Sex, racial, and APOE-ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer's disease.

INTRODUCTION: The effects of sex, race, and Apolipoprotein E (APOE) - Alzheimer's disease (AD) risk factors - on white matter integrity are not well characterized. METHODS: Diffusion MRI data from nine well-established longitudinal cohorts of aging were free-water (FW)-corrected and harmonized. This dataset included 4,702 participants (age=73.06 ± 9.75) with 9,671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FAFWcorr) were used to assess differences in white matter microstructure by sex, race, and APOE-ε4 carrier status. RESULTS: Sex differences in FAFWcorr in association and projection tracts, racial differences in FAFWcorr in projection tracts, and APOE-ε4 differences in FW limbic and occipital transcallosal tracts were most pronounced. DISCUSSION: There are prominent differences in white matter microstructure by sex, race, and APOE-ε4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted.

Evaluation of Mean Shift, ComBat, and CycleGAN for Harmonizing Brain Connectivity Matrices Across Sites.

Connectivity matrices derived from diffusion MRI (dMRI) provide an interpretable and generalizable way of understanding the human brain connectome. However, dMRI suffers from inter-site and between-scanner variation, which impedes analysis across datasets to improve robustness and reproducibility of results. To evaluate different harmonization approaches on connectivity matrices, we compared graph measures derived from these matrices before and after applying three harmonization techniques: mean shift, ComBat, and CycleGAN. The sample comprises 168 age-matched, sex-matched normal subjects from two studies: the Vanderbilt Memory and Aging Project (VMAP) and the Biomarkers of Cognitive Decline Among Normal Individuals (BIOCARD). First, we plotted the graph measures and used coefficient of variation (CoV) and the Mann-Whitney U test to evaluate different methods' effectiveness in removing site effects on the matrices and the derived graph measures. ComBat effectively eliminated site effects for global efficiency and modularity and outperformed the other two methods. However, all methods exhibited poor performance when harmonizing average betweenness centrality. Second, we tested whether our harmonization methods preserved correlations between age and graph measures. All methods except for CycleGAN in one direction improved correlations between age and global efficiency and between age and modularity from insignificant to significant with p-values less than 0.05.

Predicting Age from White Matter Diffusivity with Residual Learning.

Imaging findings inconsistent with those expected at specific chronological age ranges may serve as early indicators of neurological disorders and increased mortality risk. Estimation of chronological age, and deviations from expected results, from structural magnetic resonance imaging (MRI) data has become an important proxy task for developing biomarkers that are sensitive to such deviations. Complementary to structural analysis, diffusion tensor imaging (DTI) has proven effective in identifying age-related microstructural changes within the brain white matter, thereby presenting itself as a promising additional modality for brain age prediction. Although early studies have sought to harness DTI's advantages for age estimation, there is no evidence that the success of this prediction is owed to the unique microstructural and diffusivity features that DTI provides, rather than the macrostructural features that are also available in DTI data. Therefore, we seek to develop white-matter-specific age estimation to capture deviations from normal white matter aging. Specifically, we deliberately disregard the macrostructural information when predicting age from DTI scalar images, using two distinct methods. The first method relies on extracting only microstructural features from regions of interest (ROIs). The second applies 3D residual neural networks (ResNets) to learn features directly from the images, which are non-linearly registered and warped to a template to minimize macrostructural variations. When tested on unseen data, the first method yields mean absolute error (MAE) of 6.11 ± 0.19 years for cognitively normal participants and MAE of 6.62 ± 0.30 years for cognitively impaired participants, while the second method achieves MAE of 4.69 ± 0.23 years for cognitively normal participants and MAE of 4.96 ± 0.28 years for cognitively impaired participants. We find that the ResNet model captures subtler, non-macrostructural features for brain age prediction.

Characterizing patterns of DTI variance in aging brains.

Background: As large analyses merge data across sites, a deeper understanding of variance in statistical assessment across the sources of data becomes critical for valid analyses. Diffusion tensor imaging (DTI) exhibits spatially varying and correlated noise, so care must be taken with distributional assumptions. Purpose: We characterize the role of physiology, subject compliance, and the interaction of subject with the scanner in the understanding of DTI variability, as modeled in spatial variance of derived metrics in homogeneous regions. Methods: We analyze DTI data from 1035 subjects in the Baltimore Longitudinal Study of Aging (BLSA), with ages ranging from 22.4 to 103 years old. For each subject, up to 12 longitudinal sessions were conducted. We assess variance of DTI scalars within regions of interest (ROIs) defined by four segmentation methods and investigate the relationships between the variance and covariates, including baseline age, time from the baseline (referred to as "interval"), motion, sex, and whether it is the first scan or the second scan in the session. Results: Covariate effects are heterogeneous and bilaterally symmetric across ROIs. Inter-session interval is positively related (p ≪ 0.001) to FA variance in the cuneus and occipital gyrus, but negatively (p ≪ 0.001) in the caudate nucleus. Males show significantly (p ≪ 0.001) higher FA variance in the right putamen, thalamus, body of the corpus callosum, and cingulate gyrus. In 62 out of 176 ROIs defined by the Eve type-1 atlas, an increase in motion is associated (p < 0.05) with a decrease in FA variance. Head motion increases during the rescan of DTI (Δµ = 0.045 millimeters per volume). Conclusions: The effects of each covariate on DTI variance, and their relationships across ROIs are complex. Ultimately, we encourage researchers to include estimates of variance when sharing data and consider models of heteroscedasticity in analysis. This work provides a foundation for study planning to account for regional variations in metric variance.