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Accelerating rates of cognitive decline and imaging markers associated with β-amyloid pathology
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Abstract
Objective:
To estimate points along the spectrum of β-amyloid pathology at which rates of change of several measures of neuronal injury and cognitive decline begin to accelerate.
Methods:
In 460 patients with mild cognitive impairment (MCI), we estimated the points at which rates of florbetapir PET, fluorodeoxyglucose (FDG) PET, MRI, and cognitive and functional decline begin to accelerate with respect to baseline CSF Aβ 42. Points of initial acceleration in rates of decline were estimated using mixed-effects regression.
Results:
Rates of neuronal injury and cognitive and even functional decline accelerate substantially before the conventional threshold for amyloid positivity, with rates of florbetapir PET and FDG PET accelerating early. Temporal lobe atrophy rates also accelerate prior to the threshold, but not before the acceleration of cognitive and functional decline.
Conclusions:
A considerable proportion of patients with MCI would not meet inclusion criteria for a trial using the current threshold for amyloid positivity, even though on average, they are experiencing cognitive/functional decline associated with prethreshold levels of CSF Aβ 42. Future trials in early Alzheimer disease might consider revising the criteria regarding β-amyloid thresholds to include the range of amyloid associated with the first signs of accelerating rates of decline.
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Author and article information
Contributors
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(1) European Progression of Neurodegenerative Diseases Initiative
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(1) Alzheimer?s & Dementia: Translational Research & Clinical Interventions, Editorial Board, 2015
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(1) Alzheimer's Therapeutic Research Institute, University of Southern California, Visiting Associate Professor, 2015-present; (2) University of California, San Diego, Associate Professor, 2012-2015
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(1) Alzheimer's Disease Cooperative Study (ADCS), NIH AG010483, Biostatistician, 2005 - 2015; (2) Alzheimer's Disease Neuroimaging Initiative (ADNI), NIH AG024904, Biostatistician, 2005 - present.
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DHA therapy for apolipoprotein E4 negative ALzheimer's Disease; any potential royalties assigned in full to UCSD.
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NeuroPhage, Eisai, Bristol-Myers Squibb, Eli Lilly, Merck, Roche, Genentech, Abbott, Pfizer, Novartis, AstraZeneca, Janssen, Ichor, Lundbeck, Biogen, iPerian, Probiodrug, Anavex, Abbvie, Janssen, Cohbar, aTyr, Axovant, CogRx.
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NIA U01-AG10483 (PI), NIA U01-AG024904 (Coordinating Center Director), NIA R01-AG030048 (PI), and R01-AG16381 (Co-I)]
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Genentech 2013-2015 Banner/Genentech DSMB 2013-2016 Banner/Novartis 2014-2016
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Associate Editor, Frontiers in Human Neuroscience (current). Editorial Board Annals of Neurology, Brain Imaging and Behavior. Alzheimer's Disease and Associated Disorders, Neuroimage: Clinical (current)
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Consultant Synarc 2012, 2013, 2014, 2015, 2016 Consultant Genentech 2013, 2014, 2015 Consultant Novartis 2013, 2014, 2015, 2016
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(1) Avid Radiopharmaceuticals F-AV-45-A14 Clinical Evaluation of Florbetapir F-18 (2) GE Healthcare THK5351 pharmacokinetics
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NIH, Principal Investigator on the following grants: AG034570 AG025303 AG044292 NIH Co-Investigator on the following grants: AG012435 AG021028 AG031563 AG019724 AG030048 AG032306 AG024904
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Tau Consortium (Rainwater Foundation) Michael J Fox foundation
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Pfizer, BOLT International, Neurotrope Bioscience, Eli Lilly, U. of Penn?s Neuroscience of Behavior Initiative, National Brain Research Centre (NBRC), India, LEARN Program at University of North Carolina, Dolby Family Ventures, LP, and ADNI.
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The following entities have provided funding for travel; Pfizer, Neuroscience School of Advanced Studies (NSAS), Kenes, Intl., ADRC, UCLA, UCSD; ADCS, Sanofi-Aventis Groupe, University Center Hospital, Toulouse, Araclon, AC Immune, Nutricia, Eli Lilly, New York Academy of Sciences (NYAS), National Brain Research Center, India for Johns Hopkins Medicine, Consortium for Multiple Sclerosis Centers (CMSC), Northwestern University, Fidelity Biosciences Research Initiative, University of Pennsylvania, The Alzheimer?s Association, Merck, ADPD, Alzheimer?s Drug Discovery Foundation (ADDF), Tokyo University, Kyoto University, Cornell-Weill University, Rockafeller University, Memorial Sloan-Kettering Cancer Center, and Biogen Idec.
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University of California, San Francisco; San Francisco VA Medical Center (WOC employment)
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Synarc, Pfizer, Janssen, KLJ Associates, Easton Associates, University of California, Los Angeles (UCLA), Alzheimer?s Drug Discovery Foundation (ADDF), Neurotrope Bioscience, Avid Radiopharmaceuticals, Clearview Healthcare Partners, Perceptive Informatics, Smartfish AS, Decision Resources, Inc., Araclon, Merck, Defined Health, Howard University, Biogen Idec, BioClinica, Genentech, and Howard University.
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I received research support from Merck, Avid, Lilly, Alzheimer's Diseases Discovery Foundation (ADDF), the Veterans Administration (VA) and Department of Defense (DOD).
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Dr. Weiner received support for his work from the following grants; 2U01AG024904, W81XWH-13-1-0259, W81XWH-12-2-0012, R01 AG10897, 1P41 EB015904, P01 AG19724, R01 AG032306, R01A G03879, ADNI 2-12-233036, 20110506, R01 MH098062-01 from the following sources; NIH/NIA/National Institute of Mental Health, DOD, Alzheimer?s Association, Alzheimer?s Drug Discovery Foundation, Merck, Avid, and the Veterans Administration (VA).
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NIH, DOD, VA Stock/Stock Options, Medical Equipment & Materials: Alzheon, Inc.
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Author notes
Coinvestigators are listed on the Neurology® Web site at Neurology.org.
Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database ( adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at https://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.