TY - JOUR
T1 - Microglial activation, tau and amyloid deposition in TREM2 p.R47H carriers and mild cognitive impairment patients
T2 - a multi-modal/multi-tracer PET/MRI imaging study with influenza vaccine immune challenge
AU - Cousins, Oliver
AU - Schubert, Julia J.
AU - Chandra, Avinash
AU - Veronese, Mattia
AU - Valkimadi, Polena
AU - Creese, Byron
AU - Khan, Zunera
AU - Arathimos, Ryan
AU - Hampshire, Adam
AU - Rosenzweig, Ivana
AU - Ballard, Clive
AU - Corbett, Anne
AU - Aasland, Dag
AU - Velayudhan, Latha
AU - O’Neill, Michael
AU - Collier, David
AU - Awais, Ramla
AU - Sander, Kerstin
AU - Årstad, Erik
AU - Howes, Oliver
AU - Turkheimer, Federico
AU - Hodges, Angela
N1 - Funding Information:
We would like to thank all the participants for their involvement in this study. We would also like to thank all those who helped with recruitment, including those involved with the PROTECT, IRIS, AddNeuroMed, KHP-DCR and INcOSA studies, the memory services at the South London and Maudsley NHS Foundation Trust and the online join dementia research platform.
Funding Information:
This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115976. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. This project received funding and access to the [F]florbetapir and [F]AV1451 PET tracers from Avid and Lilly UK. Avid and Lilly UK were not involved in data analysis and interpretation. This project has received funding from the National Institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. This research was supported by the NIHR Collaboration for Leadership in Applied Health Research and Care South West Peninsula. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. This research was supported by researchers at the National Institute for Health Research University College London Hospitals Biomedical Research Centre. A partnership between UCL and University College London Hospitals NHS Foundation Trust. This work was funded in part through the MRC Proximity to Discovery: Industry Engagement Fund (External Collaboration, Innovation and Entrepreneurism: Translational Medicine in Exeter 2 (EXCITEME2) ref. MC_PC_17189) awarded to Dr Creese and MRC grant MR/N015746/1. 18 18
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/11/21
Y1 - 2023/11/21
N2 - 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.
AB - 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.
KW - Humans
KW - Middle Aged
KW - Aged
KW - Alzheimer Disease/diagnostic imaging
KW - Influenza Vaccines
KW - Microglia/metabolism
KW - Positron-Emission Tomography/methods
KW - Magnetic Resonance Imaging/methods
KW - Cognitive Dysfunction/diagnostic imaging
KW - Amyloid/metabolism
KW - Amyloid beta-Peptides/metabolism
KW - tau Proteins/metabolism
KW - Membrane Glycoproteins/genetics
KW - Receptors, Immunologic/genetics
KW - Receptors, GABA/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85177649078&partnerID=8YFLogxK
U2 - 10.1186/s12974-023-02945-0
DO - 10.1186/s12974-023-02945-0
M3 - Article
C2 - 37990275
AN - SCOPUS:85177649078
SN - 1742-2094
VL - 20
JO - Journal of neuroinflammation
JF - Journal of neuroinflammation
IS - 1
M1 - 272
ER -
