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Free-water imaging of the cholinergic basal forebrain and pedunculopontine nucleus in Parkinson’s disease

Lookup NU author(s): Dr Rachael LawsonORCiD, Dr Hilmar SigurdssonORCiD, Joanna Wilson, Dr Brook Galna, Dr Susan Lord, Dr Lisa AlcockORCiD, Dr Gordon Duncan, Dr Tien Kheng Khoo, Professor John O'Brien, Professor David Burn, Professor John-Paul TaylorORCiD, Professor Lynn RochesterORCiD, Professor Alison Yarnall



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Background: Free-water imaging can predict and monitor dopamine system degeneration in people with Parkinson’s disease. It can also enhance the sensitivity of traditional diffusion tensor imaging (DTI) metrics for indexing neurodegeneration. However, these tools are yet to be applied to investigate cholinergic system degeneration in Parkinson’s (which involves both the pedunculopontine nucleus (PPN) and cholinergic basal forebrain (cBF)). Methods: Free-water imaging, free-water-corrected DTI, and volumetry were used to extract structural metrics from the cBF and PPN in 99 people with Parkinson’s and 46 age-matched controls. Cognitive ability was tracked over 4.5-years.ResultsPearson’s partial correlations revealed that free-water-corrected DTI metrics in the PPN were associated with performance on cognitive tasks that required participants to make rapid choices (behavioural flexibility). Volumetric, free-water content and DTI metrics in the cBF were elevated in a sub-group of people with Parkinson’s with evidence of cognitive impairment, and linear mixed modelling revealed that these metrics were differently associated with current and future changes to cognition. Conclusions: Free water and free-water-corrected DTI can index cholinergic degeneration that could enable stratification of patients in clinical trials of cholinergic interventions for cognitive decline. In addition, degeneration of the PPN impairs behavioural flexibility in Parkinson’s, which may explain this region’s role in increased risk of falls.

Publication metadata

Author(s): Ray NH, Lawson RA, Martin SL, Sigurdsson HP, Wilson J, Galna B, Lord S, Alcock L, Duncan GW, Khoo TK, O'Brien JT, Burn DJ, Taylor JP, Rea R, Bergamino M, Rochester L, Yarnall AJ

Publication type: Article

Publication status: Published

Journal: Brain

Year: 2022

Volume: 146

Issue: 3

Pages: 1053–1064

Print publication date: 01/03/2023

Online publication date: 29/04/2022

Acceptance date: 25/02/2022

Date deposited: 21/07/2022

ISSN (print): 0006-8950

ISSN (electronic): 1460-2156

Publisher: Oxford University Press


DOI: 10.1093/brain/awac127


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Funder referenceFunder name
J-0802Parkinson`s UK (formerly Parkinson`s Disease Society)
National Institute for Health Research (NIHR) Biomedical Research Unit
Lockhart Parkinson’s disease Research Fund
Newcastle CRF Infrastructure funding
NIHR Newcastle Biomedical Research Centre