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

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 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 [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.

Keywords: Astrocytes; Deprenyl; MAO-B; PET.

Fig. 1

A, B [¹⁸F]F-DED cardiac blood input curves and hippocampal time-activity-curves in comparison of PS2APP (green) and wild-type (grey) mice. C Image-derived input function derived [¹⁸F]F-DED V_T in hippocampus and cerebellum of PS2APP and age matched wild-type mice at 5 and 19 months of age. D Coronal and sagittal slices of [¹⁸F]F-DED V_T in PS2APP and age-matched wild-type mice are illustrated upon a MRI template. E Immunohistochemistry of similar GFAP and MAO-B levels in the cerebellum of PS2APP and wild-type mice at 19 months of age

Fig. 2

A Quantitative [¹⁸F]F-DED PET in comparison of PS2APP and age-matched wild-type mice animals at different ages. B Coronal planes of [¹⁸F]F-DED mean DVR maps at different ages of PS2APP animals and wild-type animals projected upon a MRI mouse atlas (gray scale). C Correlation of [¹⁸F]F-DED DVRs calculated from 60-min dynamic small-animal PET recordings with corresponding 30–60 min SUVR (reference region cerebellum). 95% confidence intervals are represented by color shaded areas

Fig. 3

A MAO-B expression in GFAP-positive astrocytes (%) in comparison of PS2APP and age-matched wild-type mice together with B illustration of immunohistochemical staining in the hippocampus. C Correlation of [¹⁸F]F-DED PET DVRs with MAO-B in GFAP-positive astrocytes (%). 95% confidence intervals are represented by color shaded areas

Fig. 4

A Life-course kinetics for PS2APP mice as expressed by standardized differences (z-score) in hippocampus for the 3 radiotracers. B Coronal planes of z-scores for the three radiotracers. C Sagittal plane of the hippocampus/subiculum of wild type and PS2APP mice stained against GFAP, Iba1 and Aβ at 5, 13 and 19 months of age. D Mean (± SD) GFAP, Iba1 and Aβ staining (area-%) for PS2APP animals at different ages compared to age-matched wild-type animals

Fig. 5

Axial and sagittal planes show [¹⁸F]F-DED volumes of distribution (V_T) based on the 1TC2k compartment model at levels of neocortical regions, basal ganglia, hippocampus, cerebellum (all coronal) and brainstem (sagittal). The lesions of patients with autoimmune encephalitis and oligodendroglioma are indicated with white arrows. ATN indicates biomarker positivity for β-amyloid, tau and neurodegeneration in patients belonging to the AD continuum. MSA = multiple systems atrophy