Association of peripheral inflammatory markers with connectivity in large-scale functional brain networks of non-demented older adults |
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| Affiliation: | 1. Department of Neurology, Johns Hopkins University, Baltimore, United States;2. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States;3. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States;4. Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, United States;5. Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States;6. Laboratory of Behavioral Neuroscience, Intramural Research Program, National Institute on Aging, Baltimore, United States;7. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, United States;8. Division of Geriatric Medicine and Gerontology, Center on Aging and Health, Johns Hopkins University School of Medicine, Baltimore, United States;1. Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA;2. Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA;3. Department of Neurology, Duke University School of Medicine, Durham, NC, USA;4. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA;5. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA;1. Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA;2. Department of Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA;3. Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, USA;4. Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA;5. Division of General Internal Medicine, Department of Medicine, GeneSTAR Research Program, Johns Hopkins School of Medicine, Baltimore, MD, USA;6. Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA;7. Divisions of Diagnostic Radiology and Neuroradiology, Department of Radiology, Johns Hopkins School of Medicine, Baltimore, MD, USA;1. Gerontology Research Programme, Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore;2. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A1STAR), Singapore;1. Department of Neurology, Johns Hopkins University, Baltimore, MD, USA;2. Laboratory of Clinical Investigation, National Institute on Aging, Intramural Research Program, Baltimore, MD, USA;3. Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA;4. Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MS, USA;5. Department of Radiology, Mayo Clinic, Rochester, MN, USA;1. Cardiff University Brain Research Imaging Centre, Department of Psychology, Cardiff, United Kingdom;2. Division of Psychological Medicine and Neuroscience, Department of Medicine, Cardiff University, Cardiff, United Kingdom;1. Department of Psychology, University of Pittsburgh, Pittsburgh, PA 15260, United States;2. Center for the Neural Basis of Cognition, University of Pittsburgh and Carnegie Mellon University, Pittsburgh, PA 15213, United States |
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| Abstract: | BackgroundSystemic inflammation has emerged as a risk factor for cognitive decline and Alzheimer’s disease, but inflammation’s effect on distributed brain networks is unclear. We examined the relationship between peripheral inflammatory markers and subsequent functional connectivity within five large-scale cognitive networks and evaluated the modifying role of cortical amyloid and APOE ε4 status.MethodsBlood levels of soluble tumor necrosis factor-alpha receptor-1 and interleukin 6 were assessed in 176 participants (at baseline mean age: 65 (SD 9) years; 63% women; 85% cognitively normal, 15% mild cognitive impairment (MCI)) and were combined to derive an Inflammatory Index. Approximately six years later, participants underwent resting-state functional magnetic resonance imaging to quantify functional connectivity; a subset of 137 participants also underwent 11C Pittsburgh compound-B (PiB) PET imaging to assess cortical amyloid burden.ResultsUsing linear regression models adjusted for demographic characteristics and cardiovascular risk factors, a higher Inflammatory Index was associated with lower connectivity within the Default Mode (β = −0.013; 95% CI: −0.023, −0.003) and the Dorsal Attention Networks (β = −0.017; 95% CI: −0.028, −0.006). The strength of these associations did not vary by amyloid status (positive/negative). However, there was a significant interaction between Inflammatory Index and APOE ε4 status, whereby ε4-positive participants with a higher Inflammatory Index demonstrated lower connectivity. Inflammatory Index was unrelated to connectivity within other large-scale cognitive networks (Control, Limbic, and Salience/Ventral Attention networks).ConclusionPeripheral pro-inflammatory signaling in older adults without dementia, especially among APOE ε4-positive individuals, is associated with altered connectivity within two large-scale cognitive networks. |
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| Keywords: | Alzheimer’s disease Inflammation Tumor necrosis factor Interleukin 6 Functional connectivity Resting-state functional magnetic resonance imaging Default mode network Dorsal attention network |
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