BackgroundWe investigated the effect of crenezumab, a humanized anti-amyloid-beta (Aβ) immunoglobulin (Ig)G4 monoclonal antibody, on biomarkers of amyloid pathology, neurodegeneration, and disease progression in patients with mild-to-moderate Alzheimer’s disease (AD).MethodsThis double-blind, placebo-controlled, randomized phase II study enrolled patients with mild-to-moderate AD and a Mini-Mental State Examination (MMSE) score of 18–26. In part 1 of the study, patients were 2:1 randomized to receive low-dose subcutaneous (SC) 300 mg crenezumab every 2 weeks (q2w) or placebo for 68 weeks; in part 2, patients were 2:1 randomized to receive high-dose intravenous (IV) 15 mg/kg crenezumab every 4 weeks (q4w) or placebo for 68 weeks. The primary endpoint was change in amyloid burden from baseline to week 69 assessed by florbetapir positron emission tomography (PET) in the modified intent-to-treat population. Secondary endpoints were change from baseline to week 69 in cerebrospinal fluid (CSF) biomarkers and fluorodeoxyglucose PET, and change from baseline to week 73 in 12-point Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-Cog12) and Clinical Dementia Rating Sum of Boxes (CDR-SB). Safety was assessed in patients who received at least one dose of study treatment.ResultsFrom August 2011 to September 2012, 91 patients were enrolled and randomized (low-dose SC cohort: crenezumab (n = 26) or placebo (n = 13); high-dose IV cohort: crenezumab (n = 36) or placebo (n = 16)). The primary endpoint was not met using a prespecified cerebellar reference region to calculate standard uptake value ratios (SUVRs) from florbetapir PET. Exploratory analyses using subcortical white matter reference regions showed nonsignificant trends toward slower accumulation of plaque amyloid in the high-dose IV cohort. In both cohorts, a significant mean increase from baseline in CSF Aβ(1–42) levels versus placebo was observed. Nonsignificant trends toward ADAS-Cog12 and CDR-SB benefits were identified in a mild (MMSE 20–26) subset of the high-dose IV cohort. No amyloid-related imaging abnormalities due to edema/effusion were observed.ConclusionThe primary endpoint was not met. Exploratory findings suggest potential Aβ target engagement with crenezumab and possible slower accumulation of plaque amyloid. Studies investigating the effects of higher doses of crenezumab on amyloid load and disease progression are ongoing.Trial registrationClinicalTrials.gov, NCT01397578. Registered on 18 July 2011.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0424-5) contains supplementary material, which is available to authorized users.

Geometric distortions and poor image resolution are well known shortcomings of single-shot echo-planar imaging (ss-EPI). Yet, due to the motion immunity of ss-EPI, it remains the most common sequence for diffusion-weighted imaging (DWI). Moreover, both navigated DW interleaved EPI (iEPI) and parallel imaging (PI) methods, such as sensitivity encoding (SENSE) and generalized autocalibrating parallel acquisitions (GRAPPA), can improve the image quality in EPI. In this work, DW-EPI accelerated by PI is proposed as a self-calibrated and unnavigated form of interleaved acquisition. The PI calibration is performed on the b ‫؍‬ 0 s/mm 2 data and applied to each shot in the rest of the DW data set, followed by magnitude averaging. Central in this study is the comparison of GRAPPA and SENSE in the presence of off-resonances and motion. The results show that GRAPPA is more robust than SENSE against both off-resonance and motion-related artifacts. The SNR efficiency was also investigated, and it is shown that the SNR/scan time ratio is equally high for one-to three-shot high-resolution diffusion scans due to the shortened EPI readout train length. The image quality improvements without SNR efficiency loss, together with motion tolerance, make the GRAPPAdriven DW-EPI sequence clinically attractive. Magn Reson Med 57:881-890, 2007.

ObjectiveTo evaluate the safety and efficacy of crenezumab in patients with mild to moderate Alzheimer disease (AD).MethodsIn this phase 2 trial, 431 patients with mild to moderate AD 50 to 80 years of age were randomized 2:1 (crenezumab:placebo). Patients received low-dose subcutaneous crenezumab 300 mg or placebo every 2 weeks (n = 184) or high-dose intravenous crenezumab 15 mg/kg or placebo every 4 weeks (n = 247) for 68 weeks. Primary outcome measures were change in Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog12) and Clinical Dementia Rating–Sum of Boxes scores from baseline to week 73.ResultsThe primary and secondary endpoints were not met. In an exploratory post hoc analysis, a reduction in decline on the ADAS-Cog12 was observed in the high-dose group. Separation from the placebo group on the ADAS-Cog12 was greatest in the milder subsets of AD patients and reached statistical significance in the group with Mini-Mental State Examination scores of 22 to 26. In both groups, there was a significant increase in CSF β-amyloid1-42 levels that correlated with crenezumab CSF levels. The overall rate of adverse events was balanced between groups. One case of amyloid-related imaging abnormalities indicative of vasogenic edema or effusions was reported.ConclusionsAlthough prespecified criteria for testing treatment effects were not met, these data suggest a potential treatment effect in patients with mild AD treated with high-dose crenezumab. Together with the safety profile for crenezumab, these data support the exploration of crenezumab treatment at even higher doses in patients with early AD.Clinicaltrials.gov identifierNCT 01343966.Classification of evidenceThis study provides Class II evidence that, for people with AD, crenezumab does not significantly improve cognition or function at 18 months. The study is rated Class II because <80% of enrolled patients completed the study.