Parkinson's Disease Mild Cognitive Impairment with MRI evidence of Cholinergic Nucleus 4 Degeneration: A New Subtype?

Subtyping Parkinson's disease with mild cognitive impairment (PD-MCI) could improve clinical trial design and personalized treatments. Cholinergic nucleus 4 (Ch4) volume has been linked to cognitive impairment severity and future decline in PD. This study investigates whether PD-MCI patients with MRI evidence of Ch4 degeneration have distinct clinical profiles and cognitive trajectories. Baseline MRI scans of 148 PD-MCI participants from the Parkinson's Progression Markers Initiative (PPMI) were analyzed. Patients with low Ch4 grey matter density (GMD) had worse motor, autonomic, and olfactory symptoms, and were more likely to belong to the diffuse malignant PD subtype (51.6% vs. 23.4%; P < 0.01). They also had faster progression to cognitive milestones (P = 0.0046). These findings identify PD-MCI with low Ch4 as a distinct subtype with more severe symptoms and faster cognitive decline, highlighting the importance of considering this group in PD-MCI clinical trials, particularly for cholinergic therapies.