Imaging Hot Microglia….Not!

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Hot microglia are at the centre of smouldering MS and we ask how do we masure this. The Imagers have again been telling us porkies as they imply that they have a marker they can image to detect hot activated microglia. We have bought into the idea that TSPO can detect hot microglial and have invented imaging agents to do this. Give this to people with MS and we can see hot microglia. Only one problem…..Yep you guessed it…it is a pile of pants and when you actually look at what is expressingt the 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, which is predominately localized to the outer mitochondrial membrane, in the brain of people with MS and it is all over the place….microglia yes…but its on astrocytes and nerves and so when you are doing the imaging you dont have a real clue what it is detecting.

Assessment of 18F-PBR-111 in the Cuprizone Mouse Model of Multiple Sclerosis. Diagnostics (Basel). 2021 Apr 27;11(5):786….”18F-PBR-111 uptake in anatomic locations correlated with activated microglia”

TSPO PET imaging of natalizumab-associated progressive multifocal leukoencephalopathy. Brain. 2021 Mar 23:awab127. doi: 10.1093/brain/awab127. “Histological analysis revealed a reticular accumulation of TSPO expressing phagocytes in PML lesions”,

However, whilst ProfLove and chumbs do find accumulation of TSPO and this relates to microglia macrophages it is number not activity that is being detected. I suppose seeing accumulations mean there are lesions

Nutma E, Gebro E, Marzin MC, van der Valk P, Matthews PM, Owen DR, Amor S. Activated microglia do not increase 18 kDa translocator protein (TSPO) expression in the multiple sclerosis brain. Glia. 2021 Jun 19. doi: 10.1002/glia.24052.

To monitor innate immune responses in the CNS, the 18 kDa Translocator protein (TSPO) is a frequently used target for PET imaging. The frequent assumption that increased TSPO expression in the human CNS reflects pro-inflammatory activation of microglia has been extrapolated from rodent studies. However, TSPO expression does not increase in activated human microglia in vitro. Studies of multiple sclerosis (MS) lesions reveal that TSPO is not restricted to pro-inflammatory microglia/macrophages, but also present in homeostatic or reparative microglia. Here, we investigated quantitative relationships between TSPO expression and microglia/macrophage phenotypes in white matter and lesions of brains with MS pathology. In white matter from brains with no disease pathology, normal appearing white matter (NAWM), active MS lesions and chronic active lesion rims, over 95% of TSPO+ cells are microglia/macrophages. Homeostatic microglial markers in NAWM and control tissue are lost/reduced in active lesions and chronic active lesion rims, reflecting cell activation. Nevertheless, pixel analysis of TSPO+ cells (n = 12,225) revealed that TSPO expression per cell is no higher in active lesions and chronic active lesion rims (where myeloid cells are activated) relative to NAWM and control. This data suggests that whilst almost all the TSPO signal in active lesions, chronic active lesion rims, NAWM and control is associated with microglia/macrophages, their TSPO expression predominantly reflects cell density and not activation phenotype. This finding has implications for the interpretation of TSPO PET signal in MS and other CNS diseases, and further demonstrates the limitation of extrapolating TSPO biology from rodents to humans

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MouseDoctor

6 comments

  • I remember I saw pictures of MS brain by PET with TSPO and there were many spots. I think the clue could come from repeated analyses: the lesion can be repaired. If so microglia will leave once the scavenging is completed. otherwise if microglia is damaging will stay there and the spot will increase in size. Maybe in the same brain we can see both phenomena but if we get rid of smouldering and inflammation then no spot should be seen, correct? If so, PET can be useful. There is a trial ongoing about this with cladribine, we need to wait and see.

  • Microglia are indeed key cellular elements is MS. They act as transporters of damaging influences that cause oligodendrocyte dysfunstion that leads to demyelination. The cornerstone for microglial malfunction is DUSP (MKP)-underperformance, this due to effects of herpes infection, possibly delivered here by B-cells. Please visit doi: 10.1007/s00109-021-02080-4 or e-mail me in order to receive this paper electronically.

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