Dissecting real-world memory clinical cohort heterogeneity: analysis of neuroanatomical subtypes using HYDRA

There is significant evidence for neuroanatomical heterogeneity in neurodegenerative disorders, which has been demonstrated predominantly through analyses of well-characterized research cohorts. Despite the known diversity in clinical presentations among patients attending memory clinics, studies exploring neuroanatomical heterogeneity in such clinically diverse groups remain sparse.

To address this gap, we applied the semi-supervised Heterogeneity through Discriminative Analysis (HYDRA) (Neuroimage 145:346-364 2017) machine learning method to magnetic resonance imaging (MRI) data from the Open Access Series of Imaging Studies (OASIS) (NeuroImage 26:102248 2020) to uncover patterns of neurostructural heterogeneity in memory clinic attendees. Cross-validation was used to assess clustering stability via the Adjusted Rand Index (ARI), Silhouette Score, and Calinski-Harabasz Index (CHI). We performed survival analyses using Kaplan-Meier curves and mixed-effects models for longitudinal cognitive data (e.g., memory, executive function, and language assessments) to examine differences in disease progression.

Cross-validation analyses indicated two highly stable subtypes of cognitively impaired individuals (ARI = 0.552), exhibiting significant neuroanatomical differences. Subtype 1, termed the Temporal-Sparing Atrophy (TSA) Subtype, was defined by relatively mild atrophy, especially in temporal areas, with slower cognitive decline and preserved Function across most domains. Subtype 2, termed the Temporal-Parietal Predominated Atrophy (TPPA) Subtype, was marked by notable alterations in areas critically affected in neurodegenerative disorders. These included key areas critical for executive function and memory, such as the frontal, temporal, and parietal cortices including the precuneus. Longitudinal analysis of neuroimaging and cognitive data revealed contrasting trajectories. The TSA Subtype demonstrated a gradual decline in cognitive functions over time, particularly in the assessments that are memory-focused tests. Conversely, the TPPA Subtype exhibited a more severe decline in these functions.

This research illustrates that neurodegenerative diseases present a spectrum of structural brain changes rather than uniform pathology, suggesting that future research may benefit from stratified therapeutic approaches and targeted recruitment strategies for clinical trials. By leveraging detailed clinical assessments and longitudinal data, including uncertain diagnoses and Clinical Dementia Rating (CDR) scores, this study contributes to better understanding/characterizing memory clinic populations, which could help with optimizing interventions.