MRI Can Assess the Burden of Inflammatory Microglia in the Living Brain

Given the growing evidence for inflammatory and senescent microglia and astrocytes to drive the progression of neurodegenerative conditions such as Alzheimer's disease, there is a need for practical, cost-effective ways to assess the burden of inflamed supporting cells in the brain. The senolytic combination of dasatinib and quercetin has been shown to clear senescent cells in the brain, and improve symptoms in animal models of neurodegeneration. Similarly, CSF1R inhibitors such as PLX3397 can clear microglia from the brain, a beneficial procedure when performed in mice with neuroinflammation. Trials in human patients will be that much easier to justify to the powers that be given a way to clearly assess the degree to which harmful cells are cleared by such treatments.

Researchers have demonstrated that diffusion-weighted MRI (dw-MRI) can noninvasively and differentially detect the activation of microglia and astrocytes, two types of brain cells that are at the basis of neuroinflammation and its progression. Degenerative brain diseases such as Alzheimer's and other dementias, Parkinson's, or multiple sclerosis are a pressing and difficult problem to address. Sustained activation of two types of brain cells, microglia and astrocytes leads to chronic inflammation in the brain that is one of the causes of neurodegeneration and contributes to its progression.

This is the first time it has been shown that the signal from this type of MRI can detect microglial and astrocyte activation, with specific footprints for each cell population. The researchers have also shown that this technique is sensitive and specific for detecting inflammation with and without neurodegeneration, so that both conditions can be differentiated. In addition, it makes it possible to discriminate between inflammation and demyelination characteristic of multiple sclerosis.

To validate the model, the researchers used an established paradigm of inflammation in rats based on intracerebral administration of lipopolysaccharide (LPS). In this paradigm, neuronal viability and morphology are preserved, while inducing, first, an activation of microglia, and in a delayed manner, an astrocyte response. This temporal sequence of cellular events allows glial responses to be transiently dissociated from neuronal degeneration and the signature of reactive microglia investigated independently of astrogliosis. To isolate the imprint of astrocyte activation, the researchers repeated the experiment by pretreating the animals with an inhibitor that temporarily ablates about 90% of microglia.


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