Chapter 14 - Cholinergic systems, attentional-motor integration, and cognitive control in Parkinson's disease

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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.

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.

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