Cholinergic Nucleus 4 Degeneration and Cognitive Impairment in isolated REM Sleep Behavior Disorder
Christopher Tan1, Huma Nawaz2, Sarah Lageman2, Leslie Cloud2, Amy Amara3, Jason Druzgal4, Brian Berman2, Nitai Mukhopadhyay2, Matthew Barrett2
1VCU School of Medicine, 2Virginia Commonwealth University, 3Neurology, University of Alabama at Birmingham, 4University of Virginia
Objective:

To determine if there is evidence of cholinergic nucleus 4 (Ch4) degeneration in patients with isolated REM sleep behavior disorder (iRBD) and whether Ch4 degeneration is associated with cognitive impairment in iRBD.

Background:

Cholinergic dysfunction is an important contributor to cognitive impairment in Parkinson’s disease and dementia with Lewy bodies. REM sleep behavior disorder (RBD) is also associated with cognitive impairment and often presents prior to diagnosis of Parkinson’s disease or dementia with Lewy bodies. Imaging studies using positron emission topography have shown reduced cholinergic innervation of the neocortex in RBD, but it is unclear whether there is cholinergic degeneration in iRBD and if present whether this is associated with cognitive impairment in iRBD.

Design/Methods:

We analyzed data for 35 iRBD patients and 35 age- and sex-matched healthy controls (HC) from the Parkinson’s Progression Markers Initiative. Both groups completed cognitive assessments including Montreal Cognitive Assessment (MoCA), Hopkins Verbal Learning Test, Letter Number Sequencing (LNS), Symbol Digit Modalities Test, Judgement of Line Orientation, and Semantic Fluency Animals Test (SFT-animals). Regional grey matter density (GMD) was calculated for Ch4 and cholinergic nuclei 1, 2, and 3 (Ch123) from high-resolution structural MRI scans using probabilistic maps applied to brain MRIs.

Results:

Ch4 GMD was significantly lower in the iRBD group compared to HC (0.417 vs. 0.441; p=0.02). There was no significant difference in Ch123 GMD between groups (p=0.85). In the iRBD group, Ch4 GMD was significantly correlated with MoCA score (r=0.41, p=0.01), LNS scaled score (r=0.37, p=0.04), and SFT-animals scaled score (r=0.39, p=0.03). After adjustment for age, sex, scanner type, and TIV in a multivariate linear regression model, Ch4 GMD was found to be a significant predictor of LNS (β-coefficient=58.31, p=0.026, 95% CI [7.47, 109.15]), a measure of working memory.

Conclusions:

iRBD is associated with Ch4 degeneration and this degeneration may contribute to impairment in working memory.

10.1212/WNL.0000000000201759