@article{621bc21372784c76b0ed62792c84a8f1,
title = "Comparing cortical signatures of atrophy between late-onset and autosomal dominant Alzheimer disease",
abstract = "Defining a signature of cortical regions of interest preferentially affected by Alzheimer disease (AD) pathology may offer improved sensitivity to early AD compared to hippocampal volume or mesial temporal lobe alone. Since late-onset Alzheimer disease (LOAD) participants tend to have age-related comorbidities, the younger-onset age in autosomal dominant AD (ADAD) may provide a more idealized model of cortical thinning in AD. To test this, the goals of this study were to compare the degree of overlap between the ADAD and LOAD cortical thinning maps and to evaluate the ability of the ADAD cortical signature regions to predict early pathological changes in cognitively normal individuals. We defined and analyzed the LOAD cortical maps of cortical thickness in 588 participants from the Knight Alzheimer Disease Research Center (Knight ADRC) and the ADAD cortical maps in 269 participants from the Dominantly Inherited Alzheimer Network (DIAN) observational study. Both cohorts were divided into three groups: cognitively normal controls (nADRC = 381; nDIAN = 145), preclinical (nADRC = 153; nDIAN = 76), and cognitively impaired (nADRC = 54; nDIAN = 48). Both cohorts underwent clinical assessments, 3T MRI, and amyloid PET imaging with either 11C-Pittsburgh compound B or 18F-florbetapir. To generate cortical signature maps of cortical thickness, we performed a vertex-wise analysis between the cognitively normal controls and impaired groups within each cohort using six increasingly conservative statistical thresholds to determine significance. The optimal cortical map among the six statistical thresholds was determined from a receiver operating characteristic analysis testing the performance of each map in discriminating between the cognitively normal controls and preclinical groups. We then performed within-cohort and cross-cohort (e.g. ADAD maps evaluated in the Knight ADRC cohort) analyses to examine the sensitivity of the optimal cortical signature maps to the amyloid levels using only the cognitively normal individuals (cognitively normal controls and preclinical groups) in comparison to hippocampal volume. We found the optimal cortical signature maps were sensitive to early increases in amyloid for the asymptomatic individuals within their respective cohorts and were significant beyond the inclusion of hippocampus volume, but the cortical signature maps performed poorly when analyzing across cohorts. These results suggest the cortical signature maps are a useful MRI biomarker of early AD-related neurodegeneration in preclinical individuals and the pattern of decline differs between LOAD and ADAD.",
keywords = "Alzheimer disease, Amyloid, Autosomal dominant Alzheimer disease, Cortical signature, Cortical thickness, Preclinical",
author = "{for the Dominantly Inherited Alzheimer Network DIAN} and Aylin Dincer and Gordon, {Brian A.} and Amrita Hari-Raj and Keefe, {Sarah J.} and Shaney Flores and McKay, {Nicole S.} and Paulick, {Angela M.} and {Shady Lewis}, {Kristine E.} and Feldman, {Rebecca L.} and Hornbeck, {Russ C.} and Ricardo Allegri and Ances, {Beau M.} and Berman, {Sarah B.} and Brickman, {Adam M.} and Brooks, {William S.} and Cash, {David M.} and Chhatwal, {Jasmeer P.} and Farlow, {Martin R.} and {la Foug{\`e}re}, Christian and Fox, {Nick C.} and Fulham, {Michael J.} and Jack, {Clifford R.} and Nelly Joseph-Mathurin and Karch, {Celeste M.} and Athene Lee and Johannes Levin and Masters, {Colin L.} and McDade, {Eric M.} and Hwamee Oh and Perrin, {Richard J.} and Cyrus Raji and Salloway, {Stephen P.} and Schofield, {Peter R.} and Yi Su and Villemagne, {Victor L.} and Qing Wang and Weiner, {Michael W.} and Chengjie Xiong and Igor Yakushev and Morris, {John C.} and Bateman, {Randall J.} and {L.S. Benzinger}, Tammie",
note = "Funding Information: This work was supported by The Dominantly Inherited Alzheimer Network (DIAN, UF1AG032438) and funded by the National Institutes of Health (U19AG03243808, P01AG003991, P01AG026276, P01AG005681, K01AG053474, R01AG03158, and P30AG019610), the German Center for Neurodegenerative Diseases (DZNE), XNAT (R01EB009352), Neuroimaging Informatics and Analysis Center (P30NS098577), the Center for High-Performance Computing (1S10RR022984-01A1 and 1S10OD018091-0), ADHS Grant No. CTR040636 (previously ADHS Grant No. ADHS14-052688), Alzheimer{\textquoteright}s Association (AARG-17-532945), the BrightFocus Foundation (ADR A2017272S), Alzheimer Association International Research Program (AARFD-20-681815), and the Raul Carrea Institute for Neurological Research (FLENI). This work was also supported by the generous support of Barnes-Jewish Hospital, the Paula and Rodger O. Riney Fund, the Danial J Brennan MD Fund, the Fred Simmons and Olga Mohan Fund, and the Willman Fund, the Arizona Alzheimer{\textquoteright}s Consortium, DHS of the State of Arizona, the Research and Development Grants for Dementia from Japan Agency for Medical Research and Development, AMED, and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI). This manuscript has been reviewed by DIAN Study investigators for scientific content and consistency of data interpretation with previous DIAN Study publications. Funding Information: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The following authors have no conflicts of interest regarding this study: AD, AHR, BAG, SJK, SF, AMP, KESL, RLF, RCH, NSM, SBB, MRF, CF, MJF, CMK, AL, HO, VLV, QW, BMA, DMC, NCF, JL, CLM, MWW, RJP, CX. RA reports grants from CONICET. AMB is a scientific consultant for Regeneron Pharmaceuticals and Cognition Therapeutics, Inc., owns stocks in Venus Medtech, which were awarded for past service on an advisory board for Keystone Heart Ltd, and has a patent (US patent #9867566) for technologies for white matter hyperintensity quantification. WSB paid for DIAN expenses from NIH and other grants as declared in funding from Washington University School of Medicine. He also received grants from the Roth Charitable Foundation. JPC is a consultant for Otsuka pharmaceuticals. CRJ has consulted for Lily, serves on an independent data monitoring board for Roche, and as a speaker for Eisai, but he receives no personal compensation from any commercial entity. He receives research support from NIH and the Alexander Family Alzheimer{\textquoteright}s Disease Research Professorship of the Mayo Clinic. SPS reports fees from Biogen, Lilly, Eisai, Genentech, Roche, Novartis, and Avid, outside the submitted work. PRS received grants from NIA, grants from Anonymous Foundation, grants from Roth Charitable Foundation, during the conduct of the study. YS is supported by the Arizona Alzheimer{\textquoteright}s Consortium, DHS and the State of Arizona, ADHS Grant, the BrightFocus Foundation, and the Alzheimer{\textquoteright}s Association. JCM received grants from NIH grants. IY reports personal fees from Piramal, Blue Earth Diagnostics, and ABC-CRO and received grants from German Research Foundation and Federal Ministry of Education and Research, outside the submitted work. RJB receives lab research funding from the National Institutes of Health, Alzheimer{\textquoteright}s Association, BrightFocus Foundation, Rainwater Foundation Tau Consortium, Association for Frontotemporal Degeneration, the Cure Alzheimer{\textquoteright}s Fund, the Tau SILK Consortium (AbbVie, Biogen, and Eli Lilly and Co.), and an anonymous foundation. Funding for clinical trials includes the National Institutes of Health, Alzheimer's Association, Eli Lilly and Co, Hoffmann-La Roche, Janssen, Avid Radiopharmaceuticals, GHR Foundation, and an anonymous foundation. RJB also receives research funding from the DIAN-TU Pharma Consortium (Abbvie, Biogen, Eisai, Eli Lilly and Co/Avid Radiopharmaceuticals, Hoffmann-La Roche/Genentech, Janssen, and United Neuroscience). RJB has received honoraria from Roche as an Advisory Board member. Washington University and RJB have equity ownership interest in C2N Diagnostics and receive royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. RJB receives income from C2N Diagnostics for serving on the scientific advisory board. Washington University, with RJB as co-inventor, has submitted the US nonprovisional patent application “Methods for Measuring the Metabolism of CNS Derived Biomolecules In Vivo” and provisional patent application “Plasma Based Methods for Detecting CNS Amyloid Deposition”. NJM is supported partly by the Alzheimer Association International Research Program. CR reports other from Brainreader ApS, other from Neurevolution LLC, other from Apollo Health, outside the submitted work. EMM reports serving on a Data Safety Committee for Eli Lilly and Alector; personal honorarium for Continuing Medical Education activities for Esai and Eli Lilly and UpToDate; Institutional grant support from Eli Lilly, Hoffman-La Roche and Janssen. TLSB has investigator initiated research funding from the NIH, the Alzheimer's Association, the Barnes-Jewish Hospital Foundation and Avid Radiopharmaceuticals (a wholly owned subsidiary of Eli Lilly). TLSB participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly, Biogen, Eisai, Jaansen, and Roche. She serves as an unpaid consultant to Eisai and Siemens. She is on the Speaker's Bureau for Biogen. Funding Information: We acknowledge the altruism of the participants and their families and contributions of the DIAN and the Knight ADRC research and support staff at each of the participating sites for their contributions to this work. Without the generous contribution and time the participants gave for these studies, this work would not be possible. Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = jan,
doi = "10.1016/j.nicl.2020.102491",
language = "English",
volume = "28",
journal = "NeuroImage: Clinical",
issn = "2213-1582",
}