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Systemic inflammation and disease progression in Alzheimer disease

From the Clinical Neurosciences Division (C.H., E.Z., C.D., D.C.) and School of Biological Science (V.H.P.), University of Southampton, UK; Trinity College Institute of Neuroscience (C.C.), School of Biochemistry and Immunology, Trinity College Dublin, Republic of Ireland; and Memory Assessment and Research Centre (J.W., S.K.), Moorgreen Hospital, Southampton, UK.

Address correspondence and reprint requests to Prof. Clive Holmes, University of Southampton, Memory Assessment and Research Centre, Botley Rd., Southampton, UK, SO30 3JB ch4{at}soton.ac.uk

Background: Acute and chronic systemic inflammation are characterized by the systemic production of the proinflammatory cytokine tumor necrosis factor (TNF-) that plays a role in immune to brain communication. Previous preclinical research shows that acute systemic inflammation contributes to an exacerbation of neurodegeneration by activation of primed microglial cells.

Objective: To determine whether acute episodes of systemic inflammation associated with increased TNF- would be associated with long-term cognitive decline in a prospective cohort study of subjects with Alzheimer disease.

Methods: Three hundred community-dwelling subjects with mild to severe Alzheimer disease were cognitively assessed, and a blood sample was taken for systemic inflammatory markers. Each subject’s main caregiver was interviewed to assess the presence of incident systemic inflammatory events. Assessments of both patient and caregiver were repeated at 2, 4, and 6 months.

Results: Acute systemic inflammatory events, found in around half of all subjects, were associated with an increase in the serum levels of proinflammatory cytokine TNF- and a 2-fold increase in the rate of cognitive decline over a 6-month period. High baseline levels of TNF- were associated with a 4-fold increase in the rate of cognitive decline. Subjects who had low levels of serum TNF- throughout the study showed no cognitive decline over the 6-month period.

Conclusions: Both acute and chronic systemic inflammation, associated with increases in serum tumor necrosis factor , is associated with an increase in cognitive decline in Alzheimer disease.

Abbreviations: AD = Alzheimer disease; ADAS-COG = Alzheimer’s Disease Assessment Scale–Cognitive subscale; ANOVA = analysis of variance; CheI = cholinesterase inhibitor; CI = confidence interval; CRP = C-reactive protein; IQR = interquartile range; MSD = Meso Scale Discovery; NINCDS-ADRDA = National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association; SIE = systemic inflammatory event; TNF- = tumor necrosis factor .

Supported by the Alzheimer’s Society.

Disclosure: Author disclosures are provided at the end of the article.

Received January 27, 2009. Accepted in final form June 16, 2009.