Early neuroinflammation is associated with lower amyloid and tau levels in cognitively normal older adults |
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| Affiliation: | 1. Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, United States;2. Department of Physiology and Neuroscience and the Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, United States;3. Alzheimer Disease Research Center, Department of Neurology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, United States;4. Department of Neurology, Department of Radiology, and Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States;1. Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan;2. Department of Psychiatry, Cathay General Hospital, Taipei, Taiwan;3. School of Medicine, Fu Jen Catholic University, Taipei 24205, Taiwan;4. College of Medicine, China Medical University, Taichung, Taiwan;5. Tainan Municipal An-Nan Hospital-China Medical University, Tainan, Taiwan;1. Institute of Global Health, University of North Carolina-Chapel Hill, Chapel Hill, NC, United States;2. Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, United States;3. Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, United States;4. Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, United States;5. Division of Biostatistics and Bioinformatics at The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States;6. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States;7. Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, United States;8. Johns Hopkins University School of Arts and Sciences, Baltimore, United States;9. Department of Psychiatry, Makerere University, Kampala, Uganda;10. Rakai Health Sciences Program, Kalisizo, Uganda;11. Division of Intramural Research, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, United States;12. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States;13. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States;14. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, United States;1. Department of Neurology of University Hospital Würzburg, Josef-Schneider-Straße 2, 97080 Würzburg, Germany;2. Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;3. Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA;4. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA;5. Department of Neurology of University Hospital Essen, Hufelandstraße 55, 45147 Essen, Germany |
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| Abstract: | CNS inflammation is a key factor in Alzheimer’s Disease (AD), but its relation to pathological Aβ, tau, and APOE4 is poorly understood, particularly prior to the onset of cognitive symptoms. To better characterize early relationships between inflammation, APOE4, and AD pathology, we assessed correlations between cerebrospinal fluid (CSF) inflammatory markers and brain levels of Aβ and tau in cognitively normal older adults.Each participant received a lumbar puncture to collect and quantify CSF levels of TNFα, IL-6, IL-8, and IL-10, a T1-weighted MRI, and PET scanning with [18F]flortaucipir (FTP; n = 57), which binds to tau tangles and/or [18F]florbetapir (FBP; n = 58), which binds to Aβ. Parallel voxelwise regressions assessed relationships between each CSF inflammatory marker and FTP and FBP SUVR, as well as APOE4*CSF inflammation interactions.Unexpectedly, we detected significant negative associations between regional Aβ and tau PET uptake and CSF inflammatory markers. For Aβ PET, we detected negative associations with CSF IL-6 and IL-8 in regions known to show early accumulation of Aβ (i.e. lateral and medial frontal lobes). For tau PET, negative relationships were observed with CSF TNFα and IL-8, predominantly in regions known to exhibit early tau accumulation (i.e. medial temporal lobe). In subsequent analyses, significant interactions between APOE4 status and IL-8 on Aβ and tau PET levels were observed in spatially distinct regions from those showing CSF–Aβ/tau relationships.Results from the current cross-sectional study support previous findings that neuroinflammation may be protective against AD pathology at a given stage of the disease, and extend these findings to a cognitively normal aging population. This study provides new insight into a dynamic relationship between neuroinflammation and AD pathology and may have implications for whom and when neuroinflammatory therapies may be appropriate. |
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| Keywords: | Glial activation Amyloid-β Tau Neuroinflammation PET imaging Cytokine Chemokine |
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