Reinforcing the Weakest Links: Modernizing SIENA with Targeted Deep Learning Integration

Percentage Brain Volume Change (PBVC) derived from Magnetic Resonance Imaging (MRI) is a widely used biomarker of brain atrophy, with SIENA among the most established methods for its estimation. However, SIENA relies on classical image processing steps, particularly skull stripping and tissue segmentation, whose failures can propagate through the pipeline and bias atrophy estimates. In this work, we examine whether targeted deep learning substitutions can improve SIENA while preserving its established and interpretable framework. To this end, we integrate SynthStrip and SynthSeg into SIENA and evaluate three pipeline variants on the ADNI and PPMI longitudinal cohorts. Performance is assessed using three complementary criteria: correlation with longitudinal clinical and structural decline, scan-order consistency, and end-to-end runtime. Replacing the skull-stripping module yields the most consistent gains: in ADNI, it substantially strengthens associations between PBVC and multiple measures of disease progression relative to the standard SIENA pipeline, while across both datasets it markedly improves robustness under scan reversal. The fully integrated pipeline achieves the strongest scan-order consistency, reducing the error by up to 99.1%. In addition, GPU-enabled variants reduce execution time by up to 46% while maintaining CPU runtimes comparable to standard SIENA. Overall, these findings show that deep learning can meaningfully strengthen established longitudinal atrophy pipelines when used to reinforce their weakest image processing steps. More broadly, this study highlights the value of modularly modernizing clinically trusted neuroimaging tools without sacrificing their interpretability. Code is publicly available at https://github.com/Raciti/Enhanced-SIENA.git.