Select Atrophied Regions in Alzheimer disease (SARA): An improved volumetric model for identifying Alzheimer disease dementia.

Volumetric biomarkers for Alzheimer disease (AD) are attractive due to their wide availability and ease of administration, but have traditionally shown lower diagnostic accuracy than measures of neuropathological contributors to AD. Our purpose was to optimize the diagnostic specificity of structural MRIs for AD using quantitative, data-driven techniques. This retrospective study assembled several non-overlapping cohorts (total n = 1287) with publicly available data and clinical patients from Barnes-Jewish Hospital (data gathered 1990-2018). The Normal Aging Cohort (n = 383) contained amyloid biomarker negative, cognitively normal (CN) participants, and provided a basis for determining age-related atrophy in other cohorts. The Training (n = 216) and Test (n = 109) Cohorts contained participants with symptomatic AD and CN controls. Classification models were developed in the Training Cohort and compared in the Test Cohort using the receiver operating characteristics areas under curve (AUCs). Additional model comparisons were done in the Clinical Cohort (n = 579), which contained patients who were diagnosed with dementia due to various etiologies in a tertiary care outpatient memory clinic. While the Normal Aging Cohort showed regional age-related atrophy, classification models were not improved by including age as a predictor or by using volumetrics adjusted for age-related atrophy. The optimal model used multiple regions (hippocampal volume, inferior lateral ventricle volume, amygdala volume, entorhinal thickness, and inferior parietal thickness) and was able to separate AD and CN controls in the Test Cohort with an AUC of 0.961. In the Clinical Cohort, this model separated AD from non-AD diagnoses with an AUC 0.820, an incrementally greater separation of the cohort than by hippocampal volume alone (AUC of 0.801, p = 0.06). Greatest separation was seen for AD vs. frontotemporal dementia and for AD vs. non-neurodegenerative diagnoses. Volumetric biomarkers distinguished individuals with symptomatic AD from CN controls and other dementia types but were not improved by controlling for normal aging.

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Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Competing Interest GS Day is supported by a mentored career development award (K23AG064029), through additional research/grant support from the National Institutes of Health (P01AG03991, R56AG057195, U01AG057195) and from philanthropic support of the BJHF Willman Scholar Fund. Prior research has benefited from an in-kind gift of radiopharmaceuticals from Avid Radiopharmaceuticals. GS Day holds stock in ANI Pharmaceuticals, Inc., serves as a topic editor on dementia for DynaMed Plus (EBSCO Industries, Inc.), and has provided record review and expert medical testimony on legal cases pertaining to management of Wernicke. Amber Salter receives consulting fees for statistical reviews for the journal Circulation: Cardiovascular Imaging. Joy Snider does consulting with Eisai. Cyrus Raji does consulting for Brainreader ApS and Neurevolution LLC. Nupur Ghoshal has participated or is currently participating in clinical trials of anti-dementia drugs sponsored by the following companies: Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals, Janssen Immunotherapy, Novartis, Pfizer, Wyeth, SNIFF (The Study of Nasal Insulin to Fight Forgetfulness) study, and A4 (The Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease) trial. Ghoshal receives research support from Tau Consortium and Association for Frontotemporal Dementia and is funded by the NIH. Michelle Miller-Thomas received payment as a site investigator for a multiple sclerosis imaging study sponsored by Biogen MA Inc. (completed May 2019), which is unrelated to this work. Miller-Thomas receives ongoing salary support from the Barnes Jewish Hospital Foundation to support her work on Neuroradiology Advanced Imaging, which is directly related to this manuscript. JC Morris is funded by NIH grants # P50AG005681; P01AG003991; P01AG026276 and UF1AG032438. Neither Dr. Morris nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. Tammie Benzinger participated in clinical trials sponsored by Eli Lilly, Roche, and Biogen. Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly) provided doses of (18)F-florbetapir, partial funding for (18)F-florbetapir scanning, precursor for (18)F-flortaucipir, and technology transfer for manufacturing of (18)F-flortaucipir. *DIAN Consortium: Ricardo Allegri, Fatima Amtashar, Randy Bateman, Tammie Benzinger, Sarah Berman, Courtney Bodge, Susan Brandon, William (Bill) Brooks, Jill Buck, Virginia Buckles, Sochenda Chea, Jasmeer Chhatwal, Patricio Chrem, Helena Chui, Jake Cinco, Jack Clifford, Carlos Cruchaga, Mirelle D'Mello, Tamara Donahue, Jane Douglas, Noelia Edigo, Nilufer Erekin-Taner, Anne Fagan, Marty Farlow, Angela Farrar, Howard Feldman, Gigi Flynn, Nick Fox, Erin Franklin, Hisako Fujii, Cortaiga Gant, Samantha Gardener, Bernardino Ghetti, Alison Goate, Jill Goldman, Brian Gordon, Neill Graff-Radford, Julia Gray, Jenny Gurney, Jason Hassenstab, Mie Hirohara, David Holtzman, Russ Hornbeck, Siri Houeland DiBari, Takeshi Ikeuchi, Snezana Ikonomovic, Gina Jerome, Mathias Jucker, Celeste Karch, Kensaku Kasuga, Takeshi Kawarabayashi, William (Bill) Klunk, Robert Koeppe, Elke Kuder-Buletta, Christoph Laske, Jae-Hong Lee, Johannes Levin, Daniel Marcus, Ralph Martins, Neal Scott Mason, Colin Masters, Denise Maue-Dreyfus, Eric McDade, Lucy Montoya, Hiroshi Mori, John Morris, Akem Nagamatsu, Katie Neimeyer, James Noble, Joanne Norton, Richard Perrin, Marc Raichle, John Ringman, Jee Hoon Roh, Jee Hoon Roh, Stephen Salloway, Peter Schofield, Hiroyuki Shimada, Tomoyo Shiroto, Mikio Shoji, Wendy Sigurdson, Hamid Sohrabi, Paige Sparks, Kazushi Suzuki, Laura Swisher, Kevin Taddei, Jen Wang, Peter Wang, Mike Weiner, Mary Wolfsberger, Chengjie Xiong, Xiong Xu