In vivo assessment of non-dopaminergic systems in Parkinson’s disease with Positron Emission Tomography

Abstract

Parkinson's disease (PD) is characterized by a progressive loss of nigrostriatal dopaminergic neurons. Non-dopaminergic neurotransmission is also impaired. Intraneuronal Lewy bodies, the pathological hallmark of PD, have been observed in serotoninergic, noradrenergic, and cholinergic neurons. Dysfunction of these systems could play a role in the occurrence of non-motor symptoms including fatigue. However, the extent of non-dopaminergic degeneration in PD, rates of its progression, and its contribution to the development of non-motor symptoms is unclear. First, I used 18F-dopa Positron Emission Tomography (PET), a marker of monoaminergic terminal function, to assess the involvement of dopaminergic, noradrenergic, and serotoninergic pathways in PD and in parkin-linked parkinsonism, a genetic form of PD. I found that parkin patients and PD patients have distinct patterns of monoaminergic involvement, with more widespread dysfunction in PD. In a second study, I used serial 18F-dopa PET to assess longitudinal changes in tracer uptake in brain monoaminergic structures over a 3-year period in a group of PD patients. I also assessed the relationship between striatal function decline and dysfunction in extra-striatal areas in the same patients. I found that the degeneration in extrastriatal monoaminergic structures in PD occurs independently from nigrostriatal degeneration and at a slower rate. Brain compensatory mechanisms disappear within the first years of disease. I then used 18F-dopa and 11C-DASB PET to investigate whether fatigue in PD is associated with dysfunction of dopaminergic/serotoninergic innervation. I found that PD patients with fatigue show severe loss of serotoninergic innervation in basal ganglia and limbic areas. Finally, I assessed the relationship between 18F-dopa uptake and measurements of serotonin transporter availability by 11C-DASB PET within brain serotoninergic structures and I provided evidence for the hypothesis that 18F-dopa PET can be used to evaluate the distribution and the function of serotoninergic systems in the brain of PD patients