Objective:

This study aims to investigate whether PD-MCI patients exhibiting cholinergic degeneration, evidenced by reduced Ch4 grey matter density (GMD) on brain MRIs, constitute a distinct clinical PD-MCI subtype with clinical implications.

Background:

Parkinson’s disease with mild cognitive impairment (PD-MCI) significantly affects patients’ quality of life, contributing to cognitive deficits and psychosis. Previous research has identified a correlation between cholinergic degeneration in the Ch4 area and olfaction, apathy, and cognitive impairment among PD patients. This study seeks to delineate a PD-MCI subtype characterized by Ch4 degeneration.

Method:

We assessed baseline MRI scans of 175 PD-MCI patients from the Parkinson’s Progression Markers Initiative (PPMI). We employed voxel-based morphometry and probabilistic mapping to calculate Ch4 GMD. Patients were categorized into two groups based on Ch4 z-scores, using a -1 SD cutoff from the mean. Comparisons were made concerning MDS-UPDRS scores, REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ), neuropsychological assessments, and Alzheimer’s disease biomarkers.​​​​​​

Results: Of the participants, 109 had normal Ch4 GMD, while 66 demonstrated low Ch4 GMD. Patients with low Ch4 GMD experienced significantly more severe symptoms across MDS-UPDRS total and parts 1 and 2 scores (P<0.01), and underperformed in cognitive tests including letter-number sequencing, Symbol Digit Modalities, and Judgment of Line Orientation (P<0.05). Furthermore, they had higher RBDSQ scores and exhibited more pronounced issues with cognition, hallucinations, depression, anxiety, apathy, and sleep disturbances (P<0.01).

Conclusion: Our findings suggest that PD-MCI patients with low Ch4 GMD likely represent a distinct clinical subtype, with a markedly different clinical and neuropsychological profile compared to PD-MCI patients with normal Ch4 GMD. Future research should investigate the stability of this subtype and consider it in the design of upcoming clinical trials.

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References: (1) Barrett MJ, Blair JC, Sperling SA, Smolkin ME, Druzgal TJ. Baseline symptoms and basal forebrain volume predict future psychosis in early Parkinson disease. Neurology. 2018 May 1;90(18):e1618-e1626. doi: 10.1212/WNL.0000000000005421. Epub 2018 Apr 4. PMID: 29618627.

(2) Sperling SA, Druzgal J, Blair JC, Flanigan JL, Stohlman SL, Barrett MJ. Cholinergic nucleus 4 grey matter density is associated with apathy in Parkinson’s disease. Clin Neuropsychol. 2023 Apr;37(3):676-694. doi: 10.1080/13854046.2022.2065362. Epub 2022 Apr 21. PMID: 35443870.

(3) Tan C, Nawaz H, Lageman SK, Cloud LJ, Amara AW, Newman BT, Druzgal TJ, Berman BD, Mukhopadhyay N, Barrett MJ. Cholinergic Nucleus 4 Degeneration and Cognitive Impairment in Isolated Rapid Eye Movement Sleep Behavior Disorder. Mov Disord. 2023 Mar;38(3):474-479. doi: 10.1002/mds.29306. Epub 2023 Jan 4. PMID: 36598142; PMCID: PMC10033349.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/subtyping-parkinsons-disease-mild-cognitive-impairment-pd-mci-by-cholinergic-degeneration/