age across time points (ß = 0.10, p < .001). Moreover, annualized change in pubertal development was weakly related to the rate of change in brain age (ß = .047, p = 0.04). These results demonstrate a link between sexual development and brain maturation in early adolescence, and provides a basis for further investigations of the complex sociobiological impacts of puberty on life outcomes.

The value of arterial spin labelling perfusion MRI in brain age prediction.

Current structural MRI-based brain age estimates and their difference from chronological age-the brain age gap (BAG)-are limited to late-stage pathological brain-tissue changes. The addition of physiological MRI features may detect early-stage pathological brain alterations and improve brain age prediction. This study investigated the optimal combination of structural and physiological arterial spin labelling (ASL) image features and algorithms. Healthy participants (n = 341, age 59.7 ± 14.8 years) were scanned at baseline and after 1.7 ± 0.5 years follow-up (n = 248, mean age 62.4 ± 13.3 years). From 3 T MRI, structural (T1w and FLAIR) volumetric ROI and physiological (ASL) cerebral blood flow (CBF) and spatial coefficient of variation ROI features were constructed. Multiple combinations of features and machine learning algorithms were evaluated using the Mean Absolute Error (MAE). From the best model, longitudinal BAG repeatability and feature importance were assessed. The ElasticNetCV algorithm using T1w + FLAIR+ASL performed best (MAE = 5.0 ± 0.3 years), and better compared with using T1w + FLAIR (MAE = 6.0 ± 0.4 years, p < .01). The three most important features were, in descending order, GM CBF, GM/ICV, and WM CBF. Average baseline and follow-up BAGs were similar (-1.5 ± 6.3 and - 1.1 ± 6.4 years respectively, ICC = 0.85, 95% CI: 0.8-0.9, p = .16). The addition of ASL features to structural brain age, combined with the ElasticNetCV algorithm, improved brain age prediction the most, and performed best in a cross-sectional and repeatability comparison. These findings encourage future studies to explore the value of ASL in brain age in various pathologies.

Auditory Cortex Thickness Is Associated With N100 Amplitude in Schizophrenia Spectrum Disorders.

Background and Hypothesis: The auditory cortex (AC) may play a central role in the pathophysiology of schizophrenia and auditory hallucinations (AH). Previous schizophrenia studies report thinner AC and impaired AC function, as indicated by decreased N100 amplitude of the auditory evoked potential. However, whether these structural and functional alterations link to AH in schizophrenia remain poorly understood. Study Design: Patients with a schizophrenia spectrum disorder (SCZspect), including patients with a lifetime experience of AH (AH+), without (AH-), and healthy controls underwent magnetic resonance imaging (39 SCZspect, 22 AH+, 17 AH-, and 146 HC) and electroencephalography (33 SCZspect, 17 AH+, 16 AH-, and 144 HC). Cortical thickness of the primary (AC1, Heschl's gyrus) and secondary (AC2, Heschl's sulcus, and the planum temporale) AC was compared between SCZspect and controls and between AH+, AH-, and controls. To examine if the association between AC thickness and N100 amplitude differed between groups, we used regression models with interaction terms. Study Results: N100 amplitude was nominally smaller in SCZspect (P = .03, d = 0.42) and in AH- (P = .020, d = 0.61), while AC2 was nominally thinner in AH+ (P = .02, d = 0.53) compared with controls. AC1 thickness was positively associated with N100 amplitude in SCZspect (t = 2.56, P = .016) and AH- (t = 3.18, P = .008), while AC2 thickness was positively associated with N100 amplitude in SCZspect (t = 2.37, P = .024) and in AH+ (t = 2.68, P = .019). Conclusions: The novel findings of positive associations between AC thickness and N100 amplitude in SCZspect, suggest that a common neural substrate may underlie AC thickness and N100 amplitude alterations.

Cardiometabolic health across menopausal years is linked to white matter hyperintensities up to a decade later.

Introduction: The menopause transition is associated with several cardiometabolic risk factors. Poor cardiometabolic health is further linked to microvascular brain lesions, which can be detected as white matter hyperintensities (WMHs) using T2-FLAIR magnetic resonance imaging (MRI) scans. Females show higher risk for WMHs post-menopause, but it remains unclear whether changes in cardiometabolic risk factors underlie menopause-related increase in brain pathology. Methods: In this study, we assessed whether cross-sectional measures of cardiometabolic health, including body mass index (BMI) and waist-to-hip ratio (WHR), blood lipids, blood pressure, and long-term blood glucose (HbA1c), as well as longitudinal changes in BMI and WHR, differed according to menopausal status at baseline in 9,882 UK Biobank females (age range 40-70 years, n premenopausal = 3,529, n postmenopausal = 6,353). Furthermore, we examined whether these cardiometabolic factors were associated with WMH outcomes at the follow-up assessment, on average 8.78 years after baseline. Results: Postmenopausal females showed higher levels of baseline blood lipids (HDL ß = 0.14, p < 0.001, LDL ß = 0.20, p < 0.001, triglycerides ß = 0.12, p < 0.001) and HbA1c (ß = 0.24, p < 0.001) compared to premenopausal women, beyond the effects of age. Over time, BMI increased more in the premenopausal compared to the postmenopausal group (ß = -0.08, p < 0.001), while WHR increased to a similar extent in both groups (ß = -0.03, p = 0.102). The change in WHR was however driven by increased waist circumference only in the premenopausal group. While the group level changes in BMI and WHR were in general small, these findings point to distinct anthropometric changes in pre- and postmenopausal females over time. Higher baseline measures of BMI, WHR, triglycerides, blood pressure, and HbA1c, as well as longitudinal increases in BMI and WHR, were associated with larger WMH volumes (ß range = 0.03-0.13, p ≤ 0.002). HDL showed a significant inverse relationship with WMH volume (ß = -0.27, p < 0.001). Discussion: Our findings emphasise the importance of monitoring cardiometabolic risk factors in females from midlife through the menopause transition and into the postmenopausal phase, to ensure improved cerebrovascular outcomes in later years.