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3 Publications visible to you, out of a total of 3
Deciphering sources of PET signals in the tumor microenvironment of glioblastoma at cellular resolution.

Abstract (Expand)

Various cellular sources hamper interpretation of positron emission tomography (PET) biomarkers in the tumor microenvironment (TME). We developed an approach of immunomagnetic cell sorting after in … vivo radiotracer injection (scRadiotracing) with three-dimensional (3D) histology to dissect the cellular allocation of PET signals in the TME. In mice with implanted glioblastoma, translocator protein (TSPO) radiotracer uptake per tumor cell was higher compared to tumor-associated microglia/macrophages (TAMs), validated by protein levels. Translation of in vitro scRadiotracing to patients with glioma immediately after tumor resection confirmed higher single-cell TSPO tracer uptake of tumor cells compared to immune cells. Across species, cellular radiotracer uptake explained the heterogeneity of individual TSPO-PET signals. In consideration of cellular tracer uptake and cell type abundance, tumor cells were the main contributor to TSPO enrichment in glioblastoma; however, proteomics identified potential PET targets highly specific for TAMs. Combining cellular tracer uptake measures with 3D histology facilitates precise allocation of PET signals and serves to validate emerging novel TAM-specific radioligands.

Authors: L. M. Bartos, S. V. Kirchleitner, Z. I. Kolabas, S. Quach, A. Beck, J. Lorenz, J. Blobner, S. A. Mueller, S. Ulukaya, L. Hoeher, I. Horvath, K. Wind-Mark, A. Holzgreve, V. C. Ruf, L. Gold, L. H. Kunze, S. T. Kunte, P. Beumers, H. E. Park, M. Antons, A. Zatcepin, N. Briel, L. Hoermann, R. Schaefer, D. Messerer, P. Bartenstein, M. J. Riemenschneider, S. Lindner, S. Ziegler, J. Herms, S. F. Lichtenthaler, A. Erturk, J. C. Tonn, L. von Baumgarten, N. L. Albert, M. Brendel

Date Published: 27th Oct 2023

Publication Type: Journal

Amyloid-associated increases in soluble tau relate to tau aggregation rates and cognitive decline in early Alzheimer's disease.

Abstract (Expand)

For optimal design of anti-amyloid-β (Aβ) and anti-tau clinical trials, we need to better understand the pathophysiological cascade of Aβ- and tau-related processes. Therefore, we set out to investigate … how Aβ and soluble phosphorylated tau (p-tau) relate to the accumulation of tau aggregates assessed with PET and subsequent cognitive decline across the Alzheimer's disease (AD) continuum. Using human cross-sectional and longitudinal neuroimaging and cognitive assessment data, we show that in early stages of AD, increased concentration of soluble CSF p-tau is strongly associated with accumulation of insoluble tau aggregates across the brain, and CSF p-tau levels mediate the effect of Aβ on tau aggregation. Further, higher soluble p-tau concentrations are mainly related to faster accumulation of tau aggregates in the regions with strong functional connectivity to individual tau epicenters. In this early stage, higher soluble p-tau concentrations is associated with cognitive decline, which is mediated by faster increase of tau aggregates. In contrast, in AD dementia, when Aβ fibrils and soluble p-tau levels have plateaued, cognitive decline is related to the accumulation rate of insoluble tau aggregates. Our data suggest that therapeutic approaches reducing soluble p-tau levels might be most favorable in early AD, before widespread insoluble tau aggregates.

Authors: Alexa Pichet Binette, Nicolai Franzmeier, Nicola Spotorno, Michael Ewers, Matthias Brendel, Davina Biel, Olof Strandberg, Shorena Janelidze, Sebastian Palmqvist, Niklas Mattsson-Carlgren, Ruben Smith, Erik Stomrud, Rik Ossenkoppele, Oskar Hansson

Date Published: 4th Nov 2022

Publication Type: Journal

White matter aging drives microglial diversity.

Abstract (Expand)

Aging results in gray and white matter degeneration, but the specific microglial responses are unknown. Using single-cell RNA sequencing from white and gray matter separately, we identified white … matter-associated microglia (WAMs), which share parts of the disease-associated microglia (DAM) gene signature and are characterized by activation of genes implicated in phagocytic activity and lipid metabolism. WAMs depend on triggering receptor expressed on myeloid cells 2 (TREM2) signaling and are aging dependent. In the aged brain, WAMs form independent of apolipoprotein E (APOE), in contrast to mouse models of Alzheimer's disease, in which microglia with the WAM gene signature are generated prematurely and in an APOE-dependent pathway similar to DAMs. Within the white matter, microglia frequently cluster in nodules, where they are engaged in clearing degenerated myelin. Thus, WAMs may represent a potentially protective response required to clear degenerated myelin accumulating during white matter aging and disease.

Authors: S. Safaiyan, S. Besson-Girard, T. Kaya, L. Cantuti-Castelvetri, L. Liu, H. Ji, M. Schifferer, G. Gouna, F. Usifo, N. Kannaiyan, D. Fitzner, X. Xiang, M. J. Rossner, M. Brendel, O. Gokce, M. Simons

Date Published: 7th Apr 2021

Publication Type: Journal

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