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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, ?01 = -0.03 ± 0.01, p = 0.002) and poorer attention in older women (>50y, ?01 = -0.024 ± 0.007, p < 0.004) and African-Americans (?01 = -0.029 ± 0.008, p < 0.001). ESR was related to faster decline on verbal memory among older men (>50y, ?11 = -0.008 ± 0.003, P = 0.009); with poorer performance on attention tests overall (?01 = -0.010 ± 0.003, P = 0.003) and among African-Americans (?01 = -0.013 ± 0.004, P = 0.002); on verbal fluency among older women (>50y,?01 = -0.037 ± 0.013, P = 0.004) and on executive function: overall (?01 = +0.62 ± 0.21, P = 0.004), older men (>50y, ?01 = +1.69 ± 0.53, P = 0.001) and African-Americans (?01 = +0.84 ± 0.28, P = 0.002). Albumin was linked to slower attention decline among older men (>50y, ?11 = +0.329 ± 0.103, P = 0.009), over-time improvement in executive function overall (?11 = -6.00 ± 2.26, P = 0.008), and better baseline psychomotor speed among African-Americans (?01 = +0.56 ± 0.19, P = 0.003). Finally, ICS predicted faster decline on visual memory/visuo-constructive abilities among older men (>50y, ?11 = +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.

Project description:PURPOSE:Evaluate and compare the retinal microvasculature in the superficial capillary plexus (SCP) in Alzheimer's disease (AD), mild cognitive impairment (MCI), and cognitively intact controls using OCT angiography. OCT parameters were also compared. DESIGN:Cross-sectional study. PARTICIPANTS:Seventy eyes from 39 AD participants, 72 eyes from 37 MCI participants, and 254 eyes from 133 control participants were enrolled. METHODS:Participants were imaged using Zeiss Cirrus HD-5000 with AngioPlex (Carl Zeiss Meditec, Dublin, CA) and underwent cognitive evaluation with Mini-Mental State Examination. MAIN OUTCOME MEASURES:Vessel density (VD) and perfusion density (PD) in the SCP within the Early Treatment Diabetic Retinopathy Study 6-mm circle, 3-mm circle, and 3-mm ring were compared between groups. Foveal avascular zone (FAZ) area, central subfield thickness (CST), macular ganglion cell-inner plexiform layer (GC-IPL) thickness, and peripapillary retinal nerve fiber layer (RNFL) thickness were also compared. RESULTS:Alzheimer's participants showed significantly decreased SCP VD and PD in the 3-mm ring (P = 0.001 and P = 0.002, respectively) and 3-mm circle (P = 0.003 and P = 0.004, respectively) and decreased SCP VD in the 6-mm circle (P = 0.047) compared with MCI and significantly decreased SCP VD and PD in the 3-mm ring (P = 0.008 and P = 0.004, respectively) and 3-mm circle (P = 0.015 and P = 0.009, respectively) and SCP PD in the 6-mm circle (P = 0.033) when compared with cognitively intact controls. There was no difference in SCP VD or PD between MCI and controls (P > 0.05). FAZ area and CST did not differ significantly between groups (P > 0.05). Alzheimer's participants showed significantly decreased GC-IPL thickness over the inferior (P = 0.032) and inferonasal (P = 0.025) sectors compared with MCI and significantly decreased GC-IPL thickness over the entire (P = 0.012), superonasal (P = 0.041), inferior (P = 0.004), and inferonasal (P = 0.006) sectors compared to controls. MCI participants showed significantly decreased temporal RNFL thickness (P = 0.04) compared with controls. CONCLUSIONS:Alzheimer's participants showed significantly reduced macular VD, PD, and GC-IPL thickness compared with MCI and controls. Changes in the retinal microvasculature may mirror small vessel cerebrovascular changes in AD.

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

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

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