Prospects and challenges of imaging neuroinflammation beyond TSPO in Alzheimer's disease

Delphine Boche, Alexander Gerhard, Elena Rodriguez-Vieitez, MINC Faculty, Delphine Boche, Alexander Gerhard, Elena Rodriguez-Vieitez, MINC Faculty

Abstract

Neuroinflammation, as defined by the activation of microglia and astrocytes, has emerged in the last years as a key element of the pathogenesis of neurodegenerative diseases based on genetic findings and preclinical and human studies. This has raised the need for new methodologies to assess and follow glial activation in patients, prompting the development of PET ligands for molecular imaging of glial cells and novel structural MRI and DTI tools leading to a multimodal approach. The present review describes the recent advancements in microglia and astrocyte biology in the context of health, ageing, and Alzheimer's disease, the most common dementia worldwide. The review further delves in molecular imaging discussing the challenges associated with past and present targets, including conflicting findings, and finally, presenting novel methodologies currently explored to improve our in vivo knowledge of the neuroinflammatory patterns in Alzheimer's disease. With glial cell activation as a potential therapeutic target in neurodegenerative diseases, the translational research between cell biologists, chemists, physicists, radiologists, and neurologists should be strengthened.

Keywords: Alzheimer’s disease; Astrocyte; MRI; Microglia; PET; TSPO.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Illustration of different microglial morphologies in human brain identified with Iba1. (a-g) From ramified to ameboid microglia; (h) cluster of microglia around amyloid plaques as observed only in Alzheimer’s disease. Counterstaining Haematoxylin, scale bar = 30 μm
Fig. 2
Fig. 2
Microglial proteins expressed in human brain and associated with different functions: Iba1 (Motility); CD68 (phagocytosis); HLA-DR (antigen presentation); CD64 (FcγRI high-affinity activating receptor reflecting presence of immunoglobulins); P2Y12 (homeostasis); CD16 (FcγRIII low-affinity activating receptor for immune complexes). Counterstaining Haematoxylin, scale bar = 30 μm
Fig. 3
Fig. 3
Cartoon illustrating emerging targets and PET tracers for the selective in vivo visualisation of activated microglia and astrocytes in Alzheimer’s disease
Fig. 4
Fig. 4
a Parametric 11C-(R)-PK11195 PET images of microglial activation in one MCI patient (upper row) and one healthy volunteer (lower row); PET images are displayed on each subject’s respective T1-weighted MRI scan normalised to the SPM5 T1 brain template and the colour bar indicates non-displaceable binding potential (BPND) values. b Parametric 11C-deuterium-L-deprenyl PET images of astrocyte activation in one Aβ-positive MCI patient (upper row) and one healthy volunteer (lower row); PET images are displayed on each subject’s respective T1-weighted MRI scan normalised to the SPM5 T1 brain template and the colour bar indicates modified-reference (cerebellar grey matter) Patlak slope values; the 11C-deuterium-L-deprenyl PET imaging data were kindly provided by Prof. Agneta Nordberg, Karolinska Institutet, Sweden
Fig. 5
Fig. 5
GFAP-positive astrocytes in human brain observed (a, b) in the grey matter; (c, d) with the endfeet of the processes forming a component of the blood-brain barrier; and (e, f) in the white matter. Counterstaining: Haematoxylin, scale bar = 50 μm

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