Multicentre phase 3 trial on florbetaben for beta-amyloid brain PET in Alzheimer's disease

Validation of florbetaben PET as a diagnostic imaging biomarker of Alzheimer disease requires comparison between brain PET and post mortem tissue. 238 end-of-life patients were recruited from 17 centers across 4 continents. 204 of these individuals underwent MRI and florbetaben PET scanning. 10 healthy individuals were also included to support specificity. Cortical presence or absence of tracer uptake was determined by 3 independent blinded readers on a regional basis for 6 pre-specified regions and on a subject level taking into account a visual scoring method proposed for clinical practice. A total of 31 brains were included in the analysis. The brain autopsy was photo-documented in detail to allow for precise alignment of the tissue samples with the MRI/PET images. b-amyloid in the tissue was detected by silver-staining and immunohistochemistry and the presence or absence of b-amyloid in the cortical regions was determined by a consensus panel of 3 neuropathologists blinded to all clinical and imaging data. Comparison of the subject level analysis with the post mortem diagnosis yielded 100% sensitivity and 92% specificity. For the regional comparison florbetaben detected b-amyloid with a sensitivity of 77% and a specificity of 94%. The inter-reader agreement was 0.87 for the subject level comparison and 0.66 for the regional assessment, respectively. This global phase 3 trial confirmed that florbetaben PET can detect b-amyloid in the brain using a visual scoring method proposed for clinical practice with 100% sensitivity and 92% specificity. Moreover, this is the first study to have undergone: 1) a precise determination of b-amyloid status in post mortem cortical brain tissue, and an 2) exact determination of the presence or absence of PET tracer uptake. The results of this trial confirm that florbetaben is able to detect b -amyloid in the brain during life with a high sensitivity and specificity and thus, is a more than suitable as a biomarker for this purpose.