Cognitive Pathology in Parkinson's Disease: a cholinergic perspective

Cognitive impairment is a common non-motor symptom with a debilitating effect on functional capacity and quality of life in people with Parkinson's disease (PD). Mild cognitive impairment in PD already manifests in newly diagnosed patients and approximately 80% of PD patients eventually develop PD dementia over the course of the disease. The underlying pathology of cognitive impairment in PD is complex and includes the degeneration of multiple neurotransmitter systems, of which the cholinergic system is of particular importance. However, detailed assessment of the regional cortical and subcortical role of the cholinergic system in cognitive impairment across stages of PD is lacking. This dissertation broadens the knowledge on the cognitive pathology in PD from a cholinergic perspective, by providing new insights on the in vivo assessment of cholinergic imaging, and evaluating the relationship between cholinergic system and cognitive functioning in the early and more advanced stages of the disease. We demonstrated that [18F]FEOBV PET imaging allows for reliable and detailed assessment of the cholinergic system. In addition, we found early involvement of the cholinergic system in PD, demonstrating both cholinergic denervation as well as increased cholinergic binding in newly diagnosed PD patients. The latter might indicate a cholinergic compensation mechanism related to cognitive functioning in PD. Furthermore we demonstrated the regional cholinergic vulnerability related to cognitive domain functioning in more advanced PD, showing involvement of overlapping cholinergic regions. These findings provide new directions for clinical practice and future studies on the cholinergic pathology of cognitive impairment in PD