Selective Effects of Substantia Nigra and Locus Coeruleus Degeneration on Cognition in Parkinson's Disease

Abstract Background The substantia nigra (SN) and locus coeruleus (LC) are among the first brain regions to degenerate in Parkinson's disease (PD). This has important implications for early cognitive deficits because these nuclei are sources of ascending neuromodulators (i.e., dopamine and noradrenaline) that support various cognitive functions such as learning, memory, and executive function. Objective Our aim was to investigate the selective and independent contributions of SN and LC degeneration to cognitive deficits in PD. Methods We ran a cross‐sectional study testing patients with PD and older adults on tasks of positive reinforcement learning, attention/working memory, executive function, and memory to measure cognitive performance in domains thought to be related to dopaminergic and noradrenergic function. Participants also underwent neuromelanin‐sensitive magnetic resonance imaging as a measure of degeneration. Results Reduced SN neuromelanin signal in PD was independently associated with impaired positive reinforcement learning ( β = 0.41, 95% confidence interval [CI]: 0.08, 0.74) controlling for changes in the LC. In contrast, reduced LC neuromelanin signal was independently associated with impairments in attention/working memory ( β = 0.20, 95% CI [−0.47, −0.10]) and executive function ( β = 0.22, 95% CI: −0.57, −0.24), controlling for changes in the SN. Conclusions These results suggest that SN and LC degeneration may contribute to different cognitive deficits, potentially explaining the heterogeneity that exists in the cognitive manifestations of PD. These results also highlight the potential value of leveraging brain‐behavior relationships to develop performance‐based measures of cognition that could be used to characterize the phenotypic differences associated with underlying patterns of neurodegeneration. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.