Systemic infection exacerbates cerebrovascular dysfunction in Alzheimer's disease.

Daniel Asby,Seth Love,Stuart Allan,J Scott Miners,Delphine Boche

doi:10.1093/brain/awab094

Abstract

We studied the effects of systemic infection on brain cytokine level and cerebral vascular function in Alzheimer's disease and vascular dementia, in superior temporal cortex (Brodmann area 22) from Alzheimer's disease patients (n = 75), vascular dementia patients (n = 22) and age-matched control subjects (n = 46), stratified according to the presence or absence of terminal systemic infection. Brain cytokine levels were measured using Mesoscale Discovery Multiplex Assays and markers of cerebrovascular function were assessed by ELISA. Multiple brain cytokines were elevated in Alzheimer's disease and vascular dementia: IL-15 and IL-17A were maximally elevated in end-stage Alzheimer's disease (Braak tangle stage V-VI) whereas IL-2, IL-5, IL12p40 and IL-16 were highest in intermediate Braak tangle stage III-IV disease. Several cytokines (IL-1β, IL-6, TNF-α, IL-8 and IL-15) were further raised in Alzheimer's disease with systemic infection. Cerebral hypoperfusion-indicated by decreased MAG:PLP1 and increased vascular endothelial growth factor-A (VEGF)-and blood-brain barrier leakiness, indicated by raised levels of fibrinogen, were exacerbated in Alzheimer's disease and vascular dementia patients, and also in non-dementia controls, with systemic infection. Amyloid-β42 level did not vary with infection or in association with brain cytokine levels. In controls, cortical perfusion declined with increasing IFN-γ, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-13 and tumour necrosis factor-α (TNF-α) but these relationships were lost with progression of Alzheimer's disease, and with infection (even in Braak stage 0-II brains). Cortical platelet-derived growth factor receptor-β (PDGFRβ), a pericyte marker, was reduced, and endothelin-1 (EDN1) level was increased in Alzheimer's disease; these were related to amyloid-β level and disease progression and only modestly affected by systemic infection. Our findings indicate that systemic infection alters brain cytokine levels and exacerbates cerebral hypoperfusion and blood-brain barrier leakiness associated with Alzheimer's disease and vascular dementia, independently of the level of insoluble amyloid-β, and highlight systemic infection as an important contributor to dementia, requiring early identification and treatment in the elderly population.

Highlights

Systemic infection may be associated with delirium and cognitive decline,[1,2] and cognitive impairment is commonly observed in survivors of sepsis.[3]
We studied 143 cases comprising 75 Alzheimer’s disease (42 with terminal systemic infection and 33 without), 22 vascular dementia/mixed and 46 age-matched controls (22 with and 24 without terminal systemic infection)
tumour necrosis factor-a (TNF-a) was an exception, in that the level did not correlate with EDN1 in the absence of infection; in cases with terminal infection, TNF-a showed a weak negative correlation with EDN1 in Braak stages 0–II (BS0–II) disease and a strong positive correlation in advanced Alzheimer’s disease (BSV–VI). In this post-mortem study, we show that brain cytokine levels and markers of cerebrovascular dysfunction in the superior temporal gyrus are exacerbated in the presence of terminal systemic infection in Alzheimer’s disease and vascular dementia, and in healthy age-matched controls

Summary

Introduction

Systemic infection may be associated with delirium and cognitive decline,[1,2] and cognitive impairment is commonly observed in survivors of sepsis.[3]. Modelling of acute systemic infection in rodents induces microglial activation and elevated pro-inflammatory cytokine production (IL-1b, IL-6 and TNF-a), and exacerbates cognitive decline, neurodegeneration, and Alzheimer’s disease-like (amyloid-b and tau) pathology in mouse models.[8,9,10,11] Post-mortem brain studies indicate that terminal systemic infection, recorded as the primary cause of death, is associated with activation of endothelial cells, perivascular macrophages and microglia,[12,13,14] and we recently reported that the neuroinflammatory response to terminal systemic infection is modified in end-stage Alzheimer’s disease.[15]. CSF changes in markers of pericyte injury and imaging of blood–brain barrier breakdown predicted cognitive decline in patients with mild cognitive impairment independently of changes in amyloid-b and tau.[20,23]

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Results

Conclusion