Locus Coeruleus Integrity Is Linked to Response Inhibition Deficits in Parkinson's Disease and Progressive Supranuclear Palsy.

Autor:	Ye R; Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230032, China ronye.uk@gmail.com.; School of Mental Health and Psychological Sciences, Anhui Medical University, Hefei, Anhui, 230032, China.; Department of Clinical Neurosciences, Cambridge University Hospitals NHS Trust, University of Cambridge, Cambridge, CB2 0SZ, United Kingdom., Hezemans FH; Department of Clinical Neurosciences, Cambridge University Hospitals NHS Trust, University of Cambridge, Cambridge, CB2 0SZ, United Kingdom.; MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, CB2 7EF, United Kingdom.; Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6525 GD Nijmegen, The Netherlands., O'Callaghan C; Department of Psychiatry, University of Cambridge, Cambridge, CB2 0SZ, United Kingdom.; Brain and Mind Centre and School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney 2050, New South Wales, Australia., Tsvetanov KA; MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, CB2 7EF, United Kingdom.; Department of Psychology, University of Cambridge, Cambridge, CB2 3EA, United Kingdom., Rua C; Department of Clinical Neurosciences, Cambridge University Hospitals NHS Trust, University of Cambridge, Cambridge, CB2 0SZ, United Kingdom., Jones PS; Department of Clinical Neurosciences, Cambridge University Hospitals NHS Trust, University of Cambridge, Cambridge, CB2 0SZ, United Kingdom., Holland N; Department of Clinical Neurosciences, Cambridge University Hospitals NHS Trust, University of Cambridge, Cambridge, CB2 0SZ, United Kingdom., Malpetti M; Department of Clinical Neurosciences, Cambridge University Hospitals NHS Trust, University of Cambridge, Cambridge, CB2 0SZ, United Kingdom., Murley AG; Department of Clinical Neurosciences, Cambridge University Hospitals NHS Trust, University of Cambridge, Cambridge, CB2 0SZ, United Kingdom., Barker RA; John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0SZ, United Kingdom.; Wellcome-MRC Stem Cell Institute, University of Cambridge, Cambridge, CB2 0AW, United Kingdom., Williams-Gray CH; John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0SZ, United Kingdom., Robbins TW; Department of Psychology, University of Cambridge, Cambridge, CB2 3EA, United Kingdom.; Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EA, United Kingdom., Passamonti L; Department of Clinical Neurosciences, Cambridge University Hospitals NHS Trust, University of Cambridge, Cambridge, CB2 0SZ, United Kingdom.; Institute of Molecular Bioimaging and Physiology, National Research Council, 88100, Catanzaro, Italy., Rowe JB; Department of Clinical Neurosciences, Cambridge University Hospitals NHS Trust, University of Cambridge, Cambridge, CB2 0SZ, United Kingdom.; MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, CB2 7EF, United Kingdom.; Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, CB2 3EA, United Kingdom.
Jazyk:	angličtina
Zdroj:	The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2023 Oct 18; Vol. 43 (42), pp. 7028-7040. Date of Electronic Publication: 2023 Sep 05.
DOI:	10.1523/JNEUROSCI.0289-22.2023
Abstrakt:	Parkinson's disease (PD) and progressive supranuclear palsy (PSP) both impair response inhibition, exacerbating impulsivity. Inhibitory control deficits vary across individuals and are linked with worse prognosis, and lack improvement on dopaminergic therapy. Motor and cognitive control are associated with noradrenergic innervation of the cortex, arising from the locus coeruleus (LC) noradrenergic system. Here we test the hypothesis that structural variation of the LC explains response inhibition deficits in PSP and PD. Twenty-four people with idiopathic PD, 14 with PSP-Richardson's syndrome, and 24 age- and sex-matched controls undertook a stop-signal task and ultrahigh field 7T magnetization-transfer-weighted imaging of the LC. Parameters of "race models" of go- versus stop-decisions were estimated using hierarchical Bayesian methods to quantify the cognitive processes of response inhibition. We tested the multivariate relationship between LC integrity and model parameters using partial least squares. Both disorders impaired response inhibition at the group level. PSP caused a distinct pattern of abnormalities in inhibitory control with a paradoxically reduced threshold for go responses, but longer nondecision times, and more lapses of attention. The variation in response inhibition correlated with the variability of LC integrity across participants in both clinical groups. Structural imaging of the LC, coupled with behavioral modeling in parkinsonian disorders, confirms that LC integrity is associated with response inhibition and LC degeneration contributes to neurobehavioral changes. The noradrenergic system is therefore a promising target to treat impulsivity in these conditions. The optimization of noradrenergic treatment is likely to benefit from stratification according to LC integrity. SIGNIFICANCE STATEMENT Response inhibition deficits contribute to clinical symptoms and poor outcomes in people with Parkinson's disease and progressive supranuclear palsy. We used cognitive modeling of performance of a response inhibition task to identify disease-specific mechanisms of abnormal inhibitory control. Response inhibition in both patient groups was associated with the integrity of the noradrenergic locus coeruleus, which we measured in vivo using ultra-high field MRI. We propose that the imaging biomarker of locus coeruleus integrity provides a trans-diagnostic tool to explain individual differences in response inhibition ability beyond the classic nosological borders and diagnostic criteria. Our data suggest a potential new stratified treatment approach for Parkinson's disease and progressive supranuclear palsy. (Copyright © 2023 the authors.)
Databáze:	MEDLINE
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