The Alzheimer's Disease Neuroimaging Initiative: a review of papers published since its inception.

Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, USA.
Alzheimer's & dementia: the journal of the Alzheimer's Association (Impact Factor: 14.48). 10/2011; 8(1 Suppl):S1-68. DOI: 10.1016/j.jalz.2011.09.172
Source: PubMed

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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: As the need to develop a successful disease-modifying treatment for Alzheimer's disease (AD) becomes more urgent, imaging is increasingly used in therapeutic trials. We provide an overview of how the different imaging modalities are used in AD studies and the current regulatory guidelines for their use in clinical trials as endpoints. We review the current literature for results of imaging endpoints of efficacy and safety in published clinical trials. We start with trials in mild to moderate AD, where imaging (largely magnetic resonance imaging (MRI)) has long played a role in inclusion and exclusion criteria; more recently, MRI has been used to identify adverse events and to measure rates of brain atrophy. The advent of amyloid imaging using positron emission tomography has led to trials incorporating amyloid measurements as endpoints and incidentally to the recognition of the high proportion of amyloid-negative individuals that may be recruited into these trials. Ongoing and planned trials now commonly include multimodality imaging: amyloid positron emission tomography, MRI and other modalities. At the same time, the failure of recent large profile trials in mild to moderate AD together with the realisation that there is a long prodromal period to AD has driven a push to move studies to earlier in the disease. Imaging has particularly important roles, alongside other biomarkers, in assessing efficacy because conventional clinical outcomes may have limited ability to detect treatment effects in these early stages.
    Alzheimer's Research and Therapy 01/2014; 6(9):87. DOI:10.1186/s13195-014-0087-9 · 3.50 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Until now, a disease-modifying therapy (DMT) that has an ability to slow or arrest Alzheimer's disease (AD) progression has not been developed, and all clinical trials involving AD patients enrolled by clinical assessment alone also have not been successful. Given the growing consensus that the DMT is likely to require treatment initiation well before full-blown dementia emerges, the early detection of AD will provide opportunities to successfully identify new drugs that slow the course of AD pathology. Recent advances in early detection of AD and prediction of progression of the disease using various biomarkers, including cerebrospinal fluid (CSF) Aβ1-42, total tau and p-tau181 levels, and imagining biomarkers, are now being actively integrated into the designs of AD clinical trials. In terms of therapeutic mechanisms, monitoring these markers may be helpful for go/no-go decision making as well as surrogate markers for disease severity or progression. Furthermore, CSF biomarkers can be used as a tool to enrich patients for clinical trials with prospect of increasing statistical power and reducing costs in drug development. However, the standardization of technical aspects of analysis of these biomarkers is an essential prerequisite to the clinical uses. To accomplish this, global efforts are underway to standardize CSF biomarker measurements and a quality control program supported by the Alzheimer's Association. The current review summarizes therapeutic targets of developing drugs in AD pathophysiology, and provides the most recent advances in the.
    Korean Journal of Physiology and Pharmacology 12/2014; 18(6):447-56. DOI:10.4196/kjpp.2014.18.6.447 · 1.26 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To determine baseline volume and rate of volume change of whole brain, hippocampus, and entorhinal cortex in patients with atrial fibrillation. We analyzed clinical and neuroimaging data collected as part of Alzheimer's Disease Neuroimaging Initiative in the United States and Canada. Patients with atrial fibrillation were identified based on baseline clinical/cognitive assessments, and age and gender-matched controls without atrial fibrillations were selected (1:1 ratio). All participants underwent 1.5 T structural magnetic resonance imaging (MRI) at specified intervals (6 or 12 months) for 2-3 years. A total of 33 persons with atrial fibrillation were included. There was no difference in whole brain and ventricular volumes at baseline MRI between cases and controls. There was significantly lower entorhinal cortex volume on right (p = 0.01) and left (p = 0.01) sides in patients with atrial fibrillation. There was significantly lower volume for middle temporal lobes on right (p = 0.04) and left (p = 0.001) sides. The rate of progression of atrophy in entorhinal cortex and middle temporal lobes was not different between patients with atrial fibrillation and controls. The association of atrial fibrillation with volume loss in entorhinal cortex and middle temporal lobes may provide new insights into pathophysiology of atrial fibrillation.
    Journal of vascular and interventional neurology 12/2014; 7(5):18-23.


Available from
May 22, 2014