SUMMARY
# Cholinergic System Dysfunction in DLB — Mechanisms and Therapeutic Restoration
## Background and Rationale
Clinical trial testing whether muscarinic M1 receptor-selective agonism provides superior cognitive benefit in DLB compared to current cholinesterase inhibitors, by directly targeting the post-synaptic receptor rather than modulating pre-synaptic acetylcholine availability.
**Protocol**: Phase 2 RCT, 200 DLB patients (McKeith criteria, MMSE 15-26), randomized 1:1:1: (A) HTL0018318 (M1-se
METHODOLOGY NOTES
**Phase 1: Patient Recruitment and Baseline Assessment (Months 1-3)**
• Recruit 120 participants: 40 DLB patients, 40 Alzheimer's disease patients, 40 age-matched healthy controls
• Inclusion criteria: DLB patients meeting consensus criteria, MMSE 15-26, stable medications for 4 weeks
• Exclusion criteria: other neurodegenerative diseases, severe psychiatric conditions, contraindications to PET/MRI
• Obtain informed consent and complete baseline cognitive assessment (MoCA, MMSE, DLB-specific scales)
• Collect demographic data, medication history, and clinical severity ratings
**Phase 2: Neuroimaging and Biomarker Collection (Months 2-6)**
• Perform [18F]FEOBV PET imaging to assess vesicular acetylcholine transporter (VAChT) density
• Conduct structural MRI with DTI sequences to evaluate white matter integrity
• Collect CSF samples for acetylcholine, choline acetyltransferase, and α-synuclein measurements
• Obtain blood samples for plasma cholinergic biomarkers and genetic analysis (AP