Using diffusion-weighted magnetic resonance, the researchers captured images of the activation of microglia and astrocytes, two cell types involved in neuroinflammation.
The laboratories of Dr. Silvia de Santis and Dr. Santiago Canals at the UMH-CSIC Neuroscience Institute (Alicante, Spain) have used diffusion-weighted magnetic resonance imaging to image brain inflammation not only for the first time, but also in great detail.
Specialized data collection sequences and mathematical models are needed to produce this in-depth “x-ray” of inflammation, which cannot be done with a standard MRI. After developing the technique, the researchers were able to measure changes in the morphology of different cell populations contributing to the inflammatory process in the brain.
This important discovery, recently published in the journal Scientists progress and may be key to changing the trajectory of research and treatment for neurodegenerative diseases, was made possible through an innovative strategy created by the researchers.
The study, whose first author is 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 cause neuroinflammation and its development.
Degenerative brain conditions including Parkinson’s disease, multiple sclerosis, Alzheimer’s, and other dementias are critical and difficult to solve. Chronic inflammation of the brain, caused by the sustained activation of two types of brain cells, microglia and astrocytes, is one of the causes of neurodegeneration and a factor in its progression.
However, there is a lack of non-invasive approaches capable of specifically characterizing brain inflammation in vivo. The current gold standard is positron emission tomography (PET), but it is difficult to generalize and is associated with exposure to ionizing radiation, so its use is limited in vulnerable populations and in longitudinal studies , which require the use of PET repeatedly over a period of years, as is the case in 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 ), which makes it impossible to differentiate them. .
Faced with these drawbacks, diffusion-weighted MRI has the unique ability to image the brain microstructure in vivo non-invasively and with high resolution by capturing the random movement of water molecules in the brain parenchyma to generate contrast. in MRI images.
Use an innovative strategy
In this study, researchers at the UMH-CSIC Neuroscience Institute have developed an innovative strategy that allows imaging of microglia and astrocyte activation in the gray matter of the brain using resonance imaging. diffusion-weighted magnetic field (dw-MRI).
“This is the first time that it has been demonstrated that the signal from this type of MRI (dw-MRI) can detect the activation of microglia and astrocytes, with specific fingerprints for each cell population. This strategy that we used reflects the morphological changes validated post-mortem by quantitative immunohistochemistry,” note the researchers.
They also showed that this technique is sensitive and specific for detecting inflammation with and without neurodegeneration so that the two conditions can be differentiated. In addition, it allows to discriminate the characteristics of inflammation and demyelination of multiple sclerosis.
This work was also able to demonstrate the translational value of the approach used in a high-resolution cohort of healthy humans, “in which we performed a reproducibility analysis. The significant association with known microglia density patterns in the human brain supports the utility of the method for generating reliable glial biomarkers. We believe that characterizing, using this technique, relevant aspects of tissue microstructure during inflammation, in a non-invasive and longitudinal manner, can have a significant impact on our understanding of the pathophysiology of many brain conditions. and can transform current diagnostic practices and treatment monitoring strategies for neurodegenerative diseases,” emphasizes Silvia de Santis.
To validate the model, the researchers used an established rat inflammation paradigm based on intracerebral administration of lipopolysaccharide (LPS). In this paradigm, neuronal viability and morphology are preserved, while inducing, initially, the activation of microglia (the cells of the brain’s immune system), and later, an astrocyte response. This temporal sequence of cellular events makes it possible to transiently dissociate glial responses from neuronal degeneration and to study the signature of reactive microglia independently of astrogliosis.
To isolate the fingerprint of astrocyte activation, the researchers repeated the experiment by pretreating the animals with an inhibitor that temporarily suppresses about 90% of the microglia. Subsequently, using an established neuronal damage paradigm, they tested whether the model was able to disentangle neuroinflammatory “fingerprints” with and without concomitant neurodegeneration. “This is essential to demonstrate the utility of our approach as a platform for the discovery of biomarkers of inflammatory status in neurodegenerative diseases, where glia activation and neuronal damage are key players,” they specify.
Finally, the researchers used an established paradigm of demyelination, based on the focal administration of lysolecithin, to demonstrate that the biomarkers developed do not reflect the tissue alterations frequently found in brain disorders.
Reference: “Mapping microglia and astrocyte activation in vivo using diffusion MRI” by Raquel Garcia-Hernandez, Antonio Cerdán Cerdá, Alejandro Trouve Carpena, Mark Drakesmith, Kristin Koller, Derek K. Jones, Santiago Canals and Silvia De Santis, May 27, 2022, Scientific advances.