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Microglial activation, tau and amyloid deposition in TREM2 p.R47H carriers and mild cognitive impairment patients: a multi-modal/multi-tracer PET/MRI imaging study with influenza vaccine immune challenge

BACKGROUND: Microglia are increasingly understood to play an important role in the pathogenesis of Alzheimer’s disease. The rs75932628 (p.R47H) TREM2 variant is a well-established risk factor for Alzheimer’s disease. TREM2 is a microglial cell surface receptor. In this multi-modal/multi-tracer PET/M...

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Autores principales: Cousins, Oliver, Schubert, Julia J., Chandra, Avinash, Veronese, Mattia, Valkimadi, Polena, Creese, Byron, Khan, Zunera, Arathimos, Ryan, Hampshire, Adam, Rosenzweig, Ivana, Ballard, Clive, Corbett, Anne, Aasland, Dag, Velayudhan, Latha, O’Neill, Michael, Collier, David, Awais, Ramla, Sander, Kerstin, Årstad, Erik, Howes, Oliver, Turkheimer, Federico, Hodges, Angela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10664604/
https://www.ncbi.nlm.nih.gov/pubmed/37990275
http://dx.doi.org/10.1186/s12974-023-02945-0
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author Cousins, Oliver
Schubert, Julia J.
Chandra, Avinash
Veronese, Mattia
Valkimadi, Polena
Creese, Byron
Khan, Zunera
Arathimos, Ryan
Hampshire, Adam
Rosenzweig, Ivana
Ballard, Clive
Corbett, Anne
Aasland, Dag
Velayudhan, Latha
O’Neill, Michael
Collier, David
Awais, Ramla
Sander, Kerstin
Årstad, Erik
Howes, Oliver
Turkheimer, Federico
Hodges, Angela
author_facet Cousins, Oliver
Schubert, Julia J.
Chandra, Avinash
Veronese, Mattia
Valkimadi, Polena
Creese, Byron
Khan, Zunera
Arathimos, Ryan
Hampshire, Adam
Rosenzweig, Ivana
Ballard, Clive
Corbett, Anne
Aasland, Dag
Velayudhan, Latha
O’Neill, Michael
Collier, David
Awais, Ramla
Sander, Kerstin
Årstad, Erik
Howes, Oliver
Turkheimer, Federico
Hodges, Angela
author_sort Cousins, Oliver
collection PubMed
description BACKGROUND: Microglia are increasingly understood to play an important role in the pathogenesis of Alzheimer’s disease. The rs75932628 (p.R47H) TREM2 variant is a well-established risk factor for Alzheimer’s disease. TREM2 is a microglial cell surface receptor. In this multi-modal/multi-tracer PET/MRI study we investigated the effect of TREM2 p.R47H carrier status on microglial activation, tau and amyloid deposition, brain structure and cognitive profile. METHODS: We compared TREM2 p.R47H carriers (n = 8; median age = 62.3) and participants with mild cognitive impairment (n = 8; median age = 70.7). Participants underwent two [(18)F]DPA-714 PET/MRI scans to assess TSPO signal, indicative of microglial activation, before and after receiving the seasonal influenza vaccination, which was used as an immune stimulant. Participants also underwent [(18)F]florbetapir and [(18)F]AV1451 PET scans to assess amyloid and tau burden, respectively. Regional tau and TSPO signal were calculated for regions of interest linked to Braak stage. An additional comparison imaging healthy control group (n = 8; median age = 45.5) had a single [(18)F]DPA-714 PET/MRI. An expanded group of participants underwent neuropsychological testing, to determine if TREM2 status influenced clinical phenotype. RESULTS: Compared to participants with mild cognitive impairment, TREM2 carriers had lower TSPO signal in Braak II (P = 0.04) and Braak III (P = 0.046) regions, despite having a similar burden of tau and amyloid. There were trends to suggest reduced microglial activation following influenza vaccine in TREM2 carriers. Tau deposition in the Braak VI region was higher in TREM2 carriers (P = 0.04). Furthermore, compared to healthy controls TREM2 carriers had smaller caudate (P = 0.02), total brain (P = 0.049) and white matter volumes (P = 0.02); and neuropsychological assessment revealed worse ADAS-Cog13 (P = 0.03) and Delayed Matching to Sample (P = 0.007) scores. CONCLUSIONS: TREM2 p.R47H carriers had reduced levels of microglial activation in brain regions affected early in the Alzheimer’s disease course and differences in brain structure and cognition. Changes in microglial response may underlie the increased Alzheimer’s disease risk in TREM2 p.R47H carriers. Future therapeutic agents in Alzheimer’s disease should aim to enhance protective microglial actions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02945-0.
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spelling pubmed-106646042023-11-21 Microglial activation, tau and amyloid deposition in TREM2 p.R47H carriers and mild cognitive impairment patients: a multi-modal/multi-tracer PET/MRI imaging study with influenza vaccine immune challenge Cousins, Oliver Schubert, Julia J. Chandra, Avinash Veronese, Mattia Valkimadi, Polena Creese, Byron Khan, Zunera Arathimos, Ryan Hampshire, Adam Rosenzweig, Ivana Ballard, Clive Corbett, Anne Aasland, Dag Velayudhan, Latha O’Neill, Michael Collier, David Awais, Ramla Sander, Kerstin Årstad, Erik Howes, Oliver Turkheimer, Federico Hodges, Angela J Neuroinflammation Research BACKGROUND: Microglia are increasingly understood to play an important role in the pathogenesis of Alzheimer’s disease. The rs75932628 (p.R47H) TREM2 variant is a well-established risk factor for Alzheimer’s disease. TREM2 is a microglial cell surface receptor. In this multi-modal/multi-tracer PET/MRI study we investigated the effect of TREM2 p.R47H carrier status on microglial activation, tau and amyloid deposition, brain structure and cognitive profile. METHODS: We compared TREM2 p.R47H carriers (n = 8; median age = 62.3) and participants with mild cognitive impairment (n = 8; median age = 70.7). Participants underwent two [(18)F]DPA-714 PET/MRI scans to assess TSPO signal, indicative of microglial activation, before and after receiving the seasonal influenza vaccination, which was used as an immune stimulant. Participants also underwent [(18)F]florbetapir and [(18)F]AV1451 PET scans to assess amyloid and tau burden, respectively. Regional tau and TSPO signal were calculated for regions of interest linked to Braak stage. An additional comparison imaging healthy control group (n = 8; median age = 45.5) had a single [(18)F]DPA-714 PET/MRI. An expanded group of participants underwent neuropsychological testing, to determine if TREM2 status influenced clinical phenotype. RESULTS: Compared to participants with mild cognitive impairment, TREM2 carriers had lower TSPO signal in Braak II (P = 0.04) and Braak III (P = 0.046) regions, despite having a similar burden of tau and amyloid. There were trends to suggest reduced microglial activation following influenza vaccine in TREM2 carriers. Tau deposition in the Braak VI region was higher in TREM2 carriers (P = 0.04). Furthermore, compared to healthy controls TREM2 carriers had smaller caudate (P = 0.02), total brain (P = 0.049) and white matter volumes (P = 0.02); and neuropsychological assessment revealed worse ADAS-Cog13 (P = 0.03) and Delayed Matching to Sample (P = 0.007) scores. CONCLUSIONS: TREM2 p.R47H carriers had reduced levels of microglial activation in brain regions affected early in the Alzheimer’s disease course and differences in brain structure and cognition. Changes in microglial response may underlie the increased Alzheimer’s disease risk in TREM2 p.R47H carriers. Future therapeutic agents in Alzheimer’s disease should aim to enhance protective microglial actions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02945-0. BioMed Central 2023-11-21 /pmc/articles/PMC10664604/ /pubmed/37990275 http://dx.doi.org/10.1186/s12974-023-02945-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Cousins, Oliver
Schubert, Julia J.
Chandra, Avinash
Veronese, Mattia
Valkimadi, Polena
Creese, Byron
Khan, Zunera
Arathimos, Ryan
Hampshire, Adam
Rosenzweig, Ivana
Ballard, Clive
Corbett, Anne
Aasland, Dag
Velayudhan, Latha
O’Neill, Michael
Collier, David
Awais, Ramla
Sander, Kerstin
Årstad, Erik
Howes, Oliver
Turkheimer, Federico
Hodges, Angela
Microglial activation, tau and amyloid deposition in TREM2 p.R47H carriers and mild cognitive impairment patients: a multi-modal/multi-tracer PET/MRI imaging study with influenza vaccine immune challenge
title Microglial activation, tau and amyloid deposition in TREM2 p.R47H carriers and mild cognitive impairment patients: a multi-modal/multi-tracer PET/MRI imaging study with influenza vaccine immune challenge
title_full Microglial activation, tau and amyloid deposition in TREM2 p.R47H carriers and mild cognitive impairment patients: a multi-modal/multi-tracer PET/MRI imaging study with influenza vaccine immune challenge
title_fullStr Microglial activation, tau and amyloid deposition in TREM2 p.R47H carriers and mild cognitive impairment patients: a multi-modal/multi-tracer PET/MRI imaging study with influenza vaccine immune challenge
title_full_unstemmed Microglial activation, tau and amyloid deposition in TREM2 p.R47H carriers and mild cognitive impairment patients: a multi-modal/multi-tracer PET/MRI imaging study with influenza vaccine immune challenge
title_short Microglial activation, tau and amyloid deposition in TREM2 p.R47H carriers and mild cognitive impairment patients: a multi-modal/multi-tracer PET/MRI imaging study with influenza vaccine immune challenge
title_sort microglial activation, tau and amyloid deposition in trem2 p.r47h carriers and mild cognitive impairment patients: a multi-modal/multi-tracer pet/mri imaging study with influenza vaccine immune challenge
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10664604/
https://www.ncbi.nlm.nih.gov/pubmed/37990275
http://dx.doi.org/10.1186/s12974-023-02945-0
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