Summary: Researchers create a four-dimensional brain map that reveals how MS-like lesions form, providing new insights into the early stages of the disease. Marmoset models were used instead of mice to track lesion development in real time with MRI imaging to identify vulnerable brain regions several weeks before visible damage occurred.
An important finding was the role of a specific type of astrocyte expressing the gene Serpine1, which clustered near brain boundaries and influenced immune responses and myelin repair. These findings can help detect MS early, guide future treatments, and slow or stop disease progression.
Important facts
Early MS detection: A new MRI signature reveals brain regions at risk for MS damage before the lesion is formed. Role of efflux cells: Serpentine-expressing astrocytes can contribute to both brain repair and disease progression. News Research Model: The Malmoset model mimics human MS and provides real-time tracking of lesion formation.
Source: NIH
Using animal models of multiple sclerosis (MS), researchers at the National Institutes of Health (NIH) created a four-dimensional brain map that reveals lesions similar to those found in human MS format.
These findings published in Science provide a window into early medical conditions and help identify potential targets for MS treatment and brain tissue repair.
Researchers, led by postdoctoral researcher Dr. Jing-Ping Lin and senior investigator Daniel S. Reich, both at the National Institute of Neurological Disorders and Stroke (NINDS), will track MS-liesions using repeated MRI imaging combining brain tissue analysis including expression of GENE with brain tissue analysis.
They discovered a new MRI signature that helps detect brain regions at risk of damage for weeks before visible lesions develop.
They also identified the “microenvironment” within affected brain tissue based on neural function, inflammation, immune and supportive cell responses, gene expression, and levels of damage and repair.
“Identifying early events that occur after inflammation and being teased away from those compensatory and damaging can help us identify the activity of MS disease more quickly and develop treatments that slow or stop its progress,” Dr. Reich said.
MS is caused by the body’s immune system, which attacks the protective cover of nerve fibers called myelin. This leads to inflammation, loss of myelin, and the formation of “lesions” or “plaques” within brain tissue.
Most of what is known about MS progression arises from postmortem analysis of human brain tissue. This is usually obtained several decades after the first onset of the disease. This means that early changes that occurred before the onset of symptoms have been missed.
To mimic the state of the human brain, researchers chose not to use a mouse model for MS, and instead advanced the model using Marmoset, a non-human primate. Compared to mouse brains, malmoset and human brains have a higher proportion of white matter (the brain “wire”) and gray matter (neuronal cell bodies).
The Marmoset model creates multiple lesions that resemble those found in human MS and can be tracked in real time using MRI imaging. Because these lesions can be induced experimentally, the model looks at the early stages of inflammation and immune responses leading to MS-like demyelination.
One of the key players identified was a specific type of astrocyte, one of the supporting cell types in the brain, which turned on a gene called Serpine1 or plasminogen activator inhibitor-1 (PAI1). They discovered astrocytes expressing meandering 1 at the boundaries of the fragile brain before visible damage occurred, clustering ventricles near blood vessels and in the brain fluid-filled ventricles, signaling future areas of lesion development.
These astrocytes also appeared to affect the ability of immune cells to invade the brain and contribute to inflammation, as well as the behavior of other cells near the lesion area, including the progenitor cells involved in myelin repair.
Given that the meandering 1-expressing astrocytes also accumulate at the edge of the lesion where damage occurs but begins to heal, the potential dual role in regulating signals that could lead to tissue repair or further damage was an unexpected wrinkle that required further study.
The earliest responses can be part of a protective mechanism that can be overwhelmed as the injury progresses. The same mechanism itself can also cause illness.
“If we imagine a fort under siege, the walls might initially stop the attack,” Dr. Reich said. “However, if those walls are violated, all the defenses inside can be turned towards the fort itself.”
These findings can also affect brain damage beyond what is seen in MS. There are many different types of local brain damage, including traumatic brain damage, stroke, inflammation, and infection, but there are limited ways in which tissues react to the damage.
In fact, many of the responses seen here to inflammation, stress, and tissue damage are likely to be common among types of injury, and the brain map created in this study serves as a resource for making comparisons in a more human-like context.
The science team is building new models of different autoimmune conditions that affect brain boundaries. They are also considering expanding the dataset to include aging animals. This may help to improve understanding of progressive MS, a condition of disease with important and unmet therapeutic needs.
Funding: This research was supported in part by the NIH’s Intramural Research Program with additional support from Dr. Miriam and the Sheldon G. Adelson Medical Research Foundation and the National Multis Sclerosis Society.
About this multiple sclerosis and brain mapping research news
Author: Carl Wonders
Source: NIH
Contact: Carl Wonders – NIH
Image: Image credited to Neuroscience News
Original Research: Closed Access.
“The brain map of the 4D marmoset reveals MRI and molecular signatures for the development of multiple sclerosis-like lesions,” Daniel S. Reich et al. Science
Abstract
Brain maps of 4D marmosets reveal MRI and molecular signatures for the development of lesions like multiple sclerosis
introduction
Multiple sclerosis (MS) is a complex disease characterized by local inflammation, myelin loss of the central nervous system, and ultimately neurodegeneration. The exact cause of MS remains unknown, but the disease involves an inappropriate immune response and subsequent failure to repair myelin.
Although MS therapy has been effective in controlling peripheral inflammation, understanding the cellular dynamics of lesion progression at the early stage is important to develop treatments that promote timely remyelination and repair.
basis
Current understanding of MS pathology comes from mostly postmortem human tissue studies or rare brain biopsies. To address this limitation, we used the common malmoset (Callithrix Jacchus), a clinically relevant model using experimental autoimmune encephalomyelitis (EAE) to study MS-like lesions.
This model closely mimics the development and evolution of MS lesions and provides insights that allow for transition into the clinical setting. Structural magnetic resonance imaging (MRI) is non-invasive and effective in monitoring lesion changes, but lacks the specificity required to reveal cellular and molecular diversity within a lesion.
Therefore, longitudinal MRI, histopathology, spatial transcriptomics, and single nuclear RNA profiling were integrated to examine signaling profiles involved in lesion development and resolution.
result
We identified five microenvironmental (ME) groups that emerged during lesion evolution and associated with neural function, immune and glial responses, tissue destruction and repair, and regulatory networks at brain boundaries. Before visible demyelination, astrocyte and upper membrane secretion signals marked the perivascular and periventricular regions, later becoming demyelinated hotspots.
The ratio of the proton density-weighted signal to the MRI biomarker, T1 relaxation time, was identified. This was sensitive to the high cell phase prior to myelin destruction. A global shift in cell connectivity was observed at the onset of the lesions, particularly in signaling via the extracellular matrix. Early reactions involved proliferation and diversification of microglia and oligodendrocyte progenitor cells (OPCs).
As lesions developed, EAE-associated glia were replaced by lesion-centered monocyte derivatives, with persistent lymphocytes seen in older lesions. Concurrent with demyelination, ten days after the establishment of the lesion, a complementary signaling module appeared at the edge of the lesion.
It also focuses on overexpression of genes involved in aging-related secretory phenotypes (SASPs) at brain boundaries and the formation of concentric glial barriers at the lesion margins, encourage perturbation analysis, contextualize changes associated with EAE, identify potential treatments, and enhance repair.
Conclusion
It identifies subtypes of serpentine + astrocytes and acts as secretory hubs in the perivascular and periventricular zones, and underlies the development of both malmosett EAE and MS lesions. Our work provides spatially resolved molecular maps as a resource to benefit MS research and guide candidates for treatment intervention identification.
