Regional Deep Atrophy: a Self-Supervised Learning Method to Automatically Identify Regions Associated With Alzheimer's Disease Progression From Longitudinal MRI

Longitudinal assessment of brain atrophy, particularly in the hippocampus, is a well-studied biomarker for neurodegenerative diseases, such as Alzheimer's disease (AD). In clinical trials, estimation of brain progressive rates can be applied to track therapeutic efficacy of disease modifying treatments. However, most state-of-the-art measurements calculate changes directly by segmentation and/or deformable registration of MRI images, and may misreport head motion or MRI artifacts as neurodegeneration, impacting their accuracy. In our previous study, we developed a deep learning method DeepAtrophy that uses a convolutional neural network to quantify differences between longitudinal MRI scan pairs that are associated with time. DeepAtrophy has high accuracy in inferring temporal information from longitudinal MRI scans, such as temporal order or relative inter-scan interval. DeepAtrophy also provides an overall atrophy score that was shown to perform well as a potential biomarker of disease progression and treatment efficacy. However, DeepAtrophy is not interpretable, and it is unclear what changes in the MRI contribute to progression measurements. In this paper, we propose Regional Deep Atrophy (RDA), which combines the temporal inference approach from DeepAtrophy with a deformable registration neural network and attention mechanism that highlights regions in the MRI image where longitudinal changes are contributing to temporal inference. RDA has similar prediction accuracy as DeepAtrophy, but its additional interpretability makes it more acceptable for use in clinical settings, and may lead to more sensitive biomarkers for disease monitoring in clinical trials of early AD.

DeepAtrophy: Teaching a Neural Network to Differentiate Progressive Changes from Noise on Longitudinal MRI in Alzheimer's Disease

Volume change measures derived from longitudinal MRI (e.g. hippocampal atrophy) are a well-studied biomarker of disease progression in Alzheimer's Disease (AD) and are used in clinical trials to track the therapeutic efficacy of disease-modifying treatments. However, longitudinal MRI change measures can be confounded by non-biological factors, such as different degrees of head motion and susceptibility artifact between pairs of MRI scans. We hypothesize that deep learning methods applied directly to pairs of longitudinal MRI scans can be trained to differentiate between biological changes and non-biological factors better than conventional approaches based on deformable image registration. To achieve this, we make a simplifying assumption that biological factors are associated with time (i.e. the hippocampus shrinks overtime in the aging population) whereas non-biological factors are independent of time. We then formulate deep learning networks to infer the temporal order of same-subject MRI scans input to the network in arbitrary order; as well as to infer ratios between interscan intervals for two pairs of same-subject MRI scans. In the test dataset, these networks perform better in tasks of temporal ordering (89.3%) and interscan interval inference (86.1%) than a state-of-the-art deformation-based morphometry method ALOHA (76.6% and 76.1% respectively) (Das et al., 2012). Furthermore, we derive a disease progression score from the network that is able to detect a group difference between 58 preclinical AD and 75 beta-amyloid-negative cognitively normal individuals within one year, compared to two years for ALOHA. This suggests that deep learning can be trained to differentiate MRI changes due to biological factors (tissue loss) from changes due to non-biological factors, leading to novel biomarkers that are more sensitive to longitudinal changes at the earliest stages of AD.