title: Post-mortem histopathology underlying β-amyloid PET imaging following flutemetamol F 18 injection.
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.
authors.affiliation: Department of Neurology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.|Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, 15213, USA.|Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, USA.
authors.forename: Milos D
authors.initials: MD
authors.lastname: Ikonomovic
authors.affiliation: GE Healthcare, The Grove Centre (GC18), White Lion Road, Amersham, Buckinghamshire, HP7 9LL, UK.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Buckley
authors.affiliation: GE Healthcare, 75184, Uppsala, Sweden.|Department of Surgical Sciences, Uppsala University, 75185, Uppsala, Sweden.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Heurling
authors.affiliation: GE Healthcare, Marlborough, MA, 01752, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Sherwin
authors.affiliation: GE Healthcare, The Grove Centre (GC18), White Lion Road, Amersham, Buckinghamshire, HP7 9LL, UK.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Jones
authors.affiliation: GE Healthcare, Marlborough, MA, 01752, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Zanette
authors.affiliation: Department of Radiology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
authors.forename: Chester A
authors.initials: CA
authors.lastname: Mathis
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Klunk
authors.affiliation: Pathology and Tumour Biology, Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, UK.
authors.forename: Aruna
authors.initials: A
authors.lastname: Chakrabarty
authors.affiliation: National CJD Research & Surveillance Unit University of Edinburgh Western General Hospital Edinburgh, EH4 2XU, Edinburgh, UK.
authors.forename: James
authors.initials: J
authors.lastname: Ironside
authors.affiliation: Pathology and Tumour Biology, Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, UK.
authors.forename: Azzam
authors.initials: A
authors.lastname: Ismail
authors.affiliation: Academic Department of Neuropathology, Centre for Clinical Brain Sciences, Edinburgh, EH16 4SB, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Smith
authors.affiliation: Department of Neuroscience - Laboratory for Neuropathology, KU-Leuven, Leuven, Belgium.|Department of Pathology, UZ Leuven, Leuven, Belgium.
authors.forename: Dietmar R
authors.initials: DR
authors.lastname: Thal
authors.affiliation: Banner Sun Health Research Institute, Sun City, AZ, 85351, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Beach
authors.affiliation: GE Healthcare, The Grove Centre (GC18), White Lion Road, Amersham, Buckinghamshire, HP7 9LL, UK.
authors.forename: Gill
authors.initials: G
authors.lastname: Farrar
authors.affiliation: GE Healthcare, The Grove Centre (GC18), White Lion Road, Amersham, Buckinghamshire, HP7 9LL, UK. Adrian.Smith@ge.com.
authors.forename: Adrian P L
authors.initials: AP
authors.lastname: Smith
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000814:Aniline Compounds; D052160:Benzothiazoles; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology*; D016657:Cerebral Amyloid Angiopathy / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D016037:Single-Blind Method; D006113:United Kingdom; D014481:United States
chemical_list: D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D052160:Benzothiazoles; D019275:Radiopharmaceuticals; C581552:flutemetamol
keywords: Alzheimer’s disease; Amyloid; Flutemetamol; Neuropathology (4-6 allowed); PET