Mapping neuromodulatory systems in Parkinson’s disease: lessons learned beyond dopamine

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease with mixed motor and non-motor symptoms. Dopaminergic drugs remain the mainstay of therapy for PD. However, some motor symptoms (e.g., gait problems) and a broad range of non-motor symptoms (e.g., cognitive impairment and depression) are often unresponsive to dopaminergic drugs. It is because the pathology of PD is not limited to the loss of midbrain dopamine neurons. Recent in vivo human brain imaging studies have provided novel insights into the dysfunction of multiple non-dopaminergic systems in PD. I review positron emission tomography, single photon emission computed tomography, neuromelanin-sensitive magnetic resonance imaging, and functional magnetic resonance imaging studies demonstrating the parallel alteration of noradrenergic, serotonergic, and cholinergic systems in PD. These studies shed light on the relationship between neuromodulators and vulnerable cognitive, affective, and motor functions. I finally discuss open questions in the field. More human pharmacological imaging studies are needed to reach a mechanistic understanding of the non-dopaminergic modulation of human brains.

Funding

National Natural Science Foundation of China,(31961133025); Ministry of Science and Technology of the People's Republic of China,(2021ZD0203600)