Disease-driven domain generalization for neuroimaging-based assessment of Alzheimer's disease.

Development of deep learning models to evaluate structural brain changes caused by cognitive impairment in MRI scans holds significant translational value. The efficacy of these models often encounters challenges due to variabilities arising from different data generation protocols, imaging equipment, radiological artifacts, and shifts in demographic distributions. Domain generalization (DG) techniques show promise in addressing these challenges by enabling the model to learn from one or more source domains and apply this knowledge to new, unseen target domains. Here we present a framework that utilizes model interpretability to enhance the generalizability of classification models across various cohorts. We used MRI scans and clinical diagnoses from four independent cohorts: Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 1821), the Framingham Heart Study (FHS, n = 304), the Australian Imaging Biomarkers & Lifestyle Study of Ageing (AIBL, n = 661), and the National Alzheimer's Coordinating Center (NACC, n = 4647). With this data, we trained a deep neural network to focus on areas of the brain identified as relevant to the disease for model training. Our approach involved training a classifier to differentiate between structural neurodegeneration in individuals with normal cognition (NC), mild cognitive impairment (MCI), and dementia due to Alzheimer's disease (AD). This was achieved by aligning class-wise attention with a unified visual saliency prior, which was computed offline for each class using all the training data. Our method not only competes with state-of-the-art approaches but also shows improved correlation with postmortem histology. This alignment with the gold standard evidence is a significant step towards validating the effectiveness of DG frameworks, paving the way for their broader application in the field.

AI-based differential diagnosis of dementia etiologies on multimodal data.

Differential diagnosis of dementia remains a challenge in neurology due to symptom overlap across etiologies, yet it is crucial for formulating early, personalized management strategies. Here, we present an AI model that harnesses a broad array of data, including demographics, individual and family medical history, medication use, neuropsychological assessments, functional evaluations, and multimodal neuroimaging, to identify the etiologies contributing to dementia in individuals. The study, drawing on 51,269 participants across 9 independent, geographically diverse datasets, facilitated the identification of 10 distinct dementia etiologies. It aligns diagnoses with similar management strategies, ensuring robust predictions even with incomplete data. Our model achieved a micro-averaged area under the receiver operating characteristic curve (AUROC) of 0.94 in classifying individuals with normal cognition, mild cognitive impairment and dementia. Also, the micro-averaged AUROC was 0.96 in differentiating the dementia etiologies. Our model demonstrated proficiency in addressing mixed dementia cases, with a mean AUROC of 0.78 for two co-occurring pathologies. In a randomly selected subset of 100 cases, the AUROC of neurologist assessments augmented by our AI model exceeded neurologist-only evaluations by 26.25%. Furthermore, our model predictions aligned with biomarker evidence and its associations with different proteinopathies were substantiated through postmortem findings. Our framework has the potential to be integrated as a screening tool for dementia in various clinical settings and drug trials, with promising implications for person-level management.

Disease-driven domain generalization for neuroimaging-based assessment of Alzheimer's disease.

Development of deep learning models to assess the degree of cognitive impairment on magnetic resonance imaging (MRI) scans has high translational significance. Performance of such models is often affected by potential variabilities stemming from independent protocols for data generation, imaging equipment, radiology artifacts, and demographic distributional shifts. Domain generalization (DG) frameworks have the potential to overcome these issues by learning signal from one or more source domains that can be transferable to unseen target domains. We developed an approach that leverages model interpretability as a means to improve generalizability of classification models across multiple cohorts. Using MRI scans and clinical diagnosis obtained from four independent cohorts (Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 1,821), the Framingham Heart Study (FHS, n = 304), the Australian Imaging Biomarkers and Lifestyle Study of Ageing (AIBL, n = 661), and the National Alzheimer's Coordinating Center (NACC, n = 4,647)), we trained a deep neural network that used model-identified regions of disease relevance to inform model training. We trained a classifier to distinguish persons with normal cognition (NC) from those with mild cognitive impairment (MCI) and Alzheimer's disease (AD) by aligning class-wise attention with a unified visual saliency prior computed offline per class over all training data. Our proposed method competes with state-of-the-art methods with improved correlation with postmortem histology, thus grounding our findings with gold standard evidence and paving a way towards validating DG frameworks.