Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies

Anika Finze; Gloria Biechele; Boris Stephan Rauchmann; Nicolai Franzmeier; Carla Palleis; Sabrina Katzdobler; Endy Weidinger; Selim Guersel; Sebastian Schuster; Stefanie Harris; Julia Schmitt; Leonie Beyer; Johannes Gnörich; Simon Lindner; Nathalie L. Albert; Christian H. Wetzel; Rainer Rupprecht; Axel Rominger; Adrian Danek; Lena Burow; Carolin Kurz; Maia Tato; Julia Utecht; Boris Papazov; Mirlind Zaganjori; Lena Katharina Trappmann; Oliver Goldhardt; Timo Grimmer; Jan Haeckert; Daniel Janowitz; Katharina Buerger; Daniel Keeser; Sophia Stoecklein; Olaf Dietrich; Estrella Morenas-Rodriguez; Henryk Barthel; Osama Sabri; Peter Bartenstein; Mikael Simons; Christian Haass; Günter U. Höglinger; Johannes Levin; Robert Perneczky; Matthias Brendel

doi:10.1038/s41380-023-02188-8

Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies

Anika Finze
, Gloria Biechele
, Boris Stephan Rauchmann
, Nicolai Franzmeier
, Carla Palleis
, Sabrina Katzdobler
, Endy Weidinger
, Selim Guersel
, Sebastian Schuster
, Stefanie Harris
, Julia Schmitt
, Leonie Beyer
, Johannes Gnörich
, Simon Lindner
, Nathalie L. Albert
, Christian H. Wetzel
, Rainer Rupprecht
, Axel Rominger
, Adrian Danek
, Lena Burow

Carolin Kurz, Maia Tato, Julia Utecht, Boris Papazov, Mirlind Zaganjori, Lena Katharina Trappmann, Oliver Goldhardt, Timo Grimmer, Jan Haeckert, Daniel Janowitz, Katharina Buerger, Daniel Keeser, Sophia Stoecklein, Olaf Dietrich, Estrella Morenas-Rodriguez, Henryk Barthel, Osama Sabri, Peter Bartenstein, Mikael Simons, Christian Haass, Günter U. Höglinger, Johannes Levin, Robert Perneczky, Matthias Brendel

Ludwig-Maximilians-Universität München
Munich Cluster for Systems Neurology (SyNergy)
Göteborgs Universitet
German Center for Neurodegenerative Diseases (DZNE)
University of Regensburg
Inselspital Universitatsspital
Technical University of Munich
University Hospital Augsburg
University of Leipzig
University of Munich
Hannover Medical School
Imperial College London
University of Sheffield

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

Abstract

β-amyloid (Aβ) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer’s disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, Aβ-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of Aβ (A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional Aβ (AD: β_T = 0.412 ± 0.196 vs. β_A = 0.142 ± 0.123, p < 0.001; AD-CBS: β_T = 0.385 ± 0.176 vs. β_A = 0.131 ± 0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (β_T = 0.418 ± 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and Aβ related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neurodegenerative diseases.

Original language	English
Pages (from-to)	4438-4450
Number of pages	13
Journal	Molecular Psychiatry
Volume	28
Issue number	10
DOIs	https://doi.org/10.1038/s41380-023-02188-8
State	Published - Oct 2023

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10.1038/s41380-023-02188-8

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Finze, A., Biechele, G., Rauchmann, B. S., Franzmeier, N., Palleis, C., Katzdobler, S., Weidinger, E., Guersel, S., Schuster, S., Harris, S., Schmitt, J., Beyer, L., Gnörich, J., Lindner, S., Albert, N. L., Wetzel, C. H., Rupprecht, R., Rominger, A., Danek, A., ... Brendel, M. (2023). Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies. Molecular Psychiatry, 28(10), 4438-4450. https://doi.org/10.1038/s41380-023-02188-8

@article{37c8bc317e784b73a47e96ac3ccb8e5c,

title = "Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies",

abstract = "β-amyloid (Aβ) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer{\textquoteright}s disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, Aβ-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of Aβ (A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional Aβ (AD: βT = 0.412 ± 0.196 vs. βA = 0.142 ± 0.123, p < 0.001; AD-CBS: βT = 0.385 ± 0.176 vs. βA = 0.131 ± 0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (βT = 0.418 ± 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and Aβ related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neurodegenerative diseases.",

author = "Anika Finze and Gloria Biechele and Rauchmann, \{Boris Stephan\} and Nicolai Franzmeier and Carla Palleis and Sabrina Katzdobler and Endy Weidinger and Selim Guersel and Sebastian Schuster and Stefanie Harris and Julia Schmitt and Leonie Beyer and Johannes Gn{\"o}rich and Simon Lindner and Albert, \{Nathalie L.\} and Wetzel, \{Christian H.\} and Rainer Rupprecht and Axel Rominger and Adrian Danek and Lena Burow and Carolin Kurz and Maia Tato and Julia Utecht and Boris Papazov and Mirlind Zaganjori and Trappmann, \{Lena Katharina\} and Oliver Goldhardt and Timo Grimmer and Jan Haeckert and Daniel Janowitz and Katharina Buerger and Daniel Keeser and Sophia Stoecklein and Olaf Dietrich and Estrella Morenas-Rodriguez and Henryk Barthel and Osama Sabri and Peter Bartenstein and Mikael Simons and Christian Haass and H{\"o}glinger, \{G{\"u}nter U.\} and Johannes Levin and Robert Perneczky and Matthias Brendel",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = oct,

doi = "10.1038/s41380-023-02188-8",

language = "English",

volume = "28",

pages = "4438--4450",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Springer Nature",

number = "10",

}

Finze, A, Biechele, G, Rauchmann, BS, Franzmeier, N, Palleis, C, Katzdobler, S, Weidinger, E, Guersel, S, Schuster, S, Harris, S, Schmitt, J, Beyer, L, Gnörich, J, Lindner, S, Albert, NL, Wetzel, CH, Rupprecht, R, Rominger, A, Danek, A, Burow, L, Kurz, C, Tato, M, Utecht, J, Papazov, B, Zaganjori, M, Trappmann, LK, Goldhardt, O, Grimmer, T, Haeckert, J, Janowitz, D, Buerger, K, Keeser, D, Stoecklein, S, Dietrich, O, Morenas-Rodriguez, E, Barthel, H, Sabri, O, Bartenstein, P, Simons, M, Haass, C, Höglinger, GU, Levin, J, Perneczky, R & Brendel, M 2023, 'Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies', Molecular Psychiatry, vol. 28, no. 10, pp. 4438-4450. https://doi.org/10.1038/s41380-023-02188-8

TY - JOUR

T1 - Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies

AU - Finze, Anika

AU - Biechele, Gloria

AU - Rauchmann, Boris Stephan

AU - Franzmeier, Nicolai

AU - Palleis, Carla

AU - Katzdobler, Sabrina

AU - Weidinger, Endy

AU - Guersel, Selim

AU - Schuster, Sebastian

AU - Harris, Stefanie

AU - Schmitt, Julia

AU - Beyer, Leonie

AU - Gnörich, Johannes

AU - Lindner, Simon

AU - Albert, Nathalie L.

AU - Wetzel, Christian H.

AU - Rupprecht, Rainer

AU - Rominger, Axel

AU - Danek, Adrian

AU - Burow, Lena

AU - Kurz, Carolin

AU - Tato, Maia

AU - Utecht, Julia

AU - Papazov, Boris

AU - Zaganjori, Mirlind

AU - Trappmann, Lena Katharina

AU - Goldhardt, Oliver

AU - Grimmer, Timo

AU - Haeckert, Jan

AU - Janowitz, Daniel

AU - Buerger, Katharina

AU - Keeser, Daniel

AU - Stoecklein, Sophia

AU - Dietrich, Olaf

AU - Morenas-Rodriguez, Estrella

AU - Barthel, Henryk

AU - Sabri, Osama

AU - Bartenstein, Peter

AU - Simons, Mikael

AU - Haass, Christian

AU - Höglinger, Günter U.

AU - Levin, Johannes

AU - Perneczky, Robert

AU - Brendel, Matthias

PY - 2023/10

Y1 - 2023/10

N2 - β-amyloid (Aβ) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer’s disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, Aβ-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of Aβ (A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional Aβ (AD: βT = 0.412 ± 0.196 vs. βA = 0.142 ± 0.123, p < 0.001; AD-CBS: βT = 0.385 ± 0.176 vs. βA = 0.131 ± 0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (βT = 0.418 ± 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and Aβ related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neurodegenerative diseases.

AB - β-amyloid (Aβ) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer’s disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, Aβ-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of Aβ (A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional Aβ (AD: βT = 0.412 ± 0.196 vs. βA = 0.142 ± 0.123, p < 0.001; AD-CBS: βT = 0.385 ± 0.176 vs. βA = 0.131 ± 0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (βT = 0.418 ± 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and Aβ related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neurodegenerative diseases.

UR - https://www.scopus.com/pages/publications/85165644972

U2 - 10.1038/s41380-023-02188-8

DO - 10.1038/s41380-023-02188-8

M3 - Article

AN - SCOPUS:85165644972

SN - 1359-4184

VL - 28

SP - 4438

EP - 4450

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 10

ER -

Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies

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