Cholinergic degeneration in prodromal and early Parkinson’s disease: a link to present and future disease states

Q: What was the study trying to determine about the nucleus basalis of Meynert (NbM)?

The study investigated whether the macrostructural integrity of NbM is linked to cognitive function, clinical presentation, and disease progression in early Parkinson’s disease and isolated REM sleep behaviour disorder.

Q: What MRI finding did the researchers observe in early PD and iRBD compared with controls?

Both early PD and iRBD showed significantly lower NbM grey matter volume than controls.

Q: How does NbM volume relate to future disease conversion risk?

In early PD, higher NbM volume was associated with a lower risk of conversion to dementia. In iRBD, higher NbM volume predicted a decreased future risk of phenoconversion to Parkinson’s disease or dementia with Lewy bodies, though symptom-state associations were less pronounced than in PD.

Sep 30, 2026

Uploaded by Miles

Parkinson’s disease and Lewy body disorders involve neurodegeneration beyond the dopaminergic system, impacting cholinergic pathways crucial to clinical expression. This study evaluates whether the macrostructural integrity of the nucleus basalis of Meynert (NbM)—the main cholinergic input source to cerebral cortex—relates to cognition, clinical manifestation, and progression in non-demented early PD and isolated REM sleep behaviour disorder (iRBD). Structural MRI in 393 early PD patients, 128 iRBD patients, and 186 controls shows reduced NbM grey matter volume in both conditions versus controls. Higher NbM volume predicts better higher-order cognition and lower symptom burden and future dementia conversion in PD, and reduced phenoconversion risk in iRBD. Findings support NbM volume as a dual-utility biomarker for cognitive decline and progression in early PD and as an early indicator of conversion risk in prodromal disease.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Introduction

Cholinergic degeneration beyond dopaminergic loss

Methods and cohorts

Structural MRI in early PD, iRBD, and controls

Results

Reduced NbM grey matter volume in early PD and iRBD

Associations with cognition, symptoms, and conversion risk

Implications

NbM volume as a dual-utility biomarker

[https://doi.org/10.1093/brain/awaf168](https://doi.org/10.1093/brain/awaf168) BRAIN 2026: 149; 226–237 | 226 Cholinergic degeneration in prodromal and early Parkinson’s disease: a link to present and future disease states Tamir Eisenstein,1,2 Karolien Groenewald,1,2 Ludo van Hillegondsberg,2 Falah Al Hajraf,2,3 Tanja Zerenner,4 Michael A. Lawton,4 Yoav Ben-Shlomo,4 Ludovica Griffanti,1,2,5 Michele T. Hu2 and Johannes C. Klein1,2 The neuropathological process in Parkinson’s disease (PD) and Lewy body disorders has been shown to extend well beyond the degeneration of the dopaminergic system, affecting other neuromodulatory systems in the brain, which play crucial roles in the clinical expression and progression of these disorders. Here, we investigate the role of the macrostructural integrity of the nucleus basalisofMeynert (NbM), the main source of cholinergic input to the cerebral cortex, in cognitive function, clinical manifestation and disease progression in non-demented subjects with PD and individuals with isolated REM sleep behaviour disorder (iRBD) . Using structural MRI data from 393 early PD patients, 128 iRBD patients and 186 controls from two longitudinal cohorts, we found significantly lower NbM grey matter volume in both PD (β = −12.56, P = 0.003) and iRBD (β = −16.41, P = 0.004) compared to controls. In PD, higher NbM volume was associated with better higher-order cognitive function (β = 0.10, P = 0.045), decreased non-motor (β = −0.66, P = 0.026) and motor (β = −1.44, P = 0.023) symptom burden, and lower risk of future conversion to dementia [hazard ratio (HR) < 0.400, P < 0.004] . Higher NbM volume in iRBD was associated with decreased future risk of phenoconversion to PD or dementia with Lewy bodies (DLB) (HR < 0.490, P < 0.016) . However, despite similar NbM volume deficits to those seen in PD, associations between NbM structural deficits and current disease burden or clinical state were less pronounced in iRBD. These findings identify NbM volume as a potential biomarker with dual utility: predicting cognitive decline and disease progression in early PD, while also serving as an early indicator of phenoconversion risk in prodromal disease. The presence of structural deficits before clear clinical correlates in iRBD suggests complex compensatory mechanisms may initially mask cholinergic dysfunction, with subsequent failure of these mechanisms potentially contributing to clinical conversion. 1 Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK 2 Oxford Parkinson’s Disease Centre, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK 3 Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait 4 Population Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 2PS, UK 5 Oxford Centre for Human Brain Activity, Wellcome Centre for Integrative Neuroimaging, Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK Correspondence to: Tamir Eisenstein Oxford Parkinson’s Disease Centre, Nuffield Department of Clinical Neurosciences University of Oxford, Headley Way, Headington, Oxford OX3 9DU, UK E-mail: [tamir.eisenstein@ndcn.ox.ac.uk](tamir.eisenstein@ndcn.ox.ac.uk) Received January 02, 2025. Revised March 15, 2025. Accepted April 13, 2025. Advance access publication May 6, 2025 © The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Cholinergic deficits in early PD BRAIN 2026: 149; 226–237 | 227 Keywords: Parkinson’s disease; RE

FAQs

What was the study trying to determine about the nucleus basalis of Meynert (NbM)?

The study investigated whether the macrostructural integrity of NbM is linked to cognitive function, clinical presentation, and disease progression in early Parkinson’s disease and isolated REM sleep behaviour disorder.

What MRI finding did the researchers observe in early PD and iRBD compared with controls?

Both early PD and iRBD showed significantly lower NbM grey matter volume than controls.

How does NbM volume relate to future disease conversion risk?

In early PD, higher NbM volume was associated with a lower risk of conversion to dementia. In iRBD, higher NbM volume predicted a decreased future risk of phenoconversion to Parkinson’s disease or dementia with Lewy bodies, though symptom-state associations were less pronounced than in PD.

Sep 30, 2026

Uploaded by Miles