TY - JOUR
T1 - Identifying changepoints in biomarkers during the preclinical phase of Alzheimer's disease
AU - Younes, Laurent
AU - Albert, Marilyn
AU - Moghekar, Abhay
AU - Soldan, Anja
AU - Pettigrew, Corinne
AU - Miller, Michael I.
N1 - Funding Information:
This study was supported in part by grants from the National Institutes of Health (U19-AG03365 and P50-AG005146).
Publisher Copyright:
Copyright © 2019 Younes, Albert, Moghekar, Soldan, Pettigrew and Miller. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
PY - 2019
Y1 - 2019
N2 - Objective: Several models have been proposed for the evolution of Alzheimer's disease (AD) biomarkers. The aim of this study was to identify changepoints in a range of biomarkers during the preclinical phase of AD. Methods: We examined nine measures based on cerebrospinal fluid (CSF), magnetic resonance imaging (MRI) and cognitive testing, obtained from 306 cognitively normal individuals, a subset of whom subsequently progressed to the symptomatic phase of AD. A changepoint model was used to determine which of the measures had a significant change in slope in relation to clinical symptom onset. Results: All nine measures had significant changepoints, all of which preceded symptom onset, however, the timing of these changepoints varied considerably. A single measure, CSF t-tau, had an early changepoint (34 years prior to symptom onset). A group of measures, including the remaining CSF measures (CSF Abeta and phosphorylated tau) and all cognitive tests had changepoints 10-15 years prior to symptom onset. A second group is formed by medial temporal lobe shape composite measures, with a 6-year time difference between the right and left side (respectively nine and 3 years prior to symptom onset). Conclusion: These findings highlight the long period of time prior to symptom onset during which AD pathology is accumulating in the brain. There are several significant findings, including the early changes in cognition and the laterality of the MRI findings. Additional work is needed to clarify their significance.
AB - Objective: Several models have been proposed for the evolution of Alzheimer's disease (AD) biomarkers. The aim of this study was to identify changepoints in a range of biomarkers during the preclinical phase of AD. Methods: We examined nine measures based on cerebrospinal fluid (CSF), magnetic resonance imaging (MRI) and cognitive testing, obtained from 306 cognitively normal individuals, a subset of whom subsequently progressed to the symptomatic phase of AD. A changepoint model was used to determine which of the measures had a significant change in slope in relation to clinical symptom onset. Results: All nine measures had significant changepoints, all of which preceded symptom onset, however, the timing of these changepoints varied considerably. A single measure, CSF t-tau, had an early changepoint (34 years prior to symptom onset). A group of measures, including the remaining CSF measures (CSF Abeta and phosphorylated tau) and all cognitive tests had changepoints 10-15 years prior to symptom onset. A second group is formed by medial temporal lobe shape composite measures, with a 6-year time difference between the right and left side (respectively nine and 3 years prior to symptom onset). Conclusion: These findings highlight the long period of time prior to symptom onset during which AD pathology is accumulating in the brain. There are several significant findings, including the early changes in cognition and the laterality of the MRI findings. Additional work is needed to clarify their significance.
KW - Biomarkers
KW - CSF assessment
KW - Changepoints
KW - Cognitive assessment
KW - Preclinical Alzheimer's disease
KW - Shape analysis
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U2 - 10.3389/fnagi.2019.00074
DO - 10.3389/fnagi.2019.00074
M3 - Article
C2 - 31001108
AN - SCOPUS:85068251638
VL - 11
JO - Frontiers in Aging Neuroscience
JF - Frontiers in Aging Neuroscience
SN - 1663-4365
IS - APR
M1 - 74
ER -