Data-Driven Discovery of Movement-Linked Heterogeneity in Neurodegenerative Diseases

Neurodegenerative diseases manifest different motor and cognitive signs and symptoms that are highly heterogeneous. Parsing these heterogeneities may lead to an improved understanding of underlying disease mechanisms; however current methods are dependent on clinical assessments and somewhat arbitrary choice of behavioral tests. Herein, we present a data-driven subtyping approach using video-captured human motion and brain functional connectivity (FC) from resting-state (rs)-fMRI. We applied our framework to a cohort of individuals at different stages of Parkinson's disease (PD). The process mapped the data to low-dimensional measures by projecting them onto a canonical correlation space that identified three PD subtypes: Subtype I was characterized by motor difficulties and poor visuospatial abilities; Subtype II exhibited difficulties in non-motor components of activities of daily living and motor complications (dyskinesias and motor fluctuations); and Subtype III was characterized by predominant tremor symptoms. We conducted a convergent validity analysis by comparing our approach to existing and widely used approaches. The compared approaches yielded subtypes that were adequately well-clustered in the motion-brain representation space we created to delineate subtypes. Our data-driven approach, contrary to other forms of subtyping, derived biomarkers predictive of motion impairment and subtype memberships that were captured objectively by digital videos.