MRI-based cholinergic subtyping of Parkinson's disease with mild cognitive impairment
Parkinson's disease with mild cognitive impairment (PD-MCI) is clinically heterogeneous. Identifying pathologically distinct subtypes could improve clinical trial design and enable precision therapeutics. The cholinergic nucleus 4 (Ch4), located in the nucleus basalis of Meynert (NBM), is selectively vulnerable to alpha-synuclein pathology in PD, and its degeneration has been robustly linked to cognitive decline, neuropsychiatric symptoms, and faster disease progression.
This tool implements a normative regression-based subtyping framework that classifies PD-MCI patients as having Low Ch4 GMD (disproportionate cholinergic degeneration) or Normal Ch4 GMD based on structural MRI, adjusting for age, sex, and total intracranial volume.
| Finding | Detail |
|---|---|
| Distinct clinical profile | PD-MCI patients with Low Ch4 GMD have significantly worse motor scores (MDS-UPDRS), autonomic dysfunction, and olfactory impairment |
| Faster cognitive decline | Low Ch4 GMD subgroup progresses faster to cognitive milestones (log-rank P = 0.0017) |
| Overlap with diffuse malignant PD | 51.6% of Low Ch4 GMD patients classified as diffuse malignant vs. 23.4% in Normal Ch4 GMD |
| Outperforms existing subtypes | Ch4 subtyping outperformed tremor-dominant/PIGD, brain-first/body-first, and diffuse-malignant classifications in predicting cognitive deterioration |
Negida A, Vohra HZ, Lageman SK, Mukhopadhyay N, Berman BD, Weintraub D, Barrett MJ. Parkinson's disease mild cognitive impairment with MRI evidence of cholinergic nucleus 4 degeneration: A new subtype? Parkinsonism & Related Disorders. 2025;141:108072.
| Event | Type | Year |
|---|---|---|
| American Academy of Neurology (AAN) Annual Meeting | Oral Presentation (S32.005) | 2025 |
| International Congress of Parkinson's Disease and Movement Disorders (MDS) | Poster Presentation | 2024 |
- AAN 2025 Abstract: Neurology 2025;104(7 Supplement 1)
- MDS 2024 Abstract: MDS Abstracts
- Neurology Today (American Academy of Neurology): Coverage of AAN 2025 findings
| Parameter | Description | Units |
|---|---|---|
| Standardized Ch4 GMD | Gray matter density of the Ch4 region extracted from T1-weighted MRI using the cytoarchitectonic maps of Zaborszky et al. | 0-1 (probability) |
| Age at MRI | Patient age at time of MRI acquisition | Years |
| Sex | Biological sex | Male / Female |
| Total Intracranial Volume (TIV) | Total intracranial volume from segmentation | mL (supports mm³, L, or custom) |
Step 1 — Scaling. The standardized Ch4 GMD is transformed using healthy control reference values (mean = 0.399, SD = 0.039):
Scaled Ch4 GMD = ((Ch4_std - 0.3985) / 0.0387) * 3 + 10
Step 2 — Normative Prediction. A predicted value is computed from a multiple linear regression model derived from healthy controls:
Predicted = 1.579 + (-0.108 * Age) + (0.865 * Sex) + (0.010 * TIV_mL)
where Sex is coded as Male = 1, Female = 0.
Step 3 — Z-score & Classification. The deviation is expressed as a z-score (SDresidual = 2.225):
Z = (Scaled_Ch4_GMD - Predicted) / 2.225
Patients with z < -1.0 are classified as Low Ch4 GMD.
| Output | Description |
|---|---|
| Scaled Ch4 GMD | Participant's Ch4 GMD on the common scale |
| Predicted Value | Expected Ch4 GMD for age, sex, and TIV |
| Z-score | Standardized deviation from the normative prediction |
| Classification | Low Ch4 GMD (z < -1.0) or Normal Ch4 GMD (z ≥ -1.0) |
Ch4 GMD should be extracted from T1-weighted MRI using the stereotactic cytoarchitectonic maps of Zaborszky et al. (2008) via established VBM pipelines (e.g., CAT12/SPM). The input value is the mean gray matter density within the Ch4 (NBM) region of interest.
This tool is intended as a research decision-support aid and is not designed for standalone clinical diagnosis or treatment decisions. Results should be interpreted by qualified investigators in the context of validated imaging protocols and the full clinical picture.
If you use this tool in your research, please cite:
@article{Negida2025Ch4,
title = {Parkinson's disease mild cognitive impairment with MRI evidence of
cholinergic nucleus 4 degeneration: A new subtype?},
author = {Negida, Ahmed and Vohra, Hiba Z. and Lageman, Sarah K. and
Mukhopadhyay, Nitai and Berman, Brian D. and Weintraub, Daniel
and Barrett, Matthew J.},
journal = {Parkinsonism \& Related Disorders},
volume = {141},
pages = {108072},
year = {2025},
doi = {10.1016/j.parkreldis.2025.108072},
pmid = {41106089}
}Ahmed Negida, MD, PhD (Corresponding Author) Department of Neurology, Virginia Commonwealth University, Richmond, VA ahmed.negida@vcuhealth.org
Hiba Z. Vohra • Sarah K. Lageman, PhD • Nitai Mukhopadhyay, PhD • Brian D. Berman, MD, MS • Daniel Weintraub, MD • Matthew J. Barrett, MD, MSc
Built with React + TypeScript • Vite • shadcn/ui • Tailwind CSS
# Install dependencies
npm install
# Start development server
npm run dev
# Build for production
npm run buildAll rights reserved. For research use only.