title: Multiplex analyte assays to characterize different dementias: brain inflammatory cytokines in poststroke and other dementias.
abstract: Both the inflammatory potential and cognitive function decline during aging. The association between the repertoire of inflammatory biomarkers and cognitive decline is unclear. Inflammatory cytokines have been reported to be increased, decreased, or unchanged in the cerebrospinal fluid and sera of subjects with dementia. We assessed 112 postmortem brains from subjects diagnosed with poststroke dementia (PSD), vascular dementia, mixed dementia, and Alzheimer's disease (AD), comparing those to poststroke nondemented (PSND) subjects and age-matched controls. We analyzed 5 brain regions including the gray and white matter from the frontal and temporal lobes for a panel of cytokine and/or chemokine analytes using multiplex-array assays. Of the 37 analytes, 14 were under or near the detection limits, 7 were close to the lowest detection level, and 16 cytokines were within the linear range of the assay. We observed widely variable concentrations of C-reactive protein (CRP) and serum amyloid A at the high end (1-150 ng/mg protein), whereas several of the interleukins (IL, interferon-gamma and tumor necrosis factor) at the low end (1-10 pg/mg). There were also regional variations; most notable being high concentrations of some cytokines (e.g., CRP and angiogenesis panel) in the frontal white matter. Overall, we found decreased concentrations of several cytokines, including IL-1 beta (p = 0.000), IL-6 (p = 0.000), IL-7 (p = 0.000), IL-8 (p = 0.000), IL-16 (p = 0.001), interferon-inducible protein-10 (0.044), serum amyloid A (p = 0.011), and a trend in IL-1 alpha (p = 0.084) across all dementia groups compared to nondemented controls. IL-6 and IL-8 were significantly lower in dementia subjects than in nondemented subjects in every region. In particular, lower levels of IL-6 and IL-8 were notable in the PSD compared to PSND subjects. Because these 2 stroke groups had comparable degree of vascular pathology, the lower production of IL-6 and IL-8 in PSD reaffirms a possible specific involvement of immunosenescence in dementia pathogenesis. In contrast, CRP was not altered between dementia and nondementia subjects or between PSD and PSND. Our study provides evidence not only for the feasibility of tracking cytokines in postmortem brain tissue but also suggests differentially impaired inflammatory mechanisms underlying dementia including AD. There was a diminished inflammatory response, possibly reflecting immunosenescence and cerebral atrophy, in all dementias. Strategies to enhance anti-inflammatory cytokines and boost the immune system of the brain may be beneficial for preventing cognitive dysfunction, especially after stroke.
authors.affiliation: Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing & Vitality, Newcastle Upon Tyne, UK; Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK. Electronic address: Aiqing.chen@ncl.ac.uk.
authors.forename: Aiqing
authors.initials: A
authors.lastname: Chen
authors.affiliation: Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing & Vitality, Newcastle Upon Tyne, UK; Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Oakley
authors.affiliation: Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing & Vitality, Newcastle Upon Tyne, UK; Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Monteiro
authors.affiliation: Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing & Vitality, Newcastle Upon Tyne, UK; Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Katri
authors.initials: K
authors.lastname: Tuomela
authors.affiliation: Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing & Vitality, Newcastle Upon Tyne, UK; Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Louise M
authors.initials: LM
authors.lastname: Allan
authors.affiliation: Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing & Vitality, Newcastle Upon Tyne, UK; Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Elizabeta B
authors.initials: EB
authors.lastname: Mukaetova-Ladinska
authors.affiliation: Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing & Vitality, Newcastle Upon Tyne, UK; Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: John T
authors.initials: JT
authors.lastname: O'Brien
authors.affiliation: Neurovascular Research Group, Institute of Neuroscience, Newcastle University, Campus for Ageing & Vitality, Newcastle Upon Tyne, UK; Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, UK. Electronic address: raj.kalaria@ncl.ac.uk.
authors.forename: Raj N
authors.initials: RN
authors.lastname: Kalaria
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D015415:Biomarkers / Q000032:analysis; D001921:Brain / Q000378:metabolism*; D003071:Cognition; D016207:Cytokines / Q000032:analysis*; D003704:Dementia / Q000145:classification / Q000175:diagnosis / Q000209:etiology* / Q000276:immunology; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000032:analysis*; D008297:Male
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators
keywords: Aging; Cognitive impairment; Immunosenescence; Inflammation; Poststroke dementia; Stroke; Vascular dementia; White matter
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