Systemic infection exacerbates cerebrovascular dysfunction in Alzheimer’s disease
| Autor: | Stuart M. Allan, J Scott Miners, Daniel J. Asby, Seth Love, Delphine Boche |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Disease Blood–brain barrier blood–brain barrier neuroinflammation Sepsis 03 medical and health sciences 0302 clinical medicine systemic infection medicine Dementia Humans Vascular dementia cerebral hypoperfusion Neuroinflammation Temporal cortex Brain Diseases business.industry AcademicSubjects/SCI01870 Brain Original Articles Neuromuscular Diseases medicine.disease Editor's Choice 030104 developmental biology Cytokine medicine.anatomical_structure Immunology AcademicSubjects/MED00310 Neurology (clinical) business Alzheimer’s disease 030217 neurology & neurosurgery |
| Zdroj: | Brain Asby, D, Boche, D, Allan, S, Love, S & Miners, J S 2021, ' Systemic infection exacerbates cerebrovascular dysfunction in Alzheimer's disease ', Brain, vol. 144, no. 6, pp. 1869-1883 . https://doi.org/10.1093/brain/awab094 |
| ISSN: | 1460-2156 0006-8950 |
| DOI: | 10.1093/brain/awab094 |
| Popis: | See Huuskonen et al. (doi:10.1093/brain/awab168) for a scientific commentary on this article. Systemic infection exacerbates Alzheimer’s disease. In this postmortem study, Asby et al. provide evidence that it does so by raising the levels of multiple cytokines in the brain and by exacerbating cerebral hypoperfusion and vascular leakage in Alzheimer’s disease, independently of the level of insoluble amyloid-β42. 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. |
| Databáze: | OpenAIRE |
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