P4-347: Tau aggregation inhibitor (TAI) therapy with rember ™ arrests the trajectory of rCBF decline in brain regions affected by Tau pathology in mild and moderate Alzheimer's disease (AD)

Abstract

Background: Neurofibrillary degeneration is a hallmark pathology that defines AD and is correlated with clinical dementia. rember (methylthioninium chloride) dissolves Tau protein polymers (Paired Helical Filaments) isolated from human AD brain, and prevents Tau aggregation in cell models at the nanomolar range (0.15 0.58 M). MTC has efficacy in Tau transgenic animal models, reversing cognitive and other behavioural defects, and reverses Tau pathology in the brain. Methods: As part of an exploratory, dose-range finding, parallel design, double-blind, randomised, placebo-controlled trial of rember monotherapy in 332 subjects meeting NINCDS-ADRDA for probable AD stratified by CDR, 138 were imaged at baseline and approximately 24 weeks later using Tc HMPAO SPECT imaging at 9 sites in the UK. Of 135 suitable for analysis, 52, 15, 32 and 36 received placebo, 30mg, 60mg and 100mg tid respectively. Both ROI (region of interest) and SPM (statistical parametric mapping) image analyses were performed. Results: Both ROI and SPM analyses showed, as expected, that those receiving placebo had significant reduction in rCBF over a 24 weeks. Although subjects who were CDR-mild at baseline showed no clinical decline over 24 weeks, SPECT scan confirmed significant decline in rCBF in this group, suggesting that a masking of decline by cognitive reserve in mild AD may confound clinical outcome analysis. Those receiving rember showed no significant reduction in rCBF regardless of baseline clinical severity. Comparing the groups indicated that rember significantly (p .05 FDR corrected) reduced the rate of rCBF decline particularly in the hippocampal, medial temporal, and temporal regions (See Figure). The 60 mg dose produced the largest effect.