2014 Update of the Alzheimer's Disease Neuroimaging Initiative: A review of papers published since its inception
Michael W. Weiner,Dallas P. Veitch,Paul S. Aisen,Laurel A. Beckett,Nigel J. Cairns,Jesse M. Cedarbaum,Robert C. Green,Danielle J Harvey,Clifford R. Jack,William J. Jagust,Johan Luthman,John C. Morris,Ronald C. Petersen,Andrew J. Saykin,Leslie M. Shaw,Li Shen,Adam J. Schwarz,Arthur W. Toga,John Q. Trojanowski +18 more
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TLDR
The major accomplishments of ADNI have been the development of standardized methods for clinical tests, magnetic resonance imaging, positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting, and the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes.Abstract:
The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The initial study, ADNI-1, enrolled 400 subjects with early mild cognitive impairment (MCI), 200 with early AD, and 200 cognitively normal elderly controls. ADNI-1 was extended by a 2-year Grand Opportunities grant in 2009 and by a competitive renewal, ADNI-2, which enrolled an additional 550 participants and will run until 2015. This article reviews all papers published since the inception of the initiative and summarizes the results to the end of 2013. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are largely consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimer's Dis 2006;9(Suppl 3):151–3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers select and combine optimum features from multiple modalities, including MRI, [ 18 F]-fluorodeoxyglucose-PET, amyloid PET, CSF biomarkers, and clinical tests; (4) the development of blood biomarkers for AD as potentially noninvasive and low-cost alternatives to CSF biomarkers for AD diagnosis and the assessment of α-syn as an additional biomarker; (5) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects and are leading candidates for the detection of AD in its preclinical stages; (6) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Multimodal methods incorporating APOE status and longitudinal MRI proved most highly predictive of future decline. Refinements of clinical tests used as outcome measures such as clinical dementia rating-sum of boxes further reduced sample sizes; (7) the pioneering of genome-wide association studies that leverage quantitative imaging and biomarker phenotypes, including longitudinal data, to confirm recently identified loci, CR1, CLU , and PICALM and to identify novel AD risk loci; (8) worldwide impact through the establishment of ADNI-like programs in Japan, Australia, Argentina, Taiwan, China, Korea, Europe, and Italy; (9) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker and clinical data to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (10) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world.read more
Citations
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Journal ArticleDOI
A review on neuroimaging-based classification studies and associated feature extraction methods for Alzheimer's disease and its prodromal stages
TL;DR: The studies reviewed indicate that the classification frameworks formulated on the basis of these features show promise for individualized diagnosis and prediction of clinical progression, and a detailed account of AD classification challenges is provided.
Journal ArticleDOI
Common polygenic variation enhances risk prediction for Alzheimer's disease.
Valentina Escott-Price,Rebecca Sims,Christian Bannister,Denise Harold,Maria Vronskaya,Elisa Majounie,Nandini Badarinarayan,Kevin Morgan,Peter Passmore,Clive Holmes,John Powell,Carol Brayne,Michael Gill,Simon Mead,Alison Goate,Carlos Cruchaga,Jean-Charles Lambert,Jean-Charles Lambert,Jean-Charles Lambert,Cornelia M. van Duijn,Wolfgang Maier,Alfredo Ramirez,Peter Holmans,Lesley Jones,John Hardy,Sudha Seshadri,Gerard D. Schellenberg,Philippe Amouyel,Julie Williams +28 more
TL;DR: Alzheimer's disease has a significant polygenic component, which has predictive utility for Alzheimer's disease risk and could be a valuable research tool complementing experimental designs, including preventative clinical trials, stem cell selection and high/low risk clinical studies.
Journal ArticleDOI
Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies
Borislav Dejanovic,Melanie A. Huntley,Ann De Mazière,William J. Meilandt,Tiffany Wu,Karpagam Srinivasan,Zhiyu Jiang,Vineela D. Gandham,Brad A. Friedman,Hai Ngu,Oded Foreman,Richard A.D. Carano,Ben Chih,Judith Klumperman,Corey E. Bakalarski,Jesse E. Hanson,Morgan Sheng +16 more
TL;DR: Unbiased proteomic analysis of postsynaptic densities in Tau-P301S transgenic mice identified Tau-dependent alterations in synapses prior to overt neurodegeneration, and found striking accumulation of complement C1q in the PSDs of Tau- P301S mice and AD patients.
Journal ArticleDOI
Understanding disease progression and improving Alzheimer's disease clinical trials: Recent highlights from the Alzheimer's Disease Neuroimaging Initiative
Dallas P. Veitch,Michael W. Weiner,Paul S. Aisen,Laurel A. Beckett,Nigel J. Cairns,Robert C. Green,Danielle J Harvey,Clifford R. Jack,William J. Jagust,John C. Morris,Ronald C. Petersen,Andrew J. Saykin,Leslie M. Shaw,Arthur W. Toga,John Q. Trojanowski +14 more
TL;DR: Select topics that provide insights into AD progression are discussed and how this knowledge may improve clinical trials are outlined.
Journal ArticleDOI
The Alzheimer's Disease Neuroimaging Initiative 3: Continued innovation for clinical trial improvement
Michael W. Weiner,Dallas P. Veitch,Paul S. Aisen,Laurel A. Beckett,Nigel J. Cairns,Robert C. Green,Danielle J Harvey,Clifford R. Jack,William J. Jagust,John C. Morris,Ronald C. Petersen,Jennifer Salazar,Andrew J. Saykin,Leslie M. Shaw,Arthur W. Toga,John Q. Trojanowski +15 more
TL;DR: The overall goal of the Alzheimer's Disease Neuroimaging Initiative (ADNI) is to validate biomarkers for Alzheimer's disease clinical trials.
References
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Journal ArticleDOI
The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics
John Hardy,Dennis J. Selkoe +1 more
TL;DR: It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid β-peptide in plaques in brain tissue and the rest of the disease process is proposed to result from an imbalance between Aβ production and Aβ clearance.
Journal ArticleDOI
Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease
Reisa A. Sperling,Paul S. Aisen,Laurel A. Beckett,David A. Bennett,Suzanne Craft,Anne M. Fagan,Takeshi Iwatsubo,Clifford R. Jack,Jeffrey Kaye,Thomas J. Montine,Denise C. Park,Eric M. Reiman,Christopher C. Rowe,Eric Siemers,Yaakov Stern,Kristine Yaffe,Maria C. Carrillo,Bill Thies,Marcelle Morrison-Bogorad,Molly V. Wagster,Creighton H. Phelps +20 more
TL;DR: A conceptual framework and operational research criteria are proposed, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies and it is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD.
Journal ArticleDOI
Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B.
William E. Klunk,Henry Engler,Agneta Nordberg,Yanming Wang,G. Blomqvist,Daniel P. Holt,Mats Bergström,Irina Savitcheva,Guo Feng Huang,Sergio Estrada,Birgitta Ausén,Manik L. Debnath,Julien Barletta,Julie C. Price,Johan Sandell,Brian J. Lopresti,Anders Wall,Pernilla Koivisto,Gunnar Antoni,Chester A. Mathis,Bengt Långström +20 more
TL;DR: The results suggest that PET imaging with the novel tracer, PIB, can provide quantitative information on amyloid deposits in living subjects.
Journal ArticleDOI
Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade
Clifford R. Jack,David S. Knopman,William J. Jagust,Leslie M. Shaw,Paul S. Aisen,Michael W. Weiner,Ronald C. Petersen,John Q. Trojanowski +7 more
TL;DR: This work proposes a model that relates disease stage to AD biomarkers in which Abeta biomarkers become abnormal first, before neurodegenerative biomarkers and cognitive symptoms, and neurodegnerative biomarker become abnormal later, and correlate with clinical symptom severity.
Journal ArticleDOI
The Diagnosis of Mild Cognitive Impairment due to Alzheimer’s Disease: Recommendations from the National Institute on Aging-Alzheimer’s Association Workgroups on Diagnostic Guidelines for Alzheimer’s Disease
Marilyn S. Albert,Steven T. DeKosky,Dennis W. Dickson,Bruno Dubois,Howard Feldman,Nick C. Fox,Anthony Gamst,David M. Holtzman,William J. Jagust,Ronald C. Petersen,Peter J. Snyder,Maria C. Carrillo,Bill Thies,Creighton H. Phelps +13 more
TL;DR: Criteria for the symptomatic predementia phase of Alzheimer’s disease (AD), referred to in this article as mild cognitive impairment due to AD, has four levels of certainty, depending on the presence and nature of the biomarker findings.
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