Mapping striatal functional gradients and associated gene expression in Parkinson’s disease with continuous cognitive impairment

Cognitive impairment in Parkinson’s disease is closely tied to striatal dysfunction, yet the neurobiological interface between macroscale connectivity and molecular signatures remains unexplored. This study characterizes striatal gradient organization and its genetic underpinnings across PD cognitive trajectories. We analyzed functional connectivity gradients in 126 PD patients (spanning the cognitive spectrum from normal cognition to dementia) and 40 healthy controls, correlating spatial patterns with neurotransmitter architecture and transcriptomic profiles. Three distinct striatal gradients emerged: Gradient 1 remains stable throughout disease progression and partially aligns with canonical striatal subdivisions. Gradient 2 represents a spatial continuum closely linked to dopaminergic innervation and becomes most pronounced in the dementia stage. Gradient 3 corresponds to cortico-striatal connectivity patterns implicated in both early and advanced cognitive deficits. Spatial transcriptomic and neuroimaging correlation analyses identified significant associations between cortico-striatal gradient disruptions and specific gene expression patterns. These findings provide valuable insights into striatal macro- and microstructural changes in PD and their role in cognitive impairment.