Fast track — Articles11C-PiB PET assessment of change in fibrillar amyloid-β load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study
Introduction
Alzheimer's disease is characterised neuropathologically by deposits of extracellular amyloid-β plaques, intraneuronal neurofibrillary tangles, and cerebral neuronal loss.1 Antibodies directed against the N terminus of amyloid β reduce cerebral amyloid-β load in transgenic mice2, 3 and block the synaptotoxic effects of amyloid-β oligomers.4 Bapineuzumab, an antibody targeted against the N terminus of amyloid β, is a passive immunotherapy that is being tested in Alzheimer's disease.5 Bapineuzumab might bind to amyloid β in the brain and facilitate its clearance.2, 3
Amyloid-β load can be measured in patients with Alzheimer's disease by use of PET and the radiotracer carbon-11-labelled Pittsburgh compound B (11C-PiB).6, 7 PiB is a thioflavin analogue that binds with low nanomolar affinity to aggregated fibrillar deposits of the amyloid-β peptide, enters the brain at concentrations detectable by PET, and clears rapidly from normal brain tissue.6, 8 At the low nanomolar concentrations used in PET studies, PiB selectively binds to fibrillar amyloid-β deposits in post-mortem human brain.7, 9 Compared with healthy controls, patients with Alzheimer's disease have about two times greater retention of 11C-PiB in areas of the association cortex that are targeted by amyloid-β deposits.6, 10 11C-PiB retention is similar in patients with Alzheimer's disease and healthy controls in areas unaffected by amyloid-β deposition, such as the subcortical white matter, pons, and cerebellum.6
We aimed to investigate whether bapineuzumab-related changes in cortical amyloid-β load could be measured in vivo by use of 11C-PiB PET imaging.
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Patients
We did a phase 2, multicentre, randomised, double-blind, placebo-controlled, ascending-dose study at three clinical sites (two in the UK and one in Finland) between August, 2005, and January, 2009.
Eligible patients were aged 50–80 years inclusive, met NINCDS-ADRDA criteria for probable Alzheimer's disease,11 and had amyloid-β loads in the range expected for patients with Alzheimer's disease, defined as 11C-PiB PET retention ratios relative to the cerebellum of 1·5 or more in at least three
Results
Of 53 screened patients, 28 were randomly assigned (20 bapineuzumab vs eight placebo; ten in the 0·5 mg/kg group, ten in the 1·0 mg/kg group, and eight in the 2·0 mg/kg group; figure 1). The sponsor stopped enrolment in the 2·0 mg/kg group after a greater frequency of patients with cerebral vasogenic oedema after treatment with this dose was reported from another study.5 Eight patients did not meet the inclusion criteria because of low 11C-PiB retention. 15 patients failed to meet other
Discussion
There was a significant difference in change from baseline in the 11C-PiB PET mean retention from six targeted regions of interest in patients in the bapineuzumab group compared with those in the placebo group. A reduction in 11C-PiB retention relative to baseline was noted for the bapineuzumab group, while an increase was observed in the placebo group. Other recent studies have also reported small increases in 11C-PiB retention over time in patients with Alzheimer's disease;29, 30 however,
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