Summary: Researchers have created a four-dimensional mental image that provides fresh insight into the disease’s earliest stages. Instead of using mice, they monitored tissue development by using MRI scanning to track disease development, identifying vulnerable brain areas weeks before visible harm occurred.
The function of a particular kind of astrocyte that expressed the protein SERPINE1 in brain development and how immune responses and myelin repair were examined. These insights may aid in earlier detection of MS and inform upcoming treatments to stop or slow the progression of the disease.
Major Information
- First MS Detection: A new MRI unique reveals brain regions that are at risk of MS damage before lesions develop.
- Astrocyte Role: SERPINE1-expressing astrocytes may help to both mind maintenance and disease development.
- New Research Model: A marmoset type better resembles people MS, offering real-time monitoring of tissue development.
Origin: NIH
Researchers at the National Institutes of Health ( NIH) have created a four-dimensional brain map that shows how lesions similar to those seen in humans with MS develop using an animal model of , multiple sclerosis ( MS ).
These findings, published in , Science, provide a glass into the first disease condition and may help detect potential targets for MS treatments and mental muscle repair.
The researchers, led by doctoral fellow Jing-Ping Lin, Ph. D., and top analyst Daniel S. Reich, M. D., Ph. D., both at NIH’s National Institute of Neurological Disorders and Stroke ( NINDS ), combined repeated MRI imaging with brain-tissue analysis, including gene expression, to track the onset and development of MS-like lesions.
They found a new MRI personal that may identify brain regions that are at risk of harm weeks before any obvious lesions occur.
They also identified “microenvironments” within disturbed brain cells based on observed patterns of neural function, inflammation, defense and support mobile responses, protein expression, and levels of harm and repair.
” Recognizing the early events that occur after inflammation and teasing apart which are reparative versus which are damaging, can potentially help us identify MS disease activity sooner and develop treatments to slow or stop its progression,” said Dr. Reich.  ,  ,
The body’s immune system attacks the protective covering of nerve fibers, known as myelin, to cause MS. This leads to inflammation, loss of myelin, and formation of “lesions” or “plaques” within the brain tissue.
The majority of what is known about MS progression has been discovered through postmortem human brain tissue analysis, which is typically done decades after the disease first manifests. This means ignoring early changes that took place before symptoms started to develop.
The researchers chose to develop a model using the marmoset, a nonhuman primate, to mimic the conditions of the human brain. Compared to mouse brains, marmoset and human brains have a higher ratio of white matter ( the “wires” of the brain ) to gray matter ( neuronal cell bodies ).
Multiple lesions that resemble those seen in human MS are produced by the Marset model and can be detected in real time using MRI imaging. The model provides a look at the earliest stages of inflammation and immune responses that lead to MS-like demyelination because these lesions can be induced experimentally.
One key player identified was a specific type of astrocyte, one of the support cell types in the brain, that turns on a gene called , SERPINE1 , or plasminogen activator inhibitor-1 ( PAI1 ). Before visible damage occurs, they discovered SERPINE1-expressing astrocytes clustering near blood vessels and the fluid-filled ventricles of the brain and signaling future areas of lesion development.
Additionally, these astrocytes appeared to have an impact on the behavior of other cells close to the lesion area, including the ability of immune cells to enter the brain and cause inflammation as well as the precursor cells involved in myelin repair.
An unanticipated wrinkle that will need to be looked into was the association between SERPINE1-expressing astrocytes accumulating at the edges of growing lesions, where damage occurs but also heals, and their potential dual role in coordinating signals that could cause tissue repair or additional damage.
The earliest responses might be a part of a protective system that becomes insufficient as the injury gets worse. It’s also possible that the same mechanism could itself become disease-causing.  ,  ,  ,
” If one imagines a fort under siege, initially the walls might hold off the attack”, said Dr. Reich. However, if those walls are breached, the entire fort’s defenses can be used against it.
These findings may have implications for brain injuries beyond what are seen in MS. While there are different types of focal brain injuries, including traumatic brain injury, stroke, inflammation, and infection, there is a finite number of ways the tissue can react to injury.
In fact, many of the reactions brought on by inflammation, stress, and tissue damage are likely to be present in all types of injuries, and the brain map created in this study can serve as a reference point for comparisons in a more human-like setting.
A new model of a different autoimmune condition that affects brain borders is being developed by the scientific teams. Additionally, they are considering expanding their data set to include older animals, which might improve our understanding of progressive MS, a condition that has a significant and unmet therapeutic need.
Funding: This study received funding from the National Multiple Sclerosis Society and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation in part through the Intramural Research Program at the NIH.
About this research on brain mapping and multiple sclerosis.
Author: Carl Wonders
Source: NIH
Contact: Carl Wonders – NIH
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Multiple sclerosis-like lesions are detected by a 4D marmoset brain map that includes MRI and molecular signatures for the onset of multiple sclerosis.” by Daniel S. Reich et al. Science
Abstract
Multiple sclerosis-like lesions are detected by a 4D marmoset brain map that includes MRI and molecular signatures for the onset of multiple sclerosis.
INTRODUCTION
Multiple sclerosis ( MS ) is a complex disease characterized by focal inflammation, myelin loss in the central nervous system, and eventual neurodegeneration. Although the exact cause of MS is still undetermined, the illness results from an improper immune response and subsequent failure to repair myelin.
Although MS therapies have been successful in preventing peripheral inflammation, understanding the cellular dynamics of lesion development in its early stages is essential for developing therapies that promote timely remyelination and repair.
RATIONALE
Postmortem human tissue studies or rare brain biopsies, which primarily document MS pathology, provide a broader understanding of the disease at a single, frequently late, time point. To address this limitation, we used a clinically relevant model, the common marmoset ( Callithrix jacchus ) with experimental autoimmune encephalomyelitis ( EAE), to study MS-like lesions.
This model resembles MS lesion development and evolution closely, providing insights that can be applied to the clinical setting. Although structural magnetic resonance imaging ( MRI ) is safe and effective for detecting lesion changes, it lacks the specificity needed to identify the cellular and molecular diversity within lesions.
Therefore, we integrated longitudinal MRI, histopathology, spatial transcriptomics, and single-nucleus RNA profiling to examine the signaling profiles involved in lesion development and resolution.
RESULTS
We identified five microenvironment ( ME) groups—related to neural function, immune and glial responses, tissue destruction and repair, and regulatory networks at brain borders—that emerged during lesion evolution. Before visible demyelination, astrocytic and ependymal secretory signals marked perivascular and periventricular regions, which later became demyelination hotspots.
We identified an MRI biomarker, the ratio of proton density–weighted signal to , T1 , relaxation time, which was sensitive to the hypercellularity phase preceding myelin destruction. At lesion onset, we observed a global shift in cellular connectivity, particularly in extracellular matrix–mediated signaling. Microglia and oligodendrocyte precursor cells ( OPC ) were both proliferating and diversifying in early responses.
As lesions developed, EAE-associated glia were replaced by monocyte derivatives at the lesion center, with persistent lymphocytes seen in aged lesions. Concurrently with demyelination, reparative signaling modules appeared at the lesion edge as early as 10 days after lesion establishment.
We also observed the formation of concentric glial barriers at the lesion edge and the overrepresentation of genes involved in the SASP at the brain borders, which prompted perturbation analysis to contextualize EAE-associated changes and identify potential therapeutics to protect tissue and promote repair.
CONCLUSION
We discovered an astrocytic subtype SERPINE1+  that serves as a secretory hub at the perivascular and periventricular zones and causes lesions in both Marmoset EAE and MS. This information will help with MS research and help identify potential therapeutic interventions.
