INTRODUCTION: The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE: To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS: We identified 369 nominally genome-wide significant loci ( P < 5 × 10 ⁻⁸ ) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 360 loci for which replication data were available, 241 loci influencing surface area and 66 influencing thickness remained significant after replication, with 237 loci passing multiple testing correction ( P < 8.3 × 10 ⁻¹⁰ ; 187 influencing surface area and 50 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation ( r _G = −0.32, SE = 0.05, P = 6.5 × 10 ⁻¹² ), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 46 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION: This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function. Identifying genetic influences on human cortical structure.: ( A ) Measurement of cortical surface area and thickness from MRI. ( B ) Genomic locations of common genetic variants that influence global and regional cortical structure. ( C ) Our results support the radial unit hypothesis that the expansion of cortical surface area is driven by proliferating neural progenitor cells. ( D ) Cortical surface area shows genetic correlation with psychiatric and cognitive traits. Error bars indicate SE. IMAGE CREDITS: (A) K. COURTNEY; (C) M. R. GLASS

The macro- and microstructural architecture of human brain white matter undergoes substantial alterations throughout development and ageing. Most of our understanding of the spatial and temporal characteristics of these lifespan adaptations come from magnetic resonance imaging (MRI), including diffusion MRI (dMRI), which enables visualisation and quantification of brain white matter with unprecedented sensitivity and detail. However, with some notable exceptions, previous studies have relied on cross-sectional designs, limited age ranges, and diffusion tensor imaging (DTI) based on conventional single-shell dMRI. In this mixed cross-sectional and longitudinal study (mean interval: 15.2 months) including 702 multi-shell dMRI datasets, we combined complementary dMRI models to investigate age trajectories in healthy individuals aged 18 to 94 years (57.12% women). Using linear mixed effect models and machine learning based brain age prediction, we assessed the age-dependence of diffusion metrics, and compared the age prediction accuracy of six different diffusion models, including diffusion tensor (DTI) and kurtosis imaging (DKI), neurite orientation dispersion and density imaging (NODDI), restriction spectrum imaging (RSI), spherical mean technique multi-compartment (SMT-mc), and white matter tract integrity (WMTI). The results showed that the age slopes for conventional DTI metrics (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity [AD], radial diffusivity [RD]) were largely consistent with previous research, and that the highest performing advanced dMRI models showed comparable age prediction accuracy to conventional DTI. Linear mixed effects models and Wilk's theorem analysis showed that the 'FA fine' metric of the RSI model and 'orientation dispersion' (OD) metric of the NODDI model showed the highest sensitivity to age. The results indicate that advanced diffusion models (DKI, NODDI, RSI, SMT mc, WMTI) provide sensitive measures of age-related microstructural changes of white matter in the brain that complement and extend the contribution of conventional DTI.

The deviation between chronological age and age predicted using brain MRI is a putative marker of overall brain health. Age prediction based on structural MRI data shows high accuracy in common brain disorders. However, brain aging is complex and heterogenous, both in terms of individual differences and the underlying biological processes. Here, we implemented a multimodal model to estimate brain age using different combinations of cortical area, thickness and sub‐cortical volumes, cortical and subcortical T1/T2‐weighted ratios, and cerebral blood flow (CBF) based on arterial spin labeling. For each of the 11 models we assessed the age prediction accuracy in healthy controls (HC, n = 750) and compared the obtained brain age gaps (BAGs) between age‐matched subsets of HC and patients with Alzheimer's disease (AD, n = 54), mild (MCI, n = 90) and subjective (SCI, n = 56) cognitive impairment, schizophrenia spectrum (SZ, n = 159) and bipolar disorder (BD, n = 135). We found highest age prediction accuracy in HC when integrating all modalities. Furthermore, two‐group case–control classifications revealed highest accuracy for AD using global T1‐weighted BAG, while MCI, SCI, BD and SZ showed strongest effects in CBF‐based BAGs. Combining multiple MRI modalities improves brain age prediction and reveals distinct deviations in patients with psychiatric and neurological disorders. The multimodal BAG was most accurate in predicting age in HC, while group differences between patients and HC were often larger for BAGs based on single modalities. These findings indicate that multidimensional neuroimaging of patients may provide a brain‐based mapping of overlapping and distinct pathophysiology in common disorders.

Multimodal imaging enables sensitive measures of the architecture and integrity of the human brain, but the high-dimensional nature of advanced brain imaging features poses inherent challenges for the analyses and interpretations. Multivariate age prediction reduces the dimensionality to one biologically informative summary measure with potential for assessing deviations from normal lifespan trajectories. A number of studies documented remarkably accurate age prediction, but the differential age trajectories and the cognitive sensitivity of distinct brain tissue classes have yet to be adequately characterized. Exploring differential brain age models driven by tissue-specific classifiers provides a hitherto unexplored opportunity to disentangle independent sources of heterogeneity in brain biology. We trained machine-learning models to estimate brain age using various combinations of FreeSurfer based morphometry and diffusion tensor imaging based indices of white matter microstructure in 612 healthy controls aged 18–87 years. To compare the tissue-specific brain ages and their cognitive sensitivity, we applied each of the 11 models in an independent and cognitively well-characterized sample (n = 265, 20–88 years). Correlations between true and estimated age and mean absolute error (MAE) in our test sample were highest for the most comprehensive brain morphometry (r = 0.83, CI:0.78–0.86, MAE = 6.76 years) and white matter microstructure (r = 0.79, CI:0.74–0.83, MAE = 7.28 years) models, confirming sensitivity and generalizability. The deviance from the chronological age were sensitive to performance on several cognitive tests for various models, including spatial Stroop and symbol coding, indicating poorer performance in individuals with an over-estimated age. Tissue-specific brain age models provide sensitive measures of brain integrity, with implications for the study of a range of brain disorders.

The structure and integrity of the ageing brain is interchangeably linked to physical health, and cardiometabolic risk factors (CMRs) are associated with dementia and other brain disorders. In this mixed cross‐sectional and longitudinal study (interval mean = 19.7 months), including 790 healthy individuals (mean age = 46.7 years, 53% women), we investigated CMRs and health indicators including anthropometric measures, lifestyle factors, and blood biomarkers in relation to brain structure using MRI‐based morphometry and diffusion tensor imaging (DTI). We performed tissue specific brain age prediction using machine learning and performed Bayesian multilevel modeling to assess changes in each CMR over time, their respective association with brain age gap (BAG), and their interaction effects with time and age on the tissue‐specific BAGs. The results showed credible associations between DTI‐based BAG and blood levels of phosphate and mean cell volume (MCV), and between T1‐based BAG and systolic blood pressure, smoking, pulse, and C‐reactive protein (CRP), indicating older‐appearing brains in people with higher cardiometabolic risk (smoking, higher blood pressure and pulse, low‐grade inflammation). Longitudinal evidence supported interactions between both BAGs and waist‐to‐hip ratio (WHR), and between DTI‐based BAG and systolic blood pressure and smoking, indicating accelerated ageing in people with higher cardiometabolic risk (smoking, higher blood pressure, and WHR). The results demonstrate that cardiometabolic risk factors are associated with brain ageing. While randomized controlled trials are needed to establish causality, our results indicate that public health initiatives and treatment strategies targeting modifiable cardiometabolic risk factors may also improve risk trajectories and delay brain ageing.

The goal of the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) Stroke Recovery working group is to understand brain and behavior relationships using well‐powered meta‐ and mega‐analytic approaches. ENIGMA Stroke Recovery has data from over 2,100 stroke patients collected across 39 research studies and 10 countries around the world, comprising the largest multisite retrospective stroke data collaboration to date. This article outlines the efforts taken by the ENIGMA Stroke Recovery working group to develop neuroinformatics protocols and methods to manage multisite stroke brain magnetic resonance imaging, behavioral and demographics data. Specifically, the processes for scalable data intake and preprocessing, multisite data harmonization, and large‐scale stroke lesion analysis are described, and challenges unique to this type of big data collaboration in stroke research are discussed. Finally, future directions and limitations, as well as recommendations for improved data harmonization through prospective data collection and data management, are provided.