Clinical and biomarker correlates of region‐specific diffusion MRI metrics in a short‐term, Phase 1b clinical trial for XPro1595 in Alzheimer's disease.

Background: XPro1595 is a selective, brain penetrant neutralizer of soluble TNF with potent anti‐neuroinflammatory effects recently assessed for safety and pharmacological activity in a 12‐week, phase‐1b open‐label dose finding study in patients with AD (NCT03943264). An unbiased screen of imaging outcomes revealed signals for target engagement in gray matter (GM) cortices documented in the literature as regions most frequently affected by accumulation of amyloid‐beta (Aβ) in early and late phases of AD (Mattsson et al. 2019). Post‐hoc analyses were conducted to further investigate these signals. Method: Study results for patients (n = 9; MMSE range: 8‐27) with analyzable dMRIs who completed 12‐weeks of treatment with XPro1595 [0.3 mg/kg; n = 3) or (1.0 mg/kg; n = 6)] met inclusion criteria. Correlation matrices (uncorrected Pearson's r) were created to compare key secondary and exploratory imaging outcomes to clinical characteristics and CSF biomarkers of AD specific pathology (Roche Elecsys NeuroToolKit). Imaging outcomes included white matter free‐water (WM‐FW) as a prespecified proxy for neuroinflammation, and GM PerpPD+. PerpPD+ represents the diffusion components perpendicular to cortical GM minicolumns and serves as an indicator of worsening GM microarchitecture when increased in AD. Due to the small sample size, the threshold for identification of informative values was set at P<0.05. Result: At baseline, PerpPD in GM regions associated with early Aβ accumulation (insula, precuneus, isthmus and posterior cingulate, and lateral‐orbitofrontal cortices), and WM‐FW in the cingulum bundle, showed strong associations with CSF biomarkers of neurodegeneration (pTau and tTau), inflammatory gliosis (YKL‐40, GFAP and sTREM2), cognitive status (MMSE scores) and disease duration (Table1). Week‐12 results showed decreased PerpPD+ and WM‐FW in these regions, with a dose‐dependent signal concentrated in the isthmus cingulate GM and cingulum WM. Isthmus cingulate PerpPD+ ∆ (%) correlated positively with baseline Aβ42/40 and MMSE (Figure1), and negatively with duration of disease and cingulum WM‐FW, whereas cingulum WM‐FW ∆ (%) corelated with baseline pTau and tTau (Table 2). Conclusion: PerpPD+ in isthmus cingulate GM and WM‐FW in cingulum WM represent potential indicators of disease activity sensitive to early treatment effects in small, proof of concept clinical trials for AD. Additional research is warranted to further elucidate these signals. [ABSTRACT FROM AUTHOR]