TY - JOUR
T1 - The metabolic brain signature of cognitive resilience in the 80+
T2 - Beyond Alzheimer pathologies
AU - Arenaza-Urquijo, Eider M.
AU - Przybelski, Scott A.
AU - Lesnick, Timothy L.
AU - Graff-Radford, Jonathan
AU - MacHulda, Mary M.
AU - Knopman, David S.
AU - Schwarz, Christopher G.
AU - Lowe, Val J.
AU - Mielke, Michelle M.
AU - Petersen, Ronald C.
AU - Jack, Clifford R.
AU - Vemuri, Prashanthi
N1 - Funding Information:
This work was supported by National Institutes of Health (National Institute on Aging and National Institute of Neurological Disorders and Stroke) grants R01 AG56366 (PI: P.V.), R01 NS097495 (PI: P.V.), U01 AG06786 (PI: R.C.P.), P50 AG16574/P1 (PI: P.V.), P50 AG16574 (PI: R.C.P.), R01 AG11378 (PI: C.R.J.), R01 AG041851 (PIs: C.R.J. and D.S.K.); the Gerald and Henrietta Rauenhorst Foundation grant, the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Foundation, the Millis Family Liston Award, Elsie and Marvin Dekelboum Family Foundation, Schuler Foundation, Opus building NIH grant C06 RR018898, and was made and made possible by Rochester Epidemiology Project (R01 AG034676). The funding sources were not involved in the manuscript review or approval.
Funding Information:
The sensitivity analyses for this work as requested by the reviewer were done using Alzheimer’s Disease Neuroimaging Initiative (ADNI) data, which was funded by the ADNI grant (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12–2–0012). ADNI is funded by the National Institute on Ageing, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; Euroimmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.
PY - 2019
Y1 - 2019
N2 - Research into cognitive resilience imaging markers may help determine the clinical significance of Alzheimer's disease pathology among older adults over 80 years (80 + ). In this study, we aimed to identify a fluorodeoxyglucose (FDG)-PET based imaging marker of cognitive resilience. We identified 457 participants580 years old (357 cognitively unimpaired, 118 cognitively impaired at baseline, mean age of 83.5 3.2 years) from the population-based Mayo Clinic Study of Aging (MCSA) with baseline MRI, Pittsburgh compound B-PET and FDG-PET scans and neuropsychological evaluation. We identified a subset of 'resilient' participants (cognitively stable 80 + , n = 192) who maintained normal cognition for an average of 5 years (2-10 years). Global PIB ratio, FDG-PET ratio and cortical thickness from Alzheimer's disease signature regions were used as Alzheimer's disease imaging biomarker outcomes and global cognitive z-score was used as a cognitive outcome. First, using voxel-wise multiple regression analysis, we identified the metabolic areas underlying cognitive resilience in cognitively stable 80 + participants, which we call the 'resilience signature'. Second, using multivariate linear regression models, we evaluated the association of risk and protective factors with the resilience signature and its added value for predicting global cognition beyond established Alzheimer's disease imaging biomarkers in the full 80 + sample. Third, we evaluated the utility of the resilience signature in conjunction with amyloidosis in predicting longitudinal cognition using linear mixed effect models. Lastly, we assessed the utility of the resilience signature in an independent cohort using ADNI (n = 358, baseline mean age of 80 3.8). Our main findings were: (i) FDG-PET uptake in the bilateral anterior cingulate cortex and anterior temporal pole was associated with baseline global cognition in cognitively stable 80 + (the resilience signature); (ii) established Alzheimer's disease imaging biomarkers did not predict baseline global cognition in this subset of participants; (iii) in the full MCSA 80 + and ADNI cohorts, amyloid burden and FDG-PET in the resilience signature were the stronger predictors of baseline global cognition; (iv) sex and systemic vascular health predicted FDG-PET in the resilience signature, suggesting vascular health maintenance as a potential pathway to preserve the metabolism of these areas; and (v) the resilience signature provided significant information about global longitudinal cognitive change even when considering amyloid status in both the MCSA and ADNI cohorts. The FDG-PET resilience signature may be able to provide important information in conjunction with other Alzheimer's disease biomarkers for the determination of clinical prognosis. It may also facilitate identification of disease targeting modifiable risk factors such as vascular health maintenance.
AB - Research into cognitive resilience imaging markers may help determine the clinical significance of Alzheimer's disease pathology among older adults over 80 years (80 + ). In this study, we aimed to identify a fluorodeoxyglucose (FDG)-PET based imaging marker of cognitive resilience. We identified 457 participants580 years old (357 cognitively unimpaired, 118 cognitively impaired at baseline, mean age of 83.5 3.2 years) from the population-based Mayo Clinic Study of Aging (MCSA) with baseline MRI, Pittsburgh compound B-PET and FDG-PET scans and neuropsychological evaluation. We identified a subset of 'resilient' participants (cognitively stable 80 + , n = 192) who maintained normal cognition for an average of 5 years (2-10 years). Global PIB ratio, FDG-PET ratio and cortical thickness from Alzheimer's disease signature regions were used as Alzheimer's disease imaging biomarker outcomes and global cognitive z-score was used as a cognitive outcome. First, using voxel-wise multiple regression analysis, we identified the metabolic areas underlying cognitive resilience in cognitively stable 80 + participants, which we call the 'resilience signature'. Second, using multivariate linear regression models, we evaluated the association of risk and protective factors with the resilience signature and its added value for predicting global cognition beyond established Alzheimer's disease imaging biomarkers in the full 80 + sample. Third, we evaluated the utility of the resilience signature in conjunction with amyloidosis in predicting longitudinal cognition using linear mixed effect models. Lastly, we assessed the utility of the resilience signature in an independent cohort using ADNI (n = 358, baseline mean age of 80 3.8). Our main findings were: (i) FDG-PET uptake in the bilateral anterior cingulate cortex and anterior temporal pole was associated with baseline global cognition in cognitively stable 80 + (the resilience signature); (ii) established Alzheimer's disease imaging biomarkers did not predict baseline global cognition in this subset of participants; (iii) in the full MCSA 80 + and ADNI cohorts, amyloid burden and FDG-PET in the resilience signature were the stronger predictors of baseline global cognition; (iv) sex and systemic vascular health predicted FDG-PET in the resilience signature, suggesting vascular health maintenance as a potential pathway to preserve the metabolism of these areas; and (v) the resilience signature provided significant information about global longitudinal cognitive change even when considering amyloid status in both the MCSA and ADNI cohorts. The FDG-PET resilience signature may be able to provide important information in conjunction with other Alzheimer's disease biomarkers for the determination of clinical prognosis. It may also facilitate identification of disease targeting modifiable risk factors such as vascular health maintenance.
KW - Alzheimer's disease
KW - Amyloid-PET
KW - Cognitive reserve
KW - FDG-PET
KW - Resilience
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U2 - 10.1093/brain/awz037
DO - 10.1093/brain/awz037
M3 - Article
C2 - 30851100
AN - SCOPUS:85064287237
VL - 142
SP - 1134
EP - 1147
JO - Brain
JF - Brain
SN - 0006-8950
IS - 4
ER -