Selective effects of dopaminergic and noradrenergic degeneration on cognition in Parkinson's disease

Abstract

The substantia nigra and locus coeruleus are among the first brain regions to degenerate in Parkinson's disease. This has important implications for early cognitive deficits as these nuclei are sources of ascending neuromodulators (i.e., dopamine and noradrenaline) that support various cognitive functions like learning, memory, and executive function. However, because most studies of the relationship between patterns of degeneration and cognition have either studied these neuromodulator systems in isolation or studied specific cognitive domains in isolation, it is unknown if degeneration in the substantia nigra and degeneration in the locus coeruleus independently and selectively contribute to different cognitive deficits in Parkinson's disease. To address this gap, we tested people with Parkinson's disease and older adults on tasks of positive reinforcement learning, attention/working memory, executive function, and memory to measure performance in domains of cognition specifically thought to be related to dopaminergic and noradrenergic function. Participants also underwent neuromelanin-sensitive magnetic resonance imaging which provides a measure of degeneration of dopamine neurons in the substantia nigra and of noradrenergic neurons in the locus coeruleus. Brain-behaviour relationships were evaluated by separate linear regressions predicting cognitive performance in each domain from substantia nigra and locus coeruleus neuromelanin signal intensities controlling for age, sex, and education. As expected, Parkinson's disease patients had significantly slower learning from positive feedback and lower performance on tests of attention/working memory, executive function, and memory than controls. Parkinson's patients also had lower neuromelanin signal intensity in the substantia nigra and locus coeruleus. Examining brain-behaviour relationships, we found that reduced neuromelanin signal in the substantia nigra in Parkinson's disease patients was independently associated with impaired positive reinforcement learning, controlling for changes in the locus coeruleus, but was not associated with other domains of cognition. In contrast, reduced neuromelanin signal in the locus coeruleus was independently associated with impairments in attention/working memory and executive function, controlling for changes in the substantia nigra, but not with reinforcement learning performance. These results show that substantia nigra degeneration and locus coeruleus degeneration independently and selectively contribute to cognitive deficits and therefore suggests that individual differences in the degree of neurodegeneration in these nuclei could explain the significant heterogeneity that exists in the cognitive and behavioural manifestations of Parkinson's disease. These findings also highlight the potential value of leveraging known brain-behaviour relationships to develop performance-based measures of cognition that reflect underlying patterns of neurodegeneration.