Title: The Alzheimer’s Disease Neuroimaging Initiative: A review of papers published since its inception

Authors:
Weiner MW, Veitch DP, Aisen PS, Beckett LA, Cairns NJ, Green RC, Harvey D, Jack CR, Jagust W, Liu E, Morris JC, Petersen RC, Saykin AJ, Schmidt ME, Shaw L, Siuciak JA, Soares H, Toga AW, Trojanowski JQ; Alzheimer’s Disease Neuroimaging Initiative.

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 study aimed to enroll 400 subjects with early mild cognitive impairment (MCI), 200 subjects with early AD, and 200 normal control subjects; $67 million funding was provided by both the public and private sectors, including the National Institute on Aging, 13 pharmaceutical companies, and 2 foundations that provided support through the Foundation for the National Institutes of Health. This article reviews all papers published since the inception of the initiative and summarizes the results as of February 2011. 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 consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimers 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 combine optimum features from multiple modalities, including MRI, [(18)F]-fluorodeoxyglucose-PET, CSF biomarkers, and clinical tests; (4) 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; (5) 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. Baseline cognitive and/or MRI measures generally predicted future decline better than other modalities, whereas MRI measures of change were shown to be the most efficient outcome measures; (6) the confirmation of the AD risk loci CLU, CR1, and PICALM and the identification of novel candidate risk loci; (7) worldwide impact through the establishment of ADNI-like programs in Europe, Asia, and Australia; (8) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker data with clinical data from ADNI 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 (9) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world. The ADNI study was extended by a 2-year Grand Opportunities grant in 2009 and a renewal of ADNI (ADNI-2) in October 2010 through to 2016, with enrollment of an additional 550 participants.

Copyright © 2011 The Alzheimer’s Association. Published by Elsevier Inc. All rights reserved.

By GINA KOLATA

“In 2003, a group of scientists and executives from the National Institutes of Health, the Food and Drug Administration, the drug and medical-imaging industries, universities and nonprofit groups joined in a project that experts say had no precedent: a collaborative effort to find the biological markers that show the progression of Alzheimer’s disease in the human brain.”

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Authors: Weiner MW, Aisen PS, Jack CR Jr, Jagust WJ, Trojanowski JQ, Shaw L, Saykin AJ, Morris JC, Cairns N, Beckett LA, Toga A, Green R, Walter S, Soares H, Snyder P, Siemers E, Potter W, Cole PE, Schmidt M; Alzheimer’s Disease Neuroimaging Initiative.

Alzheimers Dement. 2010 May;6(3):202-11.e7. Review.

Read this article on Pubmed.

Some of the leading-edge technologies under study are brain-imaging techniques, such as positron emission tomography (PET), including FDG-PET (which measures glucose metabolism in the brain); PET using a radioactive compound (PiB) that measures brain beta-amyloid; and structural MRI. Brain scans are showing scientists how the brain’s structure and function change as AD starts and progresses.

Biomarkers in cerebrospinal fluid are revealing other changes that could identify which patients with MCI will develop Alzheimer’s. Scientists are looking at levels of beta-amyloid and tau in cerebrospinal fluid. (Abnormal amounts of the amyloid and tau proteins in the brain are hallmarks of Alzheimer’s disease.)

The next step is to scan and analyze the brains of people with early mild cognitive impairment (eMCI). With a generous grant from American Recovery and Reinvestment Funds ADNI researchers will be able to study people with eMCI. This new grant expands the scope of ongoing research under ADNI by allowing for the enrollment of participants at an earlier stage of MCI, when symptoms are milder.

Furthermore, the funding for this new grant will allow ADNI investigators to extend the length of the original study to better assess changes in individuals over time. All of the participants will have neuroimaging scans and blood and cerebrospinal fluid analyses to look for changes in the brain.

The overall impact of the added funding will be increased knowledge of the sequence and timing of events leading to MCI and AD, development of better clinical and imaging/fluid biomarker methods for early detection and for monitoring the progression of these conditions. This will facilitate clinical trials of treatments to slow disease progression and will ultimately contribute to the prevention of AD.

In 2009, ADNI made a significant step forward in developing a test to help diagnose the beginning stages of AD sooner and more accurately by measuring levels of two biomarkers–tau and beta-amyloid proteins–in cerebrospinal fluid.

For more information on the clinical research sites taking part in ADNI and that are looking for study participants, go to http://www.adcs.org/Studies/ImagineADNI.aspx

David M. Holtzman, MD
Andrew B. and Gretchen P. Jones Professor
and Chairman Dept. of Neurology,
Washington University School of Medicine
St. Louis, MO

David A. Bennett, M.D.
Director, Rush Alzheimer’s Disease Center
Robert C. Borwell Professor of Neurological Sciences
Rush University Medical Center
Chicago, IL

Description: Recent findings in the field of human amyloid imaging will be presented and discussed. The format will be brief talks with Q&A along with two keynote speakers. Abstract submission is now open. Please note that all submissions must be sent before 22 February 2008 and all authors will be notified of acceptance by 3 March 2008.