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Title: Assessment of Demographic, Genetic, and Imaging Variables Associated With Brain Resilience and Cognitive Resilience to Pathological Tau in Patients With Alzheimer Disease

Abstract

Importance: Better understanding is needed of the degree to which individuals tolerate Alzheimer disease (AD)-like pathological tau with respect to brain structure (brain resilience) and cognition (cognitive resilience). Objective: To examine the demographic (age, sex, and educational level), genetic (APOE-ε4 status), and neuroimaging (white matter hyperintensities and cortical thickness) factors associated with interindividual differences in brain and cognitive resilience to tau positron emission tomography (PET) load and to changes in global cognition over time. Design, setting, an participants: In this cross-sectional, longitudinal study, tau PET was performed from June 1, 2014, to November 30, 2017, and global cognition monitored for a mean [SD] interval of 2.0 [1.8] years at 3 dementia centers in South Korea, Sweden, and the United States. The study included amyloid-β-positive participants with mild cognitive impairment or AD dementia. Data analysis was performed from October 26, 2018, to December 11, 2019. Exposures: Standard dementia screening, cognitive testing, brain magnetic resonance imaging, amyloid-β PET and cerebrospinal fluid analysis, and flortaucipir (tau) labeled with fluor-18 (18F) PET. Main outcomes and measures: Separate linear regression models were performed between whole cortex [18F]flortaucipir uptake and cortical thickness, and standardized residuals were used to obtain a measure of brain resilience. The samemore » procedure was performed for whole cortex [18F]flortaucipir uptake vs Mini-Mental State Examination (MMSE) as a measure of cognitive resilience. Bivariate and multivariable linear regression models were conducted with age, sex, educational level, APOE-ε4 status, white matter hyperintensity volumes, and cortical thickness as independent variables and brain and cognitive resilience measures as dependent variables. Linear mixed models were performed to examine whether changes in MMSE scores over time differed as a function of a combined brain and cognitive resilience variable. Results: A total of 260 participants (145 [55.8%] female; mean [SD] age, 69.2 [9.5] years; mean [SD] MMSE score, 21.9 [5.5]) were included in the study. In multivariable models, women (standardized β = -0.15, P = .02) and young patients (standardized β = -0.20, P = .006) had greater brain resilience to pathological tau. Higher educational level (standardized β = 0.23, P < .001) and global cortical thickness (standardized β = 0.23, P < .001) were associated with greater cognitive resilience to pathological tau. Linear mixed models indicated a significant interaction of brain resilience × cognitive resilience × time on MMSE (β [SE] = -0.235 [0.111], P = .03), with steepest slopes for individuals with both low brain and cognitive resilience. Conclusions and relevance: Results of this study suggest that women and young patients with AD have relative preservation of brain structure when exposed to neocortical pathological tau. Interindividual differences in resilience to pathological tau may be important to disease progression because participants with both low brain and cognitive resilience had the most rapid cognitive decline over time.« less

Authors:
 [1];  [2];  [3];  [4];  [5];  [2];  [6];  [3];  [3];  [3];  [7];  [7];  [7];  [7];  [7];  [8];  [9]
  1. Lund Univ. (Sweden). Clinical Memory Research Unit; Amsterdam Univ. Medical Center (Netherlands). Amsterdam Neuroscience. Dept. of Neurology. Alzheimer Center Amsterdam
  2. Yonsei Univ., Seoul (Korea, Republic of). College of Medicine. Gangnam Severance Hospital. Dept. of Neurology
  3. Lund Univ. (Sweden). Clinical Memory Research Unit
  4. King's College, London (United Kingdom). Biomedical Engineering and Imaging Sciences; Univ. College London (United Kingdom). Dept. of Neurodegenerative Disease. Dementia Research Centre; Univ. College London (United Kingdom). Dept. of Medical Physics. Centre for Medical Image Computing
  5. Univ. College London (United Kingdom). Dept. of Neurodegenerative Disease. Dementia Research Centre
  6. Yonsei Univ., Seoul (Korea, Republic of). College of Medicine. Gangnam Severance Hospital. Dept. of Neurology; Korea Inst. Radiological and Medical Sciences, Seoul (Korea, Republic of). Division of Applied RI
  7. Univ. of California, San Francisco, CA (United States). Dept. of Neurology. Memory and Aging Center
  8. Univ. of California, San Francisco, CA (United States). Dept. of Neurology. Memory and Aging Center; Univ. of California, San Francisco, CA (United States). Dept. of Radiology and Biomedical Imaging; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics and Integrated Bioimaging Division
  9. Lund Univ. (Sweden). Clinical Memory Research Unit; Skåne Univ. Hospital, Malmö (Sweden). Memory Clinic
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
OSTI Identifier:
1629516
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
JAMA Neurology
Additional Journal Information:
Journal Volume: 77; Journal Issue: 5; Journal ID: ISSN 2168-6149
Publisher:
American Medical Association
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Ossenkoppele, Rik, Lyoo, Chul Hyoung, Jester-Broms, Jonas, Sudre, Carole H., Cho, Hanna, Ryu, Young Hoon, Choi, Jae Yong, Smith, Ruben, Strandberg, Olof, Palmqvist, Sebastian, Kramer, Joel, Boxer, Adam L., Gorno-Tempini, Maria L., Miller, Bruce L., La Joie, Renaud, Rabinovici, Gil D., and Hansson, Oskar. Assessment of Demographic, Genetic, and Imaging Variables Associated With Brain Resilience and Cognitive Resilience to Pathological Tau in Patients With Alzheimer Disease. United States: N. p., 2020. Web. doi:10.1001/jamaneurol.2019.5154.
Ossenkoppele, Rik, Lyoo, Chul Hyoung, Jester-Broms, Jonas, Sudre, Carole H., Cho, Hanna, Ryu, Young Hoon, Choi, Jae Yong, Smith, Ruben, Strandberg, Olof, Palmqvist, Sebastian, Kramer, Joel, Boxer, Adam L., Gorno-Tempini, Maria L., Miller, Bruce L., La Joie, Renaud, Rabinovici, Gil D., & Hansson, Oskar. Assessment of Demographic, Genetic, and Imaging Variables Associated With Brain Resilience and Cognitive Resilience to Pathological Tau in Patients With Alzheimer Disease. United States. https://doi.org/10.1001/jamaneurol.2019.5154
Ossenkoppele, Rik, Lyoo, Chul Hyoung, Jester-Broms, Jonas, Sudre, Carole H., Cho, Hanna, Ryu, Young Hoon, Choi, Jae Yong, Smith, Ruben, Strandberg, Olof, Palmqvist, Sebastian, Kramer, Joel, Boxer, Adam L., Gorno-Tempini, Maria L., Miller, Bruce L., La Joie, Renaud, Rabinovici, Gil D., and Hansson, Oskar. Fri . "Assessment of Demographic, Genetic, and Imaging Variables Associated With Brain Resilience and Cognitive Resilience to Pathological Tau in Patients With Alzheimer Disease". United States. https://doi.org/10.1001/jamaneurol.2019.5154. https://www.osti.gov/servlets/purl/1629516.
@article{osti_1629516,
title = {Assessment of Demographic, Genetic, and Imaging Variables Associated With Brain Resilience and Cognitive Resilience to Pathological Tau in Patients With Alzheimer Disease},
author = {Ossenkoppele, Rik and Lyoo, Chul Hyoung and Jester-Broms, Jonas and Sudre, Carole H. and Cho, Hanna and Ryu, Young Hoon and Choi, Jae Yong and Smith, Ruben and Strandberg, Olof and Palmqvist, Sebastian and Kramer, Joel and Boxer, Adam L. and Gorno-Tempini, Maria L. and Miller, Bruce L. and La Joie, Renaud and Rabinovici, Gil D. and Hansson, Oskar},
abstractNote = {Importance: Better understanding is needed of the degree to which individuals tolerate Alzheimer disease (AD)-like pathological tau with respect to brain structure (brain resilience) and cognition (cognitive resilience). Objective: To examine the demographic (age, sex, and educational level), genetic (APOE-ε4 status), and neuroimaging (white matter hyperintensities and cortical thickness) factors associated with interindividual differences in brain and cognitive resilience to tau positron emission tomography (PET) load and to changes in global cognition over time. Design, setting, an participants: In this cross-sectional, longitudinal study, tau PET was performed from June 1, 2014, to November 30, 2017, and global cognition monitored for a mean [SD] interval of 2.0 [1.8] years at 3 dementia centers in South Korea, Sweden, and the United States. The study included amyloid-β-positive participants with mild cognitive impairment or AD dementia. Data analysis was performed from October 26, 2018, to December 11, 2019. Exposures: Standard dementia screening, cognitive testing, brain magnetic resonance imaging, amyloid-β PET and cerebrospinal fluid analysis, and flortaucipir (tau) labeled with fluor-18 (18F) PET. Main outcomes and measures: Separate linear regression models were performed between whole cortex [18F]flortaucipir uptake and cortical thickness, and standardized residuals were used to obtain a measure of brain resilience. The same procedure was performed for whole cortex [18F]flortaucipir uptake vs Mini-Mental State Examination (MMSE) as a measure of cognitive resilience. Bivariate and multivariable linear regression models were conducted with age, sex, educational level, APOE-ε4 status, white matter hyperintensity volumes, and cortical thickness as independent variables and brain and cognitive resilience measures as dependent variables. Linear mixed models were performed to examine whether changes in MMSE scores over time differed as a function of a combined brain and cognitive resilience variable. Results: A total of 260 participants (145 [55.8%] female; mean [SD] age, 69.2 [9.5] years; mean [SD] MMSE score, 21.9 [5.5]) were included in the study. In multivariable models, women (standardized β = -0.15, P = .02) and young patients (standardized β = -0.20, P = .006) had greater brain resilience to pathological tau. Higher educational level (standardized β = 0.23, P < .001) and global cortical thickness (standardized β = 0.23, P < .001) were associated with greater cognitive resilience to pathological tau. Linear mixed models indicated a significant interaction of brain resilience × cognitive resilience × time on MMSE (β [SE] = -0.235 [0.111], P = .03), with steepest slopes for individuals with both low brain and cognitive resilience. Conclusions and relevance: Results of this study suggest that women and young patients with AD have relative preservation of brain structure when exposed to neocortical pathological tau. Interindividual differences in resilience to pathological tau may be important to disease progression because participants with both low brain and cognitive resilience had the most rapid cognitive decline over time.},
doi = {10.1001/jamaneurol.2019.5154},
journal = {JAMA Neurology},
number = 5,
volume = 77,
place = {United States},
year = {2020},
month = {5}
}