Magnetic resonance imaging measures of brain atrophy from the EXPEDITION3 trial in mild Alzheimer's disease

Abstract

Introduction Solanezumab is a humanized monoclonal antibody that preferentially binds to soluble amyloid β and promotes its clearance from the brain in preclinical studies. The objective of this study was to assess the effect of solanezumab in slowing global and anatomically localized brain atrophy as measured by volumetric magnetic resonance imaging (MRI). Methods In the EXPEDITION3 phase 3 trial, participants with mild Alzheimer's disease were randomized to receive intravenous infusions of either 400 mg of solanezumab or placebo every 4 weeks for 76 weeks. Volumetric MRI scans were acquired at baseline and at 80 weeks from 275 MRI facilities using a standardized imaging protocol. A subset of 1462 patients who completed both MRI and 14-item Alzheimer's Disease Assessment Scale–Cognitive Subscale assessments at both time points were selected for analysis. Longitudinal MRI volume changes were analyzed centrally by tensor-based morphometry with a standard FreeSurfer brain parcellation. Prespecified volumetric measures, including whole brain and ventricles, along with anatomically localized regions in the temporal, parietal, and frontal lobes were evaluated in those participants. Results Group-mean differences in brain atrophy rates were directionally consistent across a number of brain regions but small in magnitude (1.3–6.9% slowing) and not statistically significant when corrected for multiple comparisons. The annualized rates of change of the volumetric measures and the correlation of these changes with cognitive changes in placebo-treated subjects were similar to those reported previously. Discussion In the EXPEDITION3 trial, solanezumab did not significantly slow down rates of global or anatomically localized brain atrophy. Brain volume changes and their relationship to cognition were consistent with previous reports.

Current and Future Treatments in Alzheimer Disease: An Update

“…Intravenous immunoglobulin is obtained from plasma of healthy donors and is made up of human Abs mainly of the IgG-type. 5,74 Nevertheless, the first completed phase 3 trial of IVIg as a treatment for AD demonstrated good tolerability but lack of efficacy of the agent on clinical stability or delay of cognitive or functional decline of participants with mild and moderate AD. 74 Another strategy directed at diminishing the accumulation of Aβ in the brain is based in altering the transportation of Aβ through the BBB.…”

“…5,74 Nevertheless, the first completed phase 3 trial of IVIg as a treatment for AD demonstrated good tolerability but lack of efficacy of the agent on clinical stability or delay of cognitive or functional decline of participants with mild and moderate AD. 74 Another strategy directed at diminishing the accumulation of Aβ in the brain is based in altering the transportation of Aβ through the BBB. A recent therapeutic method performs plasma exchange (PE) with albumin replacement, inducing the shifting of the existing dynamic equilibrium between plasma and brain Aβ.…”

“…Intravenous immunoglobulin is obtained from plasma of healthy donors and is made up of human Abs mainly of the IgG-type. 5,74…”

“…Nevertheless, the first completed phase 3 trial of IVIg as a treatment for AD demonstrated good tolerability but lack of efficacy of the agent on clinical stability or delay of cognitive or functional decline of participants with mild and moderate AD. 74…”

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“…Strict inclusion criteria were applied, such as biomarker evidence of AD pathology, specifically "amyloid positivity," and enrollment of individuals with preclinical stages of the disease. Furthermore, the studies' design became more specific and targeted: the characteristics of amyloid related imaging abnormalities (ARIA) were associated with antibody dose and APOε4 genotype, necessity for higher dosing and evidence for target engagement (e.g., reduction of plaque burden on amyloid PET) was required [5,21].…”