Objective:

To determine if Parkinson’s disease (PD) with mild cognitive impairment (PD-MCI) patients and MRI evidence of cholinergic nucleus 4 (Ch4) degeneration represent a distinct subtype of PD-MCI.

Background:

Subtyping PD-MCI into clinically- and pathologically-homogenous subtypes could enhance clinical trial design and support personalized treatment approaches. Prior studies have revealed that Ch4 volume correlates with the severity of cognitive impairment and predicts future cognitive decline in PD.

Design/Methods:

We analyzed baseline MRI scans for 148 PD-MCI participants from the Parkinson’s Progression Markers Initiative (PPMI). Ch4 grey matter density (GMD) was calculated using voxel-based morphometry and probabilistic maps. PD-MCI participants were divided into those with low Ch4 and normal Ch4 based on a normed z-score cutoff of 1 SD below the mean. We compared motor and non-motor symptoms and data-driven subtype frequencies between PD-MCI with and without low Ch4. We also constructed Kaplan-Meier survival analysis curves to compare the time to reach the cognitive domain milestones. 

Results:

Of the 148 PPMI participants analyzed, 116 had normal Ch4 GMD while 32 had low Ch4 GMD. PD-MCI patients with low Ch4 GMD had significantly worse Movement Disorders Society-Unified Parkinson Disease Rating Scale (MDS-UPDRS) total, MDS-UPDRS-I, MDS-UPDRS-II, and MDS-UPDRS-III scores (all P<0.05), as well as worse autonomic symptoms and olfaction as measured by the Scales for Outcomes in Parkinson’s disease - Autonomic Dysfunction and University of Pennsylvania Smell Identification Test (all P<0.05). The PD-MCI participants with low Ch4 GMD also were more likely to have diffuse malignant PD (51.6% vs. 23.4%, respectively; P<0.01) and had faster time to reach cognitive milestones (log rank P=0.0046). 

Conclusions:

PD-MCI with low Ch4 GMD represents a distinct subtype characterized by more severe motor and non-motor symptoms and faster progression to dementia. These findings suggest that this group should be considered in PD-MCI clinical trials, particularly those investigating cholinergic therapies.