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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2023

Open Access 01-12-2023 | Mild Neurocognitive Disorder | Research

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

Authors: Oliver Cousins, Julia J. Schubert, Avinash Chandra, Mattia Veronese, Polena Valkimadi, Byron Creese, Zunera Khan, Ryan Arathimos, Adam Hampshire, Ivana Rosenzweig, Clive Ballard, Anne Corbett, Dag Aasland, Latha Velayudhan, Michael O’Neill, David Collier, Ramla Awais, Kerstin Sander, Erik Årstad, Oliver Howes, Federico Turkheimer, Angela Hodges

Published in: Journal of Neuroinflammation | Issue 1/2023

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Abstract

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 [18F]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 [18F]florbetapir and [18F]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 [18F]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.
Appendix
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Metadata
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
Authors
Oliver Cousins
Julia J. Schubert
Avinash Chandra
Mattia Veronese
Polena Valkimadi
Byron Creese
Zunera Khan
Ryan Arathimos
Adam Hampshire
Ivana Rosenzweig
Clive Ballard
Anne Corbett
Dag Aasland
Latha Velayudhan
Michael O’Neill
David Collier
Ramla Awais
Kerstin Sander
Erik Årstad
Oliver Howes
Federico Turkheimer
Angela Hodges
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2023
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-023-02945-0

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