Tag Archives: #multiplesclerosis

UCI-led Study Finds Unleashing Certain T Cells May Lead To New Treatments For Multiple Sclerosis (Medicine)

In a new University of California, Irvine-led study, researchers found that a certain protein prevented regulatory T cells (Tregs) from effectively doing their job in controlling the damaging effects of inflammation in a model of multiple sclerosis (MS), a devastating autoimmune disease of the nervous system. 

Published this month in Science Advancesthe new study illuminates the important role of Piezo1, a specialized protein called an ion channel, in immunity and T cell function related to autoimmune neuroinflammatory disorders.

“We found that Piezo1 selectively restrains Treg cells, limiting their potential to mitigate autoimmune neuroinflammation,” said Michael D. Cahalan, PhD, distinguished professor and chair in the Department of Physiology & Biophysics at the UCI School of Medicine.  “Genetically deleting Piezo1 in transgenic mice, resulted in an expanded pool of Treg cells, which were more capable of effectively reducing neuroinflammation and with it the severity of the disease.”

T cells rely on specialized proteins, like Piezo1, to detect and respond to various diseases and conditions including bacterial infections, wound healing, and even cancer.  Uncontrolled T cell activity, however, can give rise to autoimmune disorders in which the immune system attacks normal cells in the body. Tregs constantly curate immune responses and play a critical role in preventing autoimmunity. 

“Given the demonstrated ability of Piezo1 to restrain Treg cells, we believe that inhibiting Piezo1 could lead to new treatments for neuroinflammatory disorders, like MS,” explained Amit Jairaman, PhD, and Shivashankar Othy, PhD, lead authors of the study, both project scientists in the Department of Physiology & Biophysics.

Piezo1 conducts ions when cells are subjected to mechanical forces. Research over the last decade has shed light on the role of Piezo1 in regulating vital physiological functions including red blood cell (RBC) volume, blood pressure, vascular development, bone formation, and differentiation of neural stem cells. However, its role in modulating immune response has not been appreciated before. And, while it was known that calcium conducting ion channels, like Piezo1, direct various aspects of T cell function, researchers were surprised to find that Piezo1 was not essential for a whole host of T cell functions that rely on calcium, such as lymph node homing, interstitial motility, activation, proliferation, or differentiation into effector T cells.

“We found the role of Piezo1 appears to be quite specific to Tregs. Therefore, targeting Piezo1 might be a new and ideal strategy to cure MS while preserving the immune system’s ability to fight new infections,” added Othy, whose research over last 12 years has focused on finding ways to harness the therapeutic potential of Treg cells.

Further investigation of the function of Piezo1 is needed to understand therapeutic potential, and to more fully understand the processes through which cells sense and respond to mechanical stimuli during immune responses.

This research was supported by funding from the National Institutes of Health, the Howard Hughes Medical Institute and the Hewitt Foundation for Biomedical Research.

Featured image: Genetic deletion of Piezo1 in T cells leads to protection in autoimmunity: In the absence of Piezo1, Tregs expand more and, due to their increased numbers, are more effective in containing the damage inflicted by the effector T cells during an autoimmune neuroinflammation. Effector T cell function is not affected in the absence of Piezo1. © UCI School of Medicine


Provided by UCI School of Medicine

Study Finds Low Levels Of A Sugar Metabolite Associates With Disability And Neurodegeneration in MS (Medicine)

A new University of California, Irvine-led study finds low serum levels of the sugar N-acetylglucosamine (GlcNAc), is associated with progressive disability and neurodegeneration in multiple sclerosis (MS). 

The study, done in collaboration with researchers from Charité – Universitätsmedizin Berlin, Germany, and the University of Toronto, Canada, is titled, “Association of a Marker of N-Acetylglucosamine With Progressive Multiple Sclerosis and Neurodegeneration,” The study was published this week in JAMA Neurology.

The study suggests that GlcNAc, which has been previously shown to promote re-myelination and suppress neurodegeneration in animal models of MS, is reduced in serum of progressive MS patients and those with worse clinical disability and neurodegeneration. 

“We found the serum levels of a marker of GlcNAc was markedly reduced in progressive MS patients compared to healthy controls and patients with relapsing-remitting multiple sclerosis” explained Michael Demetriou, MD, PhD, FRCP(C), professor of neurology, microbiology and molecular genetics at UCI School of Medicine, and senior author on the paper.

First author of the study, Alexander Brandt, MD, adjunct associate professor of neurology at the UCI School of Medicine and previously associated with the Experimental and Clinical Research Center, Charité – Universitätsmedizin Berlin and Max Delbrueck Center for Molecular Medicine, Germany, added, “Lower GlcNAc serum marker levels correlated with multiple measures of neurodegeneration in MS, namely worse expanded disability status scale scores, lower thalamic volume, and thinner retinal nerve fiber layer. Also, low baseline serum levels correlated with a greater percentage of brain volume loss at 18 months,” he said.

GlcNAc regulates protein glycosylation, a fundamental process that decorates the surface of all cells with complex sugars. Previous preclinical, human genetic and ex vivo human mechanistic studies revealed that GlcNAc reduces proinflammatory immune responses, promotes myelin repair, and decreases neurodegeneration.  Combined with the new findings, the data suggest that GlcNAc deficiency may promote progressive disease and neurodegeneration in patients with MS. However, additional human clinical studies are required to confirm this hypothesis.

“Our findings open new potential avenues to identify patients at risk of disease progression and neurodegeneration, so clinicians can develop and adjust therapies accordingly,” said Michael Sy, MD, PhD, assistant professor in residence in the Department of Neurology at UCI and a co-author of the study.

MS is characterized by recurrent episodes of neurologic dysfunction resulting from acute inflammatory demyelination.  Progressive MS is distinguished by continuous inflammation, failure to remyelinate, and progressive neurodegeneration, causing accrual of irreversible neurologic disability.  Neurodegeneration is the major contributor to progressive neurological disability in MS patients, yet mechanisms are poorly understood and there are no current treatments for neurodegeneration.

This study was funded in part by a grant from the National Institute of Allergy and Infectious Disease and the National Center for Complimentary and Integrative Health as well as the Excellence Initiative and the Excellence Strategy of the German Federal and State Governments.

Featured image: Michael Demetriou, MD, PhD, FRCP(C), professor of neurology, microbiology and molecular genetics at UCI School of Medicine, is senior author on a new study that found low serum levels of the sugar N-acetylglucosamine (GlcNAc), is associated with progressive disability and neurodegeneration in multiple sclerosis (MS). © UCI School of Medicine


Provided by UCI School of Medicine

Verbal Fluency Deficits In Multiple Sclerosis May Reflect Impaired Language Ability (Psychology)

Researchers at Kessler Foundation upend long-held assumption that language ability is largely intact in individuals with multiple sclerosis, suggesting the need for more comprehensive neuropsychological testing

Kessler Foundation researchers showed that people with multiple sclerosis (MS) experience subtle language impairments that standard neuropsychological tests may incorrectly attribute to impaired executive functions. The article, “The role of language ability in verbal fluency of individuals with multiple sclerosis” (doi: 10.1016/j.msard.2021.102846) was published on February 16, 2021, in Multiple Sclerosis and Related Disorders.

The authors are Nancy D. Chiaravalloti, PhD, director of the Centers for Neuropsychology, Neuroscience, and Traumatic Brain Injury Research at Kessler Foundation, Lauren B. Strober, PhD, senior research scientist at the Center for Neuropsychology and Neuroscience Research, and Amy L. Lebkuecher, MS, of Pennsylvania State University, formerly of Kessler Foundation. Drs. Chiaravalotti and Strober also have research faculty appointments at Rutgers New Jersey Medical School.

Assessing language ability in people with MS is a complicated endeavor, given the vast spectrum of individual clinical experiences within this population. Yet the ability to identify any form of language impairment, not just severe language disorder, is essential to fully understanding a patient’s cognitive profile and providing optimal interventions.

While some early research suggested that language ability is largely intact in people with MS, newer studies indicate that milder language impairments may exist but are too subtle to be quantified by standard neuropsychological tests. As a result, verbal fluency deficits observed in MS are often attributed to impaired processing speed and executive functions rather than language ability. Because individuals with MS have been presumed to have intact language ability, more comprehensive tests are rarely performed, according to lead author Dr. Lebkuecher.

In this study, the Kessler research team challenged the assumption that impaired verbal fluency of individuals with MS solely reflects executive dysfunction. The team analyzed pre-existing data from 74 individuals with MS to evaluate the contribution of various cognitive factors to verbal fluency, including language ability, oral-motor speed, processing speed, and executive functions. They conducted linear multiple regression analyses with letter and category verbal fluency–which relate to a person’s ability to produce words starting with a given letter or within a semantic category–as outcome variables.

The results showed that vocabulary and processing speed predicted letter fluency, while only vocabulary predicted category fluency. Although further research is needed to better understand the relationship between verbal fluency and vocabulary and processing speed, the results suggest the observed verbal fluency deficits in MS may reflect both impaired language ability and processing speed.

“Our results indicate that language ability and domain-general factors were predictive of verbal fluency in individuals with MS,” summarized Dr. Chiaravalloti. “Specifically, language ability played a significant role. This could indicate that verbal fluency deficits in MS reflect underlying language impairment,” she added, “Our findings further demonstrate the need for more comprehensive examination of language in people with MS.”

Funding sources: National Institutes of Health (NCMRR) grant number 1R01HD04579801A1

Featured image: Dr. Strober, senior research scientist in the Center for Neuropsychology and Neuroscience Research, focuses on cognitive effects of multiple sclerosis, and its impact on quality of life. © Kessler Foundation/Jody Banks


Reference: Amy L. Lebkuecher, Nancy D. Chiaravalloti, Lauren B. Strober, “The role of language ability in verbal fluency of individuals with multiple sclerosis”, vol. 50, 2021. DOI: https://doi.org/10.1016/j.msard.2021.102846


Provided by Kessler Foundation

New Multiple Sclerosis Subtypes Identified Using Artificial Intelligence (Medicine)

Scientists at UCL have used artificial intelligence (AI) to identify three new multiple sclerosis (MS) subtypes. Researchers say the groundbreaking findings will help identify those people more likely to have disease progression and help target treatments more effectively.

MS affects over 2.8 million people globally and 130,000 in the UK, and is classified into four* ‘courses’ (groups), which are defined as either relapsing or progressive. Patients are categorised by a mixture of clinical observations, assisted by MRI brain images, and patients’ symptoms. These observations guide the timing and choice of treatment.

For this study, published in Nature Communications, researchers wanted to find out if there were any – as yet unidentified – patterns in brain images, which would better guide treatment choice and identify patients who would best respond to a particular therapy.  

Explaining the research, lead author Dr Arman Eshaghi (UCL Queen Square Institute of Neurology) said: “Currently MS is classified broadly into progressive and relapsing groups, which are based on patient symptoms; it does not directly rely on the underlying biology of the disease, and therefore cannot assist doctors in choosing the right treatment for the right patients.

“Here, we used artificial intelligence and asked the question: can AI find MS subtypes that follow a certain pattern on brain images? Our AI has uncovered three data-driven MS subtypes that are defined by pathological abnormalities seen on brain images.”

In this study, researchers applied the UCL-developed AI tool, SuStaIn (Subtype and Stage Inference), to the MRI brain scans of 6,322 MS patients. The unsupervised SuStaIn trained itself and identified three (previously unknown) patterns.

The new MS subtypes were defined as ‘cortex-led’, ‘normal-appearing white matter-led’, and ‘lesion-led.’ These definitions relate to the earliest abnormalities seen on the MRI scans within each pattern.

Once SuStaIn had completed its analysis on the training MRI dataset, it was ‘locked’ and then used to identify the three subtypes in a separate independent cohort of 3,068 patients thereby validating its ability to detect the new MS subtypes.

Dr Eshaghi added: “We did a further retrospective analysis of patient records to see how people with the newly identified MS subtypes responded to various treatments.

While further clinical studies are needed, there was a clear difference, by subtype, in patients’ response to different treatments and in accumulation of disability over time. This is an important step towards predicting individual responses to therapies.”

NIHR Research Professor Olga Ciccarelli (UCL Queen Square Institute of Neurology), the senior author of the study, said: “The method used to classify MS is currently focused on imaging changes only; we are extending the approach to including other clinical information.

“This exciting field of research will lead to an individual definition of MS course and individual prediction of treatment response in MS using AI, which will be used to select the right treatment for the right patient at the right time.”

One of the senior authors, Professor Alan Thompson, Dean of the UCL Faculty of Brain Sciences, said: “We are aware of the limitations of the current descriptors of MS which can be less than clear when applied to prescribing treatment. Now with the help of AI and large datasets, we have made the first step towards a better understanding of the underlying disease mechanisms which may inform our current clinical classification. This is a fantastic achievement and has the potential to be a real game-changer, informing both disease evolution and selection of patients for clinical trials.”

Researchers say the findings suggest that MRI-based subtypes predict MS disability progression and response to treatment and can now be used to define groups of patients in interventional trials. Prospective research with clinical trials is required as the next step to confirm these findings.

Dr Clare Walton, Head of Research at the MS Society, said: “We’re delighted to have helped fund this study through our work with the International Progressive MS Alliance. MS is unpredictable and different for everyone, and we know one of our community’s main concerns is how their condition might develop. Having an MRI-based model to help predict future progression and tailor your treatment plan accordingly could be hugely reassuring to those affected. These findings also provide valuable insight into what drives progression in MS, which is crucial to finding new treatments for everyone. We’re excited to see what comes next.”

MS is a neurological (nerve) condition and is one of the most common causes of disability in young people. It arises when the immune system mistakenly attacks the coating (myelin sheaths) that wrap around nerves in the brain and spinal cord. This results in the electrical signals, which pass messages along the nerves, to be disrupted, travel more slowly, or fail to get through at all.

Most people are diagnosed between the ages of 20 and 50, however the first signs of MS often start years earlier. Common early signs include tingling, numbness, a loss of balance and problems with vision, but because other conditions cause the same symptoms, it can take time to reach a definitive diagnosis.

Many patients have relapsing MS at first, a form of the disease where symptoms come and go as nerves are damaged, repaired and damaged again. But about half have a progressive form of the condition in which nerve damage steadily accumulates and causes ever worsening disability. Patients may experience tremors, speech problems and muscle stiffness or spasms, and may need walking aids or a wheelchair.

The study was carried out with researchers at: Montreal Neurological Institute, McGill University, Canada; Harvard Medical School, USA; and VU University Medical Centre, the Netherlands.

* In present clinical guidelines, MS is currently categorised as either clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), primary-progressive MS (PPMS) or secondary progressive MS (SPMS).

Featured image: New MS subtypes defined as ‘cortex-led’, ‘normal appearing white matter-led’ and ‘lesion-led’ © UCL


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Provided by University College London

GOSH-led Metformin Trial Dramatically Reduces Seizures For People With Tuberous Sclerosis (Medicine)

A team of researchers led by UCL Great Ormond Street Institute of Child Health (ICH) and Great Ormond Street Hospital (GOSH) has found that metformin – a drug commonly used to treat Type 2 diabetes – can successfully reduce symptoms associated with tuberous sclerosis complex (TSC), including reduction in the frequency of seizures and the size of brain tumours.

The study, which also included teams from Royal United Hospitals Bath NHS Foundation Trust (RUH) and University Hospitals Bristol and Weston NHS Foundation Trust, recruited 51 patients with TSC who were randomly assigned a placebo or metformin for one year on a dose similar to that given for Type 2 diabetes.

TSC is a genetic disorder characterised by the development of benign tumours due to loss of inhibitory regulation of the mTOR (mechanistic Target of Rapamycin) intracellular growth pathway. As a result, people with the condition may develop tumours (hamartomas) throughout the body that can affect the heart, kidneys, brain, skin and nails. Although some with the condition may experience few issues, for others it can be disfiguring or even have life threatening complications. As tumours can form in the brain, 75% of people with TSC will have epilepsy, which can lead to daily seizures.

Throughout the study, the research team wanted to see if metformin could limit the tumour growth and epilepsy associated with TSC.

Over the course of the year, the team found a 21% reduction in the size of brain tumours of those who were given metformin, compared to a 3% increase in tumour size for those taking the placebo. Patients with epilepsy and taking metformin saw a 44% drop in the frequency of their seizures, compared to a drop of only 3% for those on the placebo.

Metformin has been gaining attention in cancer research, with large population studies starting to show reduced rates of cancers in those regularly taking it.

Finbar O’Callaghan, professor of paediatric neuroscience at ICH and consultant paediatric neurologist at GOSH and lead investigator of the study said: “This is the first time a cheap, readily available, safe drug has been found to improve the symptoms of TSC. And we found metformin to be even more effective in treating young people. Some patients, who were having multiple seizures a day or week became seizure free after 12 months of treatment, while others are having far fewer seizures than before. We’re excited by what this could mean for the day-to day management of tuberous sclerosis patients.”

“We remain optimistic about the impact we’ve seen on the treatment of brain tumours and epileptic seizures, and believe this is a very promising step forward in improving quality of life for the children and adults living with TSC. Next steps for this work will be to conduct further large-scale trials in Tuberous sclerosis patients to determine the best doses to use and to demonstrate that the effect we have seen is repeatable in a larger population.”

It is estimated that between 3,700 – 11,000 people in the UK live with TSC. There is currently no cure, and only its symptoms can be treated with regular monitoring by a specialist doctor. Although the tumours in TSC patients are benign, the symptoms are not, and current treatments are not only expensive but have toxic side effects as they are immunosuppressants. GOSH treats 150 children with this condition and works closely with the two other hospitals with specialist TSC. The study team run specialist TS clinics at GOSH, the Royal United Hospital in Bath, and Bristol Royal Hospital for Children. These clinics follow up the largest number of TSC patients in the UK.

Zoe Bull, pictured above, was 18 months old when she was diagnosed with TSC, following some seizures. Doctors found benign tumours in her brain, kidneys and on her skin. After her diagnosis, Zoe was seizure-free until she had a focal-aware seizure, aged 10 on a family holiday to Disney World. “It was an unsettling wave-like sensation and what a remember feeling was a loss of control. It’s not something I could openly discuss with anyone, although eventually I was able to tell one friend and then another, until I developed a strong support network,” she said.

Zoe’s condition had been managed with medication to prevent and control her seizures but, as one of the tumours in Zoe’s kidneys was larger than 1cm, she was approached to see if she would like to be involved in the Metformin trial. Although Zoe didn’t know it at the time, she was one of the patients receiving metformin. Her results were encouraging, with a 38% reduction in brain tumour volume and a 75% reduction in seizure frequency during the course of the study.

“My hope is that medicines like this open the door for more treatment options and even a cure for TSC one day. I was fortunate enough to pass my driving test during a time when I was seizure-free but have since surrendered my licence. Hopefully, I will be able to drive again in the future, even if it was just to the shops!”


Featured image: Zoe Bull © GOSH


Reference: Sam Amin, Andrew A Mallick, Hannah Edwards et al., “The metformin in tuberous sclerosis (MiTS) study: A randomised double-blind placebo-controlled trial”, Volume 32, 100715, February 01, 2021. DOI: https://doi.org/10.1016/j.eclinm.2020.100715


Provided by GOSH for Children

TalTech Scientists Developed Novel Immune Diagnostics of Multiple Sclerosis (Medicine)

Multiple sclerosis (MS) is the most common neurological disease in young adults, affecting more than 2 million individuals worldwide, with about 1500 cases in Estonia. About 20% of MS patients experience optic neuritis (ON) as the presenting symptom, but not all ON patients develop MS.

The TalTech gene technology research unit, in collaboration with the laboratory of Protobios OÜ and medical researchers of the University of Helsinki, published their findings in the prestigious journal of EBioMedicine entitled “Identification of two highly antigenic epitope markers predicting multiple sclerosis in optic neuritis patients”. The lead author Helle Sadam and co-authors Mariliis Jaago and Annika Rähni are the PhD students of the TalTech Department of Chemistry and Biotechnology, Division of Gene Technology.

The principal investigator for the study, Kaia Palm, associate professor in the Division of Gene Technology TalTech and head of research at Protobios OÜ: “We have developed and patented a very powerful technology called Mimotope Variation Analysis (MVA) for the development of diagnostic tests and delineation of novel drug targets. It is based on the recognition of the diversity of the human B-cell immune response or antibody profile. The immune response mediated by B-lymphocytes plays an important role in the development of both (MS and ON) pathologies, so it is a promising target for detecting early diagnostic biomarkers for named diseases.”

Professor Pentti Tienari from the Department of Neurosciences at the University of Helsinki and co-author of the study said, when speaking about the significance of the work: ” Treatment of MS is most effective, when started early, but there have been only few biomarkers available to identify people at risk after the first episode of optic neuritis.”

Professor Antti Vaheri, co-author and Professor Emeritus of Virology, University of Helsinki, added: “Notably, critical involvement of viruses in neurological diseases has therapeutic implications, especially in the case of herpesviruses against which multiple antiviral agents exist.”

In the published work, more than 500 different clinical samples (incl. blood and cerebrospinal fluid samples) from Finnish, as well as Estonian patients were analyzed by MVA. The results provide a broad, high-resolution view on humoral immunity associated with different cases and report on the prognostic value of viral antibodies as novel blood biomarkers for predicting risk of MS after the first episode of ON.

Featured image: Protobios laboratory in action © Tõnu Tuulas


Reference: Helle Sadam, Arno Pihlak, Mariliis Jaago, Nadežda Pupina, Annika Rähni, Maarja Toots, Antti Vaheri, Janne K. Nieminen, Mika Siuko, Pentti J. Tienari, Kaia Palm, Identification of two highly antigenic epitope markers predicting multiple sclerosis in optic neuritis patients, EBioMedicine, Volume 64, 2021, 103211, ISSN 2352-3964, https://doi.org/10.1016/j.ebiom.2021.103211 (https://www.sciencedirect.com/science/article/pii/S2352396421000049)


Provided by Estonian Research Council

Remyelinating Drug Could Improve Vision in Patients With Multiple Sclerosis (Medicine)

UC Riverside-led mouse study stresses MS treatment should be started early

A team led by a biomedical scientist at the University of California, Riverside, reports a drug — an estrogen receptor ligand called indazole chloride (IndCl) — has the potential to improve vision in patients with multiple sclerosis, or MS.

The study, performed on mice induced with a model of MS and the first to investigate IndCl’s effect on the pathology and function of the complete afferent visual pathway, is published in Brain Pathology. The afferent visual pathway includes the eyes, optic nerve, and all brain structures responsible for receiving, transmitting, and processing visual information.

In MS, a disease in which the immune system “demyelinates” or eats away at the protective covering of nerves, the initial period of inflammation and demyelination often damages the optic nerve and other parts of the visual system first. As a result, approximately 50% of patients with MS experience optic neuritis — inflammatory demyelination of the optic nerve — prior to showing initial symptoms. Almost all MS patients have impaired vision at some point during disease progression. Symptoms can include eye pain, blurred vision, and progressive vision loss that can lead to blindness, among other visual impairments.

The optic nerve, a heavily myelinated bundle of nerves located at the back of the eye, transfers visual information from the retina to the vision centers of the brain through electrical impulses. Myelin acts as an insulating substance that speeds the transmission of these electrical impulses. Partial myelin loss slows transmission of visual information; severe myelin loss may stop the signal altogether.

The researchers used IndCl to assess its impact on demyelinating visual pathway axons. The treatment induced remyelination and mitigated some damage to the axons that resulted in partial functional improvement in vision.

“IndCl has been previously shown in mice to reduce motor disability, increase myelination, and neuroprotection in the spinal cord and corpus callosum,” said Seema Tiwari-Woodruff, a professor of biomedical sciences at the UC Riverside School of Medicine and the study’s lead author. “Its effects in the visual system, however, were not evaluated until now. Our study shows the optic nerve and optic tract, which undergo significant inflammation, demyelination, and axonal damage, are able to restore some function with IndCl treatment with successful attenuation in inflammation and an increase in remyelination.”

The visual pathway in mice is similar to that in humans. The mouse brain is, therefore, an excellent model for scientists to study vision impairment. In the lab, Tiwari-Woodruff and her research group first induced the mouse model of MS. They let the disease progress for about 60 days and when the disease reached a peak between 15 and 21 days, they administered IndCl to half the mice. At the end of the experiment, they performed functional assay to measure the visual electrical signal; and immunohistochemistry to examine the visual pathway. The mice that received the drug showed improvement in myelination, with visual function improving by about 50%.

For Tiwari-Woodruff, the next question is how IndCl treatment induces functional remyelination in the visual pathway. Her lab, in collaboration with the lab of co-author John A. Katzenellenbogen at the University of Illinois at Urbana-Champaign, is investigating new drugs that are analogues of IndCl.

“Measuring visual function and recovery in the presence of novel therapies can be used to screen more effective therapies that will protect axons, stimulate axon remyelination, and prevent ongoing axon damage,” Tiwari-Woodruff said.

Currently approved MS drugs reduce inflammation but do not prevent neurodegeneration or initiate remyelination. Further, they only partially prevent the onset of permanent disability in patients with MS.

“We treated the MS mice with IndCl at peak disease,” Tiwari-Woodruff said. “If the brain is highly diseased, some of the axons that could potentially restore visual function are too damaged and will not recover. There’s a point of no return. Our paper stresses that to acquire vision improvement, treatment must start early. Early treatment can recover 75%-80% of the original function.”

Tiwari-Woodruff stressed that although additional studies are required, the new findings show the dynamics of visual pathway dysfunction and disability in MS mice, along with the importance of early treatment to mitigate axon damage.

“There is a strong and urgent need to find a therapeutic candidate that restores neurological function in patients with MS,” Tiwari-Woodruff said. “Therapeutics must target remyelination and prevent further axonal degeneration and neuronal loss. The good estrogens, which have neuroprotective and immunomodulatory benefits, could be candidates for MS treatment.”

Tiwari-Woodruff and Katzenellenbogen were joined in the study by Maria T. Sekyi, Kelli Lauderdale, Kelley C. Atkinson, Batis Golestany, Hawra Karim, Micah Feri, Joselyn S. Soto, and Cobi Diaz at UCR; Sung Hoon Kim at the University of Illinois at Urbana-Champaign; and Marianne Cilluffo and Steven Nusinowitz at UCLA. Sekyi, now a former graduate student at UCR, is the first author of the paper.

The study was funded by grants from National Institutes of Health and National Multiple Sclerosis Society. Sekyi was supported by a National Science Foundation graduate research fellowship.

The research paper is titled “Alleviation of extensive visual pathway dysfunction by a remyelinating drug in a chronic mouse model of multiple sclerosis.”

Featured image: Maria Sekyi (left), the first author of the research paper, is seen here with Seema Tiwari-Woodruff, the study’s lead author, in a photo dated Sept. 13, 2019. © Tiwari-Woodruff lab, UC Riverside.


Reference: Sekyi, M.T., Lauderdale, K., Atkinson, K.C., Golestany, B., Karim, H., Feri, M., Soto, J.S., Diaz, C., Kim, S.H., Cilluffo, M., Nusinowitz, S., Katzenellenbogen, J.A. and Tiwari‐Woodruff, S.K. (2021), Alleviation of extensive visual pathway dysfunction by a remyelinating drug in a chronic mouse model of multiple sclerosis. Brain Pathology e12930. https://onlinelibrary.wiley.com/doi/10.1111/bpa.12930 https://doi.org/10.1111/bpa.12930


Provided by University of California Riverside

Childhood Trauma Could Affect Development, Treatment of Multiple Sclerosis (Medicine)

Childhood trauma could affect the trajectory of multiple sclerosis development and response to treatment in adulthood, a new study in mice found.

Mice that had experienced stress when young were more likely to develop the autoimmune disorder and less likely to respond to a common treatment, researchers at the University of Illinois Urbana-Champaign found. However, treatment that activated an immune-cell receptor mitigated the effects of childhood stress in the mice.

Multiple sclerosis is a progressive autoimmune disease in which the body attacks and strips away the protective coating around neurons, resulting in a wide range of neurological symptoms. Both genetic and environmental factors play a role in MS development.

Previous work has shown that early-life trauma increases susceptibility to developing more severe MS, but researchers have not been able to determine how, said Makoto Inoue, a professor of comparative biosciences at Illinois. In the new study, published in Nature Communications, Inoue’s group studied a mouse model of MS. The mice were genetically susceptible to experimental autoimmune encephalomyelitis, the model most widely used for studying MS.

The researchers watched the development and progression of EAE in mice that had been briefly separated from their mother and given a salene injection while young and compared it with mice that had not experienced the same stress.

“Mice that had early-life trauma were more susceptible to EAE disease development and suffered prolonged motor paralysis with severe neuronal damage in the central nervous system, which we found was caused by a heightened immune response,” said graduate student Yee Ming Khaw, the first author of the study.

The researchers traced the EAE triggers to the immune system – in particular, a receptor on immune cells that binds to the stress hormone norepinephrine. The researchers found that childhood stress in the mice triggered a prolonged release of norepinephrine. The receptor was activated for long periods of time, which led the cells to decrease its expression – leaving the immune system less equipped to respond to the stress and inflammation of EAE.

Importantly, mice that developed EAE after stress in their childhoods did not respond to treatment with interferon beta, one of the initial therapies most widely prescribed to individuals with MS. Meanwhile, the drug effectively prevented EAE progression in mice without childhood stress, Khaw said.

Next, the researchers treated the mice with a compound that boosts the receptor’s response. The treatment prevented paralysis and slowed damage to the spinal cord. In addition, mice that received the treatment responded to interferon beta treatment, though they had not responded before.

“This work suggests that individuals with experience of childhood trauma develop autoimmune disease with symptoms and mechanisms that greatly differ from their peers with no history of childhood trauma, and may need different medical treatment,” Inoue said. “This receptor activator may be a therapeutic drug for MS patients with a history of childhood trauma.”

Next, the researchers plan to verify the mechanisms of the receptor, and to perform translational studies to verify whether boosting the receptor in human patients with MS gives the same benefits as it did for the mice with EAE.

“We believe that the best approach to addressing autoimmune diseases in individuals with a history of childhood trauma or other risk factors is a comprehensive and personalized medicine approach that addresses the whole person,” Inoue said.

The University of Illinois and the Sumitomo Foundation supported this work.

The paper “Early-life-trauma triggers interferon-β resistance and neurodegeneration in a multiple sclerosis model via downregulated β1-adrenergic signaling” is available online (https://www.nature.com/articles/s41467-020-20302-0).

Featured image: Graduate student Yee Ming Khaw and comparative biosciences professor Makoto Inoue led a study that found that childhood trauma may affect later development of multiple sclerosis and its responsiveness to treatment. In compliance with COVID-19 safety protocols, both subjects tested negative for COVID-19 prior to the photo. Photo by L. Brian Stauffer


Provided by Illinois News Bureau

Newly Discovered Subset of Brain Cells Fight Inflammation with Instructions from the Gut (Neuroscience)

Findings on a novel anti-inflammatory pathway may guide researchers toward innovative multiple sclerosis or brain tumor treatments

Astrocytes are the most abundant type of cells within the central nervous system (CNS), but they remain poorly characterized. Researchers have long assumed that astrocytes’ primary function is to provide nutrients and support for the brain’s more closely scrutinized nerve cells; over the years, however, increasing evidence has shown that astrocytes can also actively promote neurodegeneration, inflammation, and neurological diseases. Now, a team led by researchers from Brigham and Women’s Hospital, has shown that a specific astrocyte sub-population can do the opposite, instead serving a protective, anti-inflammatory function within the brain based on signals regulated by the bacteria that reside in the gut. Findings on the new anti-inflammation pathway are published in Nature.

“Over the years, many labs, including mine, have identified important roles for astrocytes in promoting neurological diseases,” said corresponding author Francisco Quintana, PhD, of the Ann Romney Center for Neurologic Diseases at the Brigham. “This is the first case in which we’re showing that at least a subset of these cells (astrocytes) can prevent inflammation. The reason we haven’t seen this before was because we were studying these cells as if they were uniform, or one single cell type. But now we have the resolution to see the differences between these cells.”

The researchers used refined gene- and protein-analysis tools to identify the novel astrocyte subset. The astrocyte population resides close to the meninges (the membrane enclosing the brain) and expresses a protein called LAMP1, along with a protein called TRAIL, which can induce the death of other cells. These features help the LAMP1+TRAIL+ astrocytes limit CNS inflammation by inducing cell death in T-cells that promote inflammation.

To determine what mechanism controls LAMP1+TRAILastrocytes in the brain, the researchers performed a series of tests using the gene-editing tool CRISPR-Cas9. They found that a particular signaling molecule, called interferon-gamma, regulates TRAIL expression. Moreover, they found that the gut microbiome induces the expression of interferon-gamma in cells that circulate through the body and ultimately reach the meninges, where they can promote astrocyte anti-inflammatory activities.

Understanding the mechanisms driving the anti-inflammatory functions of LAMP1+TRAILastrocytes could enable researchers to develop therapeutic approaches to combat neurological diseases, like multiple sclerosis. For example, they are exploring probiotic candidates that can be used to regulate the astrocytes’ anti-inflammatory activity. Additionally, the research team’s more recent data indicates that certain brain tumors exploit this pathway to evade the body’s immune response. The investigators are therefore developing cancer immunotherapies to retaliate against the tumors’ attacks.

“Finding microbiome-controlled anti-inflammatory subsets of astrocytes is an important advance in our understanding of CNS inflammation and its regulation,” Quintana said. “This is a very novel mechanism by which the gut controls inflammation in the brain. It guides new therapies for neurological diseases, and we believe that this mechanism could contribute to the pathogenesis of brain tumors.”

Quintana’s lab identified the only other subset of astrocyte known to be regulated by the gut microbiome in 2016, but the investigators believe that there are likely others. “It’s becoming clear that the gut flora are important in many diseases,” he said. “We’re lucky that we’ve been leading the charge to identify different subsets of astrocytes and the mechanisms that control them. We have a list of other populations of astrocytes, and we’re working to see how the gut flora may control them.”

This work was supported the National Institutes of Health (NS102807, ES02530, ES029136, AI126880, AI149699, DP2AT009499, 1K99NS114111, F32NS101790, and R01AI130019), National MS Society (RG4111A1 and JF2161-A-5), the International Progressive MS Alliance (PA-1604-08459), a Chan-Zuckerberg Initiative Ben Barres Early Career award, the Burroughs Wellcome fund, the Canada Institute of Health Research, Canadian Foundation for Innovation, Dana-Farber Cancer Institute (T32CA207201), Program in Interdisciplinary Neuroscience at BWH, and the Women’s Brain Initiative at BWH, an Alfonso Martín Escudero Foundation postdoctoral fellowship, the European Molecular Biology Organization (ALTF 610-2017), the FAPESP BEPE (#2019/13731-0).


Reference: Sanmarco, LM, et al. “Gut-licensed IFN-g+ NK cells drive LAMP1+TRAIL+ anti-inflammatory astrocytes” Nature, 2021. DOI: 10.1038/s41586-020-03116-4


Provided by Brigham and Women Hospital