Objective:

To evaluate MRI’s potential to assess treatment effects, and assess the impact of neflamapimod treatment, on basal forebrain atrophy.

Background:

Neflamapimod, an oral p38α kinase inhibitor, targets molecular mechanisms underlying cholinergic degeneration and in preclinical studies basal forebrain cholinergic loss. In phase 2a and 2b ("RewinD-LB") trials, neflamapimod significantly slowed clinical progression in dementia with Lewy bodies (DLB), a disorder characterized by loss of basal forebrain cholinergic neurons. Basal forebrain atrophy by MRI is correlated to cognitive decline in DLB in natural history studies, but here are no reports of the use of MRI to monitor treatment.

Design/Methods:

A total of 159 participants were enrolled using consensus clinical criteria in a 16-week randomized, placebo-controlled period, followed by a 32-week neflamapimod-only extension. Structural and functional MRI were performed at baseline, week 16, and week 48 in the 25 participants from the UK and the Netherlands. Volumes of the left and right basal forebrain (BF) and nucleus basalis of Meynert (NbM)—the major cholinergic cluster within the BF—were quantified.

Results:

Baseline volumes (mm³) were comparable between groups in the left BF [placebo=315(SD=47), neflamapimod=296(51)], right BF [309(47), 310(47)], left NbM [185(33), 168(21)], and right NbM [269(45), 253(33)]. At week 16, mean change from baseline in right BF volume increased by +8.6 (SEM 6.0) with neflamapimod and decreased by –13.3 (6.0) with placebo (difference = –22 mm³; 95% CI –39.8 to –4.1; p = 0.019). No significant group differences were observed for other volumetric measures. At week 48, change from baseline in right NbM volume was +1.9 mm³ (95% CI –5.5 to +9.3), associated with improved right BF–default mode network static functional connectivity (p = 0.019 for increase from baseline).

Conclusions:

These findings provide preliminary evidence that neflamapimod may reduce basal forebrain atrophy in DLB and support MRI as a tool to assess treatment effects on cholinergic degeneration.