DLB Treatment Response Biomarkers — Predicting Cholinesterase Inhibitor Response

SUMMARY

# DLB Treatment Response Biomarkers — Predicting Cholinesterase Inhibitor Response ## Background and Rationale Dementia with Lewy bodies (DLB) represents the second most common neurodegenerative dementia, yet treatment remains challenging with only 50% of patients responding to cholinesterase inhibitors (ChEIs). This heterogeneous response reflects the complex pathophysiology of DLB, involving variable degrees of cholinergic denervation, alpha-synuclein pathology, and synaptic dysfunction. Curre

METHODOLOGY NOTES

Phase 1 (Months 1-6): Recruit 400 DLB patients meeting consensus criteria, obtaining informed consent and baseline demographics. Phase 2 (Months 3-24): Pre-treatment multimodal assessment within 2 weeks of ChEI initiation. Cholinergic PET using 11C-MP4A or 18F-FEOBV with regions-of-interest analysis in cortical and subcortical cholinergic terminal fields. CSF collection via lumbar puncture for alpha-synuclein seed amplification assay, phospho-tau181, neurofilament light chain, VILIP-1, and acetylcholine quantification using ELISA and mass spectrometry. EEG recording during 30-minute eyes-closed session, analyzing dominant frequency and fluctuation index via automated algorithms. Genetic analysis of CHRNA7, CHRM1, APOE, and GBA variants using targeted sequencing. MRI acquisition with T1-weighted imaging for hippocampal volumetrics and nucleus basalis of Meynert segmentation. Phase 3 (Months 6-30): Longitudinal follow-up at 12 and 24 weeks post-treatment initiation. Clinical assessments