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Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease.

ABSTRACT: BACKGROUND:Chronic neurodegeneration results in microglial activation, but the contribution of inflammation to the progress of neurodegeneration remains unclear. We have shown that microglia express low levels of proinflammatory cytokines during chronic neurodegeneration but are "primed" to produce a more proinflammatory profile after systemic challenge with bacterial endotoxin (lipopolysaccharide [LPS]). METHODS:Here, we investigated whether intraperitoneal (IP) challenge with LPS, to mimic systemic infection, in the early stages of prion disease can 1) produce exaggerated acute behavioral (n = 9) and central nervous system (CNS) inflammatory (n = 4) responses in diseased animals compared with control animals, and 2) whether a single LPS challenge can accelerate disease progression (n = 34-35). RESULTS:Injection of LPS (100 microg/kg), at 12 weeks postinoculation (PI), resulted in heightened CNS interleukin-1 beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and interferon-beta (IFN-beta) transcription and microglial IL-1beta translation in prion-diseased animals relative to control animals. This inflammation caused exaggerated impairments in burrowing and locomotor activity, and induced hypothermia and cognitive changes in prion-diseased animals that were absent in LPS-treated control animals. At 15 weeks PI, LPS (500 microg/kg) acutely impaired motor coordination and muscle strength in prion-diseased but not in control animals. After recovery, these animals also showed earlier onset of disease-associated impairments on these parameters. CONCLUSIONS:These data demonstrate that transient systemic inflammation superimposed on neurodegenerative disease acutely exacerbates cognitive and motor symptoms of disease and accelerates disease progression. These deleterious effects of systemic inflammation have implications for the treatment of chronic neurodegeneration and associated delirium.

SUBMITTER: Cunningham C

PROVIDER: S-EPMC2633437 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease.

Cunningham Colm C Campion Suzanne S Lunnon Katie K Murray Carol L CL Woods Jack F C JF Deacon Robert M J RM Rawlins J Nicholas P JN Perry V Hugh VH

Biological psychiatry 20080918 4

<h4>Background</h4>Chronic neurodegeneration results in microglial activation, but the contribution of inflammation to the progress of neurodegeneration remains unclear. We have shown that microglia express low levels of proinflammatory cytokines during chronic neurodegeneration but are "primed" to produce a more proinflammatory profile after systemic challenge with bacterial endotoxin (lipopolysaccharide [LPS]).<h4>Methods</h4>Here, we investigated whether intraperitoneal (IP) challenge with LP ...[more]

PMID: 18801476

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Project description:Objectives/Background: Systemic inflammation can affect cognitive performance over time. The current study examined associations between systemic inflammation and cognitive performance among African Americans and Whites urban adults, stratifying by sex, and age group and by race. Patients/Methods: Among 1,555-1,719 White and African-American urban adults [Agebase: 30-64y, 2004-2013, mean±SD follow-up time(y): 4.64 ± 0.93y], conducted linear mixed-effects regression models were conducted to test associations of inflammatory markers [C-reactive protein, Erythrocyte Sedimentation Rate (ESR), albumin, iron, and an inflammation composite score (ICS)] with longitudinal cognitive performance. Results: Among key findings, CRP was linked to poorer baseline mental status among younger women (≤50y, γ01 = -0.03 ± 0.01, p = 0.002) and poorer attention in older women (>50y, γ01 = -0.024 ± 0.007, p < 0.004) and African-Americans (γ01 = -0.029 ± 0.008, p < 0.001). ESR was related to faster decline on verbal memory among older men (>50y, γ11 = -0.008 ± 0.003, P = 0.009); with poorer performance on attention tests overall (γ01 = -0.010 ± 0.003, P = 0.003) and among African-Americans (γ01 = -0.013 ± 0.004, P = 0.002); on verbal fluency among older women (>50y,γ01 = -0.037 ± 0.013, P = 0.004) and on executive function: overall (γ01 = +0.62 ± 0.21, P = 0.004), older men (>50y, γ01 = +1.69 ± 0.53, P = 0.001) and African-Americans (γ01 = +0.84 ± 0.28, P = 0.002). Albumin was linked to slower attention decline among older men (>50y, γ11 = +0.329 ± 0.103, P = 0.009), over-time improvement in executive function overall (γ11 = -6.00 ± 2.26, P = 0.008), and better baseline psychomotor speed among African-Americans (γ01 = +0.56 ± 0.19, P = 0.003). Finally, ICS predicted faster decline on visual memory/visuo-constructive abilities among older men (>50y, γ11 = +0.17 ± 0.06, p = 0.003). Conclusion: In sum, strong associations between systemic inflammation and longitudinal cognitive performance were detected, largely among older individuals (>50y) and African-Americans. Randomized trials targeting inflammation are warranted.

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Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease.

Publications

Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease.

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