Abstract
In vivo imaging of fibrillar β-amyloid deposits may assist clinical diagnosis of Alzheimer’s disease (AD), aid treatment selection for patients, assist clinical trials of therapeutic drugs through subject selection, and be used as an outcome measure. A recent phase III trial of [18F]flutemetamol positron emission tomography (PET) imaging in 106 end-of-life subjects demonstrated the ability to identify fibrillar β-amyloid by comparing in vivo PET to post-mortem histopathology. Post-mortem analyses demonstrated a broad and continuous spectrum of β-amyloid pathology in AD and other dementing and non-dementing disease groups. The GE067-026 trial demonstrated 91% sensitivity and 90% specificity of [18F]flutemetamol PET by majority read for the presence of moderate or frequent plaques. The probability of an abnormal [18F]flutemetamol scan increased with neocortical plaque density and AD diagnosis. All dementia cases with non-AD neurodegenerative diseases and those without histopathological features of β-amyloid deposits were [18F]flutemetamol negative. Majority PET assessments accurately reflected the amyloid plaque burden in 90% of cases. However, ten cases demonstrated a mismatch between PET image interpretations and post-mortem findings. Although tracer retention was best associated with amyloid in neuritic plaques, amyloid in diffuse plaques and cerebral amyloid angiopathy best explain three [18F]flutemetamol positive cases with mismatched (sparse) neuritic plaque burden. Advanced cortical atrophy was associated with the seven false negative [18F]flutemetamol images. The interpretation of images from pathologically equivocal cases was associated with low reader confidence and inter-reader agreement. Our results support that amyloid in neuritic plaque burden is the primary form of β-amyloid pathology detectable with [18F]flutemetamol PET imaging. ClinicalTrials.gov NCT01165554. Registered June 21, 2010; NCT02090855. Registered March 11, 2014.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0399-z) contains supplementary material, which is available to authorized users.
Highlights
The relatively modest accuracy of a clinical diagnosis of Alzheimer’s disease (AD) when compared to the definitive neuropathological findings at autopsy [4] demonstrates a current unmet need to detect the neuropathological hallmarks of AD (β-amyloid plaques and neurofibrillary tangles) in life
Seventy-six brains (72%) were determined to be abnormal by mCERADSOT, and 30 (28%) were assessed as normal; together, these brains provided a continuous distribution of cases throughout the range of neuritic plaque pathology (Fig. 1b)
Many of the subjects without a primary diagnosis of AD had a range of coincident AD pathology, potentially allowing assessment of positron emission tomography (PET) imaging in a target population where underlying AD pathology may be coincident with other dementing disorders
Summary
The relatively modest accuracy of a clinical diagnosis of Alzheimer’s disease (AD) when compared to the definitive neuropathological findings at autopsy [4] demonstrates a current unmet need to detect the neuropathological hallmarks of AD (β-amyloid plaques and neurofibrillary tangles) in life. Plaques containing fibrillar β-amyloid are readily detectable in histological tissue specimens using dyes with high affinity for amyloid β-sheet structure (Thioflavin-S and Congo red). Analogues of these dyes have been radiolabelled to create positron emission tomography (PET) imaging tracers for detecting βamyloid plaques in vivo. PET amyloid tracers such as Pittsburgh compound B ([11C]PiB) and its derivative [18F]flutemetamol (VizamylTM) generally can distinguish between the presence of moderate or frequent amyloid plaques, required for the diagnosis of AD, or lesser densities that would rule out AD [24, 61]. Results of recent studies using PET β-amyloid tracers have shown a good association between tracer retention and underlying β-amyloid plaques in brain autopsy and biopsy samples [11, 12, 28, 31, 35,36,37,38, 47, 50,51,52, 65–67].
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