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Xiang X, Wind K, Wiedemann T, Blume T, Shi Y, Briel N, Beyer L, Biechele G, Eckenweber F, Zatcepin A, Lammich S, Ribicic S, Tahirovic S, Willem M, Deussing M, Palleis C, Rauchmann BS, Gildehaus FJ, Lindner S, Spitz C, Franzmeier N, Baumann K, Rominger A, Bartenstein P, Ziegler S, Drzezga A, Respondek G, Buerger K, Perneczky R, Levin J, Höglinger GU, Herms J, Haass C, Brendel M. Microglial activation states drive glucose uptake and FDG-PET alterations in neurodegenerative diseases. Sci Transl Med. 2021 Oct 13;13(615):eabe5640. PubMed.
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Washington University
This paper convincingly shows that microglia, and their state of activation, drive a portion of the FDG-PET signal in the brain.
It also shows that the FDG-PET signal correlates with microglial activation state in regions of the brain that have not undergone significant neurodegeneration. This appears to be the case since:
1) the FDG-PET signal correlates with TSPO PET signal in mouse models with amyloid;
2) the FDG-PET signal is decreased when microglia are removed or in TREM2 KO mice; and
3) the positive correlation between TSPO-PET signal and FDG-PET signal is occurring in the human AD and FTD brain in regions that do not have significant neurodegeneration.
Showing the neurons are still likely driving a fair amount of the FDG-PET signal in human brain is that there is still a decrease in FDG-PET signal in the temporal and parietal region in AD, which corresponds well to where there is significant synaptic and neuronal loss occurring. These findings may explain why, in the very early preclinical period—i.e., ~25 years prior to clinical symptoms when amyloid is first accumulating—there is a relative increase in FDG-PET signal in autosomal-dominant AD.
These findings are important for another reason. As disease-modifying therapies for AD and other forms of neurodegeneration emerge, if the potential therapy results in increasing or decreasing microglial activation state, this will very likely affect the FDG-PET signal from brain. Thus, use of this measure as a biomarker assessment tool will need to take this issue into account.
View all comments by David HoltzmanNYU School of Medicine
Weill Cornell Medicine/Burke Neurological Instiute
The paper takes an old observation—that inflammation, central and peripheral, is associated with increased glucose metabolism—and insightfully and experimentally develops the idea that activated microglia are in large part responsible for this effect in AD models and AD. While prior studies have associated FDG PET increases with chronic inflammatory diseases including auto-immune disease, bowel inflammation, etc., little is known about the target cells accounting for the increased uptake.
The finding that microglia manipulation can influence the FDG profile creates a very important opening to a long-questioned finding of transient increases in FDG PET uptake over the course of AD. While the authors examine living human AD and four-repeat tau groups, it remains unknown in humans what glucose metabolic changes are occurring in other cell groups when the metabolism of the microglia are increased, or conversely the impact of neuron metabolism damage on the time course of microglia activation.
Finally, these observations offer caution in the interpretation of FDG PET signals.
View all comments by Gary GibsonUniversity of Pittsburgh
This is a very interesting paper, demonstrating that microglial activation contributes to FDG PET signal. The authors showed convincing evidence of influence from microglial activation on FDG uptake using experimental models and in vivo PET imaging. Previous studies have shown that astrocytes (Zimmer et al., 2017) play an important role in FDG uptake; now the authors suggest that microglial activation is the major player compared to both neurons and astrocytes.
These results may contribute to our understanding of previous FDG observations that do not yet have a clear explanation. For example, increased microglial activation may be the major culprit in the FDG hypermetabolism seen in the early stages of AD.
Several other FDG results could be revised based on their findings. For example, we have shown that amyloid leads to distal FDG PET network dysfunction (Jun 2019 news) and, more recently, that amyloid potentiates microglial activation PET network dysfunction leading to tau pathology (Sep 2021 news). The results presented by Xiang et al. may suggest that the FDG network dysfunction reported in AD could be merely a proxy of microglial activation dysfunction.
Unfortunately, we will not be able to test this hypothesis, as the studies were performed in different cohorts that do not have both FDG and TSPO tracer. However, emerging datasets with glial markers measured in historical samples associated with FDG PET suggest that several cohorts will be able to shed light on these questions soon.
Although the authors’ cell-sorting experiment showed compelling results, their conclusion that microglial activation is responsible for FDG signal could be balanced with the fact that, when we zoom out from the cellular resolution to the PET resolution, the fact that microglia represent a much smaller subpopulation in the brain than neurons and astrocytes may play a role in the final quantifiable FDG uptake in patients. The authors’ results showing often moderate, and lack of, correlation between FDG and TSPO PET in AD and 4RT may also point to a key role of neurons and astrocytes in the pathological FDG signal.
In summary, this is important work that adds to the body of evidence suggesting that glial cells are key players in the FDG PET signal.
References:
Zimmer ER, Parent MJ, Souza DG, Leuzy A, Lecrux C, Kim HI, Gauthier S, Pellerin L, Hamel E, Rosa-Neto P. [(18)F]FDG PET signal is driven by astroglial glutamate transport. Nat Neurosci. 2017 Jan 30; PubMed.
View all comments by Tharick PascoalCNRS, CEA, Molecular Imaging Research Center
This article shows that glucose uptake is reduced in the brains of amyloid-bearing mice after depletion of microglia or after impairment of the ability of microglia to activate. Using very elegant cell-sorting technology after FDG injection, it shows at cellular resolution that microglia display higher glucose uptake than neurons and astrocytes.
Interestingly, using [14C]-2-deoxyglucose glucose microscopic imaging by autoradiography in amyloid-bearing mice, we showed that hot spots of glucose uptake surround amyloid plaques, where microglia and astrocytes accumulate (Poisnel et al., 2012). It thus seems that microglia responsible for glucose uptake are in part associated with amyloid plaques, at least in amyloid-bearing mice.
The article of Xiang et al. is clearly a great discovery with strong implications for interpretation of FDG-PET in the context of Alzheimer's disease.
References:
Poisnel G, Hérard AS, El Tannir El Tayara N, Bourrin E, Volk A, Kober F, Delatour B, Delzescaux T, Debeir T, Rooney T, Benavides J, Hantraye P, Dhenain M. Increased regional cerebral glucose uptake in an APP/PS1 model of Alzheimer's disease. Neurobiol Aging. 2011 Nov 11; PubMed.
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