DeepAD: A Robust Deep Learning Model of Alzheimer's Disease Progression for Real-World Clinical Applications

The ability to predict the future trajectory of a patient is a key step toward the development of therapeutics for complex diseases such as Alzheimer's disease (AD). However, most machine learning approaches developed for prediction of disease progression are either single-task or single-modality models, which can not be directly adopted to our setting involving multi-task learning with high dimensional images. Moreover, most of those approaches are trained on a single dataset (i.e. cohort), which can not be generalized to other cohorts. We propose a novel multimodal multi-task deep learning model to predict AD progression by analyzing longitudinal clinical and neuroimaging data from multiple cohorts. Our proposed model integrates high dimensional MRI features from a 3D convolutional neural network with other data modalities, including clinical and demographic information, to predict the future trajectory of patients. Our model employs an adversarial loss to alleviate the study-specific imaging bias, in particular the inter-study domain shifts. In addition, a Sharpness-Aware Minimization (SAM) optimization technique is applied to further improve model generalization. The proposed model is trained and tested on various datasets in order to evaluate and validate the results. Our results showed that 1) our model yields significant improvement over the baseline models, and 2) models using extracted neuroimaging features from 3D convolutional neural network outperform the same models when applied to MRI-derived volumetric features

Self-supervised Learning for Segmentation and Quantification of Dopamine Neurons in Parkinson's Disease

Parkinson's Disease (PD) is the second most common neurodegenerative disease in humans. PD is characterized by the gradual loss of dopaminergic neurons in the Substantia Nigra (SN). Counting the number of dopaminergic neurons in the SN is one of the most important indexes in evaluating drug efficacy in PD animal models. Currently, analyzing and quantifying dopaminergic neurons is conducted manually by experts through analysis of digital pathology images which is laborious, time-consuming, and highly subjective. As such, a reliable and unbiased automated system is demanded for the quantification of dopaminergic neurons in digital pathology images. Recent years have seen a surge in adopting deep learning solutions in medical image processing. However, developing high-performing deep learning models hinges on the availability of large-scale, high-quality annotated data, which can be expensive to acquire, especially in applications like digital pathology image analysis. To this end, we propose an end-to-end deep learning framework based on self-supervised learning for the segmentation and quantification of dopaminergic neurons in PD animal models. To the best of our knowledge, this is the first deep learning model that detects the cell body of dopaminergic neurons, counts the number of dopaminergic neurons, and provides characteristics of individual dopaminergic neurons as a numerical output. Extensive experiments demonstrate the effectiveness of our model in quantifying neurons with high precision, which can provide a faster turnaround for drug efficacy studies, better understanding of dopaminergic neuronal health status, and unbiased results in PD pre-clinical research. As part of our contributions, we also provide the first publicly available dataset of histology digital images along with expert annotations for the segmentation of TH-positive DA neuronal soma

Multiclass Semantic Segmentation to Identify Anatomical Sub-Regions of Brain and Measure Neuronal Health in Parkinson's Disease

Automated segmentation of anatomical sub-regions with high precision has become a necessity to enable the quantification and characterization of cells/ tissues in histology images. Currently, a machine learning model to analyze sub-anatomical regions of the brain to analyze 2D histological images is not available. The scientists rely on manually segmenting anatomical sub-regions of the brain which is extremely time-consuming and prone to labeler-dependent bias. One of the major challenges in accomplishing such a task is the lack of high-quality annotated images that can be used to train a generic artificial intelligence model. In this study, we employed a UNet-based architecture, compared model performance with various combinations of encoders, image sizes, and sample selection techniques. Additionally, to increase the sample set we resorted to data augmentation which provided data diversity and robust learning. In this study, we trained our best fit model on approximately one thousand annotated 2D brain images stained with Nissl/ Haematoxylin and Tyrosine Hydroxylase enzyme (TH, indicator of dopaminergic neuron viability). The dataset comprises of different animal studies enabling the model to be trained on different datasets. The model effectively is able to detect two sub-regions compacta (SNCD) and reticulata (SNr) in all the images. In spite of limited training data, our best model achieves a mean intersection over union (IOU) of 79% and a mean dice coefficient of 87%. In conclusion, the UNet-based model with EffiecientNet as an encoder outperforms all other encoders, resulting in a first of its kind robust model for multiclass segmentation of sub-brain regions in 2D images

Cross-Domain Self-Supervised Deep Learning for Robust Alzheimer's Disease Progression Modeling

Developing successful artificial intelligence systems in practice depends both on robust deep learning models as well as large high quality data. Acquiring and labeling data can become prohibitively expensive and time-consuming in many real-world applications such as clinical disease models. Self-supervised learning has demonstrated great potential in increasing model accuracy and robustness in small data regimes. In addition, many clinical imaging and disease modeling applications rely heavily on regression of continuous quantities. However, the applicability of self-supervised learning for these medical-imaging regression tasks has not been extensively studied. In this study, we develop a cross-domain self-supervised learning approach for disease prognostic modeling as a regression problem using 3D images as input. We demonstrate that self-supervised pre-training can improve the prediction of Alzheimer's Disease progression from brain MRI. We also show that pre-training on extended (but not labeled) brain MRI data outperforms pre-training on natural images. We further observe that the highest performance is achieved when both natural images and extended brain-MRI data are used for pre-training.Comment: This article has been removed by arXiv administrators because the submitter did not have the authority to grant the license at the time the work was submitte

Chemokine expression in the early response to injury in human airway epithelial cells

Basal airway epithelial cells (AEC) constitute stem/progenitor cells within the central airways and respond to mucosal injury in an ordered sequence of spreading, migration, proliferation, and differentiation to needed cell types. However, dynamic gene transcription in the early events after mucosal injury has not been studied in AEC. We examined gene expression using microarrays following mechanical injury (MI) in primary human AEC grown in submersion culture to generate basal cells and in the air-liquid interface to generate differentiated AEC (dAEC) that include goblet and ciliated cells. A select group of ~150 genes was in differential expression (DE) within 2–24 hr after MI, and enrichment analysis of these genes showed over-representation of functional categories related to inflammatory cytokines and chemokines. Network-based gene prioritization and network reconstruction using the PINTA heat kernel diffusion algorithm demonstrated highly connected networks that were richer in differentiated AEC compared to basal cells. Similar experiments done in basal AEC collected from asthmatic donor lungs demonstrated substantial changes in DE genes and functional categories related to inflammation compared to basal AEC from normal donors. In dAEC, similar but more modest differences were observed. We demonstrate that the AEC transcription signature after MI identifies genes and pathways that are important to the initiation and perpetuation of airway mucosal inflammation. Gene expression occurs quickly after injury and is more profound in differentiated AEC, and is altered in AEC from asthmatic airways. Our data suggest that the early response to injury is substantially different in asthmatic airways, particularly in basal airway epithelial cells

Chemokine expression in the early response to injury in human airway epithelial cells

<div><p>Basal airway epithelial cells (AEC) constitute stem/progenitor cells within the central airways and respond to mucosal injury in an ordered sequence of spreading, migration, proliferation, and differentiation to needed cell types. However, dynamic gene transcription in the early events after mucosal injury has not been studied in AEC. We examined gene expression using microarrays following mechanical injury (MI) in primary human AEC grown in submersion culture to generate basal cells and in the air-liquid interface to generate differentiated AEC (dAEC) that include goblet and ciliated cells. A select group of ~150 genes was in differential expression (DE) within 2–24 hr after MI, and enrichment analysis of these genes showed over-representation of functional categories related to inflammatory cytokines and chemokines. Network-based gene prioritization and network reconstruction using the PINTA heat kernel diffusion algorithm demonstrated highly connected networks that were richer in differentiated AEC compared to basal cells. Similar experiments done in basal AEC collected from asthmatic donor lungs demonstrated substantial changes in DE genes and functional categories related to inflammation compared to basal AEC from normal donors. In dAEC, similar but more modest differences were observed. We demonstrate that the AEC transcription signature after MI identifies genes and pathways that are important to the initiation and perpetuation of airway mucosal inflammation. Gene expression occurs quickly after injury and is more profound in differentiated AEC, and is altered in AEC from asthmatic airways. Our data suggest that the early response to injury is substantially different in asthmatic airways, particularly in basal airway epithelial cells.</p></div

Expression of genes clustered for other physiologic processes important to the epithelial reparative response in the first 24 hr after MI such as cell cycle and proliferation, migration, and differentiation.

<p>Heat maps of these time points and conditions demonstrated few genes in DE.</p