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

Ballweg, Anna; Klaus, Carolin; Vogler, Letizia; Katzdobler, Sabrina; Wind, Karin; Zatcepin, Artem; Ziegler, Sibylle I.; Secgin, Birkan; Eckenweber, Florian; Bohr, Bernd; Bernhardt, Alexander; Fietzek, Urban; Rauchmann, Boris-Stephan; Stoecklein, Sophia; Quach, Stefanie; Beyer, Leonie; Scheifele, Maximilian; Simmet, Marcel; Joseph, Emanuel; Lindner, Simon; Berg, Isabella; Koglin, Norman; Mueller, Andre; Stephens, Andrew W.; Bartenstein, Peter; Tonn, Joerg C.; Albert, Nathalie L.; Kuempfel, Tania; Kerschensteiner, Martin; Perneczky, Robert; Levin, Johannes; Paeger, Lars; Herms, Jochen und Brendel, Matthias (2023): [18F]F-DED PET imaging of reactive astrogliosis in neurodegenerative diseases: preclinical proof of concept and first-in-human data. In: Journal of Neuroinflammation, Bd. 20, Nr. 1, 68

Abstract

ObjectivesReactive 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.MethodsA cross-sectional cohort of 24 transgenic (PS2APP) and 25 wild-type mice (age range: 4.3-21.0 months) underwent 60 min dynamic [F-18]fluorodeprenyl-D2 ([F-18]F-DED), static 18 kDa translocator protein (TSPO, [F-18]GE-180) and beta-amyloid ([F-18]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 [F-18]F-DED PET and the data were analyzed using equivalent quantification strategies.ResultsWe 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 [F-18]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 [F-18]F-DED DVR increases of PS2APP mice occurred earlier when compared to signal alterations in TSPO and beta-amyloid PET and [F-18]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 [F-18]F-DED V-T 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 [F-18]F-DED binding following the known physiological MAO-B expression in brain.Conclusions[F-18]F-DED PET imaging is a promising approach to assess reactive astrogliosis in AD mouse models and patients with neurological diseases.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198