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    Home > Active Ingredient News > Study of Nervous System > Science & Progress: For the first time, we have imaging technology to visualize neuroinflammation in the brain!

    Science & Progress: For the first time, we have imaging technology to visualize neuroinflammation in the brain!

    • Last Update: 2022-10-01
    • Source: Internet
    • Author: User
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    With the acceleration of the global aging process, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and multiple sclerosis have become major health issues that need to be solved urgently in an aging society [1-3



    A growing body of research shows that chronic neuroinflammation caused by the continuous activation of microglia and astrocytes strongly affects neurodegenerative diseases and promotes disease progression



    Based on the above vision, how to achieve continuous monitoring of the inflammatory response of glial cells in the brain and provide biomarkers for diagnosing neurodegenerative diseases has become a hot topic



    Recently, a team of researchers led by Silvia De Santis and Santiago Canals of the UMH-CSIC Institute of Neuroscience in Spain published a groundbreaking research in



    They successfully used magnetic resonance imaging to record the activation of microglia and astrocytes in vivo [7].



    Screenshot of the first page of the paper


    Given the difficulty of biopsy sampling of neurological disorders, so far, the diagnosis of neurological diseases has mainly relied on imaging techniques such as CT, MRI, and PET



    Currently, the "gold standard" for diagnosing neuroinflammation is based on a positron emission scan (PET) test



    The diffusion-weighted magnetic resonance imaging (dw-MRI) captures the imaging principle of the random movement of water molecules in the brain parenchyma, making it have a unique non-invasive, high-spatial resolution imaging ability


    Based on this characteristic, researchers have conducted a series of studies around MRI sequences, but the current design mainly targets white matter and axons, and it is impossible to distinguish which type of cells
    these structures come from.

    Since different types of neurodegenerative diseases have different mechanisms, involve specific cell populations, and the specific role played by different types of cell populations in the etiology and progression of the
    disease, cell type specificity for imaging is critical.

    However, to date, no technique has been able to achieve specific imaging
    of microglia and/or astrocytes in vivo.

    Existing research has measured the diffusion characteristics of specific tissue gaps and even cell types by combining advanced dw-MRI sequences with mathematical models based on knowledge of brain parenchymal cell morphology [9].


    Based on the above ideas, the Santis team used knowledge of microglia and astrocyte morphology to develop a new set of magnetic resonance imaging sequences to record the activation responses of small glial cells and astrocytes in gray matter by constructing microstructured multi-chamber tissue models
    .

    Let's take a look at how scientists cleverly implemented this idea
    .

    First, the researchers established a gray matter diffusion model
    based on the corresponding sphere size and stick branches based on the histological morphology of microglia and astrocytes.

    In simple terms, microglia in the activated state are "amoeba-like", and their models are small spheroids and rod-like branches, small spheres simulate the degree of water diffusion in microglia cell bodies at dw-MRI, and the rod-like structure of radial branches mimics the diffusion parameters of microglia emitting branches; Large spheres mimic astrocytes
    in the activated state.

    Microglia gray matter diffusion model (top) and astrocyte gray matter diffusion model (bottom)

    Finally, by collecting and analyzing the sphere radius representing glial cell size, the stick fraction representing the branch emitted by glial cells, the stick dispersion degree representing the number of branches emitted during the occurrence or resolution of inflammation, and the tissue fraction representing the number of glial cells during the occurrence or resolution of inflammation.
    To distinguish between microglia and/or astrocytes in gray matter activated or not
    .

    After the model parameters were determined, the scientists used tissue immunochemical staining and dw-MRI to compare and verify
    the model.

    Design of experiments

    First, the scientists used Iba-1+ immunohistochemical staining and dw-MRI to compare and analyze the activation response of
    microglia.

    At different time points after the injection of the inflammatory inducer lipopolysaccharide (LPS), histomorphological analysis of tissue Iba-1+ cells showed that within 8 hours, microglia responded rapidly and there were significant changes in tissue density, cell size, and process dispersion until 24 h
    .

    The above glial morphological changes
    were not detected when LPS and microglia depletion (PLX5622) were used simultaneously, or after 2 weeks of self-disappearance of the LPS-induced inflammatory response.

    Iba-1+ immunohistochemical staining

    In the figure below, the stick fraction, small sphere radius, and stick dispersion of diffusion-weighted magnetic resonance imaging have time-dependent changes consistent with Iba-1+ cells, indicating that the activation response of microglia in vivo can be captured using dw-MRI
    .

    dw-MRI

    In addition, when looking at the differences between individuals, they found that there was a strong correlation between the parameters recorded by the MRI and their corresponding histological changes at all measured time points (8h and 24h), with the correlation coefficient r 2=0.
    997 (p=0.
    0026) at 8h and the correlation coefficient r2=0.
    9381 (p=0.
    0314)
    at 24h.

    Iba-1+ immunohistochemical staining and dw-MRI correlation analysis

    The above results demonstrate that dw-MRI can record the microglial activation response in vivo and its specific signals
    after recovery.

    Next, the researchers used GFAP immunohistochemical staining and dw-MRI to compare and analyze the activation response process
    of astrocytes.

    Unlike microglia, after 8 h of LPS injection, immunohistochemical staining showed that the density and morphology of astrocytes did not change significantly, but their volume increased significantly after 24 h, and the phenomenon disappeared after 2 weeks of inflammation on their own
    .

    Moreover, after the injection of microglial depletion (PLX5622), the phenomenon of a significant increase in astrocyte volume persists (Figure C
    ).

    The large bulb volume parameters of dw-MRI undergo time-dependent changes consistent with GFAP (Figure D
    ).

    When looking at the differences between individuals, they also found a strong correlation between the parameters recorded by the MRI and their corresponding histological changes in the sample at all measurement time points, with a correlation coefficient r2=0.
    926 (p=0.
    0375).

    GFAP immunohistochemical staining and dw-MRI correlation analysis

    In general, the causes of inflammatory diseases of the nervous system can be roughly divided into two categories: one is induced by spontaneous apoptosis and/or necrosis of neuronal cells, which in turn promotes the inherent immunity of the nervous system to accelerate the progression of diseases; The other category is substances other than neuronal cell degeneration, which cause a simple inflammatory response
    in brain tissue.

    It is not difficult to see that separating the inflammatory response with neurodegeneration from the simple inflammatory response is of great significance for the differential diagnosis of
    the cause.

    The researchers then tried to see if they could distinguish
    the two with the model they developed.

    They injected the left cerebral hemisphere of a group of animals with the neurotoxin Amanita ammonia (IBO) and the right cerebral hemisphere with physiological saline, and the left side of the brain developed neurodegeneration, and the right side of the brain served as a control of
    itself in the physiological state.

    Comparative analysis of MRI imaging and NeuN immunohistochemical staining is performed after 2 weeks
    .

    Design of experiments

    The experimental results show that unlike the simple inflammatory response (microglial activation) caused by LPS, which disappears after 2 weeks, the microglial activation state caused by IBO-mediated neuronal degeneration persists (Figure A), and the resulting MRI parameters are also significantly different
    .

    For example, the dw-MRI stick fraction and tissue fraction parameters of the IBO treatment group were significantly reduced.
    However, the small sphere radius, small sphere fraction, and stick dispersion were significantly higher (Figure C
    ).

    The above results show that the simple inflammatory response and the inflammatory response with neurodegeneration can be distinguished by
    the small sphere parameters and tissue density parameters in the dw-MRI results.

    To further verify the reliability of the model, the researchers tried to observe the corresponding histological changes and desirable changes in MRI parameters after using the neuroprotective agent minocycline
    .

    The results were also ideal, with Neun staining demonstrating the protective effect of minocycline on IBO-induced neuronal degeneration, and the MRI parameter tissue density also captures this effect (Figure D
    ).

    The above results suggest that dw-MRI can distinguish between a simple inflammatory response and an inflammatory response
    with neurodegeneration.

    Neun immunohistochemical staining and dw-MRI correlation analysis

    To further explore the reproducibility and effectiveness of the model's transition to clinical applications, the researchers validated
    it in humans.

    The results show that the coefficient of variation (CoV) values of the model in the same subjects are between 1.
    5-8%, and the CoV values between different subjects are between 2.
    6-15%, which are within the range of MRI measurements used in clinical routines, indicating that this model has diagnostic value
    .

    In addition, multiple linear regression models show a significant correlation between histological results and MRI parameters (p=0.
    03
    ).

    Multiple linear regression models

    Overall, this study shows that dw-MRI has great potential in revealing the diagnosis and differential diagnosis of neurodegenerative diseases that accompany inflammatory responses, providing researchers and patients with new, non-invasive, gliocyte-centric MRI biomarkers that greatly facilitate
    research into diseases associated with glial cell activation.

    Given that inflammation is a potential cause of many neurological disorders, the technique developed by Santis' team to detect the activation response of glial cells promises to be a powerful marker of early diagnosis and/or prognosis
    .

    References:

    [1].
    Ransohoff RM.
    How neuroinflammation contributes to neurodegeneration.
    Science.
    2016; 353(6301):777-783.
    doi:10.
    1126/science.
    aag2590

    [2].
    Lassmann H, van Horssen J, Mahad D.
    Progressive multiple sclerosis: pathology and pathogenesis.
    Nat Rev Neurol.
    2012; 8(11):647-656.
    doi:10.
    1038/nrneurol.
    2012.
    168

    [3].
    Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH.
    Mechanisms underlying inflammation in neurodegeneration.
    Cell.
    2010; 140(6):918-934.
    doi:10.
    1016/j.
    cell.
    2010.
    02.
    016

    [4].
    Janus C, Pearson J, McLaurin J, et al.
    A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease.
    Nature.
    2000; 408(6815):979-982.
    doi:10.
    1038/35050110

    [5].
    Wilbanks B, Maher LJ 3rd, Rodriguez M.
    Glial cells as therapeutic targets in progressive multiple sclerosis.
    Expert Rev Neurother.
    2019; 19(6):481-494.
    doi:10.
    1080/14737175.
    2019.
    1614443

    [6].
    Zella MAS, Metzdorf J, Ostendorf F, et al.
    Novel Immunotherapeutic Approaches to Target Alpha-Synuclein and Related Neuroinflammation in Parkinson's Disease.
    Cells.
    2019; 8(2):105.
    Published 2019 Jan 31.
    doi:10.
    3390/cells8020105

    [7].
    Garcia-Hernandez R, Cerdán Cerdá A, Trouve Carpena A, et al.
    Mapping microglia and astrocyte activation in vivo using diffusion MRI.
    Sci Adv.
    2022; 8(21):eabq2923.
    doi:10.
    1126/sciadv.
    abq2923

    [8].
    Owen DR, Gunn RN, Rabiner EA, et al.
    Mixed-affinity binding in humans with 18-kDa translocator protein ligands.
    J Nucl Med.
    2011; 52(1):24-32.
    doi:10.
    2967/jnumed.
    110.
    079459

    [9].
    Barazany D, Basser PJ, Assaf Y.
    In vivo measurement of axon diameter distribution in the corpus callosum of rat brain.
    Brain.
    2009; 132(Pt 5):1210-1220.
    doi:10.
    1093/brain/awp042

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