The Cholinergic Brain in Parkinson's Disease

Abstract

The central cholinergic system includes the basal forebrain nuclei, mainly projecting to the cortex, the mesopontine tegmental nuclei, mainly projecting to the thalamus and subcortical structures, and other groups of projecting neurons and interneurons. This system regulates many functions of human behavior such as cognition, locomotion, and sleep. In Parkinson's disease (PD), disruption of central cholinergic transmission has been associated with cognitive decline, gait problems, freezing of gait (FOG), falls, REM sleep behavior disorder (RBD), neuropsychiatric manifestations, and olfactory dysfunction. Neuropathological and neuroimaging evidence suggests that basal forebrain pathology occurs simultaneously with nigrostriatal denervation, whereas pathology in the pontine nuclei may occur before the onset of motor symptoms. These studies have also detailed the clinical implications of cholinergic dysfunction in PD. Degeneration of basal forebrain nuclei and consequential cortical cholinergic denervation are associated with and may predict the subsequent development of cognitive decline and neuropsychiatric symptoms. Gait problems, FOG, and falls are associated with a complex dysfunction of both pontine and basal forebrain nuclei. Olfactory impairment is associated with cholinergic denervation of the limbic archicortex, specifically hippocampus and amygdala. Available evidence suggests that cholinergic dysfunction, alongside failure of the dopaminergic and other neurotransmitters systems, contributes to the generation of a specific set of clinical manifestations. Therefore, a “cholinergic phenotype” can be identified in people presenting with cognitive decline, falls, and RBD. In this review, we will summarize the organization of the central cholinergic system and the clinical correlates of cholinergic dysfunction in PD.

Enhanced Taste Recognition Following Subacute Treatment With The Dopamine D2/D3 Receptor Agonist Pramipexole in Healthy Volunteers

“…Alternatively, because the neurochemistry of PD is complex and involves several other neurotransmitter systems than dopamine, it could be the case that taste recognition in PD patients is additionally influenced by non-dopaminergic pathology ( Brichta et al, 2013 ). In line with this idea, Cecchini et al (2019) recently demonstrated that chemosensory impairments in PD were associated with mild cognitive impairment, a symptom of PD that has also been linked to non-dopaminergic neurochemical abnormalities ( Pasquini et al, 2021 ).…”

The Contribution of Noradrenergic Activity to Anxiety‐Induced Freezing of Gait

“…However, the implications of our findings extend beyond FOG and reveal a missing piece of the puzzle to the pathophysiology of PD. Given the inherent complexity of PD and our current understanding of the contributions of the dopaminergic system to pathophysiology of PD, it is likely that other neuromodulatory systems (ie, cholinergic, serotonergic) are involved in the diversity of symptoms of PD 63,64 . It has previously been established that both acute and chronic anxiety plays a distinct role in PD 65 .…”

“…Given the inherent complexity of PD and our current understanding of the contributions of the dopaminergic system to pathophysiology of PD, it is likely that other neuromodulatory systems (ie, cholinergic, serotonergic) are involved in the diversity of symptoms of PD. 63,64 It has previously been established that both acute and chronic anxiety plays a distinct role in PD. 65 Other studies have established that anxiety worsens other symptoms of PD, such as bradykinesia 66 and tremor.…”

Molecular Imaging in Parkinsonian Disorders—What’s New and Hot?

“…The development of novel cholinergic fluorine-based PET tracers, including 18F-Fluoroethoxybenzovesamicol (18F-FEOBV) binding to the vesicular acetylcholine transporter [ 102 ], has enabled rapid advances in the last five years to pinpoint the role of basal forebrain cholinergic dysfunction for falls and freezing of gait in PD [ 103 ], as well as multi-domain cognitive impairment [ 104 ], as reviewed in [ 105 ]. Indeed, in contrast with 11C-MP4A or 11C-donepezil, which indicates cholinesterase activity in both the pre- and post-synaptic compartment and synaptic cleft, but with low sensitivity in subcortical structures, 18F-FEOBV binds with high affinity to the vesicular transporter, notably in the striatum [ 106 ].…”