P334 Connectivity-based tau propagation and PET microglial activation in the Alzheimer’s disease spectrum
Marco Öchsner1*, Matthias Brendel2,3, Nicolai Franzmeier4, Lena Trappmann⁵, Mirlind Zaganjori⁵, Ersin Ersoezlue⁵, Estrella Morenas-Rodriguez5,6, Selim Guersel5,6, Lena Burow⁵, Carolin Kurz⁵, Jan Haeckert5,8, Maia Tatò⁵, Julia Utecht⁵, Boris Papazov⁹, Oliver Pogarell⁵, Daniel Janowitz⁴, Katharina Buerger4,6, Michael Ewers⁴, Carla Palleis3,6,10, Endy Weidinger¹⁰, Gloria Biechele2, Sebastian Schuster², Anika Finze², Florian Eckenweber², Rainer Rupprecht¹¹, Axel Rominger2,12, Oliver Goldhardt13, Timo Grimmer13, Daniel Keeser1,5,9, Sophia Stoecklein⁹, Olaf Dietrich⁹, Peter Bartenstein2,3, Johannes Levin3,6,10, Günter Höglinger6,14, Robert Perneczky1,3,5,6,15,16and Boris-Stephan Rauchmann1,5,6,16
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Department of Neuroradiology, LMU University Hospital, Ludwig Maximilian University of Munich, Germany
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Department of Nuclear Medicine, University Hospital, Ludwig Maximilian University of Munich, Germany
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Munich Cluster for Systems Neurology, Munich, Germany
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Institute for Stroke and Dementia Research, University Hospital, Ludwig Maximilian University of Munich, Germany
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Department of Psychiatry and Psychotherapy, LMU University Hospital, Ludwig Maximilian University of Munich, Germany
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German Center for Neurodegenerative Diseases, Munich, Germany
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Biomedical Center, Faculty of Medicine, Ludwig Maximilian University of Munich, Germany
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Department of Psychiatry, Psychotherapy, and Psychosomatics, University of Augsburg, Germany
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Department of Radiology, LMU University Hospital, Ludwig Maximilian University of Munich, Germany
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Department of Neurology, University Hospital, Ludwig Maximilian University of Munich, Germany
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Department of Psychiatry and Psychotherapy, University of Regensburg, Germany
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Department of Nuclear Medicine, University of Bern, Inselspital, Bern, Switzerland
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Department of Psychiatry and Psychotherapy, Rechts der Isar Hospital, Technical University of Munich, Germany
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Department of Neurology, Hannover Medical School, Germany
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Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, United Kingdom
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Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield
* Email: marco.oechsner@med.lmu.de
Introduction
Microglial activation is increasingly recognized as central to Alzheimer's disease spectrum (ADS) progression, potentially influencing or responding to pathological tau accumulation [1]. Recent evidence suggests microglial activation and tau pathology spread along highly interconnected brain regions, implying connectivity-driven propagation mechanisms [2]. Yet, the impact of changes in microglial activation for Tau accumulation remain unclear. We aimed to determine: (a) longitudinal differences in microglial activation between ADS and healthy controls (HC), (b) relationships between microglial activation changes and tau accumulation, and (c) how these changes affect functional connectivity based relationships between Tau and microglial activation.
Methods
As part of the longitudinal ActiGliA prospective cohort study [3], [18F]GE-180 TSPO (microglia) PET, [18F]Flutemetamol (Tau) PET, resting-state fMRI, and structural MRI in ADS (n=36; defined by CSF Aβ42/Aβ40 ratio or an Aβ PET composite of ADS) and HC (n=20; with CDR=0 and no Aβ pathology) at baseline and 18-month follow-up (n=6 each). PET imaging was intensity-normalized to cerebellar gray matter, and SUVR values extracted based on the Schaefer200 parcellation. fMRI preprocessing (fMRIPrep v1.2.1) was used to derive atlas-based, r-to-z-transformed functional connectivity matrices, after filtering, smoothing, and confound regression. Group comparisons and correlations utilized Cohen’s d, Mann-Whitney U, linear regression and Spearman’s ρ.
Results
Baseline TSPO was lower (d=-1.05, p<0.01) and tau higher (d=1.69, p<0.01) in ADS vs. HC. TSPO strongly correlated with tau levels in both groups (ADS:ρ=0.69, HC:ρ=0.86, p<0.01). Over 18 months, TSPO SUVRs increased significantly more in ADS compared to HC (d=2.61, p<0.01). Increased TSPO ratios (β=-1.4, ρ=-0.14, p=0.03), and ADS-HC TSPO ratio difference (β=-1.43, ρ=-0.25, p<0.01) correlated negatively with tau levels in ADS, while in HC only with HC-ADS ratio differences (β=0.47, p<0.01, ρ=0.13). In ADS, high TSPO-change regions showed significant negative connectivity correlations with tau (β=-2.36, ρ=-0.50, p<0.01), while high Tau regions showed only a weak connectivity based association with TSPO ratios, relationships absent in HC.
Discussion
Our findings indicate a longitudinal increase in microglial activation in ADS, despite initially lower activation compared to HC. Higher baseline microglial activation correlated with tau accumulation, particularly in regions differentiating ADS from HC. However, tau levels negatively correlated with longitudinal TSPO changes, suggesting limited further microglial activation in regions already exhibiting elevated baseline activation. Although TSPO ratio changes varied across individuals, group-level connectivity relationships between regions with high TSPO changes and tau support a connectivity-mediated propagation of tau pathology modulated by microglial activation.
Acknowledgements
This study was supported by the German Center for Neurodegenerative Disorders (Deutsches Zentrum für Neurodegenerative Erkrankungen), Hirnliga (Manfred-Strohscheer Stiftung), and the German Research Foundation (Deutsche Forschungsgemeinschaft) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198).
References
● Fan, Z., Brooks, D. J., Okello, A., & Edison, P. (2017). An early and late peak in microglial activation in Alzheimer's disease trajectory. Brain, 140(3), 792–803.
● Pascoal, T. A., Benedet, A. L., Ashton, N. J., et al. (2021). Microglial activation and tau propagate jointly across Braak stages. Nature Medicine, 27(9), 1592–1599.
● Rauchmann, B.-S., Brendel, M., Franzmeier, N., et al. (2022). Microglial activation and connectivity in Alzheimer disease and aging. Annals of Neurology, 92(5), 768–781.
