NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease

Alzheimer's & Dementia - Tập 14 Số 4 - Trang 535-562 - 2018
Clifford R. Jack1,2,3,4,5, David A. Bennett1,1,2,4,5, Kaj Blennow1,2,2,4,5, María C. Carrillo1,2,6,4,5, Billy Dunn1,2,4,5,5, Samantha Budd Haeberlein1,2,3,4,5, David M. Holtzman1,7,2,4,5, William J. Jagust1,2,8,4,5, Frank Jessen1,2,9,4,5, Jason Karlawish10,1,2,4,5, Enchi Liu1,2,3,4,5, José Luís Molinuevo11,1,2,4,5, Thomas S. Wingo1,12,2,4,5, Creighton H. Phelps1,2,13,4,5, Katherine P. Rankin1,14,2,4,5, Christopher C. Rowe15,1,2,4,5, Philip Scheltens1,16,2,4,5, Eric Siemers1,2,17,4,5, Heather M. Snyder1,2,6,4,5, Reisa A. Sperling1,18,2,4,5, Cerise Elliott1,2,3,4,5, Eliezer Masliah1,2,3,4,5, Laurie Ryan1,2,3,4,5, Nina Silverberg1,2,3,4,5
1Department of Neurological Sciences Rush University Chicago IL USA
2Department of Psychiatry and Neurochemistry, University of Gothenburg, Gothenburg, Sweden
3Department of Radiology, Mayo Clinic, Rochester, MN, USA
4Medical & Scientific Relations Alzheimer's Association Chicago IL USA
5Office of Drug Evaluation FDA Silver Spring MD USA
6Medical & Scientific Relations, Alzheimer's Association, Chicago, IL, USA
7Department of Neurology, Washington University, St. Louis, MO, USA
8Department of Public Health and Neuroscience, University of California Berkeley, Berkeley, CA, USA
9Department of Psychiatry, University of Cologne, Medical Faculty, Cologne, Germany
10Department of Medicine, University of Pennsylvania, Philadelphia, Pa. USA
11BarcelonaBeta Brain Research Center, Pasqual Maragall Foundation and Hospital Clinic-IDIBAPS, Barcelona, Spain
12Department of Pathology, Stanford University, Standford, CA, USA
13Formerly at National Institute on Aging, Bethesda, MD, USA
14Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
15Department of Molecular Imaging, Austin Health, University of Melbourne, Melbourne, Australia
16Department of Neurology, VU University Medical Center, Amsterdam, Netherlands
17Formerly at Eli Lilly and Company, Indianapolis, IN, USA
18Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA

Tóm tắt

Abstract

In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a “research framework” because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six‐stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker‐based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker‐based research should not be considered a template for all research into age‐related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β‐amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.

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Alzheimer's & Dementia

Tập 14 Số 4

535-562

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