Links Identified Between Cholinergic Nucleus 4 Degeneration, Isolated RBD, and Working Memory Impairments

Matthew Barrett, MD, MSc

Cholinergic nucleus 4 (Ch4) degeneration, a major source of cognitive impairment in patients with Parkinson disease (PD) and dementia with Lewy bodies, was found to significantly lower in patients with isolated rapid eye movement sleep behavior disorder (iRBD) and was associated with impairment in working memory. Overall, these recently published findings support the idea that Ch4 degeneration is associated with cognitive impairment in iRBD.

Senior author Matthew Barrett, MD, MSc, associate professor, Virginia Commonwealth University, and colleagues analyzed clinical and neuropsychological data from 35 patients with iRBD and 35 age- and sex-matched healthy controls. Patients with iRBD were pulled from the prodromal cohort of the prospective, longitudinal Parkinson’s Progression Markers Initiative. These individuals were at least 60 years old with a confirmation of RBD based on polysomnography.

At baseline visit, participants underwent a litany of assessments, including the Montreal Cognitive Assessment (MoCA), Hopkins Verbal Learning Test (HVLT), letter number sequencing (LNS), and Semantic Fluency Test. Other tests included Benten Judgment of Line Orientation (JLO), Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), and REM sleep behavior disorder questionnaire (RBDSQ). In the iRBD and control cohorts, an RBDSQ score of at least 5 was used as the cutoff consistent with the diagnosis of RBD.

All told, results showed a significantly lower Ch4 GMD of 5.3% in participants with iRBD (t = –2.56), whereas there was no significant difference in Ch123 between the 2 groups. Among the iRBD group, 33 MRIs were performed using a Siemens scanner and 2 were performed using a Philips scanner. Of the HCs, 25 MRIs were performed using a Philips scanner, and 5 were performed using a GE scanner. When adjusted for scanner type, group was significantly correlated with TIV-normalized Ch4 gray matter density (GMD) (r_p = –0.3479; P = .0037).

Barrett et al wrote, "It is possible that reduced Ch4 GMD in iRBD is part of greater regional atrophy as a previous VBM (voxel-based morphometry) study found reduced volumes of the anterior cerebellum, tegmental pons, and left parahippocampal gyrus in iRBD; however, we did not find a difference in Ch123 GMD between the iRBD group and HCs. This supports the presence of preferential or at least earlier Ch4 degeneration in iRBD. This would be consistent with a prior longitudinal MRI study in PD that showed that Ch4 atrophy preceded Ch1/Ch2 atrophy."

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In terms of cognitive assessments, the iRBD group performed significantly worse on all measures except in tasks of executive function. Ch4 GMD (β-coefficient = 65.26, 95% CI, 18.47-112.05; P = 0.008) and Ch123 GMD (β-coefficient = −48.34; 95% CI, −85.22 to −11.45; P = 0.012) were both significant predictors of LNS in iRBD; however, after adjusting for age, sex, scanner type, and TIV, only Ch4 GMD was a significant predictor of LNS (ß-coefficient = 58.31; 95% CI, 7.47-109.15; P = .026) in iRBD.

There were limitations to the analysis, including that HCs in PPMI were required to have MoCA of at least 26, which may have created a larger difference in cognitive function between iRBD and HC than a normally selected and matched HC group without a minimal MoCA required.

"However, a HC group with a more similar cognitive performance to iRBD would potentially be affected by other age-related pathologies," Barrett et al wrote. "Therefore, we chose to use the HC group as our comparison group. Although efforts were made to account or adjust for the heterogeneity of scanner types and specifications, this is a limitation of this data set. Another limitation is that we did not adjust for multiple comparisons in our secondary analyses, so these results require future replication."

REFERENCE
1. Tan C, Nawaz H, Lageman SK, et al. Cholinergic nucleus 4 degeneration and cognitive impairment in isolated rapid eye movement sleep behavior disorder. Mov Disord. Published online January 4, 2023. doi:10.1002/mds.29306