[18F]DED PET Imaging of Reactive Astrogliosis in Neurodegenerative Diseases: Preclinical Proof of Concept and First-in-Human Data

Objective: 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 [ 18 F]D2-deprenyl ([ 18 F]DED), static 18kDa translocator protein (TSPO, [ 18 F]GE-180) and β-amyloid ([ 18 F]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 with Alzheimer’s disease (AD, n = 2), Parkinson’s disease (PD, n = 2), multiple system atrophy (MSA, n = 2), autoimmune encephalitis (n = 1) and oligodendroglioma (n = 1) underwent 60 min dynamic [ 18 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 [ 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 [ 18 F]DED DVR increases of PS2APP mice occurred earlier when compared to signal alterations in TSPO and β-amyloid PET and [ 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 [ 18 F]DED V T patterns, matching the expected topology of reactive astrogliosis in neurodegenerative (AD, PD, MSA) and neuroinflammatory conditions, whereas the oligodendroglioma lesion indicated no altered [ 18 F]DED binding. Conclusion [ 18 F]DED PET imaging is a promising approach to assess reactive astrogliosis in AD mouse models and patients with neurological diseases.