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Temporal Ordering of Inflammatory Analytes sTNFR2 and sTREM2 in Relation to Alzheimer's Disease Biomarkers and Clinical Outcomes

Inflammatory changes are among the key markers of Alzheimer's disease (AD) related pathological changes. Pro-inflammatory analytes have been related to cognitive decline while others have been related to attenuating neuronal death. Among them, changes in cerebrospinal fluid (CSF) levels of solu...

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Autores principales: Pillai, Jagan A., Khrestian, Maria, Bena, James, Leverenz, James B., Bekris, Lynn M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279003/
https://www.ncbi.nlm.nih.gov/pubmed/34276339
http://dx.doi.org/10.3389/fnagi.2021.676744
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author Pillai, Jagan A.
Khrestian, Maria
Bena, James
Leverenz, James B.
Bekris, Lynn M.
author_facet Pillai, Jagan A.
Khrestian, Maria
Bena, James
Leverenz, James B.
Bekris, Lynn M.
author_sort Pillai, Jagan A.
collection PubMed
description Inflammatory changes are among the key markers of Alzheimer's disease (AD) related pathological changes. Pro-inflammatory analytes have been related to cognitive decline while others have been related to attenuating neuronal death. Among them, changes in cerebrospinal fluid (CSF) levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and soluble tumor necrosis factor receptor 2 (sTNFR2) have been described as impacting favorable clinical outcomes in AD. We therefore evaluate the effect of CSF sTREM2 and sTNFR2 when taken together on AD biomarkers and longitudinal clinical decline to understand their relative role on impacting AD clinical biomarkers and subsequent clinical outcomes. This longitudinal observational cohort study included 168 amyloid-positive (A+) and p-tau-positive (T+) participants with mild cognitive impairment (MCI) or AD dementia from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with 109 of them having concomitant CSF sTREM2 and sTNFR2 data and 48 A+ T+ participants with MCI from a tertiary memory clinic cohort. An exploratory analysis was performed using data from 86 cognitively normal (CN) participants from ADNI with 72 of them having concomitant CSF AD biomarkers and CSF sTREM2 and sTNFR2 data. General linear models were used to evaluate the effect of sTREM2 and sTNFR2 levels on baseline CSF Aβ42, t-tau, and p-tau, and a linear mixed-effects model was used to assess longitudinal cognitive change after controlling for well-known covariates. Among ADNI A+ T+ MCI and AD dementia participants, CSF sTNFR2 had a stronger association, than CSF sTREM2, with CSF t-tau and p-tau. This was replicated among A+ T+ MCI participants from the memory clinic cohort. On the contrary, among A+ T+ CN participants, CSF sTREM2 explained significant variance in CSF t-tau and p-tau, while CSF sTNFR2 did not. When the effects of CSF sTNFR2 and t-tau on longitudinal cognitive change were taken into account, higher CSF sTREM2 predicted slower cognitive decline in A+ T+ AD dementia participants and faster decline in A+ T+ CN participants. Our results show that given the dynamic changes in sTREM2 and sTNFR2, the clinical impact of these distinct inflammation related biomarkers in tracking AD temporal progression across disease stages are likely to differ.
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spelling pubmed-82790032021-07-15 Temporal Ordering of Inflammatory Analytes sTNFR2 and sTREM2 in Relation to Alzheimer's Disease Biomarkers and Clinical Outcomes Pillai, Jagan A. Khrestian, Maria Bena, James Leverenz, James B. Bekris, Lynn M. Front Aging Neurosci Neuroscience Inflammatory changes are among the key markers of Alzheimer's disease (AD) related pathological changes. Pro-inflammatory analytes have been related to cognitive decline while others have been related to attenuating neuronal death. Among them, changes in cerebrospinal fluid (CSF) levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and soluble tumor necrosis factor receptor 2 (sTNFR2) have been described as impacting favorable clinical outcomes in AD. We therefore evaluate the effect of CSF sTREM2 and sTNFR2 when taken together on AD biomarkers and longitudinal clinical decline to understand their relative role on impacting AD clinical biomarkers and subsequent clinical outcomes. This longitudinal observational cohort study included 168 amyloid-positive (A+) and p-tau-positive (T+) participants with mild cognitive impairment (MCI) or AD dementia from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with 109 of them having concomitant CSF sTREM2 and sTNFR2 data and 48 A+ T+ participants with MCI from a tertiary memory clinic cohort. An exploratory analysis was performed using data from 86 cognitively normal (CN) participants from ADNI with 72 of them having concomitant CSF AD biomarkers and CSF sTREM2 and sTNFR2 data. General linear models were used to evaluate the effect of sTREM2 and sTNFR2 levels on baseline CSF Aβ42, t-tau, and p-tau, and a linear mixed-effects model was used to assess longitudinal cognitive change after controlling for well-known covariates. Among ADNI A+ T+ MCI and AD dementia participants, CSF sTNFR2 had a stronger association, than CSF sTREM2, with CSF t-tau and p-tau. This was replicated among A+ T+ MCI participants from the memory clinic cohort. On the contrary, among A+ T+ CN participants, CSF sTREM2 explained significant variance in CSF t-tau and p-tau, while CSF sTNFR2 did not. When the effects of CSF sTNFR2 and t-tau on longitudinal cognitive change were taken into account, higher CSF sTREM2 predicted slower cognitive decline in A+ T+ AD dementia participants and faster decline in A+ T+ CN participants. Our results show that given the dynamic changes in sTREM2 and sTNFR2, the clinical impact of these distinct inflammation related biomarkers in tracking AD temporal progression across disease stages are likely to differ. Frontiers Media S.A. 2021-06-29 /pmc/articles/PMC8279003/ /pubmed/34276339 http://dx.doi.org/10.3389/fnagi.2021.676744 Text en Copyright © 2021 Pillai, Khrestian, Bena, Leverenz and Bekris. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Pillai, Jagan A.
Khrestian, Maria
Bena, James
Leverenz, James B.
Bekris, Lynn M.
Temporal Ordering of Inflammatory Analytes sTNFR2 and sTREM2 in Relation to Alzheimer's Disease Biomarkers and Clinical Outcomes
title Temporal Ordering of Inflammatory Analytes sTNFR2 and sTREM2 in Relation to Alzheimer's Disease Biomarkers and Clinical Outcomes
title_full Temporal Ordering of Inflammatory Analytes sTNFR2 and sTREM2 in Relation to Alzheimer's Disease Biomarkers and Clinical Outcomes
title_fullStr Temporal Ordering of Inflammatory Analytes sTNFR2 and sTREM2 in Relation to Alzheimer's Disease Biomarkers and Clinical Outcomes
title_full_unstemmed Temporal Ordering of Inflammatory Analytes sTNFR2 and sTREM2 in Relation to Alzheimer's Disease Biomarkers and Clinical Outcomes
title_short Temporal Ordering of Inflammatory Analytes sTNFR2 and sTREM2 in Relation to Alzheimer's Disease Biomarkers and Clinical Outcomes
title_sort temporal ordering of inflammatory analytes stnfr2 and strem2 in relation to alzheimer's disease biomarkers and clinical outcomes
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279003/
https://www.ncbi.nlm.nih.gov/pubmed/34276339
http://dx.doi.org/10.3389/fnagi.2021.676744
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