Abstract
The human brain undergoes continuous structural changes throughout the lifespan, driven by a complex
interplay of aging processes, environmental influences, and disease-related mechanisms. Patterns of structural change—particularly atrophy associated with tissue loss and shrinkage—emerge gradually over time
and are observable using medical imaging techniques. While these changes are shaped by common biological mechanisms, they are also highly individualized, influenced by factors such as lifestyle, and neurological
conditions like Alzheimer’s Disease (AD), Parkinson’s disease, tumors, and stroke. Understanding the progression of these changes—both at the individual level and across populations—is critical for advancing our
knowledge of healthy aging and the dynamics of neurodegenerative disease.
To study how brain structure evolves over time, researchers rely on longitudinal neuroimaging: repeated
imaging of the same individuals at multiple timepoints. Unlike cross-sectional imaging, which captures a
single snapshot per subject, longitudinal scans provide a temporal sequence that enables direct observation
of anatomical trajectories. These sequences allow for the measurement of rates of change, identification of
early biomarkers, and modeling of disease progression in a subject-specific manner.
However, acquiring complete longitudinal datasets in practice remains challenging. Subject dropout,
missed clinical visits, and protocol variability often result in missing scans, interrupting the temporal continuity required for accurate modeling. These gaps limit the effectiveness of methods that rely on temporally
complete inputs and can bias downstream analyses. Imputing the missing scan to complete the subject’s
imaging timeline is therefore a critical step toward enabling robust longitudinal modeling and improving
our understanding of neurodegenerative processes.
This thesis addresses the challenges of modeling and analyzing longitudinal brain changes by developing anatomically grounded methods for data imputation, latent space disentanglement, and downstream
trajectory analysis. We first introduce SynBADD, a deformation-based framework that synthesizes missing brain scans by predicting physiologically plausible stationary velocity fields (SVFs)—parametric fields
that encode smooth, invertible deformations over space and time—rather than directly generating full image
intensities. By operating in the deformation space, SynBADD preserves anatomical coherence and spatial
fidelity while mitigating the artifacts typically associated with intensity-based synthesis approaches.
Building on this foundation, we propose DIVA, a metadata-informed variational autoencoder designed
to learn a temporally disentangled latent space for modeling brain morphological changes. DIVA is trained
on synthetically augmented Stationary Velocity Fields (SVFs), enriching intra-subject variation and improving the model’s capacity to generalize across limited real-world samples. Age, disease label, and temporal information are explicitly disentangled through conditional bottleneck supervision, allowing the learned latent representations to reflect meaningful clinical and chronological factors. This disentanglement enhances
temporal predictability, supports more accurate subject-specific trajectory modeling, and enables the use of
powerful transformer-based architectures for latent space interpolation and prediction.
We further extend our analysis in an “Analysis by Synthesis” framework, investigating how metadatainformed conditioning affects generation quality and how different temporal reasoning strategies (past-only,
future-only, and bidirectional) impact anatomical plausibility. We perform trajectory-based analyses of generated scans, evaluating how well imputed data aligns with true subject-specific anatomical trends across
key regions of interest (ROIs) such as the hippocampus and parahippocampus. Additionally, we assess
subgroup differences by age, sex, and disease status, and evaluate downstream task performance with and
without synthetic imputation.
Through comprehensive evaluations on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) longitudinal dataset, our approaches achieve substantial improvements over state-of-the-art baselines in both
image fidelity and clinically relevant anatomical accuracy. Beyond technical advancements, this work provides new insights into the modeling of individualized brain aging patterns and opens pathways for data
augmentation in clinical studies where longitudinal completeness is often unattainable.