Parkinson's disease mild cognitive impairment with MRI evidence of cholinergic nucleus 4 degeneration: A new subtype?

BACKGROUND

Subtyping Parkinson's disease with mild cognitive impairment (PD-MCI) into clinically and pathologically homogeneous groups could improve clinical trials and enable personalized treatments. Cholinergic nucleus 4 (Ch4) degeneration has been linked to cognitive decline in PD, suggesting a distinct PD-MCI subtype with worse prognosis.

OBJECTIVE

To determine whether PD-MCI patients with MRI evidence of Ch4 degeneration exhibit a different clinical profile and cognitive trajectory than those without Ch4 degeneration.

METHODS

We analyzed baseline MRI scans from 162 PD-MCI participants in the Parkinson's Progression Markers Initiative. Ch4 grey matter density (GMD) was assessed using voxel-based morphometry and probabilistic maps. Participants were classified as having low or normal Ch4 GMD using a z-score threshold of 1 SD below the mean. We compared clinical features and time to cognitive milestones using Kaplan-Meier survival analysis.

RESULTS

Of 162 participants, 40 had low Ch4 GMD and 122 had normal Ch4 GMD. Those with low Ch4 GMD had significantly worse MDS-UPDRS total and subscale scores (II-III), greater autonomic dysfunction, and reduced olfaction (all P < 0.05). PD-MCI patients with low Ch4 GMD progressed faster to cognitive decline milestones (log-rank P = 0.0017). Subtyping PD-MCI patients by Ch4 GMD may provide more prognostic accuracy for capturing earlier cognitive progression compared to currently established PD subtypes.

CONCLUSION

PD-MCI patients with Ch4 degeneration may represent a distinct, clinically severe PD-MCI subtype with faster progression. This group may benefit from targeted inclusion in clinical trials, particularly those assessing cholinergic therapies.