Journal of Neuroinflammation (Mar 2023)

[18F]F-DED PET imaging of reactive astrogliosis in neurodegenerative diseases: preclinical proof of concept and first-in-human data

  • Anna Ballweg,
  • Carolin Klaus,
  • Letizia Vogler,
  • Sabrina Katzdobler,
  • Karin Wind,
  • Artem Zatcepin,
  • Sibylle I. Ziegler,
  • Birkan Secgin,
  • Florian Eckenweber,
  • Bernd Bohr,
  • Alexander Bernhardt,
  • Urban Fietzek,
  • Boris-Stephan Rauchmann,
  • Sophia Stoecklein,
  • Stefanie Quach,
  • Leonie Beyer,
  • Maximilian Scheifele,
  • Marcel Simmet,
  • Emanuel Joseph,
  • Simon Lindner,
  • Isabella Berg,
  • Norman Koglin,
  • Andre Mueller,
  • Andrew W. Stephens,
  • Peter Bartenstein,
  • Joerg C. Tonn,
  • Nathalie L. Albert,
  • Tania Kümpfel,
  • Martin Kerschensteiner,
  • Robert Perneczky,
  • Johannes Levin,
  • Lars Paeger,
  • Jochen Herms,
  • Matthias Brendel

DOI
https://doi.org/10.1186/s12974-023-02749-2
Journal volume & issue
Vol. 20, no. 1
pp. 1 – 16

Abstract

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Abstract Objectives Reactive gliosis is a common pathological hallmark of CNS pathology resulting from neurodegeneration and neuroinflammation. In this study we investigate the capability of a novel monoamine oxidase B (MAO-B) PET ligand to monitor reactive astrogliosis in a transgenic mouse model of Alzheimer`s disease (AD). Furthermore, we performed a pilot study in patients with a range of neurodegenerative and neuroinflammatory conditions. Methods A cross-sectional cohort of 24 transgenic (PS2APP) and 25 wild-type mice (age range: 4.3–21.0 months) underwent 60 min dynamic [18F]fluorodeprenyl-D2 ([18F]F-DED), static 18 kDa translocator protein (TSPO, [18F]GE-180) and β-amyloid ([18F]florbetaben) PET imaging. Quantification was performed via image derived input function (IDIF, cardiac input), simplified non-invasive reference tissue modelling (SRTM2, DVR) and late-phase standardized uptake value ratios (SUVr). Immunohistochemical (IHC) analyses of glial fibrillary acidic protein (GFAP) and MAO-B were performed to validate PET imaging by gold standard assessments. Patients belonging to the Alzheimer’s disease continuum (AD, n = 2), Parkinson’s disease (PD, n = 2), multiple system atrophy (MSA, n = 2), autoimmune encephalitis (n = 1), oligodendroglioma (n = 1) and one healthy control underwent 60 min dynamic [18F]F-DED PET and the data were analyzed using equivalent quantification strategies. Results We selected the cerebellum as a pseudo-reference region based on the immunohistochemical comparison of age-matched PS2APP and WT mice. Subsequent PET imaging revealed that PS2APP mice showed elevated hippocampal and thalamic [18F]F-DED DVR when compared to age-matched WT mice at 5 months (thalamus: + 4.3%; p = 0.048), 13 months (hippocampus: + 7.6%, p = 0.022) and 19 months (hippocampus: + 12.3%, p < 0.0001; thalamus: + 15.2%, p < 0.0001). Specific [18F]F-DED DVR increases of PS2APP mice occurred earlier when compared to signal alterations in TSPO and β-amyloid PET and [18F]F-DED DVR correlated with quantitative immunohistochemistry (hippocampus: R = 0.720, p < 0.001; thalamus: R = 0.727, p = 0.002). Preliminary experience in patients showed [18F]F-DED VT and SUVr patterns, matching the expected topology of reactive astrogliosis in neurodegenerative (MSA) and neuroinflammatory conditions, whereas the patient with oligodendroglioma and the healthy control indicated [18F]F-DED binding following the known physiological MAO-B expression in brain. Conclusions [18F]F-DED PET imaging is a promising approach to assess reactive astrogliosis in AD mouse models and patients with neurological diseases.

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