Research of the laboratories led by Dr. Silvia deSantis and Dr. Santiago Canals, both of the Institute of Neurosciences UMH-CSIC (Alicante, Spain), has made it possible to visualize brain inflammation for the first time using diffusion and in detail-weighted magnetic resonance imaging. This detailed “x-ray” of inflammation cannot be obtained 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 today in the journal Science Advances, and may be crucial in changing the course of study and treatment of neurodegenerative diseases.
The study, lead author of which is Raquel Garcia-Hernández, shows that diffusion-weighted MRI can non-invasively and differentially detect the activation of microglia and astrocytes, two types of brain cells underlying neuroinflammation and its progression. .
Degenerative brain diseases such as Alzheimer’s disease and other dementias, Parkinson’s or multiple sclerosis are an urgent and difficult problem to tackle. 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.
However, there is a lack of non-invasive approaches that can specifically characterize 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, requiring PET to be repeatedly tested over a period of time. used for years, as is the case with neurodegenerative diseases.
Another drawback of PET is its low spatial resolution, making it unsuitable for imaging small structures, with the added drawback that inflammation-specific radiotracers are expressed in multiple cell types (microglia, astrocytes, and endothelium), making it impossible to identify them. to distinguish.
Despite these drawbacks, diffusion-weighted MRI has the unique ability to image the brain microstructure in vivo non-invasively and at high resolution by capturing the random movement of water molecules in the brain parenchyma to generate 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 that the signal from this type of MRI (dw-MRI) has been shown to detect activation of microglia and astrocytes, with specific footprints for each cell population. This strategy we used reflects the morphological changes that have been validated post-mortem by quantitative immunohistochemistry,” the researchers note.
They have also shown that this technique is sensitive and specific for detecting inflammation with and without neurodegeneration, so that the two conditions can be distinguished. In addition, it makes it possible to distinguish between inflammation and demyelination that are characteristic of multiple sclerosis.
This work has also been 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 glia biomarkers.We believe that characterizing, using this technique, relevant aspects of tissue microstructure during inflammation, non-invasively and longitudinally, could have a huge impact on our understanding of the pathophysiology of many brain disorders, and can transform current diagnostic practice and treatment monitoring strategies for neurodegenerative diseases,” emphasizes Silvia de Santis.
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 first inducing an 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 allows to temporally separate glial responses from neuronal degeneration and examine 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 temporarily removes about 90% of the microglia. Then, using an established paradigm of neuronal damage, they tested whether the model was able to unravel neuroinflammatory “footprints” with and without concurrent neurodegeneration. “This is critical to demonstrate the utility of our approach as a platform for the discovery of biomarkers of inflammatory status in neurodegenerative diseases, where both glia activation and neuronal damage are key players,” they clarify.
Finally, the researchers used an established paradigm of demyelination, based on focal administration of lysolecithin, to show that the biomarkers developed do not reflect the tissue changes commonly found in brain disorders.
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