Cholinergic system changes in Parkinson's disease: emerging therapeutic approaches

Abstract

In patients with Parkinson's disease, heterogeneous cholinergic system changes can occur in different brain regions. These changes correlate with a range of clinical features, both motor and non-motor, that are refractory to dopaminergic therapy, and can be conceptualised within a systems-level framework in which nodal deficits can produce circuit dysfunctions. The topographies of cholinergic changes overlap with neural circuitries involved in sleep and cognitive, motor, visuo-auditory perceptual, and autonomic functions. Cholinergic deficits within cognition network hubs predict cognitive deficits better than do total brain cholinergic changes. Postural instability and gait difficulties are associated with cholinergic system changes in thalamic, caudate, limbic, neocortical, and cerebellar nodes. Cholinergic system deficits can involve also peripheral organs. Hypercholinergic activity of mesopontine cholinergic neurons in people with isolated rapid eye movement (REM) sleep behaviour disorder, as well as in the hippocampi of cognitively normal patients with Parkinson's disease, suggests early compensation during the prodromal and early stages of Parkinson's disease. Novel pharmacological and neurostimulation approaches could target the cholinergic system to treat motor and non-motor features of Parkinson's disease.

Figure 1:. Anatomical location of cholinergic cell groups and their projections

Cholinergic cells and projections in the forebrain (A) and brainstem (B). Topographic projections from specific cholinergic nuclei are shown as coloured arrows. DMN=dorsal motor nucleus of the vagus. hDB=horizontal limb nucleus of the diagonal band of Broca. MS=medial septal nuclei. MVN=medial vestibular nucleus. nBM=nucleus basalis of Meynert. PPN-LDT=pedunculopontine nucleus-laterodorsal tegmental complex. SN=substantia nigra. STN=subthalamic nucleus. vDB=vertical limb nucleus of the diagonal band of Broca.

Figure 2:. Cholinergic PET imaging in patients with Parkinson’s disease or isolated REM sleep behaviour disorder

(A) Decreased ¹¹C-donepezil colon signals in a patient with isolated REM sleep behaviour disorder, and a patient with Parkinson’s disease with REM sleep behaviour disorder. Arrows point to the ascending colon. Colouring reflects intensity of Cholinergic PET binding but does not reflect statistical information. (B) Increased ¹⁸F-fluoroethoxybenzovesamicol-PET binding in a group of patients with isolated REM sleep behaviour disorder compared with a group of healthy volunteers. REM=rapid eye movement.

Figure 3:. Expression patterns of muscarinic and nicotinic acetylcholine receptors relevant to Parkinson’s disease

(A) mAChRs and nAChRs have a diverse expression profile throughout the striatum, with several mAChRs and nAChRs expressed on presynaptic inputs from the cortex, thalamus, cholinergic interneurons, and dopaminergic terminals, as well as postsynaptically in spiny projection neurons of the direct and indirect pathways. (B) Relative to the striatum, the expression of mAChR and nAChR subtypes in the substantia nigra pars reticulata is less diverse. D₁=dopamine receptors type 1. D₂=dopamine receptors type 2. GPe=globus pallidus pars externa. GPi=globus pallidus internus. mAChR=muscarinic acetylcholine receptor. nAChR=nicotinic acetylcholine receptor. PPN=pedunculopontine nucleus. SNr=substantia nigra pars reticulata. SPN=spiny projection neuron.