Objective A major contributor to dementia in Parkinson disease (PD) is degeneration of the cholinergic basal forebrain. This study determined whether cholinergic nucleus 4 (Ch4) density is associated with cognition in early and more advanced PD.
Methods We analysed brain MRIs and neuropsychological test scores for 228 newly diagnosed PD participants from the Parkinson’s Progression Markers Initiative (PPMI), 101 healthy controls from the PPMI and 125 more advanced PD patients from a local retrospective cohort. Cholinergic basal forebrain nuclei densities were determined by applying probabilistic maps to MPRAGE T1 sequences processed using voxel-based morphometry methods. Relationships between grey matter densities and cognitive scores were analysed using correlations and linear regression models.
Results In more advanced PD, greater Ch4 density was associated with Montreal Cognitive Assessment (MoCA) score (β=14.2; 95% CI=1.5 to 27.0; p=0.03), attention domain z-score (β=3.2; 95% CI=0.8 to 5.5; p=0.008) and visuospatial domain z-score (β=7.9; 95% CI=2.0 to 13.8; p=0.009). In the PPMI PD cohort, higher Ch4 was associated with higher scores on MoCA (β=9.2; 95% CI=1.9 to 16.5; p=0.01), Judgement of Line Orientation (β=20.4; 95% CI=13.8 to 27.0; p<0.001), Letter Number Sequencing (β=16.5; 95% CI=9.5 to 23.4; p<0.001) and Symbol Digit Modalities Test (β=41.8; 95% CI=18.7 to 65.0; p<0.001). These same relationships were observed in 97 PPMI PD participants at 4 years. There were no significant associations between Ch4 density and cognitive outcomes in healthy controls.
Conclusion In de novo and more advanced PD, lower Ch4 density is associated with impaired global cognition, attention and visuospatial function.
- Parkinson disease
- basal forebrain
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Contributors MJB and TJD contributed to the conception and design of the research; MJB, SAS, JCB, CSF, JLF, MES, CAM and TJD contributed to the acquisition, analysis and interpretation of data; MJB drafted the text; and MJB, SAS, JCB, CSF, JLF, MES, CAM and TJD reviewed and critiqued the text.
Funding This work was supported by the Commonwealth of Virginia's Alzheimer's and Related Diseases Research Award Fund, administered by the Virginia Center on Aging, School of Allied Health Professions, Virginia Commonwealth University; and the Office of the Assistant Secretary of Defense for Health Affairs through the Neurotoxin Exposure Treatment Parkinson's Research (NETPR) under Award No. W81XWH-16-1-0768. Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense.
Disclaimer MJB: salary: University of Virginia; clinical trials: National Institutes of Health, Azevan, Axovant, Merck, Eisai, Biogen and Acadia. SAS: salary: University of Virginia; grants: US Department of Health and Human Services—Administration for Community Living and Virginia Dementia Specialized Supportive Services. JCB: grants: UVA Neuroscience Presidential Fellowship and UVA Data Science Presidential Fellowship. CSF: salary: University of Virginia. JLF: salary: University of Virginia; salary support: Acadia. MES: salary: University of Virginia. CAM: salary: University of Virginia; grants: US Department of Health and Human Services—Administration for Community Living and Virginia Dementia Specialized Supportive Services. TJD: salary: University of Virginia; grants: Biocore, LLC, UVA Data Science Presidential Fellowship, UVA Neuroscience Presidential fellowship and UVA Health Sciences.
Competing interests MJB, SAS, JCB, JLF, MES and TJD received grant support from the Department of Defense and the Commonwealth of Virginia’s Alzheimer’s and Related Diseases Research Award Fund.
Patient consent for publication Not required.
Ethics approval The institutional review board at the University of Virginia approved this study.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request, and may be obtained from a third party and are not publicly available.