Abstract
Background: The Alzheimer's Disease Neuroimaging Initiative (ADNI) was created to develop standards for brain imaging and biomarkers for diagnosis and treatment trials. Using the ADNI dataset, experts have found that low cerebrospinal fluid amyloid-β1-42 (CSF Aβ1-42) concentration and high total-tau/Aβ1-42 ratio are highly predictive of progression in amnestic mild cognitive impairment (aMCI), and recommended these biomarkers to support the diagnosis of prodromal Alzheimer’s disease and select patients for clinical trials. However, biomarker selection criteria may introduce systematic bias that undermines their utility.
Methods: We tested for systematic biases among individuals undergoing lumbar puncture in the ADNI dataset who fulfilled the following entry criteria: (1) aMCI with CSF Aβ1-42 ≤ 192 pG/mL, compared to aMCI with Aβ1-42 > 192 pG/mL, and (2) aMCI with total-tau/Aβ1-42 > 0.39, compared to aMCI with total-tau/Aβ1-42 ≤ 0.39, as well as comparisons between participants with aMCI with and without lumbar puncture.
Findings: Individuals with low CSF Aβ1-42 scored significantly poorer than individuals with high Aβ1-42 on several baseline measures of disease severity, including Logical Memory II (3.24 vs 4.73; p<0.001), Functional Activities Questionnaire (4.30 vs 2.37; p<0.001), and Alzheimer's Disease Assessment Scale-cognitive (12.23 vs 10.09; p=0.002). Similar results were found using high total-tau/Aβ1-42. No differences were found for individuals with and without lumbar puncture except for marital status.
Interpretations: Individuals with aMCI with low Aβ1-42 in the ADNI dataset appear to have more advanced disease than those with high Aβ1-42. Selection criteria based on ADNI, as well as design of future studies, must account for potential confounds between biomarker status and disease severity to ensure that the former, and not the latter, is the true determinant of predictive accuracy.
Keywords: ADNI, Alzheimer’s disease, amyloid, biomarker, clinical trials, confounding, prediction, Neuroimaging Initiative, ApoE genotyping
Current Alzheimer Research
Title:Biomarker Positive and Negative Subjects in the ADNI Cohort: Clinical Characterization
Volume: 9 Issue: 10
Keywords: ADNI, Alzheimer’s disease, amyloid, biomarker, clinical trials, confounding, prediction, Neuroimaging Initiative, ApoE genotyping
Abstract: Background: The Alzheimer's Disease Neuroimaging Initiative (ADNI) was created to develop standards for brain imaging and biomarkers for diagnosis and treatment trials. Using the ADNI dataset, experts have found that low cerebrospinal fluid amyloid-β1-42 (CSF Aβ1-42) concentration and high total-tau/Aβ1-42 ratio are highly predictive of progression in amnestic mild cognitive impairment (aMCI), and recommended these biomarkers to support the diagnosis of prodromal Alzheimer’s disease and select patients for clinical trials. However, biomarker selection criteria may introduce systematic bias that undermines their utility.
Methods: We tested for systematic biases among individuals undergoing lumbar puncture in the ADNI dataset who fulfilled the following entry criteria: (1) aMCI with CSF Aβ1-42 ≤ 192 pG/mL, compared to aMCI with Aβ1-42 > 192 pG/mL, and (2) aMCI with total-tau/Aβ1-42 > 0.39, compared to aMCI with total-tau/Aβ1-42 ≤ 0.39, as well as comparisons between participants with aMCI with and without lumbar puncture.
Findings: Individuals with low CSF Aβ1-42 scored significantly poorer than individuals with high Aβ1-42 on several baseline measures of disease severity, including Logical Memory II (3.24 vs 4.73; p<0.001), Functional Activities Questionnaire (4.30 vs 2.37; p<0.001), and Alzheimer's Disease Assessment Scale-cognitive (12.23 vs 10.09; p=0.002). Similar results were found using high total-tau/Aβ1-42. No differences were found for individuals with and without lumbar puncture except for marital status.
Interpretations: Individuals with aMCI with low Aβ1-42 in the ADNI dataset appear to have more advanced disease than those with high Aβ1-42. Selection criteria based on ADNI, as well as design of future studies, must account for potential confounds between biomarker status and disease severity to ensure that the former, and not the latter, is the true determinant of predictive accuracy.
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Cite this article as:
Biomarker Positive and Negative Subjects in the ADNI Cohort: Clinical Characterization, Current Alzheimer Research 2012; 9 (10) . https://dx.doi.org/10.2174/156720512804142976
DOI https://dx.doi.org/10.2174/156720512804142976 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
Call for Papers in Thematic Issues
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
Deep Learning for Advancing Alzheimer's Disease Research
Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
Diagnostic and therapeutic biomarkers of dementia
Dementia affects 18 million people worldwide. Dementia is a syndrome of symptoms caused by brain disease, usually chronic or progressive, clinically characterized by multiple impairments of higher cortical functions such as memory, thinking, orientation, and learning. In addition, in the course of dementia, cognitive deficits are observed, which often hinder ...read more
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