Cerebrospinal Fluid and Plasma Levels of Inflammation Differentially Relate to CNS Markers of Alzheimer’s Disease Pathology and Neuronal Damage

Article type: Research Article

Authors: Bettcher, Brianne M.^{a; *} | Johnson, Sterling C.^{b; d} | Fitch, Ryan^c | Casaletto, Kaitlin B.^c | Heffernan, Kate S.^a | Asthana, Sanjay^{b; d} | Zetterberg, Henrik^{e; f; g} | Blennow, Kaj^{e; f} | Carlsson, Cynthia M.^{b; d} | Neuhaus, John^h | Bendlin, Barbara B.^b | Kramer, Joel H.^c

Affiliations: [a] Departments of Neurosurgery and Neurology, University of Colorado Anschutz Medical Campus, Rocky Mountain Alzheimer’s Disease Center, Aurora, CO, USA | [b] Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA | [c] Department of Neurology, University of California San Francisco, Memory and Aging Center, San Francisco, CA, USA | [d] Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial Veterans Hospital, Madison, WI, USA | [e] Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden | [f] Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden | [g] Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK | [h] Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA

Correspondence: [*] Correspondence to: Brianne Bettcher, PhD, Departments of Neurosurgery and Neurology, University of Colorado Anschutz Medical Campus, Rocky Mountain Alzheimer’s Disease Center, 12631 E. 17th Avenue, C307, Aurora, CO 80045, USA. Tel.: +1 303 724 3941; Fax: +1 303 724 2300; E-mail: [email protected].

Abstract: Inflammatory markers have been shown to predict neurocognitive outcomes in aging adults; however, the degree to which peripheral markers mirror the central nervous system remains unknown. We investigated the association between plasma and cerebrospinal fluid (CSF) markers of inflammation, and explored whether these markers independently predict CSF indicators of Alzheimer’s disease (AD) pathology or neuronal damage. Plasma and CSF samples were analyzed for inflammatory markers in a cohort of asymptomatic older adults (n = 173). CSF samples were analyzed for markers of AD pathology (Aβ42, phosphorylated tau [p-tau], sAβPPβ) or neuronal damage (total tau; neurofilament light chain) (n = 147). Separate linear models for each analyte were conducted with CSF and plasma levels entered simultaneously as predictors and markers of AD pathology or neuronal damage as outcome measures. Strong associations were noted between CSF and plasma MIP-1β levels, and modest associations were observed for remaining analytes. With respect to AD pathology, higher levels of plasma and CSF IL-8, CSF MIP-1β, and CSF IP-10 were associated with higher levels of p-tau. Higher levels of CSF IL-8 were associated with higher levels of CSF Aβ42. Higher CSF sAβPPβ levels were associated with higher plasma markers only (IL-8; MCP-1). In terms of neuronal injury, higher levels of plasma and CSF IL-8, CSF IP-10, and CSF MIP-1β were associated with higher levels of CSF total tau. Exploratory analyses indicated that CSF Aβ42 modifies the relationship between plasma inflammatory levels and CSF tau levels. Results suggest that both plasma and CSF inflammatory markers independently relay integral information about AD pathology and neuronal damage.

Keywords: Aging, Alzheimer’s disease, biomarkers, neuroinflammation, preclinical AD, systemic inflammation

DOI: 10.3233/JAD-170602

Journal: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 385-397, 2018