Garcia-Hernandez R, Cerdán Cerdá A, Trouve Carpena Al, Drakesmith M, Koller K, Jones DK, Canals S, De Santis S. Mapping microglia and astrocyte activation in vivo using diffusion MRI. bioRxiv. June 11, 2021 bioRxiv

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  1. This report is very interesting and questions the current assumption by researchers imaging TSPO with PET that they are detecting activated inflammatory microglia in neurodegenerations and multiple sclerosis. The authors find that TSPO expression can be seen at postmortem by microglia that do not have an inflammatory phenotype and, conversely, inflammatory microglia do not necessarily express TSPO. The authors suggest that TSPO PET is a marker of activated microglial density rather than inflammatory activity.

    My view has always been that TSPO expression by microglia is nonspecific and could reflect activation of a phagic or protective microglial phenotype as well as toxic inflammatory activity. Paul Edison and I have suggested that, in Alzheimer’s disease, prodromal cases first show raised cortical TSPO signals due to a rise in protective microglia trying to clear amyloid aggregates, which fails.

    TSPO signal then falls but, as tau tangles form, it rises again, reflecting microglial activation that now is inflammatory and toxic. By the time of end-stage disease seen at postmortem, microglial signal becomes very low as extensive neuronal death has occurred.

    What is clear is that researchers will have to stop referring to TSPO PET as a marker of inflammatory activity in human disease. Nutma et al.'s data makes it clear that raised TSPO signal primarily reflects microglial density and that these cells could have non-inflammatory phenotypes.

    View all comments by David Brooks

  2. This study combines animal models of AD proteinopathies and human tissue, analyzed with various techniques, to support results suggesting that while in rodents TSPO levels represent activated microglia, in humans TSPO better portrays microglia density than activation. This paper is one of the most comprehensive I have seen in this arena. It has a high methodological standard and presents robust results. The study is relevant because the uptake of PET tracers that quantify TSPO availability is currently interpreted as a proxy of microglial activation and, more broadly, neuroinflammation.

    The results presented in this preprint refine the interpretation of TSPO PET findings, suggesting that high uptake depicts a high density of inflammatory cells rather than a combination of their density and activation. High TSPO PET uptake showing microglia cell density, regardless of activation state, could still represent sustained inflammation. In addition, that TSPO availability represents the regional number of microglia would further support results with TSPO PET suggesting that microglia and tau physically propagate together across Braak stages (Sep 2021 news)

    The results raise important questions. If TSPO availability represents microglia density, what is the cause of the abnormally elevated microglial density in AD? And what is the role of neurons and astrocytes? To begin to answer these questions, it would be necessary to phenotypically characterize microglia in regions showing high density. This does not significantly differ from the current challenges ahead of TSPO PET studies, because it is known that the so-far-believed activation state observed with TSPO PET can be heterogeneous, requiring phenotypical characterization.

    These results need to be evaluated in the context of previous literature suggesting increased activation rather than an increase in the total number of microglia in AD (Hopperton et al., 2018). Understanding the reason for these conflicting results is crucial. Specificity/selectivity of TSPO antibodies for humans? Difference in the control groups (controls in the present study were up to Braak IV)?

    In summary, this is an important study that raises important questions about the complex link between AD and glial cells that need further elucidation.

    References:

    Hopperton KE, Mohammad D, Trépanier MO, Giuliano V, Bazinet RP. Markers of microglia in post-mortem brain samples from patients with Alzheimer's disease: a systematic review. Mol Psychiatry. 2018 Feb;23(2):177-198. Epub 2017 Dec 12 PubMed.

    View all comments by Tharick Pascoal

  3. Although this is a preprint version and we should wait for the peer-review process to run its course, this paper addresses the question of the source of the increase in TSPO PET signal (i.e., increase in expression and/or increase in number of microglial cells) when imaging neuroinflammation in brain diseases, which has never been truly elucidated so far. This work is in agreement with numerous other reports showing that TSPO expression in microglia is not directly involved in neuroinflammatory processes but is more a by-product of microglia activation, and is actually more likely reflecting an increase in microglia metabolic activity and/or proliferation rather than a pro- or anti-inflammatory phenotype.

    However, one must note some limitations of the work in its current form, such as the low n number in many experiments, which underpowers the statistical analysis. Nevertheless, this work clearly underscores the urgent need to develop new imaging biomarkers and PET tracers that truly reflect the pro- or anti-inflammatory status of microglia in brain diseases such as Alzheimer’s disease.

    View all comments by Herve Boutin

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  1. Does TSPO PET Measure Microglia Activation or Density?