At the onset of a neurodegenerative disease, the brain’s immune cells called microglia take up more glucose, a new study shows. In this way, the microglia possibly cover an increased energy requirement for defense reactions against the first pathological changes. The result is relevant for the interpretation of brain scans, which are used, among other things, in dementia diagnostics. It could also help to monitor the success of therapeutic approaches.
The sugar distribution in the brain provides information about which regions are particularly active. If brain cells die as a result of neurodegenerative diseases, the need for sugar in the corresponding regions decreases. This can be made visible with special brain scans, the so-called FDG positron emission tomography (FDG-PET). The patient receives a solution with radioactively labeled glucose, which is distributed in the brain. The radiation emanating from the sugar molecules is then recorded by a scanner and displayed in images. The method is used, among other things, to diagnose diseases such as dementia and Parkinson’s. However, the results are paradoxical in some cases, in which the sugar requirement initially increases rather than decreases.
Glucose not only for nerve cells
A team led by Xianyuan Xiang from the Ludwig Maximilians University in Munich has now found an explanation for this phenomenon. So far, researchers have assumed that the fluctuations in the distribution of glucose are mainly due to the different glucose requirements of the nerve cells in the brain. “Glucose is an energy source. It is therefore assumed that where glucose accumulates in the brain, the energy requirement and, consequently, the brain activity are particularly high, ”explains Xiang’s colleague Matthias Brendel. “However, the spatial resolution of the FDG-PET is not sufficient to recognize in which cells the glucose accumulates. Ultimately, you get a mixed signal that comes not only from nerve cells, but also from the microglia and other cell types that occur in the brain, ”says Brendel.
To find out from which cells the signal originates, the researchers first examined mice in whose brains misfolded proteins had accumulated – similar to Alzheimer’s disease. Brain scans of these mice showed a significantly higher glucose uptake compared to healthy animals. If, on the other hand, the researchers administered a substance to the mice that destroyed the microglia in their brain, the amplified glucose signal did not appear. The glucose uptake in these animals was even lower than in healthy, untreated mice. “This suggests that the FDG-PET signal increase is mainly caused by microglia,” the researchers conclude.
Microglia active in the early stages
The researchers confirmed the result by taking cells from the brains of the mice, sorting them according to cell type in the laboratory and measuring their sugar intake individually. It was found that the microglia took up a particularly large amount of the radioactively labeled glucose. In the next step, the researchers turned to human patients. To do this, they examined 30 men and women who either suffered from Alzheimer’s disease or another form of dementia. They found that glucose uptake was increased, especially in regions of the brain that had not yet been damaged by the dementia. “The data suggest that activation of the microglia is associated with increased FDG-PET signal in regions with no significant neuronal damage,” they write.
The researchers conclude that the microglia take up more glucose, especially in the early stages of the disease, when the nerve damage has not yet progressed that far. “This seems to be necessary to enable them to have an acute, very energy-consuming defense reaction. This can be directed against protein aggregates caused by illness, for example, ”says Xiang’s colleague Christian Haass. “Only in the later course of the disease is the FDG-PET signal apparently dominated by the nerve cells.”
Monitor therapy success
“Since FDG-PET is used both in dementia research and in the context of clinical care, our results are important for the correct interpretation of such images of the brain,” says Brendel. “They also let some previously puzzling observations appear in a new light. However, this does not question existing diagnoses. Rather, it is about a better understanding of the disease mechanisms. “
Haass hopes that the results can also help to better check the success of therapy in the future: “In recent years it has been shown that the microglia play a decisive, protective role in Alzheimer’s and other neurodegenerative diseases. It would be very helpful if the activity and reaction of these cells to drugs, for example, could be monitored non-invasively – especially to determine whether a therapy is working. Our findings suggest that this could be possible with PET. “
Source: Xianyuan Xiang (LMU Munich) et al., Science Translational Medicine, doi: 10.1126 / scitranslmed.abe5640