Diagnostic Accuracy of Amyloid versus FDG PET in Patients with Cognitive Impairment and Autopsy

Abstract

Background: β-Amyloid and Flurodeoxyglucose (FDG) PET are clinically available diagnostic tools in the assessment of neurodegenerative disorders. We compared the diagnostic accuracy of [11C]Pittsburgh Compound B (PIB) and [18F]FDG PET in a large sample of patients with cognitive decline and neuropathology. Methods: 101 individuals underwent PIB and FDG during life and post-mortem neuropathological assessment. PET scans were visually interpreted by three raters blinded to clinical information. PIB scans were rated as positive or negative for cortical retention while FDG scans were read as showing an Alzheimer’s disease (AD) or non-AD metabolic pattern. AD neuropathological changes (ADNC) were measured at autopsy. Majority visual reads were compared to intermediate-high ADNC as the gold standard. Findings: 60 males and 41 females were included (average age: 67·2Y, mean MMSE: 21·9, mean PET-to-autopsy interval: 4·4Y). At autopsy, 32 patients showed pure AD pathology, 13 mixed AD and non-AD and 56 non-AD neuropathology. Compared to FDG, PIB showed higher sensitivity for detecting intermediate-high ADNC (96% [95% confidence interval: 89-100%] vs 80% [68-92%] for FDG, p=0·02) and higher negative predictive value (96% [91-100%] vs 84% [74-93%], p=0·01), but equivalent specificity (86% [76-95%] vs 84% [74-93%], p=0·80) and positive predictive value (84% [74-94%] vs 80% [68-92%], p=0·53). In patients with congruent PIB and FDG reads (77/101), combined sensitivity was 97% [92-100%] and specificity 98% [93-100%]. Nine of 24 patients with incongruent reads were found to have co-occurrence of AD and non-AD pathologies. Interpretation: PIB had higher sensitivity to detect intermediate-high ADNC compared to FDG, particularly at early clinical stages, with similar specificity. When both modalities are congruent, sensitivity and specificity approach 100%, while mixed pathology should be considered when PIB and FDG are incongruent. Funding Statement: National Institute of Health (R01-AG045611, P01-AG1972403, P50-AG023501, P30-AG010129, R01-AG032306, K24-AG053435, R01-AG038791, K08-AG052648, P30-AG010129, K23-AG045289), the Alzheimer’s Association (AARF-16-443577), Bluefield Project to Cure FTD, Tau Consortium. Declaration of Interests: Orit H Lesman-Segev – none, Renaud La Joie – none, Iryna Lobach - none, Howard J Rosen - Dr Rosen has received research support from Biogen Pharmaceuticals, has consulting agreements with Wave Neuroscience and Ionis Pharmaceuticals, and receives research support from NIH. Sang Won Seo - none, Mustafa Janabi - none, Suzanne L Baker - consult for Genentech, Lauren Edwards - none, Julie Pham - none, John Olichney - has received grant funding from Roche/Genentech, Adam Boxer - Dr. Boxer receives research support from NIH, the Tau Research Consortium, the Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Corticobasal Degeneration Solutions, the Alzheimer’s Drug Discovery Foundation and the Alzheimer's Association. He has served as a consultant for Aeton, Abbvie, Alector, Amgen, Arkuda, Arvinas, Asceneuron, Ionis, Lundbeck, Novartis, Passage BIO, Sangamo, Samumed, Third Rock, Toyama and UCB, and received research support from Avid, Biogen, BMS, C2N, Cortice, Eli Lilly, Forum, Genentech, Janssen, Novartis, Pfizer, Roche and TauRx. Eric Huang - none, Marilu Gorno-Tempini – none, Ji-Hye L. Hwang - none, Charles DeCarli - none, Mackenzie Hepker - none, Salvatore Spina - none, Bruce L Miller – Dr. Miller receives grants in support of the Memory and Aging Center from the NIH/NIA, the Quest Diagnostics Dementia Pathway Collaboration, Cornell University and The Bluefield Project to Cure Frontotemporal Dementia. He serves as Medical Director for the John Douglas French Foundation; Scientific Director for the Tau Consortium; Director/Medical Advisory Board of the Larry L. Hillblom Foundation; and Past President of the International Society of Frontotemporal Dementia (ISFTD). Lea T Grinberg - Dr. Grinberg receives research support from Avid Radiopharmaceuticals, Eli Lilly. She has received consulting fees from Simon Foundation and Cura Sen Inc. She serves as associate editor for Frontiers in Aging Neurosciences, Frontiers in Dementia and Journal of Alzheimer Disease William W. Seeley - Dr. Seeley has received consulting fees from Biogen Idec, Third Rock Ventures, and Guidepoint Global Advisors. He serves on the editorial board of Acta Neuropathologica and Neuroimage Clinical. William J Jagust - Dr. Jagust has received honoraria as a consultant to Novartis, Genentech, and Curasen Gil D Rabinovici – Dr. Rabinovici receives research support from Avid Radiopharmaceuticals, Eli Lilly, GE Healthcare and Life Molecular Imaging. He has received honoraria as a consultant for Axon Neurosciences, Eisai and Merck, and speaking honoraria from GE Healthcare. Dr. Rabinovici serves as Associate Editor for JAMA Neurology. Ethics Approval Statement: Informed consent was obtained from all subjects or their surrogate decision makers, and the UCSF, UCD, University of California Berkeley (UCB) and/or Lawrence Berkeley National Laboratory (LBNL) Institutional Review Boards for human research approved the study.