Cholinergic systems, attentional-motor integration, and cognitive control in Parkinson's disease

Abstract

Dysfunction and degeneration of CNS cholinergic systems is a significant component of multi-system pathology in Parkinson's disease (PD). We review the basic architecture of human CNS cholinergic systems and the tools available for studying changes in human cholinergic systems. Earlier post-mortem studies implicated abnormalities of basal forebrain corticopetal cholinergic (BFCC) and pedunculopontine-laterodorsal tegmental (PPN-LDT) cholinergic projections in cognitive deficits and gait-balance deficits, respectively. Recent application of imaging methods, particularly molecular imaging, allowed more sophisticated correlation of clinical features with regional cholinergic deficits. BFCC projection deficits correlate with general and domain specific cognitive deficits, particularly for attentional and executive functions. Detailed analyses suggest that cholinergic deficits within the salience and cingulo-opercular task control networks, including both neocortical, thalamic, and striatal nodes, are a significant component of cognitive deficits in non-demented PD subjects. Both BFCC and PPN-LDT cholinergic projection systems, and striatal cholinergic interneuron (SChI), abnormalities are implicated in PD gait-balance disorders. In the context of experimental studies, these results indicate that disrupted attentional functions of BFCC and PPN-LDT cholinergic systems underlie impaired gait-balance functions. SChI dysfunction likely impairs intra-striatal integration of attentional and motor information. Thalamic and entorhinal cortex cholinergic deficits may impair multi-sensory integration. Overt degeneration of CNS systems may be preceded by increased activity of cholinergic neurons compensating for nigrostriatal dopaminergic deficits. Subsequent dysfunction and degeneration of cholinergic systems unmasks and exacerbates functional deficits secondary to dopaminergic denervation. Research on CNS cholinergic systems dysfunctions in PD requires a systems-level approach to understanding PD pathophysiology.

Keywords: Acetylcholine; Attention; Basal forebrain; Cognition; Mild cognitive impairment; Pedunculopontine nucleus; Striatum.

FIG. 1

[¹⁸F]FEOBV binding in human brain: Dorsal to ventral survey of averaged transaxial images for 29 normal subjects. Images scaled to peak SUVR of 3.0. Regions with notable [¹⁸F]FEOBV binding include the striatal complex, thalamus, amygdala, hippocampal formation, neocortical mantle, mesopontine junction, and portions of the cerebellum. Reprinted with permission from Albin, R.L., Bohnen, N.I., Muller, M.L.T.M., et al., 2018a. Regional vesicular acetylcholine transporter distribution in human brain: A [(18)F]fluoroethoxybenzovesamicol positron emission tomography study. J. Comp. Neurol. 526, 2884–2897.

FIG. 2

VChT deficits in Parkinson’s disease brain: Statistical parametric voxel-based analysis (false discovery rate corrected P < 0.05) showing significantly diminished [¹⁸F]FEOBV binding in moderately advanced, non-demented Parkinson’s disease subjects (N = 89) compared with healthy controls. Extensive depletion of tracer binding in posterior cortices. Reprinted with permission from van der Zee, S., Müller, M.L.T.M., Kanel, P., van Laar, T., Bohnen, N.I., 2021. Cholinergic denervation patterns across cognitive domains in Parkinson’s disease. Mov. Disord. 36, 642–650

FIG. 3

Attentional-motor interfaces: Schematic of major brain cholinergic projection systems, BFCC and PPN-LDT, and their interactions with important cortical and subcortical targets. Convergence-integration of attentional and motor information at SChIs. Important cholinergic inputs to attentional and cognitive control circuit nodes in MFCx, ACC-I, RSC, and THAL. BF = basal forebrain, Str = striatum, MFCx = medial frontal cortex, ACC-I = anterior cingulate cortex–insular cortex, RSC = retrosplenial cortex, THAL = thalamus, VTA = ventral tegmental area, SN = substantia nigra, PPN = pedunculopontine-laterodorsotegmental nucleus.