Proinflammatory cytokines, sickness behavior, and Alzheimer disease

Background: In Alzheimer disease (AD), systemic inflammation is known to give rise to a delirium. However, systemic inflammation also gives rise to other centrally mediated symptoms in the absence of a delirium, a concept known as sickness behavior. Systemic inflammation is characterized by the systemic production of the proinflammatory cytokines tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6) that mediate immune to brain communication and the development of sickness behavior. Objective: To determine if raised serum TNF alpha or IL-6 are associated with the presence of sickness behavior symptoms, independent of the development of delirium, in a prospective cohort study of subjects with AD. Methods: A total of 300 subjects with mild to severe AD were cognitively assessed at baseline and a blood sample taken for inflammatory markers. Cognitive assessments, including assessments to detect the development of a delirium, and blood samples were repeated at 2, 4, and 6 months. The development of neuropsychiatric symptoms in the subject with AD over the 6-month follow-up period was assessed independently by carer interview at 2, 4, and 6 months. Results: Raised serum TNF alpha and IL-6, but not CRP, were associated with an approximately 2-fold increased frequency of neuropsychiatric symptoms characteristic of sickness behavior. These relationships are independent of the development of delirium. Conclusions: Increased serum proinflammatory cytokines are associated with the presence of symptoms characteristic of sickness behavior, which are common neuropsychiatric features found in AD. This association was independent of the presence of delirium. Neurology (R) 2011;77:212-218