North American Alzheimer’s Disease Neuroimaging Initiative
Since its inception in 2003, the NA-ADNI has focused on structural neuroimaging and fluid biomarkers for AD [
9], assessing their validity as both surrogate markers for treatment trials and as a way to reduce trial cost and speed up drug development [
10]. The ADNI was constituted as a public (National Institute on Aging, National Institute of Mental Health, National Institute of Biomedical Imaging and Bioengineering, National Institute for Alcohol Abuse and Alcoholism and the US Food and Drug Administration)-private (pharmaceutical companies along with private nonprofit philanthropic organizations, such as the Alzheimer’s Drug Discovery Foundation, Foundation of the National Institutes of Health and Alzheimer’s Association) collaboration, combining forces and sharing resources, infrastructure and information from diverse groups of academia, industry, nonprofit organizations and government in order to provide the foundation for the testing of new therapeutic approaches while at the same time speeding their development.
The initial phase of the NA-ADNI (ADNI 1) assessed more than 800 participants from about 60 centers in the USA and Canada. ADNI 1 was divided into five different cores: a neuroimaging core that included MRI [
11] and fluorodeoxyglucose (FDG) positron emission tomography (PET); a clinical core that included the neuropsychological assessments; a biomarker core primarily focused on cerebrospinal fluid (CSF) and plasma analytes; a statistics core; and an informatics core. This initial phase included longitudinal assessments of cognition, MRI and blood in older cognitively unimpaired individuals, subjects classified as having mild cognitive impairment (MCI) and AD patients. About one-half of them also underwent lumbar puncture and/or FDG PET studies [
12], and about 100 participants had amyloid-beta (Aβ) imaging with
11C-Pittsburgh Compound B (PiB) PET. To better characterize the prodromal stage of AD, a second phase of ADNI (ADNI-GO) incorporated individuals in the early stages of MCI [
13]. The latest round of funding supported ADNI 2, which recruited ~700 new participants to the longitudinal study that, counting those participants retained from ADNI 1 and ADNI-GO, constitutes a cohort of about 1,100 participants.
Since its inception there has been a steady output of publications from the different cores of the NA-ADNI [
7]. The tight collaboration of the different cores has already allowed integration of data, increasing the predictive power of the different markers along the spectrum of the disease but also to order them in time, with Aβ markers becoming abnormal first followed by changes in markers of neurodegeneration [
14]. The clinical core, the cornerstone of all the other streams, has been refining and redefining the classifications of the different phases of the disease, trying to better characterize the early stages of the AD spectrum, evaluating not only their diagnostic performance but also their predictive power [
15],[
16]. The biomarkers core has focused on fluid biomarkers trying to better characterize the known AD profile in CSF [
17],[
18], but also searching for a plasma biomarker(s) profile that could predict disease progression especially at the predementia stages of the disease [
14],[
19]. Furthermore, longitudinal CSF data from NA-ADNI has made it possible to trace the dynamic changes in CSF Aβ, T-tau and p-tau over time, showing that Aβ becomes abnormal about 16 years before the onset of AD dementia [
20]. The formation of the NA-ADNI and similar consortia allowed the combination of samples of multiple sites allowing new genome-wide association studies, which not only confirmed the relevance of certain gene candidates such as CLU and PICALM [
21] but also revealed novel gene candidates and biological pathways [
22].
The structural neuroimaging core has successfully standardized image acquisition and image processing and analysis protocols across multiple MRI scanners and across different MRI field strengths [
11],[
23], maintaining methodological consistency throughout the different stages of the NA-ADNI [
24]. Protocols have been updated and all new enrollments undergo a 3T MRI and a core set of three sequences: a T1 magnetization-prepared rapid acquisition with gradient echo for brain volumetrics; fluid attenuated inversion recovery for the detection and quantification of white matter hyperintensities; and gradient echo MRI for the detection of microhemorrhages. Some centers also add new sequences such as arterial spin labeling for the quantification of brain perfusion, resting-state functional MRI to assess brain connectivity and diffusion tensor imaging for tractography mapping [
24]. The PET core started by focusing on glucose metabolism and how to standardize studies acquired across multiple sites [
12],[
25],[
26], standardization that has not only confirmed previous FDG findings [
25],[
27] but has also provided new insights through novel analytical paradigms [
26],[
28],[
29]. The PET core was expanded to include Aβ imaging, initially with
11C-PiB [
30] and then with
18F-florbetapir [
31],[
32]. More than 1,000 NA-ADNI participants have undergone
18F-florbetapir imaging.
The establishment of the NA-ADNI with its particular weltanschauung set in motion similar consortia around the world imbued of the same spirit, a movement that is gaining momentum and adherents; a movement that will provide an extraordinary wealth of data for the scientific world to share, dissect and examine for years to come.
European Alzheimer’s Disease Neuroimaging Initiative
Founded in 2005, initially the E-ADNI was a pilot project funded by the Alzheimer's Association [
33] in order to evaluate how many sites from a network of more than 50 clinical and research centers already participating in the European Alzheimer's Disease Consortium had the expertise, willingness and infrastructure to adopt the NA-ADNI structure and protocols [
34]. The pilot study demonstrated not only that the selected centers were able to recruit healthy older volunteers as well as MCI and AD subjects, but that the clinical, imaging and biological data collected were equivalent to those from the NA-ADNI [
34]. This pilot study led the European Commission to financially support the development of neuGRID in 2008 and neuroGRID4U later on [
35].
One of the differences between the E-ADNI and the NA-ADNI was the inclusion of nonamnestic MCI as well as cases with subcortical vascular cognitive impairment and dementia. This approach allowed a wider assessment of different underlying etiologies of dementia, resulting in a more comprehensive look at aging.
The NA-ADNI and the E-ADNI had also joined forces in an effort to standardize and harmonize the landmarks and basic image analysis procedures for the segmentation of the hippocampus, measurement that can be used reliably and consistently across clinical settings and could eventually be useful as a surrogate marker for drug trials [
36],[
37]. A similar effort has concentrated on reaching a consensus for assessing FDG-PET data in a standardized unbiased way [
38].
The collaboration between different European centers helped increase understanding of the clinical and predictive nature of Aβ imaging [
39], and also helped to develop a predictive model combining information from MRI, FDG and CSF Aβ [
40].
The efforts of the E-ADNI were not only concentrated in neuroimaging but also in fluid biomarkers, using the pilot data to validate and standardize results from across six different centers [
41]. The integration of procedures and datasets of the ADNI with AddNeuroMed, a private-public consortium looking at the discovery of novel peripheral biomarkers, led to the identification and validation of markers such as α
2-macroglobulin and complement factor C3 that are elevated in AD [
42] and also of how plasma proteins correlated with markers of neurodegeneration [
43] or cytokines combined with brain atrophy can be used as predictive markers of disease progression [
44]. Further collaboration compared the diagnostic and predictive accuracy of several rating approaches for mesial temporal atrophy [
45]-[
47].
Australian Alzheimer’s Disease Neuroimaging Initiative
The Australian ADNI, better known as the AIBL [
48], was launched in 2006 as a prospective study of more than 1,000 older individuals [
49],[
50]. One of the distinctive features of AIBL was the inclusion of a large proportion (~70%) of healthy older individuals who, along with MCI (12%) and AD subjects (20%), were followed-up every 18 months, collecting data on demographic, genetic and lifestyle factors, cognitive function and fluid biomarkers. About one-third of the participants underwent structural MRI and Aβ imaging scans with PiB PET [
50],[
51]. While the AIBL adopted a very similar approach to neuropsychological assessments, blood biomarkers and structural MRI, the approach to disease-specific biomarkers differed - the AIBL concentrated from the very beginning on Aβ imaging, while the NA-ADNI initially focused on FDG and CSF biomarkers.
Another particular feature of the AIBL is the inclusion of a dedicated lifestyle research stream assessing the effects of exercise and/or dietary modifications on cognition or biomarkers, which showed that higher intensity exercise was associated with better cognitive function in older controls [
52]. In the area of fluid biomarkers, lower plasma Aβ
1–42/Aβ
1–40 ratio was associated with disease progression in controls and with brain Aβ in MCI and AD cases [
53]. Also, AD patients had significantly lower total plasma apolipoprotein E (ApoE) levels than controls or MCI patients [
54], but higher luteinizing hormone in serum [
55]. A perfect example of the cross-validation afforded by sharing databases is an AIBL study where a panel of biomarkers predicting brain Aβ burden with a sensitivity and specificity of 80% and 82%, respectively, were further validated using independent biomarker data from the NA-ADNI [
56].
Initial neuroimaging results showed that the prevalence of high Aβ burden (Aβ+) in cognitively unimpaired individuals increased with age, and was higher in individuals carrying at least one APOE ε4 allele [
51]. Furthermore, the Aβ burden was related to worse cognitive performance in cognitively unimpaired females, raising questions with regard to gender susceptibility to Aβ [
57]. While memory in the cognitively unimpaired adults with low Aβ burden (Aβ-) remained stable over 18 months, all aspects of episodic memory were observed to deteriorate substantially in Aβ+ nondemented participants [
58],[
59].
From a clinical perspective, some biomarkers have been shown to serve as predictors of disease progression. For example, Aβ imaging data demonstrated that Aβ+ amnestic MCI cases were much more likely to progress to AD over 18 to 36 months than Aβ- MCI cases [
60],[
61]. Subtle memory impairment in Aβ+ healthy individuals indicated that these individuals were at high risk to progress to MCI or AD within 3 years [
61]. Aβ deposition was also found to be strongly related to grey matter atrophy, where the rates of grey matter atrophy were significantly higher in Aβ+ cognitively unimpaired individuals [
62],[
63]. Moreover, the hippocampal volume and temporal Aβ deposition provided independent contributions to memory deficits, suggesting that both factors should be independently targeted in therapeutic trials aimed at reducing cognitive decline [
64]. These associations were not observed at the MCI and AD stages, suggesting that other pathological, probably downstream, events might be responsible for the progressive atrophy and cognitive decline [
65]. When assessing whether brain-derived neurotrophic factor polymorphism moderated the relationship between cognition, brain volume and Aβ burden in cognitively unimpaired individuals, carrying a Met allele was associated with moderate decline in episodic memory, reductions in hippocampal volume and increased risk of progression to MCI when compared with Val/Val homozygotes [
66], but that it did not affect rates of Aβ accumulation [
66].
The prospective longitudinal design of the study allowed the examination of changes in Aβ burden over time, where small but significant increases in neocortical Aβ burden were observed in the AD and MCI groups, and in Aβ+ controls, confirming the notion that Aβ deposition precedes cognitive impairment [
60]. Furthermore, higher rates of Aβ deposition were associated with higher Aβ burden and identified the existence of Aβ accumulators and Aβ nonaccumulators, with Aβ accumulators even found among Aβ+ controls [
67]. Consequently, Aβ imaging data from the 3-year follow-up were then used to calculate the rates of Aβ deposition over time, showing that Aβ deposition is a slow and protracted process that takes about two decades to go from the threshold of abnormal Aβ burden to the levels usually observed in AD [
68] and that Aβ deposition precedes by more than a decade hippocampal atrophy and memory impairment [
68].
Renovated efforts are aimed at obtaining structural and Aβ imaging on all participants enrolled in the study. To date, the AIBL has enrolled almost an additional 600 individuals undergoing longitudinal Aβ imaging studies either with 11C-PiB (n = 65), 18F-flutemetamol (n = 204), 18F-florbetaben (n = 127) or 18F-florbetapir (n = 195).
Japanese Alzheimer’s Disease Neuroimaging Initiative
Discussions for the launch of the J-ADNI [
69] started in 2006, as a result of the urgent need to meet the requirements for global clinical trials of AD disease-modifying drugs that were about to start in Japan. Japanese neurologists, psychiatrists, geriatricians and neuroradiologists, despite their high scientific performance in dementia, had little experience in nationwide or global-level clinical studies of AD [
70],[
71]. Second, Japan did not have sufficient infrastructures, such as the Alzheimer’s Disease Cooperative Study, that are required to conduct clinical studies or trials of AD. Therefore, in 2007 the J-ADNI was funded by the two major governmental funding agencies: the Ministry of Health, Labor and Welfare; and the New Energy and Industrial Technology Development Organization (a foundation of the Ministry of Economy, Technology, and Industry) [
70],[
71]. Seven domestic pharmas (Astellas, Eisai, Daiichi-Sankyo, Dainippon-Sumitomo, Shionogi, Takeda, Tanabe-Mitsubishi) and four international pharmas (Bristol-Myers Squibb, Eli-Lilly, Merck-Banyu, Pfizer) organized an industry scientific advisory board and contributed one-third of the total 500,000,000Y/year J-ADNI budget.
The J-ADNI research protocol was designed to maximize compatibility with the NA-ADNI, including structural MRI, FDG and Aβ imaging with PET, CSF sampling and APOE genotyping, combined with a set of clinical and psychometric tests. The initially planned sample size for the study was 300 individuals with amnestic MCI, 150 early AD individuals and 150 cognitively normal individuals. In total, 38 clinical sites participated in the J-ADNI. The clinical core ensures that the registration and clinical evaluation of the participants closely collaborates with the neuropsychology core, the latter being responsible for maximizing the harmonization between English and Japanese versions of psychometric tests. The MRI core has established an algorithm to achieve the standardization of MRI scans among clinical sites using different MRI scanners from various vendors, based on a three-dimensional magnetization-prepared rapid acquisition with gradient echo scan protocol using the ADNI phantom. Researchers at the J-ADNI have created programs for the correction and calibration of signal equity or distortion of the images, which enabled the rigorous volumetric analysis of MRI data [
72]. The PET core has established the standardized protocol for PET imaging in the J-ADNI. Twenty-eight sites are conducting FDG PET, covering ~67% of participants, and analysis of the multicenter data has started [
73]-[
75]. Aβ imaging using
11C-PiB started in ~15 sites, with two sites also performing Aβ imaging studies using
11C-BF-227. About 40% of the J-ADNI cohort had undergone Aβ imaging. The biomarker core established the J-ADNI biosample repository in Niigata University, centralizing the nationwide collection network of biofluid samples. Blood samples are collected from all participants at every visit, and ~40% of the participants had lumbar puncture for CSF samples without severe adverse events. The biomarker core has recently achieved the harmonization of protocol for X-MAP quantitation of CSF samples using Alzbio3 enzyme-linked immunosorbent assay, in collaboration with NA-ADNI biomarker core and Innogenetics. The APOE genotype is also characterized at the Niigata site.
By spring 2012 the 38 clinical sites had enrolled 545 participants meeting the inclusion criteria (239 amnestic MCI individuals, 154 cognitively normal older individuals, and 152 early AD individuals). More than 3,600 visits (that comprise ~97% of the total scheduled visits) were completed by autumn 2013, and all data continue to be analyzed, with analysis to be completed by mid 2014. Briefly, the conversion rate of late amnestic MCI individuals appears to be slightly higher than those in the NA-ADNI, at similar levels to those of the late amnestic MCI cases from the National Alzheimer’s Coordinating Center, USA, with Aβ-positive MCI individuals exhibiting higher rates of conversion to dementia. The rates of hippocampal atrophy were comparable with those measured in the NA-ADNI and, as in the NA-ADNI, lower Aβ1-42 in CSF was in good accordance with Aβ + PET scans.
Currently, the second phase of the J-ADNI (J-ADNI2) is being launched, focusing on the two populations of older individuals with very early stages of AD; that is, preclinical AD and early/late amnestic MCI. The first participant was screened on 11 December 2013. J-ADNI2 is comprised of two studies. The first is aimed at preclinical AD, where ~700 cognitively normal older individuals will undergo Aβ imaging at 31 PET sites with one of several probes, either 11C-PiB, 18F-florbetapir or 18F-flutemetamol. The scans will allow selection and recruitment of 150 cognitively normal, Aβ + individuals meeting the criteria of preclinical AD that will be followed-up in an annual fashion for 3 years. The second study of J-ADNI2 is the MCI study, devoted to the longitudinal investigation of early and late amnestic MCI, according to the criteria used by the NA-ADNI2. CSF sampling and Aβ imaging, together with structural MRI using 3T scanners and either of the three optional sequences (resting-state functional MRI, arterial spin labeling, or diffusion tensor imaging) will be performed in all participants of preclinical AD and MCI studies. These studies will pave the way towards the upcoming clinical trials of prodromal AD (or MCI due to AD) and the future very early treatment of preclinical AD in Japan, similar to the A4 anti-Aβ treatment of asymptomatic AD in the USA.