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Time to amyloid positivity and preclinical changes in brain metabolism, atrophy, and cognition : Evidence for emerging amyloid pathology in alzheimer's disease

Insel, Philip S. LU ; Ossenkoppele, Rik; Gessert, Devon; Jagust, William J; Landau, Susan M; Hansson, Oskar LU ; Weiner, Michael W; Mattsson, Niklas LU and , (2017) In Frontiers in Neuroscience 11(MAY).
Abstract

Background: Aβ pathology is associated with longitudinal changes of brain metabolism, atrophy, and cognition, in cognitively healthy elders. However, Aβ information is usually measured cross-sectionally and dichotomized to classify subjects as Aβ-positive or Aβ-negative, making it difficult to evaluate when brain and cognitive changes occur with respect to emerging Aβ pathology. In this study, we use longitudinal Aβ information to combine the level and rate of change of Aβ to estimate the time to Aβ-positivity for each subject and test this temporal proximity to significant Aβ pathology for associations with brain structure, metabolism, and cognition. Methods: In 89 cognitively healthy elders with up to 10 years of follow-up, we... (More)

Background: Aβ pathology is associated with longitudinal changes of brain metabolism, atrophy, and cognition, in cognitively healthy elders. However, Aβ information is usually measured cross-sectionally and dichotomized to classify subjects as Aβ-positive or Aβ-negative, making it difficult to evaluate when brain and cognitive changes occur with respect to emerging Aβ pathology. In this study, we use longitudinal Aβ information to combine the level and rate of change of Aβ to estimate the time to Aβ-positivity for each subject and test this temporal proximity to significant Aβ pathology for associations with brain structure, metabolism, and cognition. Methods: In 89 cognitively healthy elders with up to 10 years of follow-up, we estimated the points at which rates of fluorodeoxyglucose (FDG) PET, MRI, and cognitive and functional decline begin to accelerate with respect to the time to Aβ-positivity. Points of initial acceleration in rates of decline were estimated using mixed-effects models with penalized regression splines. Results: Acceleration of rates of FDG PET were observed to occur 20+ years before the conventional threshold for Aβ-positivity. Subtle signs of cognitive dysfunction were observed 10+ years before Aβ-positivity. Conclusions: Aβ may have subtle associations with other hallmarks of Alzheimer's disease before Aβ biomarkers reach conventional thresholds for Aβ-positivity. Therefore, we propose that emerging Aβ pathology occurs many years before cognitively healthy elders reach the current threshold for Aβ positivity (preclinical AD). To allow prevention in the earliest disease stages, AD clinical trials may be designed to also include subjects with Aβ biomarkers in the sub-threshold range.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Alzheimer's disease, Atrophy, Cognition, Metabolism, Preclinical, β-amyloid
in
Frontiers in Neuroscience
volume
11
issue
MAY
publisher
Frontiers
external identifiers
  • scopus:85019578770
  • wos:000406523400001
ISSN
1662-4548
DOI
10.3389/fnins.2017.00281
language
English
LU publication?
yes
id
73139be4-1e78-42bf-a675-55f4f561feaa
date added to LUP
2017-06-09 09:35:35
date last changed
2017-09-18 11:40:01
@article{73139be4-1e78-42bf-a675-55f4f561feaa,
  abstract     = {<p>Background: Aβ pathology is associated with longitudinal changes of brain metabolism, atrophy, and cognition, in cognitively healthy elders. However, Aβ information is usually measured cross-sectionally and dichotomized to classify subjects as Aβ-positive or Aβ-negative, making it difficult to evaluate when brain and cognitive changes occur with respect to emerging Aβ pathology. In this study, we use longitudinal Aβ information to combine the level and rate of change of Aβ to estimate the time to Aβ-positivity for each subject and test this temporal proximity to significant Aβ pathology for associations with brain structure, metabolism, and cognition. Methods: In 89 cognitively healthy elders with up to 10 years of follow-up, we estimated the points at which rates of fluorodeoxyglucose (FDG) PET, MRI, and cognitive and functional decline begin to accelerate with respect to the time to Aβ-positivity. Points of initial acceleration in rates of decline were estimated using mixed-effects models with penalized regression splines. Results: Acceleration of rates of FDG PET were observed to occur 20+ years before the conventional threshold for Aβ-positivity. Subtle signs of cognitive dysfunction were observed 10+ years before Aβ-positivity. Conclusions: Aβ may have subtle associations with other hallmarks of Alzheimer's disease before Aβ biomarkers reach conventional thresholds for Aβ-positivity. Therefore, we propose that emerging Aβ pathology occurs many years before cognitively healthy elders reach the current threshold for Aβ positivity (preclinical AD). To allow prevention in the earliest disease stages, AD clinical trials may be designed to also include subjects with Aβ biomarkers in the sub-threshold range.</p>},
  articleno    = {281},
  author       = {Insel, Philip S. and Ossenkoppele, Rik and Gessert, Devon and Jagust, William J and Landau, Susan M and Hansson, Oskar and Weiner, Michael W and Mattsson, Niklas and , },
  issn         = {1662-4548},
  keyword      = {Alzheimer's disease,Atrophy,Cognition,Metabolism,Preclinical,β-amyloid},
  language     = {eng},
  month        = {05},
  number       = {MAY},
  publisher    = {Frontiers},
  series       = {Frontiers in Neuroscience},
  title        = {Time to amyloid positivity and preclinical changes in brain metabolism, atrophy, and cognition : Evidence for emerging amyloid pathology in alzheimer's disease},
  url          = {http://dx.doi.org/10.3389/fnins.2017.00281},
  volume       = {11},
  year         = {2017},
}