Horti AG, Naik R, Foss CA, Minn I, Misheneva V, Du Y, Wang Y, Mathews WB, Wu Y, Hall A, LaCourse C, Ahn HH, Nam H, Lesniak WG, Valentine H, Pletnikova O, Troncoso JC, Smith MD, Calabresi PA, Savonenko AV, Dannals RF, Pletnikov MV, Pomper MG. PET imaging of microglia by targeting macrophage colony-stimulating factor 1 receptor (CSF1R). Proc Natl Acad Sci U S A. 2019 Jan 29;116(5):1686-1691. Epub 2019 Jan 11 PubMed.

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  1. This is an interesting paper describing the development of a new microglia PET tracer that binds to the CSF1 receptor. Several experimental models have been tested in vitro and in vivo in the paper showing a good binding that can be blocked. Many questions can be raised regarding its relevance for Alzheimer’s disease. What is the binding affinity in postmortem AD brain tissue? Maximum binding load? Regional brain distribution? What is the correlation or the binding with immunohistochemistry using different antibodies for microglia?

    PET studies of microglia are especially of interest in early stages of AD disease as well as in other non-AD dementia disorders. Is this PET tracer expected to detect microglia subtypes present early in the course of disease? I assume the histopathological studies have shown a number of microglia subtypes in human brain. Some recent PET studies with TPSO microglia tracers suggest a biphasic change in microglia at different stages of AD (Fan et al., 2017). This CSF1R microglia PET tracer might be promising, but it is somewhat difficult to judge its clinical value for AD patients.

    References:

    Fan Z, Brooks DJ, Okello A, Edison P. An early and late peak in microglial activation in Alzheimer's disease trajectory. Brain. 2017 Mar 1;140(3):792-803. PubMed.

    View all comments by Agneta Nordberg

  2. There is indeed a real need for tools to image neuroinflammation in the human brain. This neuroinflammatory response is dominated by an innate immune response by cells of the myeloid lineage: thus new PET ligands to identify macrophages and microglia in the CNS in vivo is important.

    The current PET ligands, especially to TSPO, have well-known limitations including binding to other cell types beyond microglia (e.g., astrocytes and endothelial cells).

    The use of a ligand that binds a receptor exclusively expressed on macrophages and microglia, CSF1R, is a welcome and potentially important advance. However to avoid the limitations that have bedeviled TSPO ligands it would have been useful to demonstrate at a cellular level using autoradiography that [3H]CPPC only binds microglia and perivascular macrophages in brain parenchyma.

    The differential signal reported across the different brain regions is relatively small despite the fact that the microglia density varies considerably between cerebellum and cortex/hippocampus. Similarly, depletion of the microglia and studies in several disease models also report rather modest changes in binding. Studies to determine whether the sensitivity will be sufficient for clinical studies to detect early changes in human pathology will be eagerly awaited.

    View all comments by Hugh Perry

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