The Alzheimer's Disease Neuroimaging Initiative 2 Biomarker Core: A review of progress and plans

Ju-Hee Kang, Magdalena Korecka, Michal J. Figurski, Jon B. Toledo, Kaj Blennow, Henrik Zetterberg, Teresa Waligorska, Magdalena Brylska, Leona Fields, Nirali Shah, Holly Soares, Robert A. Dean (+7 others)
2015 Alzheimer's & Dementia  
Introduction-We describe Alzheimer's Disease Neuroimaging Initiative (ADNI) Biomarker Core progress including: the Biobank; cerebrospinal fluid (CSF) amyloid beta (Aβ 1-42 ), t-tau, and p-tau 181 analytical performance, definition of Alzheimer's disease (AD) profile for plaque, and tangle burden detection and increased risk for progression to AD; AD disease heterogeneity; progress in standardization; and new studies using ADNI biofluids. Methods-Review publications authored or coauthored by
more » ... Biomarker core faculty and selected non-ADNI studies to deepen the understanding and interpretation of CSF Aβ 1-42 , t-tau, and p-tau 181 data. Results-CSFAD biomarker measurements with the qualified AlzBio3 immunoassay detects neuropathologic AD hallmarks in preclinical and prodromal disease stages, based on CSF studies in non-ADNI living subjects followed by the autopsy confirmation of AD. Collaboration across ADNI cores generated the temporal ordering model of AD biomarkers varying across individuals because of genetic/environmental factors that increase/decrease resilience to AD pathologies. Discussion-Further studies will refine this model and enable the use of biomarkers studied in ADNI clinically and in disease-modifying therapeutic trials. contributes to the variable timeline for the progression of AD [6] as reflected in the imaging, CSF biomarkers, and clinical features of patients with dementia of the AD type (DAT) (Fig. 1 ). AD can be divided into different phases: (1) a preclinical phase in which subjects are cognitively normal but have mild AD pathology, (2) a prodromal phase known as mild cognitive impairment (MCI), and (3) a phase when patients show dementia with impairments in multiple domains and loss of function in activities of daily living [4, [7] [8] [9] . On the basis of the prevailing scientific evidence, CSF Aβ 1-42 and the tau proteins have been incorporated into the revised research diagnostic criteria for AD together with β-amyloid positron emission tomography (PET) imaging [10] [11] [12] [13] , and tau amyloid PET imaging is now also available [14, 15] . It is being added to the ADNI portfolio of imaging technologies. ADNI-1 studies reported evidence of AD pathology in one-third of the cognitively intact elderly NC subjects solely based on CSF Aβ 1-42 [16, 17] . It is time to consider developing strategies to identify AD at the presymptomatic and prodromal phases to optimize the potential efficacy of disease-modifying therapies, and to enable drug development aimed at AD prevention. A key goal of ADNI continues to be the improvement of the standardization of biomarker measurements to enable their use in clinical AD trials, across multiple testing laboratories, and in routine clinical practice. Thus, the standardization of both preanalytical (at the level of biofluid sample collection, handling, aliquot preparation, and storage) and analytical sources of variability continues to be a priority of the Penn Biomarker Core and we continue to collaborate with biomarker scientists on these issues. We participated in recent consensus group and we are part of the Alzheimer's Biomarker Standardization Initiative, providing a set of recommendations for 10 preanalytical factors [18] . We have continued the work of analytical method standardization in the Penn Biomarker Core of ADNI and also have collaborated with colleagues in the Global Biomarker Standardization Consortium (GBSC) in support of Aβ 1-42 calibrator standardization, based on mass spectrometry, across various immunoassay platforms [19] . We expect that an outcome of all these efforts will be the availability of the most highly standardized methods for CSF Aβ 1-42 and tau proteins. In this review, we summarize progress by the Penn Biomarker Core of ADNI using the developed pathological CSF biomarker profile that sensitively detects Aβ amyloid plaque burden (below the threshold for the CSF Aβ 1-42 concentration) and NFTs, synapse loss, and neurodegeneration (above-threshold for CSF tau protein concentrations) [16] . We continue the collaborative work to develop biomarker tests for α-synuclein (α-syn) to indicate the presence of concomitant LBs and forTDP-43 as an indicator of inclusions of this biomarker in early AD, early and late MCI, and NC subjects. The Penn Biomarker Core has collaborated with other ADNI Cores in multimodal data analyses across ADNI to temporally order changes in clinical measures, imaging data, and chemical biomarkers that refine and expand our understanding and interpretation of the pathophysiology involved in the disease progression from NC to MCI and from MCI to AD. The hypothetical model of the temporal evolution of changes in the AD biomarkers will be further developed within the Biomarker Core studies in the ADNI-2 grant (Fig. 1) and informs our plans for the ADNI-3 competing renewal application. Kang et al. From 2010 through 2015, the ADNI-1 and II biofluid repository at Penn continuously receives biofluids (CSF, plasma, and serum) shipped from all ADNI sites followed by aliquoting and monitoring after storage in −80°C freezers. This effort requires 24/7 attention by the Penn Biomarker Core team. Since its inception in 2004, no lost samples or other untoward misadventures were recorded. The biofluid samples are collected and shipped in accordance with ADNI biomarker standard operating procedures (SOPs) established in ADNI-1 after consultation with members of the Private Partners Scientific Board (PPSB) and other ADNI advisory biomarker scientists. We continue to work closely with the ADNI Clinical Core on recording essential details for each collected sample from the jointly developed biofluid tracking form. These SOPs are essential to ensure the integrity of samples, accurate identification of the samples received and aliquots prepared from them, and sample stability. Continuous vigilance of the characteristics of each received sample by Biomarker Core staff and regular communication with Clinical Core staff and individual sites regarding any issues that may arise involving mislabeled samples or other issues has enabled the correction of the issues related to this function of the Biomarker Core, and the regular communication between this Core and the ADNI sites facilitates the collection of accurate data for every collected sample. Current status of the ADNI biofluid bank 2.2.1. ADNI-1, 2, and Grand Opportunity-From April 21, 2010 and from March 7, 2011, the dates that the first ADNI-Grand Opportunity (GO) and first ADNI-2 biofluid samples were received, respectively, through January 26, 2015, a total of 9461 biofluids were received, processed, and 164,120 aliquots prepared (1279 CSF, 8182 plasma, and serum samples; 39,561 CSF aliquots, 124,559 plasma and serum aliquots), bar code labeled, and stored in dedicated ADNI freezers at −80°C (Fig. 2) . The totals for ADNI-1, ADNI-2, and ADNI-GO are summarized in Fig. 2 . Temperature monitoring of each freezer is done everyday, 365 days a year, with a telephone alarm system, and one Penn Biomarker Core staff person is always "oncall" to respond to an alarm. For each primary biofluid sample collected, the following information is maintained in the ADNI Biomarker Core database at Penn: biofluid type (CSF, plasma, serum, urine [only ADNI-1]), coded subject and visit ID, six digit license plate number, visit date and time, date and time of receipt, condition of samples as received, biofluid sample volume and number of aliquots, and the details of sample preparation such as time from collection to time of transfer, and to time of freezing are recorded for each sample from each study site. The database is backed up daily on each of two external "brick" hard drives. The latter are stored outside the Biomarker Core laboratory in a secure location in a different building to ensure data security in the event of a catastrophic failure of the server in which the database resides. Rationale for sample preparation preanalytical steps- The preanalytical steps involved in sample preparation and the analytical method itself are two well-known sources of variability in CSF biomarker measurements. An important basis for the preparation procedure for samples at each ADNI site was the principle of keeping the Kang et al.
doi:10.1016/j.jalz.2015.05.003 pmid:26194312 pmcid:PMC5127404 fatcat:77q3x2e5kfbyjfwy3osagd264q