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Functions of the ADNI MRI core fall into three categories: (1) those of the central MRI core lab at Mayo Clinic, Rochester, Minnesota, needed to generate high quality MRI data in all subjects at each time point; (2) those of the funded ADNI MRI core imaging analysis groups responsible for analyzing the MRI data, and (3) the joint function of the entire MRI core in designing and problem solving MR image acquisition, pre-processing and analyses methods. The primary objective of ADNI was and continues to be improving methods for clinical trials in Alzheimer's disease. Our approach to the present (“ADNI-GO”) and future (“ADNI-2”, if funded) MRI protocol will be to maintain MRI methodological consistency in previously enrolled “ADNI-1” subjects who are followed longitudinally in ADNI-GO and ADNI-2. We will modernize and expand the MRI protocol for all newly enrolled ADNI-GO and ADNI-2 subjects. All newly enrolled subjects will be scanned at 3T with a core set of three sequence types: 3D T1-weighted volume, FLAIR, and a long TE gradient echo volumetric acquisition for micro hemorrhage detection. In addition to this core ADNI-GO and ADNI-2 protocol, we will perform vendor specific pilot sub-studies of arterial spin labeling perfusion, resting state functional connectivity and diffusion tensor imaging. One each of these sequences will be added to the core protocol on systems from each MRI vendor. These experimental sub-studies are designed to demonstrate the feasibility of acquiring useful data in a multi-center (but single vendor) setting for these three emerging MRI applications.
The major purpose of this paper is to describe past, present, and future activities of the ADNI MRI core. In doing so, we hope that the ADNI MRI database (available at www.loni.ucla.edu/ADNI) will become more transparent and more easily accessible to potential users. This paper is divided into two main sections: 1) a description of MRI activities during the first 5 years of ADNI funding, approximately from 2005 – 2010, referred to as “ADNI-1”; 2) plans for the second 5 years of ADNI running through 2015. “ADNI-GO” is the currently active extension of ADNI (GO stands for “Grand Opportunity”, a type of stimulus grant from the NIH). “ADNI-2” is the 5 year competitive renewal of ADNI, which if funded, will be active from late 2010 through 2015.
MRI core activities fall into three categories: (1) service activities of the central MRI lab at Mayo Clinic, Rochester, MN, needed to generate high quality MRI data in all subjects at each time point; (2) the funded ADNI MRI core imaging analysis groups responsible for analyzing the MRI data using state-of-the-art methods and making numeric summary data publicly available, and (3) the joint function of the entire MRI core in designing and problem solving MR image acquisition, pre-processing and analyses methods. Although separated geographically, the MRI core communicates regularly and operates in a consensus-driven manner on all major decisions relating to operations and future planning.
The primary objective of ADNI-1 was to improve methods for clinical trials. In addition, however, the data generated by ADNI-1 has improved understanding of relationships between imaging and chemical biomarkers of Alzheimer's disease (AD) and clinical manifestations of the disease. The main focus of the ADNI-1 MRI acquisition protocol was on structural MRI of the brain, and the imaging sequence selected for this purpose was a 3D T1-weighted sequence known as MPRAGE (Magnetization Prepared Gradient Echo). The MPRAGE sequence was repeated back-to-back in ADNI-1 to increase the likelihood of acquiring at least one good quality MPRAGE scan (and hence decrease the need to repeat exams) and also to permit signal averaging if desired. In addition, a dual fast spin echo (proton density/T2) sequence was acquired at each time point to evaluate the presence/state of vascular disease and general pathology detection. All subjects received a 1.5T protocol exam at multiple time points which varied by baseline clinical diagnosis: MCI at 0, 6, 12, 24 and 36 months; AD at 0, 6, 12 and 24 months; and controls at 0, 6, 12, 24 and 36 months. A sub-set of participants (approximately 25%) were enrolled in a 3T arm which involved MRI scanning at both 1.5T and 3T at each scheduled time point.
Functions primarily managed by the central ADNI MRI lab at the Mayo Clinic included the following:
Seven different research groups were funded to perform analysis of ADNI-1 MRI data at 0, 6 and 12 month time points. The principal investigators and the analyses performed were:
ADNI MRI core activities led to meaningful conclusions in areas ranging from MRI technology to the biology of AD. Some are briefly described below.
In summary, ADNI-1 has shown that with proper implementation methods, high quality MRI acquisition can be achieved in a large multi-site study. The excellent measurement precision of MRI in a multi-site environment points to MRI as an attractive endpoint for clinical trials. MRI measures, both global and regional, are sensitive to longitudinal and cross-sectional associations with cognition and other biological indicators which underscores the validity of MRI as a biomarker for clinical trials. Vascular brain injury is common even in carefully selected clinical trial designs and independently influences common cognitive outcome measures,
The objectives of ADNI-GO and ADNI-2 (if funded) for the MRI core will include steps to further evaluate methodological improvements for clinical trials and evaluate biomarkers in AD and its prodromal and preclinical stages. ADNI-GO and ADNI-2 will follow 3 cohorts of subjects. 1) Cognitively Normal (CN) and late MCI (LMCI) subjects carried forward from ADNI-1 (followed at 1.5T); 2) EMCI (early MCI) enrolled in GO and carried forward into ADNI-2 (scanned at 3T); 3) CN, LMCI, and Alzheimer's Disease (AD) subjects newly enrolled in ADNI- 2 (scanned at 3T).
Next, we describe the rationale that led to the selection of the MRI protocol for ADNI-GO and ADNI-2. Our approach to the ADNI-GO and ADNI-2 MRI protocol will be to maintain MRI methodological consistency to the greatest extent possible in previously enrolled ADNI-1 subjects, to maximize the value of the longitudinal MRI data in these subjects. However, for newly enrolled subjects in GO (and ADNI-2 if funded), we will modernize and expand the MRI protocol to remain technically current, within the constraints imposed by having to operate in a reasonably consistent manner across many individual scanner models representing the three largest MRI vendors. Given the sensitivity of MRI as a biological marker demonstrated in ADNI-1, ADNI-GO and ADNI-2 are designed to further assess usefulness among individuals who are cognitively normal or have even more subtle cognitive impairment. This approach will serve to address two important objectives: how well does MRI identify the earliest change in brain pathology and what is the particular pattern of regional brain change?
The ADNI-GO and ADNI-2 protocol is divided into a core set of sequences that will be performed on all scanners in all subjects, and a series of more experimental vendor specific sub-studies. This approach was arrived at after extensive discussion within the ADNI MRI core, aligned external investigators, the ADNI Steering committee, and the industry scientific advisory board (ISAB).
A 3D T1-weighted volume and a 2D FLAIR sequence were considered the minimum requirements for the protocol. The 3D T1-weighted volume is the primary sequence for structural MRI analysis, while FLAIR is the sequence most widely used in clinical neuroradiology for general pathology detection – including cerebrovascular disease. We then considered adding one or two additional sequences to this minimum core from the following: long-TE (i.e., 20 ms) gradient echo (GRE) micro hemorrhage imaging, resting-state functional connectivity (RSFC), Arterial Spin Labeling Perfusion imaging (ASL), and diffusion tensor imaging (DTI). Criteria for selecting additional sequences to include in the core protocol were: relevance to clinical trials, availability among the major MR vendors, ability to standardize across various models and platforms from a single vendor, reliability of quantitative measurements, evidence of test-retest precision of longitudinal measures, availability of data (cross-sectional and longitudinal) indicating evidence of diagnostic efficacy, and interest on the part of the ISAB and associated ADNI scientific investigators. All three emerging MRI applications (ASL, DTI and RSFC) selected for inclusion in ADNI-2 are generally considered to be “signal-starved”; that is, they all benefit from the increased SNR at 3T compared to 1.5T even more than the typical MR application. This benefit of 3T also applies to the accelerated version of the T1-volumetric acquisition. We elected to include GRE imaging as part of the core protocol on all systems. GRE imaging has become a routine component of the MRI protocol for all anti-amyloid clinical trials. Up to 20% of all AD subjects enrolled in anti-amyloid clinical trials have an abnormality detectable on GRE images 37.
Features of the ADNI-GO and ADNI-2 protocol for newly enrolled subjects are:
We elected not to include ASL, RSFC or DTI in the core protocol for all sites for several reasons. These include; general uncertainty about long-term test-retest precision, minimal evidence of diagnostic efficacy in AD, questionable relevance to clinical trials in the near term, absence of widely available phantoms to calibrate measurements of perfusion, diffusion, or connectivity, and the need to keep the protocol to an acceptable time for patient acceptance purposes. Perhaps most importantly, we note that due to rapidly developing technology and differing design choices among vendors it is not currently practical to standardize DTI and especially ASL across vendors using manufacturer-available sequences. A key guideline for ADNI-GO and ADNI-2 is that only manufacturer-available sequences will be used. We believe that placing fundamentally incompatible across-vendor MRI data into the public domain would not be helpful to the scientific community. At the same time, we did think that it was important to consider including each of these important and emerging sequence types in ADNI-GO and ADNI-2 in order to pilot these approaches for potential use in multi-center clinical trials. These considerations led us to conclude that a viable approach would be to add a different one of each of the three experimental sequence types to the core protocol of each of the three major MRI vendors – creating vendor-specific protocols, while retaining the vendor independent three “core” pulse sequences. Including only one experimental sequence per vendor protocol will keep the duration of the protocol to an acceptable time (~30 minutes) for patients (who will undergo MRI exams at four time points in the first 12 months of ADNI-GO) to limit motion artifact, patient discomfort, and attrition.
In summary, present and future plans for ADNI MRI acquisition were dictated by many considerations. Chief among these were improving methods for clinical trials in AD, modernizing the acquisition from ADNI-1, patient comfort and acceptance, and incorporating lessons learned from ADNI-1. These principles point to a multi-track MRI acquisition approach with the following features:
NIH Alzheimer's Disease Neuroimaging Initiative (AG24904); NIH Identifying Mechanisms of Dementia – Role for MRI (AG11378); NIH Construction Grant (NIH C06 RR018898); Denise Reyes
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