Key inflammatory pathway activations in the MCI stage of Alzheimer’s disease

for the Alzheimer’s Disease Neuroimaging Initiative

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Objective: To determine the key inflammatory pathways that are activated in the peripheral and CNS compartments at the mild cognitive impairment (MCI) stage of Alzheimer’s disease (AD). Methods: A cross-sectional study of patients with clinical and biomarker characteristics consistent with MCI-AD in a discovery cohort, with replication in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Inflammatory analytes were measured in the CSF and plasma with the same validated multiplex analyte platform in both cohorts and correlated with AD biomarkers (CSF Aβ42, total tau (t-tau), phosphorylated tau (p-tau) to identify key inflammatory pathway activations. The pathways were additionally validated by evaluating genes related to all analytes in coexpression networks of brain tissue transcriptome from an autopsy confirmed AD cohort to interrogate if the same pathway activations were conserved in the brain tissue gene modules. Results: Analytes of the tumor necrosis factor (TNF) signaling pathway (KEGG ID:4668) in the CSF and plasma best correlated with CSF t-tau and p-tau levels, and analytes of the complement and coagulation pathway (KEGG ID:4610) best correlated with CSF Aβ42 levels. The top inflammatory signaling pathways of significance were conserved in the peripheral and the CNS compartments. They were also confirmed to be enriched in AD brain transcriptome gene clusters. Interpretation: A cell-protective rather than a proinflammatory analyte profile predominates in the CSF in relation to neurodegeneration markers among MCI-AD patients. Analytes from the TNF signaling and the complement and coagulation pathways are relevant in evaluating disease severity at the MCI stage of AD.

Original languageEnglish (US)
Pages (from-to)1248-1262
Number of pages15
JournalAnnals of Clinical and Translational Neurology
Volume6
Issue number7
DOIs
StatePublished - Jul 1 2019

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Alzheimer Disease
Transcriptome
Brain
Tumor Necrosis Factor-alpha
Biomarkers
Cognitive Dysfunction
Gene Regulatory Networks
Multigene Family
Neuroimaging
Autopsy
Cross-Sectional Studies
Genes

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology

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Key inflammatory pathway activations in the MCI stage of Alzheimer’s disease. / for the Alzheimer’s Disease Neuroimaging Initiative.

In: Annals of Clinical and Translational Neurology, Vol. 6, No. 7, 01.07.2019, p. 1248-1262.

Research output: Contribution to journalArticle

for the Alzheimer’s Disease Neuroimaging Initiative. / Key inflammatory pathway activations in the MCI stage of Alzheimer’s disease. In: Annals of Clinical and Translational Neurology. 2019 ; Vol. 6, No. 7. pp. 1248-1262.
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abstract = "Objective: To determine the key inflammatory pathways that are activated in the peripheral and CNS compartments at the mild cognitive impairment (MCI) stage of Alzheimer’s disease (AD). Methods: A cross-sectional study of patients with clinical and biomarker characteristics consistent with MCI-AD in a discovery cohort, with replication in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Inflammatory analytes were measured in the CSF and plasma with the same validated multiplex analyte platform in both cohorts and correlated with AD biomarkers (CSF Aβ42, total tau (t-tau), phosphorylated tau (p-tau) to identify key inflammatory pathway activations. The pathways were additionally validated by evaluating genes related to all analytes in coexpression networks of brain tissue transcriptome from an autopsy confirmed AD cohort to interrogate if the same pathway activations were conserved in the brain tissue gene modules. Results: Analytes of the tumor necrosis factor (TNF) signaling pathway (KEGG ID:4668) in the CSF and plasma best correlated with CSF t-tau and p-tau levels, and analytes of the complement and coagulation pathway (KEGG ID:4610) best correlated with CSF Aβ42 levels. The top inflammatory signaling pathways of significance were conserved in the peripheral and the CNS compartments. They were also confirmed to be enriched in AD brain transcriptome gene clusters. Interpretation: A cell-protective rather than a proinflammatory analyte profile predominates in the CSF in relation to neurodegeneration markers among MCI-AD patients. Analytes from the TNF signaling and the complement and coagulation pathways are relevant in evaluating disease severity at the MCI stage of AD.",
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