Chapter 14 - Cholinergic systems, attentional-motor integration, and cognitive control in Parkinson's disease
Introduction
Parkinson's disease (PD) is now recognized widely as a multi-system neurodegenerative syndrome with multiple clinical manifestations. The multi-system nature of PD explains the diversity of PD clinical manifestations, but involvement of multiple brain systems is a challenge for identifying the pathophysiologic underpinnings of important clinical features. Unlike the cardinal motor deficits of bradykinesia, rigidity, and tremor, associated with deficient nigrostriatal dopaminergic signaling, the highly varied cognitive and behavioral deficits of PD likely reflect combined effects of varying degrees of pathology in numerous CNS systems with both cortical and subcortical components. Of particular importance may be consequences of pathologies within subcortical cholinergic neurons, Basal Forebrain Cholinergic Corticopetal (BFCC) and Pedunculopontine-Laterodorsal Tegmental (PPN-LDT) projection systems, and striatal cholinergic interneurons (SChIs). An interesting convergence of clinical research and expanding understanding of the normal functions of these systems implicates dysfunction and/or degeneration of these cholinergic systems in important clinical features of PD. These results also emphasize the importance of interpreting clinical features of PD and underlying pathologies though the lens of modern systems level neuroscience concepts (see also chapter “Cognitive control and Parkinson's disease” by Cavanagh et al. in this volume). Anti-muscarinic cholinergic agents were historically used to ameliorate PD tremor but largely abandoned because of cognitive side-effects. Acetylcholinesterase inhibitors are presently used to treat cognitive deficits but with modest benefits (Seppi et al., 2019). Improved understanding of the effects of cholinergic systems deficits in PD may provide avenues for improved symptomatic therapies.
Section snippets
Cholinergic systems organization and functions
Acetylcholine (ACh) is the primary (small molecule) neurotransmitter of several brain projection systems and one major population of brain interneurons (see below). It is important to bear in mind that many cholinergic neurons also express peptide neurotransmitters-neuromodulators and some cholinergic neurons co-express other small molecule neurotransmitters. Cholinergic neuron populations not discussed in this chapter are motor neurons, preganglionic autonomic system neurons, and spinal
Tools to study cholinergic systems in humans
Identification of cholinergic deficits in and correlation with clinical features of PD is a direct function of the availability of methods that can be deployed in human studies. Until relatively recently, studies of cholinergic system changes in PD were limited to analysis of post-mortem tissues. These studies used either biochemical methods measuring the expression of cholinergic terminal markers, mainly regional ChAT activity, or conventional histopathologic, histochemical, or
Cholinergic system changes in PD: Post-mortem studies
Documentation of BF neurodegeneration in PD has a venerable history. Lewy initially described the eponymous Lewy body (LB) and neuronal loss in magnocellular nBM-SI cells, now known to be BFCC neurons, as well as in dorsal motor nucleus of the vagus neurons. The discovery of LBs in and substantia nigra neuronal loss came later. Lewy's findings were subsequently confirmed by Hassler, who later suggested that nBM-SI pathology in PD was related to cognitive impairment (summarized in Liu et al.,
Cholinergic system changes in PD: Imaging studies and cognitive deficits
The initial IBVM SPECT study of Kuhl et al. (1996) contrasted a group of younger (N = 9; mean age = 59) non-demented PD subjects and older (N = 6; mean age = 77) demented PD (PDD) subjects. The former exhibited modest decreases, ~ 20%, in occipital cortical IBVM binding while the demented subjects exhibited more marked, ~ 40%, reductions in IBVM binding throughout the neocortical mantle. The first AChase PET studies were reported by Shinotoh et al. (1999), using MP4A PET to compare PD and PSP subjects
Cholinergic system changes in PD: Imaging studies and gait-balance deficits
Parallel data pointed to cholinergic deficits contributing to another morbid aspect of PD; gait and balance problems (Bohnen et al., 2009, Bohnen et al., 2013). PD subjects with cortical AChase deficits had slower gaits, independent of striatal dopaminergic denervation, indeed, PD subjects without cortical AChase deficits had normal gait speed under these test conditions (Bohnen et al., 2013). In a complementary, recent MRI morphometry study of more advanced PD subjects, Dalrymple et al. (2021)
Cholinergic system changes in PD: Early compensation: Upregulation?
As discussed above, work with the rat DL model is consistent with a scenario in which BFCC neuron activity compensates for impaired nigrostriatal dopaminergic signaling. When BFCC function fails, this unmasks DRT-refractory deficits. A possible mechanism of compensation for dopaminergic deficits is upregulation of cholinergic neurotransmission. Some PET imaging study data is consistent with cholinergic systems upregulation in response to nigrostriatal dopaminergic deficits. van der Zee et al.
Conclusions
The confluence of earlier post-mortem and recent imaging data indicates that dysfunction-degeneration of CNS cholinergic systems is an important contributor to morbid features of PD, particularly the DRT-refractory features of cognitive impairment and gait-balance deficits. Recent imaging data, in conjunction with expanding knowledge of the normal structure and functions of brain cholinergic systems, points to specific roles of several cholinergic system dysfunctions in these important PD
Acknowledgments
The authors acknowledge support from P50NS123067, the Parkinson's Foundation, the Michael J. Fox Foundation, and the W. Garfield Weston Foundations' Weston Brain Institute. We thank our research participants in the United States and the Netherlands.
References (100)
- et al.
Acetylcholine efflux from retrosplenial areas and hippocampal sectors during maze exploration
Behav. Brain Res.
(2009) - et al.
Basal forebrain cholinergic circuits and signaling in cognition and cognitive decline
Neuron
(2016) - et al.
Brain cholinergic alterations in idiopathic REM sleep behaviour disorder: a PET imaging study with 18F-FEOBV
Sleep Med.
(2019) - et al.
Staging of brain pathology related to sporadic Parkinson's disease
Neurobiol. Aging
(2003) - et al.
Hyperexcitable neurons enable precise and persistent information encoding in the superficial retrosplenial cortex
Cell Rep.
(2020) - et al.
The current status of the cortical cholinergic system in Alzheimer's disease and Parkinson's disease
Prog. Brain Res.
(1986) - et al.
Nicotinic receptors, allosteric proteins and medicine
Trends Mol. Med.
(2008) - et al.
Volumetric analysis of the substantia innominata in patients with Parkinson's disease according to cognitive status
Neurobiol. Aging
(2012) The neostriatal mosaic: multiple levels of compartmental organization
Trends Neurosci.
(1992)- et al.
The input-output relationship of the cholinergic basal forebrain
Cell Rep.
(2017)
In vivo cholinergic basal forebrain degeneration and cognition in Parkinson's disease: imaging results from the COPPADIS study
Parkinsonism Relat. Disord.
Dichotomy between motor and cognitive functions of midbrain cholinergic neurons
Neurobiol. Dis.
Rat locomotion and release of acetylcholinesterase
Pharmacol. Biochem. Behav.
Compensatory dopaminergic-cholinergic interactions in conflict processing: evidence from patients with Parkinson's disease
Neuroimage
Thalamic cholinergic innervation makes a specific bottom-up contribution to signal detection: evidence from Parkinson's disease patients with defined cholinergic losses
Neuroimage
The cortical cholinergic system contributes to the top-down control of distraction: evidence from patients with Parkinson's disease
Neuroimage
Normal cognition in Parkinson's disease may involve hippocampal cholinergic compensation: a PET imaging study with [18F]-FEOBV
Parkinsonism Relat. Disord.
The impact of dopamine D(2)-like agonist/antagonist on [(18)F]VAT PET measurement of VAChT in the brain of nonhuman primates
Eur. J. Pharm. Sci.
The effect of LRRK2 mutations on the cholinergic system in manifest and premanifest stages of Parkinson's disease: a cross-sectional PET study
Lancet Neurol.
Effects of augmenting cholinergic neurotransmission on balance in Parkinson's disease
Parkinsonism Rel. Disord.
Aging-related dysfunction of striatal cholinergic interneurons produces conflict in action selection
Neuron
Rethinking the pedunculopontine nucleus: from cellular organization to function
Neuron
Presynaptic regulation of dopamine release: role of the DAT and VMAT2 transporters
Neurochem. Int.
Neuronal nicotinic receptors in the human brain
Prog. Neurobiol.
Mitochondrial abnormality associates with type-specific neuronal loss and cell morphology changes in the pedunculopontine nucleus in Parkinson disease
Am. J. Pathol.
Where attention falls: increased risk of falls from the converging impact of cortical cholinergic and midbrain dopamine loss on striatal function
Exp. Neurol.
Cholinergic double duty: cue detection and attentional control
Curr. Opin. Psychol.
Spatial topography of the basal forebrain cholinergic projections: organization and vulnerability to degeneration
Handb. Clin. Neurol.
Stereotaxic probabilistic maps of the magnocellular cell groups in human basal forebrain
Neuroimage
Biochemistry of Parkinson's disease 28 years later: a critical review
Mov. Disord.
Regional vesicular acetylcholine transporter distribution in human brain: a [(18)F]fluoroethoxybenzovesamicol positron emission tomography study
J. Comp. Neurol.
α4β2⁎ nicotinic cholinergic receptor target engagement in Parkinson disease gait-balance disorders
Ann. Neurol.
Targeting the pedunculopontine nucleus in Parkinson's disease: time to go back to the drawing board
Mov. Disord.
Complex movement control in a rat model of parkinsonian falls: bidirectional control by striatal cholinergic interneurons
J. Neurosci.
Cholinergic innervation of the cerebellum of rat, rabbit, cat, and monkey as revealed by choline acetyltransferase activity and immunohistochemistry
J. Comp. Neurol.
Lower volume, more impairment: reduced cholinergic basal forebrain grey matter density is associated with impaired cognition in Parkinson disease
J. Neurol. Neurosurg. Psychiatr.
Cholinergic interneurons are differentially distributed in the human striatum
PLoS One
Gait speed in Parkinson disease correlates with cholinergic degeneration
Neurology
Regional cerebral cholinergic nerve terminal integrity and cardinal motor features in Parkinson's disease
Brain Commun.
Cholinergic system changes of falls and freezing of gait in Parkinson's disease
Ann. Neurol.
Degree of inhibition of cortical acetylcholinesterase activity and cognitive effects by donepezil treatment in Alzheimer's disease
J. Neurol. Neurosurg. Psychiatr.
Cognitive correlates of cortical cholinergic denervation in Parkinson's disease and parkinsonian dementia
J. Neurol.
Cortical cholinergic function is more severely affected in parkinsonian dementia than in Alzheimer disease: an in vivo positron emission tomographic study
Arch. Neurol.
History of falls in Parkinson disease is associated with reduced cholinergic activity
Neurology
Heterogeneity of cholinergic denervation in Parkinson's disease without dementia
J. Cereb. Blood. Flow. Metab.
Targeted activation of cholinergic interneurons accounts for the modulation of dopamine by striatal nicotinic receptors
eNeuro
Pedunculopontine nucleus microstructure predicts postural and gait symptoms in Parkinson's disease
Mov. Disord.
Cholinergic nucleus 4 atrophy and gait impairment in Parkinson's disease
J. Neurol.
Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment
Ann. Neurol.
Asymmetric pedunculopontine network connectivity in parkinsonian patients with freezing of gait
Brain
Cited by (8)
Multi-muscle synergies in preparation for gait initiation in Parkinson's disease
2023, Clinical NeurophysiologyDeterminants of approved acetylcholinesterase inhibitor response outcomes in Alzheimer's disease: relevance for precision medicine in neurodegenerative diseases
2023, Ageing Research ReviewsCitation Excerpt :The loss of NBM cholinergic neurons and related ascending projections is associated with an imbalance of both serotonergic and noradrenergic ascending projections (Bohnen et al., 2022; Lanctôt et al., 2017). Co-occurring monoaminergic alterations are observed in experimental models of AD-like dementia with BPSD, such as psychosis, agitation, disinhibition, and aggression (Albin et al., 2022; Bohnen et al., 2022; Lanctôt et al., 2017; Pinto et al., 2011). Such a complex neurochemical landscape, characterized by elegant bidirectional regulatory feedback loops and molecular cross-talks, may partially explain heterogenous data about the efficacy of ChEI in relieving the BPSD in AD (for a more extensive overview of ChEI in PD and DLB, see the dedicated section below).
Contributions of the Basal Ganglia to Visual Perceptual Decisions
2023, Annual Review of Vision ScienceImpact of dietary vitamin A on striatal function in adult rats
2023, FASEB JournalCholinergic basal forebrain atrophy in Parkinson's disease with freezing of gait
2023, Annals of Clinical and Translational Neurology