A Nonlinear Simulation Framework Supports Adjusting for Age When Analyzing BrainAGE

Several imaging modalities, including T1-weighted structural imaging, diffusion tensor imaging, and functional MRI can show chronological age related changes. Employing machine learning algorithms, an individual's imaging data can predict their age with reasonable accuracy. While details vary according to modality, the general strategy is to: (1) extract image-related features, (2) build a model on a training set that uses those features to predict an individual's age, (3) validate the model on a test dataset, producing a predicted age for each individual, (4) define the “Brain Age Gap Estimate” (BrainAGE) as the difference between an individual's predicted age and his/her chronological age, (5) estimate the relationship between BrainAGE and other variables of interest, and (6) make inferences about those variables and accelerated or delayed brain aging. For example, a group of individuals with overall positive BrainAGE may show signs of accelerated aging in other variables as well. There is inevitably an overestimation of the age of younger individuals and an underestimation of the age of older individuals due to “regression to the mean.” The correlation between chronological age and BrainAGE may significantly impact the relationship between BrainAGE and other variables of interest when they are also related to age. In this study, we examine the detectability of variable effects under different assumptions. We use empirical results from two separate datasets [training = 475 healthy volunteers, aged 18–60 years (259 female); testing = 489 participants including people with mood/anxiety, substance use, eating disorders and healthy controls, aged 18–56 years (312 female)] to inform simulation parameter selection. Outcomes in simulated and empirical data strongly support the proposal that models incorporating BrainAGE should include chronological age as a covariate. We propose either including age as a covariate in step 5 of the above framework, or employing a multistep procedure where age is regressed on BrainAGE prior to step 5, producing BrainAGE Residualized (BrainAGER) scores

Assessing distinct patterns of cognitive aging using tissue-specific brain age prediction based on diffusion tensor imaging and brain morphometry

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

Predicting Brain Age Based on Spatial and Temporal Features of Human Brain Functional Networks

The organization of human brain networks can be measured by capturing correlated brain activity with functional MRI data. There have been a variety of studies showing that human functional connectivities undergo an age-related change over development. In the present study, we employed resting-state functional MRI data to construct functional network models. Principal component analysis was performed on the FC matrices across all the subjects to explore meaningful components especially correlated with age. Coefficients across the components, edge features after a newly proposed feature reduction method as well as temporal features based on fALFF, were extracted as predictor variables and three different regression models were learned to make prediction of brain age. We observed that individual's functional network architecture was shaped by intrinsic component, age-related component and other components and the predictive models extracted sufficient information to provide comparatively accurate predictions of brain age