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

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.

Early intraneuronal amyloid triggers neuron-derived inflammatory signaling in APP transgenic rats and human brain

“…MCI patients with higher levels of CCL2 at baseline also exhibit faster rates of cognitive decline and shorter time-to-conversion to AD, suggesting that CCL2 signaling may be most relevant during early disease stages (64,65). Similarly, increasing levels of CCL2 in patients with MCI and AD are associated with elevated levels of total-tau and phospho-tau in CSF, smaller medial temporal lobe volume, and lower cognitive memory scores (66)(67)(68). In the present study, IHC detection of CCL2 revealed that, in the absence of extracellular plaques and pathological tau, Aβ-burdened neurons represent the predominant source of CCL2 within the human medial temporal lobe.…”

Thymoma Associated Myasthenia Gravis (TAMG): Differential Expression of Functional Pathways in Relation to MG Status in Different Thymoma Histotypes

“…Furthermore, expression of the brain-type ryanodine receptor, RYR3, in thymomas has been shown to be associated with TAMG (8), but in this case we now find that the association is strongest in type B2 thymomas (Figure S2). Of note, pathways that play a role in the above mentioned neurodegenerative diseases, have been found enriched in a variety of immunobiological settings, including chronic infections, graft-vs.-host disease, cancer biology, cell death, and inflammation (15)(16)(17). Likewise, the "Adherens junction" pathway that was the most significantly downregulated TAMG-associated pathway in type AB thymomas ( Table 1) has been linked to thymic hypoplasia and lymphopenia (18) and to various autoimmune diseases in conjunction with the leakiness of several blood-tissue and inter-epithelial barriers (19,20).…”

Inflammatory pathway analytes predicting rapid cognitive decline in MCI stage of Alzheimer’s disease

“…Forty-eight MCI-AD patients at baseline in whom the diagnosis of MCI-AD with CSF Ab 42 and p-tau 181 levels consistent with a diagnosis of AD and consensus evaluation of two neurologists and a neuropsychologist the details of which have been published previously. 17,18 The study was approved by the Cleveland Clinic Institutional Review Board. Eight patients did not complete the longitudinal evaluations due to nonmedical reasons by their personal choice.…”

“…The biomarker analysis protocol used in this study has been previously described (18). In brief, CSF and plasma were collected and analyzed by an independent laboratory via the validated RBM Multi-Analyte Profile (MAP) platform from Myriad Genetics (Salt Lake City, UT).…”

“…In order to evaluate analyte levels that show higher correlation when considered together (synergistic relationship) rather than individual analyte correlation by univariate analysis alone, we performed an exhaustive search to find analyte subgroups whose aggregate levels maximally correlated with cognitive change measures. 18,24,25 Hypothesis 1 (H1) tested how likely we were to see greater or equal correlation with random analyte subgroups by sampling 10,000 random analyte subgroups from among all analytes that met the 50% detection threshold and computing the correlation values. Hypothesis 2 (H2) tested how likely we were to randomly observe greater or equal correlation between the aggregate activity of an analyte subgroup and a response marker by permuting the values of each response marker 10,000 times and computing the correlation values to the aggregate analyte levels.…”