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Post-mortem histopathology underlying β-amyloid PET imaging following flutemetamol F 18 injection.
Acta Neuropathol Commun. 2016 12 12; 4(1):130.AN

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+Show Affiliations

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.GE Healthcare, The Grove Centre (GC18), White Lion Road, Amersham, Buckinghamshire, HP7 9LL, UK.GE Healthcare, 75184, Uppsala, Sweden. Department of Surgical Sciences, Uppsala University, 75185, Uppsala, Sweden.GE Healthcare, Marlborough, MA, 01752, USA.GE Healthcare, The Grove Centre (GC18), White Lion Road, Amersham, Buckinghamshire, HP7 9LL, UK.GE Healthcare, Marlborough, MA, 01752, USA.Department of Radiology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, 15213, USA.Pathology and Tumour Biology, Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, UK.National CJD Research & Surveillance Unit University of Edinburgh Western General Hospital Edinburgh, EH4 2XU, Edinburgh, UK.Pathology and Tumour Biology, Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, UK.Academic Department of Neuropathology, Centre for Clinical Brain Sciences, Edinburgh, EH16 4SB, UK.Department of Neuroscience - Laboratory for Neuropathology, KU-Leuven, Leuven, Belgium. Department of Pathology, UZ Leuven, Leuven, Belgium.Banner Sun Health Research Institute, Sun City, AZ, 85351, USA.GE Healthcare, The Grove Centre (GC18), White Lion Road, Amersham, Buckinghamshire, HP7 9LL, UK.GE Healthcare, The Grove Centre (GC18), White Lion Road, Amersham, Buckinghamshire, HP7 9LL, UK. Adrian.Smith@ge.com.

Pub Type(s)

Clinical Trial
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27955679

Citation

Ikonomovic, Milos D., et al. "Post-mortem Histopathology Underlying Β-amyloid PET Imaging Following Flutemetamol F 18 Injection." Acta Neuropathologica Communications, vol. 4, no. 1, 2016, p. 130.
Ikonomovic MD, Buckley CJ, Heurling K, et al. Post-mortem histopathology underlying β-amyloid PET imaging following flutemetamol F 18 injection. Acta Neuropathol Commun. 2016;4(1):130.
Ikonomovic, M. D., Buckley, C. J., Heurling, K., Sherwin, P., Jones, P. A., Zanette, M., Mathis, C. A., Klunk, W. E., Chakrabarty, A., Ironside, J., Ismail, A., Smith, C., Thal, D. R., Beach, T. G., Farrar, G., & Smith, A. P. (2016). Post-mortem histopathology underlying β-amyloid PET imaging following flutemetamol F 18 injection. Acta Neuropathologica Communications, 4(1), 130.
Ikonomovic MD, et al. Post-mortem Histopathology Underlying Β-amyloid PET Imaging Following Flutemetamol F 18 Injection. Acta Neuropathol Commun. 2016 12 12;4(1):130. PubMed PMID: 27955679.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Post-mortem histopathology underlying β-amyloid PET imaging following flutemetamol F 18 injection. AU - Ikonomovic,Milos D, AU - Buckley,Chris J, AU - Heurling,Kerstin, AU - Sherwin,Paul, AU - Jones,Paul A, AU - Zanette,Michelle, AU - Mathis,Chester A, AU - Klunk,William E, AU - Chakrabarty,Aruna, AU - Ironside,James, AU - Ismail,Azzam, AU - Smith,Colin, AU - Thal,Dietmar R, AU - Beach,Thomas G, AU - Farrar,Gill, AU - Smith,Adrian P L, Y1 - 2016/12/12/ PY - 2016/11/16/received PY - 2016/11/29/accepted PY - 2016/12/14/entrez PY - 2016/12/14/pubmed PY - 2017/10/27/medline KW - Alzheimer’s disease KW - Amyloid KW - Flutemetamol KW - Neuropathology (4-6 allowed) KW - PET SP - 130 EP - 130 JF - Acta neuropathologica communications JO - Acta Neuropathol Commun VL - 4 IS - 1 N2 - 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. SN - 2051-5960 UR - https://www.unboundmedicine.com/medline/citation/27955679/Post_mortem_histopathology_underlying_β_amyloid_PET_imaging_following_flutemetamol_F_18_injection_ L2 - https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-016-0399-z DB - PRIME DP - Unbound Medicine ER -