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Summary: Neuroimaging technology allowed the researchers to capture the activity of microglia and astrocytes in the brain. Researchers were able to quantify changes in the morphology of different cell populations involved in neuroinflammation.
Source: CSIC
The research in the laboratories led by Dr. Silvia de Santis and Dr. Santiago Canals, both from the Institute of Neuroscience UMH-CSIC (Alicante, Spain), has made it possible to visualize brain inflammation for the first time and in great detail using diffusion-weighted magnetic resonance imaging.
This detailed “X-ray image” of the inflammation cannot be created with conventional MRI, but requires data acquisition sequences and special mathematical models.
Once the method was developed, the researchers were able to quantify the changes in the morphology of the different cell populations involved in the inflammatory process in the brain.
An innovative strategy developed by the researchers made possible this important breakthrough, which is published in the journal today scientific advances and which may be critical to changing the course of research and treatment of neurodegenerative diseases.
The research, first authored by Raquel Garcia-Hernández, shows that diffusion-weighted MRI can noninvasively and differentially detect the activation of microglia and astrocytes, two types of brain cells that underlie neuroinflammation and its progression.
Degenerative brain diseases such as Alzheimer’s and other forms of dementia, Parkinson’s or multiple sclerosis are an urgent problem that is difficult to solve. The sustained activation of two types of brain cells, microglia and astrocytes, leads to chronic inflammation in the brain, which is one of the causes of neurodegeneration and contributes to its progression.
However, non-invasive approaches capable of specifically characterizing encephalitis in vivo are lacking. The current gold standard is positron emission tomography (PET), but it is difficult to generalize and is associated with exposure to ionizing radiation, hence its use in vulnerable populations and in longitudinal studies investigating repeated use of PET over a period of time require is limited to years, as is the case with neurodegenerative diseases.
Another disadvantage of PET is its low spatial resolution, which makes it unsuitable for imaging small structures, with the additional disadvantage that inflammation-specific radiotracers are expressed in multiple cell types (microglia, astrocytes, and endothelium), making it impossible to switch between them differentiate.
Given these disadvantages, diffusion-weighted MRI has the unique ability to non-invasively and with high resolution image brain microstructure in vivo in vivo by capturing the random movement of water molecules in the brain parenchyma to create contrast in MRI images.
INNOVATIVE STRATEGY
In this study, researchers at the UMH-CSIC Neurosciences Institute have developed an innovative strategy that enables imaging of microglial and astrocyte activation in the gray matter of the brain using diffusion-weighted magnetic resonance imaging (dw-MRI).
“This is the first time it has been shown that the signal from this type of MRI (dw-MRI) can detect activation of microglia and astrocytes with specific traces for each cell population. This strategy we used reflects the morphological changes validated postmortem by quantitative immunohistochemistry,” the researchers note.
They also showed that this technique is sensitive and specific for detecting inflammation with and without neurodegeneration, allowing the two diseases to be differentiated. In addition, it allows differentiation between inflammation and demyelination, which are characteristic of multiple sclerosis.
This work was also able to demonstrate the translational value of the approach used in a high-resolution cohort of healthy people “in which we performed a reproducibility analysis. The significant association with known microglial density patterns in the human brain supports the utility of the method for generating reliable glial biomarkers.
“We believe that the noninvasive and longitudinal characterization of relevant aspects of tissue microstructure during inflammation using this technique can have an enormous impact on our understanding of the pathophysiology of many brain diseases and can transform current diagnostic practice and treatment monitoring strategies for neurodegenerative diseases,” emphasizes Silvia de Santis .
To validate the model, 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 first inducing activation of microglia (the cells of the brain’s immune system) and, in a delayed manner, an astrocyte response.
This temporal sequence of cellular events makes it possible to transiently separate glial responses from neuronal degeneration and to study the signature of reactive microglia independently of astrogliosis.
To isolate the imprint of astrocyte activation, the researchers repeated the experiment by pretreating the animals with an inhibitor that transiently ablates about 90% of the microglia.
Using an established paradigm of neuronal damage, they then tested whether the model was able to unravel neuroinflammatory “footprints” with and without concomitant neurodegeneration.
“This is crucial to demonstrate the utility of our approach as a platform for the discovery of biomarkers of inflammatory status in neurodegenerative diseases, in which both glial activation and neuronal damage play key roles,” they clarify.
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Finally, the researchers used an established demyelination paradigm based on focal administration of lysolecithin to show that the developed biomarkers do not reflect the tissue changes commonly found in brain diseases.
About this news from neuroimaging research
Author: Alda Olafsson
Source: CSIC
Contact: Alda Olafsson – CSIC
Picture: Image is credited to IN-CSIC-UMH
Original research: Open access.
“Mapping of microglia and astrocyte activation in vivo using diffusion MRI” by Raquel Garcia-Hernández et al. scientific advances
abstract
Mapping of microglia and astrocyte activation in vivo using diffusion MRI
While glial cells are increasingly implicated in the pathophysiology of psychiatric and neurodegenerative disorders, available methods for imaging these cells in vivo include either invasive methods or radiotracers of positron emission tomography, which offer poor resolution and specificity.
Here we present a non-invasive diffusion-weighted magnetic resonance imaging (MRI) method to image changes in glial morphology.
Using rat models of neuroinflammation, degeneration, and demyelination, we show that diffusion-weighted MRI carries a fingerprint of microglial and astrocyte activation and that specific signatures from each population can be noninvasively quantified.
The procedure is sensitive to changes in glial morphology and proliferation and provides a quantitative representation of neuroinflammation regardless of the presence of concomitant neuronal loss or demyelinating injury.
We demonstrate the translational value of the approach and show significant associations between MRI and histological microglial markers in humans.
This framework has the potential to transform basic and clinical research by elucidating the role of inflammation in health and disease.
