Journal Article

DZNE-2023-00348

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png [18F]F-DED PET imaging of reactive astrogliosis in neurodegenerative diseases: preclinical proof of concept and first-in-human data.

Ballweg, A. ; Klaus, C. (First author)DZNE* ; Vogler, L. ; Katzdobler, S.Extern* ; Wind, K.DZNE* ; Zatcepin, A.DZNE* ; Ziegler, S. I. ; Secgin, B. ; Eckenweber, F. ; Bohr, B. ; Bernhardt, M. A.Extern* ; Fietzek, U.Extern* ; Rauchmann, B.-S. (Last author)DZNE* ; Stoecklein, S. ; Quach, S. ; Beyer, L. ; Scheifele, M. ; Simmet, M. ; Joseph, E. ; Lindner, S. ; Berg, I. ; Koglin, N. ; Mueller, A. ; Stephens, A. W. ; Bartenstein, P. ; Tonn, J. C. ; Albert, N. L. ; Kümpfel, T. ; Kerschensteiner, M. ; Perneczky, R.DZNE* ; Levin, J.DZNE* ; Paeger, L.DZNE* ; Herms, J.DZNE* ; Brendel, M. (Last author)DZNE*

2023
BioMed Central London

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Please use a persistent id in citations: doi:10.1186/s12974-023-02749-2

Abstract: 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.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.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.[18F]F-DED PET imaging is a promising approach to assess reactive astrogliosis in AD mouse models and patients with neurological diseases.

Keyword(s): Humans (MeSH) ; Mice (MeSH) ; Animals (MeSH) ; Infant (MeSH) ; Gliosis: pathology (MeSH) ; Neurodegenerative Diseases: metabolism (MeSH) ; Oligodendroglioma: metabolism (MeSH) ; Oligodendroglioma: pathology (MeSH) ; Cross-Sectional Studies (MeSH) ; Pilot Projects (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Positron-Emission Tomography: methods (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Brain: metabolism (MeSH) ; Mice, Transgenic (MeSH) ; Inflammation: metabolism (MeSH) ; Monoamine Oxidase: metabolism (MeSH) ; Receptors, GABA: metabolism (MeSH) ; Astrocytes ; Deprenyl ; MAO-B ; PET ; Amyloid beta-Peptides ; Monoamine Oxidase ; TSPO protein, human ; Receptors, GABA

Note: CC BY

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Contributing Institute(s):

1. ALS, FTLD and Zebrafish models (AG Haass old)
2. Translational Brain Research (AG Herms)
3. Vascular Cognitive Impairment & Post-Stroke Dementia (AG Dichgans)
4. Clinical Dementia Research München (Clinical Dementia Research München)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2023

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