Compensatory dopaminergic-cholinergic interactions in conflict processing: Evidence from patients with Parkinson's disease

Abstract

Executive functions are complex both in the cognitive operations involved and in the neural structures and functions that support those operations. This complexity makes executive function highly vulnerable to the detrimental effects of aging, brain injury, and disease, but may also open paths to compensation. Neural compensation is often used to explain findings of additional or altered patterns of brain activations by older adults or patient populations compared to young adults or healthy controls, especially when associated with relatively preserved performance. Here we test the hypothesis of an alternative form of compensation, between different neuromodulator systems. 135 patients with Parkinson's Disease (PD) completed vesicular monoamine transporter type2 (VMAT2) and acetylcholinesterase PET scanning to assess the integrity of nigrostriatal dopaminergic, thalamic cholinergic, and cortical cholinergic pathways, and a behavioral test (Stroop + task-switching) that puts high demands on conflict processing, an important aspect of executive control. Supporting the compensatory hypothesis, regression models controlling for age and other covariates revealed an interaction between caudate dopamine and cortical cholinergic integrity: Cortical cholinergic integrity was a stronger predictor of conflict processing in patients with relatively low caudate dopaminergic function. These results suggest that although frontostriatal dopaminergic function plays a central role in executive control, cholinergic systems may also make an important contribution. The present results suggest potential pathways for remediation, and that the appropriate interventions for each patient may depend on their particular profile of decline. Furthermore, they help to elucidate the brain systems that underlie executive control, which may be important for understanding other disorders as well as executive function in healthy adults.

Altered Cholinergic Innervation in De Novo Parkinson's Disease with and Without Cognitive Impairment

“… 36 , 37 Bohnen et al and Kim et al expanded on these findings by showing both independent and interactive roles of the cholinergic and dopaminergic systems in cognitive functioning in PD. 17 , 38 In the context of dopaminergic losses, preservation or even upregulation of cholinergic innervation may help preserve cognitive functioning. 39 In addition, Liu et al reported increased cortical acetylcholinesterase activity related to LRRK2 gene mutation in (premanifest) PD.…”

Imaging Markers of Progression in Parkinson's Disease

“…34 For example, Kim and colleagues showed that cortical cholinergic integrity was a stronger predictor of conflict processing in PD patients with relatively low caudate dopaminergic function. 35 These findings imply also a more-nuanced perspective that diverges from the dual-syndrome hypothesis given that the cholinergic system may make an important contribution to executive dysfunction in PD.…”

“…Conversely, combined dopaminergic and cholinergic neurotransmitter system losses may aggravate cognitive, especially executive, function deficits and jointly increase the risk of conversion to PDD . For example, Kim and colleagues showed that cortical cholinergic integrity was a stronger predictor of conflict processing in PD patients with relatively low caudate dopaminergic function . These findings imply also a more‐nuanced perspective that diverges from the dual‐syndrome hypothesis given that the cholinergic system may make an important contribution to executive dysfunction in PD.…”

Molecular Imaging of the Cholinergic System in Parkinson's Disease

“…Recently, we reported on the so-called ‘compensatory’ hypothesis to better understand dynamic changes in both dopaminergic and cholinergic systems in PD (N. I. Bohnen et al, 2015; Kim, Bohnen, Muller, & Lustig, 2018). The ‘compensatory’ hypothesis posits that frontostriatal dopaminergic losses may lead to compensatory reliance in cortical cholinergic circuits.…”