This is a pseudo-coloured image of high-resolution gradient-echo MRI scan of a fixed cerebral hemisphere from a person with multiple sclerosis. Credit: Govind Bhagavatheeshwaran, Daniel Reich, National Institute of Neurological Disorders and Stroke, National Institutes of Health
Fampridine is currently used to improve walking ability in multiple sclerosis. A new study shows that it could also help individuals with reduced working memory, as seen in mental health conditions like schizophrenia or depression.
Working memory allows a memory to be actively retained for a few seconds, for cognitive tasks such as remembering an email address to save it, or participating in a conversation. Certain conditions, such as schizophrenia or depression, as well as ADHD, impair working memory. Those affected lose track in conversations and struggle to organise their thoughts.
Fampridine is a drug that could help in such cases, as shown in a study led by Professors Andreas Papassotiropoulos and Dominique de Quervain at the University of Basel. The team has reported their findings in the journal Molecular Psychiatry.
Effective only if working memory is poor
In their study, the researchers tested the effectiveness of fampridine on working memory in 43 healthy adults. It was in those participants whose baseline working memory was at a low level that fampridine showed a more pronounced effect: after taking the active substance for three days, they scored better in the relevant tests than those who took the placebo. In contrast, in people who already had good baseline working memory, the drug showed no effect.
The researchers also observed that fampridine increased brain excitability in all participants, thus enabling faster processing of stimuli. The study was randomized and double-blind.
Established drug, new application
“Fampridine doesn’t improve working memory in everyone. But it could be a treatment option for those with reduced working memory,” explains Andreas Papassotiropoulos. Dominique de Quervain adds: “That’s why, together with researchers from the University Psychiatric Clinics Basel (UPK), we’re planning studies to test the efficacy of fampridine in schizophrenia and depression.”
The drug is currently used to improve walking ability in multiple sclerosis (MS). Particularly in capsule form, which releases the active ingredient slowly in the body, fampridine has shown effects on cognitive performance in MS patients: for some, it alleviates the mental fatigue that can accompany MS.
The researchers did not select the drug at random: this study followed comprehensive analyses of genome data in order to find starting points for repurposing established drugs. Fampridine acts on specific ion channels in nerve cells that, according to the researchers’ analyses, also play a role in mental disorders such as schizophrenia.
This is a pseudo-colored image of high-resolution gradient-echo MRI scan of a fixed cerebral hemisphere from a person with multiple sclerosis.
Credit: Govind Bhagavatheeshwaran, Daniel Reich, National Institute of Neurological Disorders and Stroke, National Institutes of Health
The question of what causes complex neurological diseases such as Alzheimer’s or multiple sclerosis continues to confound scientists and doctors, with the unknowns standing in the way of early diagnoses and effective treatments.
Even among identical twins who share the same genetic risk factors, one may develop a particular neurological disease while the other does not.
That’s because unlike diseases such as cystic fibrosis or sickle-cell anaemia, which are caused by a single gene, most neurological disorders are associated with many, sometimes hundreds, of rare genetic variants. And on their own, these variants can’t predict who will develop disease, as neurological conditions are also strongly influenced by environmental factors and vascular risks such as high blood pressure, aging, heart disease, or obesity.
But there’s one often-overlooked thread that connects most neurological diseases, says Katerina Akassoglou, PhD, a senior investigator at Gladstone Institutes: They’re marked by a toxic immune reaction caused by blood that leaks into the brain through damaged blood vessels.
“Interactions between the brain, blood vessels, and the immune system are a common thread in the development and progression of many neurological diseases that have been traditionally viewed as very different conditions,” says Akassoglou. “Knowing that leaked blood is a key driver of brain inflammation, we can now approach these diseases from a different angle.”
She and her collaborators share their insights on this topic in a commentary article published in Cell’s 50th anniversary “Focus on Neuroscience” issue.
Neutralising the Culprit
Akassoglou and her lab have long investigated how blood that leaks into the brain triggers neurologic diseases, essentially by hijacking the brain’s immune system and setting off a cascade of harmful often-irreversible effects that result in damaged neurons.
One blood protein in particular, fibrin, normally involved in blood coagulation, is responsible for setting off this detrimental cascade. The process has been observed in conditions as diverse as Alzheimer’s, traumatic brain injury, multiple sclerosis, premature birth, and even COVID-19. However, Akassoglou and her team found that the process could be prevented or interrupted by “neutralising” fibrin to deactivate its toxic properties – an approach that appears to protect against many neurological diseases when tested in animal models.
“As a first step, we know that neutralizing fibrin reduces the burden posed by vascular dysfunction,” Akassoglou says. Regardless of what initially caused the blood leaks, be it a head injury, autoimmunity, genetic mutations, brain amyloid or infection, neutralizing fibrin appears to be protective in multiple animal models of disease.
The scientists previously developed a drug, a therapeutic monoclonal antibody, that specifically targets fibrin’s inflammatory properties without affecting its essential role in blood coagulation. This fibrin-targeting immunotherapy has shown, in mice, to protect from multiple sclerosis and Alzheimer’s, and to treat neurological effects of COVID-19. A humanized version of this first-in-class fibrin immunotherapy is already in Phase 1 safety clinical trials by Therini Bio, a biotech company launched to advance discoveries from Akassoglou’s lab.
A New Era of Brain Research
In the Cell commentary, Akassoglou and her colleagues make the case that seemingly disparate neurological diseases must be viewed differently in light of new research on the blood-brain-immune interface.
They say that in the coming decade, scientific breakthroughs will emerge from collaborative networks of immunologists, neuroscientists, haematologists, geneticists, computer scientists, physicists, bioengineers, drug developers, and clinical researchers. These partnerships, forged across academia, industry, and foundations, will catalyse innovation in drug discovery and transform medical practice for neurological diseases.
“This is a new opportunity for drug discovery that goes beyond addressing genes alone or environmental factors alone,” Akassoglou says. “To usher in this new era, we must leverage new technologies and embrace an interdisciplinary approach that accounts for the important roles of immune and vascular systems in neurodegeneration.”
Almost 3 million people worldwide have multiple sclerosis (MS) – an autoimmune disease caused by the immune system mistakenly attacking the brain and central nervous system.
While treatments for MS have improved over the years, there’s still no cure. This is largely because researchers still don’t fully understand what goes wrong in the immune system to cause MS. But our latest research has revealed new insights into the way certain immune cells behave in people with MS. This discovery brings us closer to understanding why some people get MS – and may also be a crucial step in developing better treatments and even cures.
EBV typically infects people during childhood without causing any symptoms – so most early infections go unnoticed. But if the infection occurs during adolescence, it may cause glandular fever (infectious mononucleosis) which, although debilitating in the short-term, usually has no long-term effects.
Most viral infections are rapidly cleared by the body’s immune system, but EBV is cleverer than most viruses. Although the immune system controls the infection, it is unable to completely eradicate the virus as it hides inside a type of immune cell called a B cell (which normally produce antibodies that bind to and destroy invading viruses or bacteria). Once you’re infected with EBV you carry it for life – although for most people this causes no problems.
By adulthood about 95% of people are infected with EBV, but in people with MS nearly 100% are infected. Large epidemiological studies have shown that EBV infection increases the risk of developing MS over 30-fold. For people who have had glandular fever the risk is even higher. Research has also shown that in people with MS, EBV infection occurs before the very earliest stages of disease.
Many researchers now believe being infected with EBV is more than a risk factor in MS – it’s essential.
But how does EBV cause MS – and why does a common virus only cause MS in a few people? Several theories are currently being investigated.
One theory is that in some people the immune cells activated by EBV mistakenly attack parts of the brain and central nervous system. This process, called molecular mimicry, also occurs in other autoimmune diseases, such as Guillain-Barré syndrome. This could explain why drugs which prevent immune cells from entering the brain are shown to dramatically improve MS symptoms.
Research into EBV molecular mimicry in MS has mainly focused on the viral protein EBNA1. Without EBNA1 EBV cannot live in B cells, and MS patients have higher levels of antibodies towards EBNA1.
But EBV makes over 80 different proteins during its life cycle. In our latest work we investigated immune responses to these other viral proteins in people with MS.
Altered immunity
We compared the immune responses of 31 people with MS, 33 healthy people and 11 people who had recently recovered from glandular fever. We wanted to see if each group reacted to EBV infections differently.
We found that antibodies targeting EBNA1 and another viral protein called VCA were higher in people with MS compared to the other groups. People with MS were also more likely to have antibodies targeting several other viral proteins. This suggests EBV antibodies are more altered in MS than previously thought – but it isn’t certain whether these antibodies are fighting infection or if they have a role in MS disease.
Scanning electron micrograph of a T cell lymphocyte. Credit: NIH / NIAID
Antibodies aren’t the full story. Previous research has suggested another type of immune cell, called a T cell, may also play an important role as they’re found in high numbers in MS brain lesions. As such, we wanted to understand whether T cells which fight EBV were different in people with MS.
By analysing blood samples we found that, although EBV T cell numbers were similar in MS and healthy people, these cells behaved differently in people with MS. T cells from people with MS produced slightly higher amounts of an inflammatory substance called interleukin-2. The body normally produces this substance in response to injury or infection, but too much interleukin-2 can cause chronic disease.
We also looked at molecular mimicry, wondering whether EBV T-cells mistakenly target brain proteins rather than fighting the virus.
Surprisingly, we found that in both people with MS and healthy people, their EBV T cells reacted to multiple proteins found in the brain. Notably, most people had EBV T cells that targeted a protein called myelin oligodendrocyte glycoprotein, or Mog, which surrounds the nerves.
Looking at one person with MS in more detail, we found individual T cells that directly recognised both EBNA1 and Mog. This means that, rather than just fighting infection, some EBV T cells could also target nerve cells in the brain.
This widespread misdirection between EBV T cells and the brain goes some way to suggest how infection with this common virus can lead to MS. But its presence in healthy people is slightly confusing. One possible explanation could be that EBV T cells are better able to cross the blood-brain barrier (a tight-knit lining of cells that protect the brain) in people with MS. This idea is something we’re keen to explore in future research.
While there’s still much we don’t know about these misdirected EBV T cells in the brain, our latest findings provide fresh evidence for researchers and hopefully will lead to the development of new, targeted treatments for MS.
This is a pseudo-coloured image of high-resolution gradient-echo MRI scan of a fixed cerebral hemisphere from a person with multiple sclerosis.
Credit: Govind Bhagavatheeshwaran, Daniel Reich, National Institute of Neurological Disorders and Stroke, National Institutes of Health
A new study has found some cancers to be slightly more frequent in people with multiple sclerosis (MS) than in people without MS. The study is published online in Neurology®, the medical journal of the American Academy of Neurology. Types of cancers found to have a small increased risk include bladder, brain and cervical cancers.
“People with MS undergo an increased number of tests to monitor MS, making it more likely to detect other diseases,” said study author Emmanuelle Leray, PhD, of Rennes University in France. “We found an association between some types of cancer and MS which may have different explanations depending on a person’s age and the types of cancer. Overall, our study found the increased risk of cancer was quite small.”
For the study, researchers reviewed 10 years of data in the French national health care database. Researchers identified 140 649 people with MS and matched them for factors such as age, sex and residence to 562 596 people without MS. All participants were cancer free three years before the study. They were followed for an average of eight years.
During the study, 8,368 people with MS and 31,796 people without MS developed cancer.
Researchers determined there were 799 cancers per 100 000 person-years for people with MS and 736 cancers per 100 000 person-years for people without MS. Person-years represent both the number of people in the study and the amount of time each person spends in the study.
Researchers found people with MS had a 6% increased risk of developing any type of cancer regardless of age, sex and residence. They also found cancer risk was higher in those under 55 and lower in people 65 and older when compared to people without MS.
Researchers then looked at cancer types. People with MS had a 71% increased risk for bladder cancer, a 68% increased risk for brain cancer and a 24% increased risk for cervical cancer. However, they also had a 20% lower risk of prostate cancer, a 10% lower risk of colorectal cancer and a 9% lower risk of breast cancer.
“While our study found a higher risk for brain cancer, it may be due in part to earlier detection in those with MS since they regularly have brain scans which may detect cancers earlier, before a person has symptoms,” said Leray. “Frequent urinary tract infections in people with MS and the use of immunosuppressant drugs may contribute to their higher risk of bladder and cervical cancers.”
Leray added, “The lower risk for colorectal and breast cancers may be due in part to fewer people with MS getting screened for cancer in older age when they may be experiencing more MS symptoms. More research is needed, including studies that look at more closely at how cancer screenings may play a role.”
A limitation of the study was that researchers were unable to adjust for factors such as education, income, smoking and alcohol consumption since this information was not available in the national database.
Researchers from have found a potential new way to improve the treatment of multiple sclerosis (MS) using a novel combined therapy. The results, published in the Journal of Clinical Investigation, builds on two harmonised Phase I clinical trials, focusing on the use of Vitamin D3 tolerogenic dendritic cells (VitD3-tolDCs) to regulate the immune response in MS patient.
Multiple Sclerosis (MS) is a long-term disease where the immune system mistakenly attacks the protective myelin sheath around nerve cells. This leads to nerve damage and worsening disability. Current treatments, like immunosuppressants, help reduce these harmful attacks but also weaken the overall immune system, leaving patients vulnerable to infections and cancer. Scientists are now exploring a more targeted therapy using special immune cells, called tolerogenic dendritic cells (tolDCs), from the same patients.
TolDCs can restore immune balance without affecting the body’s natural defences. However, since a hallmark of MS is precisely the dysfunction of the immune system, the effectiveness of these cells for auto transplantation might be compromised. Therefore, it is essential to better understand how the disease affects the starting material for this cellular therapy before it can be applied.
In this study, researchers from Barcelona’s Germans Trias i Pujol Institute and Josep Carreras Leukaemia Research Institute, examined CD14+ monocytes, mature dendritic cells (mDCs), and Vitamin D3-treated tolerogenic dendritic cells (VitD3-tolDCs) from MS patients who had not yet received treatment, as well as from healthy individuals. The clinical trials (NCT02618902 and NCT02903537) are designed to assess the effectiveness of VitD3-tolDCs, which are loaded with myelin antigens to help “teach” the immune system to stop attacking the nervous system. This approach is groundbreaking as it uses a patient’s own immune cells, modified to induce immune tolerance, in an effort to treat the autoimmune nature of MS.
The study, led by Dr Eva Martinez-Cáceres and Dr Esteban Ballestar, with Federico Fondelli as first author, found that the immune cells from MS patients (monocytes, precursors of tolDCs) have a persistent “pro-inflammatory” signature, even after being transformed into VitD3-tolDCs, the actual therapeutic cell type. This signature makes these cells less effective compared to those derived from healthy individuals, missing part of its potential benefits.
Using state-of-the-art research methodologies, the researchers identified a pathway, known as the Aryl Hydrocarbon Receptor (AhR), that is linked to this altered immune response. By using an AhR-modulating drug, the team was able to restore the normal function of VitD3-tolDCs from MS patients, in vitro. Interestingly, Dimethyl Fumarate, an already approved MS drug, was found to mimic the effect of AhR modulation and restore the cells’ full efficacy, with a safer toxic profile.
Finally, studies in MS animal models showed that a combination of VitD3-tolDCs and Dimethyl Fumarate led to better results than using either treatment on its own. This combination therapy significantly reduced symptoms in mice, suggesting enhanced potential for treating human patients.
These results could lead to a new, more potent treatment option for multiple sclerosis, offering hope to the millions of patients worldwide who suffer from this debilitating disease. This study represents a significant step forward in the use of personalised cell therapies for autoimmune diseases, potentially revolutionising how multiple sclerosis is treated.
The team is now preparing to move into Phase II trials to further explore these findings.
This is a pseudo-colored image of high-resolution gradient-echo MRI scan of a fixed cerebral hemisphere from a person with multiple sclerosis.
Credit: Govind Bhagavatheeshwaran, Daniel Reich, National Institute of Neurological Disorders and Stroke, National Institutes of Health
In people with primary progressive multiple sclerosis (MS), a new study has found no difference in the amount of time before disability worsened between people taking certain medications and those not receiving treatment. The study is published in Neurology®, the medical journal of the American Academy of Neurology.
With MS, the body’s immune system attacks the myelin sheaths of nerves. People with primary progressive MS experience a steady decline in symptoms. About 10 to 15% of people with the disease have this type of MS.
The study looked at rituximab and ocrelizumab, anti-CD20 infusion therapies that target a protein called CD20 found on some white blood cells called B-cells. Removing these cells from the bloodstream is believed to reduce inflammation and damage that can occur to the myelin.
Ocrelizumab is approved by the US Food and Drug Administration (FDA) for primary progressive MS and for people with relapses, but rituximab is not. Rituximab is FDA approved for other diseases like rheumatoid arthritis and prescribed off label for MS in the US.
“MS is a disabling disease, so treatments that slow the progression to worse disability are sorely needed,” said study author Laure Michel, MD, PhD, of Rennes University in France. “Anti-CD20 therapies are widely prescribed, in part because there are few alternate treatments. However, our study suggests they may not slow disability from worsening for people with primary progressive MS.”
The study involved 1184 people with primary progressive MS who had an average age of 56. They did not take MS medications in the two years prior to the study. For the study, 295 people were treated with rituximab, 131 were treated with ocrelizumab and 728 were untreated.
They were followed for an average of four years. Participants’ level of disability was measured on a scale with scores ranging from zero, meaning no symptoms, to 10 points, meaning death due to MS. At the start of the study, all participants had a score of 6.5 or less. Researchers then measured how long it took for people to advance to their first confirmed disability progression.
For those whose score was less than 5.5 at the start of the study, advancing one point on the scale was considered progressing in disability. If their score was 5.5 or more, advancing 0.5 points on the scale was disability progression.
After adjusting for possible differences between the treated and untreated groups, researchers found there was no difference in the time it took to progress to the next level of disability between those taking a medication and those taking no medication. “
Medications for MS can be expensive and come with risks of side effects,” said Michel. “Our results indicate that there should be a constant evaluation of MS therapies to determine if the benefits outweigh the risks for people with primary progressive MS.”
A limitation of the study was that it was retrospective and did not follow people in real time. Also, among those taking medications, most were taking rituximab with fewer people taking ocrelizumab. More research is needed in larger groups of people to confirm the findings.
Neurons in the brain of an Alzheimer’s patient, with plaques caused by tau proteins. Credit: NIH
People with multiple sclerosis (MS) are far less likely than those without the condition to have the molecular hallmarks of Alzheimer’s disease, according to a paper published in the Annals of Neurology.
The study from Washington University School of Medicine in St. Louis, suggests a new direction for researching Alzheimer’s treatments, said Matthew Brier, MD PhD, an assistant professor of neurology and radiology and the study’s first author.
“Our findings imply that some component of the biology of multiple sclerosis, or the genetics of MS patients, is protective against Alzheimer’s disease,” Brier said. “If we could identify what aspect is protective and apply it in a controlled way, that could inform therapeutic strategies for Alzheimer’s disease.”
A collaboration between WashU Medicine experts in Alzheimer’s and MS, the study was prompted by a suspicion Brier’s mentor and collaborator Anne Cross, MD, had developed over decades of treating patients with MS, an immune-mediated disease that attacks the central nervous system. Although her patients were living long enough to be at risk of Alzheimer’s or had a family history of the neurodegenerative disease, they weren’t developing the disease.
“I noticed that I couldn’t find a single MS patient of mine who had typical Alzheimer’s disease,” said Cross, the Manny and Rosalyn Rosenthal and Dr. John Trotter MS Center Chair in Neuroimmunology. “If they had cognitive problems, I would send them to the memory and aging specialists here at the School of Medicine for an Alzheimer’s assessment, and those doctors would always come back and tell me, ‘No, this is not due to Alzheimer’s disease.’”
Cognitive impairment caused by MS can be confused with symptoms of Alzheimer’s disease; Alzheimer’s can be confirmed with blood and other biological tests.
To confirm Cross’ observation, the research team used a new, FDA-approved blood test that was developed by Washington University researchers. Known as PrecivityAD2, the blood test is highly effective at predicting the presence of amyloid plaques in the brain. Such plaques are an indicator of Alzheimer’s disease and previously only could be verified with brain scans or spinal taps.
Brier, Cross and their colleagues recruited 100 patients with MS to take the blood test, 11 of whom also underwent PET scans at the School of Medicine’s Mallinckrodt Institute of Radiology. Their results were compared with the results from a control group of 300 individuals who did not have MS but were similar to those with MS in age, genetic risk for Alzheimer, and cognitive decline.
“We found that 50% fewer MS patients had amyloid pathology compared to their matched peers based on this blood test,” Brier said. This finding supported Cross’ observation that Alzheimer’s appeared to be less likely to develop among those with MS. It is not clear how amyloid accumulation is linked to the cognitive impairment typical of Alzheimer’s, but the accumulation of plaques is generally understood to be the first event in the biological cascade that leads to cognitive decline.
The researchers also found that the more typical the patient’s MS history was, in terms of age of onset, severity and overall disease progression, the less likely they were to have amyloid plaque accumulation in that patient’s brain compared with those with atypical presentations of MS. This suggests there is something about the nature of MS itself that is protective against Alzheimer’s disease, which Brier and Cross are planning to investigate.
MS patients generally have multiple flare-ups of the illness over the course of their lifetimes. During these flare-ups, the immune system attacks the central nervous system, including within the brain. It’s possible that this immune activity also reduces amyloid plaques, the researchers said.
“Perhaps when the Alzheimer’s disease amyloid pathology was developing, the patients with MS had some degree of inflammation in their brains that was spurred by their immune responses,” Brier said. Referring to work by co-author David M. Holtzman, MD, Brier noted that activated microglia, which are part of the brain’s immune response in MS, have been shown to clear amyloid from the brain in animal models.
Brier and Cross have begun the next steps of this research, both to tease out the possible human genetics involved, as well as to test amyloid plaque development in animal models representing MS.
This is a pseudo-colored image of high-resolution gradient-echo MRI scan of a fixed cerebral hemisphere from a person with multiple sclerosis.
Credit: Govind Bhagavatheeshwaran, Daniel Reich, National Institute of Neurological Disorders and Stroke, National Institutes of Health
A key feature of multiple sclerosis (MS) is that it causes the patient’s own immune system to attack and destroy the myelin sheaths in the central nervous system. To date, it hasn’t been possible to visualise the myelin sheaths well enough to use this information for the diagnosis and monitoring of MS. Now researchers have developed a new magnetic resonance imaging (MRI) procedure that maps the condition of the myelin sheaths more accurately than was previously possible.
The researchers successfully tested the procedure on healthy people for the first time, and published their results in Magnetic Resonance in Medicine.
In the future, the MRI system with its special head scanner could help doctors to recognise MS at an early stage and better monitor the progression of the disease.
This technology, developed by the researchers at ETH Zurich and University of Zurich, led by Markus Weiger and Emily Baadsvik from the Institute for Biomedical Engineering, could also facilitate the development of new drugs for MS. But it doesn’t end there: the new MRI method could also be used by researchers to better visualise other solid tissue types such as connective tissue, tendons and ligaments.
Quantitative myelin maps
Conventional MRI devices capture only inaccurate, indirect images of the myelin sheaths because these devices typically work by reacting to water molecules in the body that have been stimulated by radio waves in a strong magnetic field.
But the myelin sheaths, which wrap around the nerve fibres in several layers, consist mainly of fatty tissue and proteins. That said, there is some water – known as myelin water – trapped between these layers.
Standard MRIs build their images primarily using the signals of the hydrogen atoms in this myelin water, rather than imaging the myelin sheaths directly.
The ETH researchers’ new MRI method solves this problem and measures the myelin content directly.
It puts numerical values on MRI images of the brain to show how much myelin is present in a particular area compared to other areas of the image.
A number 8, for instance, means that the myelin content at this point is only 8 percent of a maximum value of 100, which indicates a significant thinning of the myelin sheaths.
Essentially, the darker the area and the smaller the number in the image, the more the myelin sheaths have been reduced.
This information ought to enable doctors to better assess the severity and progression of MS.
Measuring signals within millionths of a second
It is difficult however to image the myelin sheaths directly, since the signals that the MRI triggers in the tissue are very short-lived; the signals that emanate from the myelin water last much longer.
“Put simply, the hydrogen atoms in myelin tissue move less freely than those in myelin water. That means they generate much briefer signals, which disappear again after a few microseconds,” Weiger says, adding: “And bearing in mind a microsecond is a millionth of a second, that’s a very short time indeed.” A conventional MRI scanner can’t capture these fleeting signals because it doesn’t take the measurements fast enough.
To solve this problem, the researchers used a specially customised MRI head scanner that they have developed over the past ten years together with the companies Philips and Futura.
This scanner is characterised by a particularly strong gradient in the magnetic field.
“The greater the change in magnetic field strength generated by the three scanner coils, the faster information about the position of hydrogen atoms can be recorded,” Baadsvik says.
Generating such a strong gradient calls for a strong current and a sophisticated design.
As the researchers scan only the head, the magnetic field is more contained and concentrated than with conventional devices.
In addition, the system can quickly switch from transmitting radio waves to receiving signals; the researchers and their industry partners have developed a special circuit for this purpose.
The researchers have already successfully tested their MRI procedure on tissue samples from MS patients and on two healthy individuals. Next, they want to test it on MS patients themselves. Whether the new MRI head scanner will make its way into hospitals in the future now depends on the medical industry. “We’ve shown that our process works,” Weiger says. “Now it’s up to industry partners to implement it and bring it to market.”
This is a pseudo-colored image of high-resolution gradient-echo MRI scan of a fixed cerebral hemisphere from a person with multiple sclerosis.
Credit: Govind Bhagavatheeshwaran, Daniel Reich, National Institute of Neurological Disorders and Stroke, National Institutes of Health
For decades, scientists have noted an intriguing similarity between a deficiency in vitamin B12 – an essential nutrient that supports healthy development and functioning of the central nervous system (CNS) – and multiple sclerosis (MS), a chronic disease in which the body’s immune system attacks the CNS and which can produce neurodegeneration.
Both vitamin B12 deficiency and MS produce similar neurological symptoms, including numbness or tingling in hands and feet, vision loss, difficulty walking or speaking normally and cognitive dysfunction, such as problems with memory.
In a new study, published in Cell Reports, researchers at Sanford Burnham Prebys, with collaborators elsewhere, describe a novel molecular link between vitamin B12 and MS that takes place in astrocytes – important non-neuronal glial cells in the brain.
The findings by senior study author Jerold Chun, MD, PhD, professor and senior vice president of neuroscience drug discovery, and Yasuyuki Kihara, PhD, research associate professor and co-corresponding author, and colleagues suggest new ways to improve the treatment of MS through CNS-B12 supplementation.
“The shared molecular binding of the brain’s vitamin B12 carrier protein, known as transcobalamin 2 or TCN2, with the FDA-approved MS drug fingolimod provides a mechanistic link between B12 signaling and MS, towards reducing neuroinflammation and possibly neurodegeneration,” said Chun.
“Augmenting brain B12 with fingolimod or potentially related molecules could enhance both current and future MS therapies.”
In their paper, the team at Sanford Burnham Prebys, with collaborators at University of Southern California, Juntendo University in Japan, Tokyo University of Pharmacy and Life Sciences and State University of New York, focused on the molecular functioning of FTY720 or fingolimod (Gilenya®), a sphingosine 1-phosphate (S1P) receptor modulator that suppresses distribution of T and B immune cells errantly attacking the brains of MS patients.
Working with an animal model of MS as well as human post-mortem brains, the researchers found that fingolimod suppresses neuroinflammation by functionally and physically regulating B12 communication pathways, specifically elevating a B12 receptor called CD320 needed to take up and use needed B12 when it is bound to TCN2, which distributes B12 throughout the body, including the CNS. This known process was newly identified for its interactions with fingolimod within astrocytes. Importantly, the relationship was also observed in human MS brains.
Of particular note, the researchers reported that lower levels of CD320 or dietary B12 restriction worsened the disease course in an animal model of MS and reduced the therapeutic efficacy of fingolimod, which occurred through a mechanism in which fingolimod hitchhikes by binding to the TCN2-B12 complex, allowing delivery of all to the astrocytes via interactions with CD320, with component losses disrupting the process and worsening disease.
These new findings further support to the use of B12 supplementation – especially in terms of delivering the vitamin to astrocytes within the brain – while revealing that fingolimod can correct the impaired astrocyte-B12 pathway in people with MS.
The scientists said it is possible that other S1P receptor modulators on the market, such as Mayzent®, Zeposia® and Ponvory®, may access at least parts of this CNS mechanism. The study supports B12 supplementation with S1P receptor modulators with the goal of improving drug efficacy for this class of medicines.
The study also opens new avenues on how the B12-TCN2-CD320 pathway is regulated by sphingolipids, specifically sphingosine, a naturally occurring and endogenous structural analogue of fingolimod, toward improving future MS therapies, Chun said.
“It supports creating brain-targeted B12 formulations. In the future, this mechanism might also extend to novel treatments of other neuroinflammatory and neurodegenerative conditions.”
This is a pseudo-colored image of high-resolution gradient-echo MRI scan of a fixed cerebral hemisphere from a person with multiple sclerosis.
Credit: Govind Bhagavatheeshwaran, Daniel Reich, National Institute of Neurological Disorders and Stroke, National Institutes of Health
Researchers have found in pre-clinical studies of a small molecule drug that it has promise as a potential new treatment for multiple sclerosis (MS). The results from the Centre for Addiction and Mental Health-led study have been published in the journalScience Advances.
Expanding on Dr Fang Liu’s earlier work that identified a novel drug target for the treatment of MS, she and her team have now created a small molecule compound that is effective in two different animal models of MS. This represents a key advancement that brings this MS research closer to the clinic to impact patient care.
MS is a progressive neurological disease that currently has no cure.
It is associated with a wide-range of debilitating symptoms, including problems with coordination, cognition, muscle weakness and depression. For unknown reasons, it is more common in northern latitudes and more than twice as common in women.
It is known that MS damages myelin, a protective sheath that forms around nerves in the brain and spinal cord. As the myelin damage is triggered by inflammation in the immune system, up until now all current drug treatments for MS target the immune system.
In this study, CAMH Senior Scientist Dr Fang Liu and her team treated MS in a completely different way – targeting the glutamate system. Study results showed that the newly synthesised lead compound not only reduced MS-like symptoms, it also may repair the damaged myelin in two different pre-clinical models of MS.
“Our compound had a stunning effect on rescuing myelin and motor function in the lab models, and I hope these effects will translate to the clinic to add to current treatments and bring new hope to patients with MS,” said Dr Liu.
“As with cancer chemotherapy drug cocktails, simultaneous targeting of the MS disease pathway at multiple points can have synergistic effects and result in better outcomes.”
Dr Iain Greig, Reader in Medicinal Chemistry at the University of Aberdeen, alongside his team, are working to turn the molecules identified by Dr Liu into advanced “drug-like” molecules suitable for continued development towards clinical use in patients.
He added: “In all my years as a medicinal chemist, I have never seen a more promising starting point for a drug development project. It has been a huge pleasure to be involved in this program and I am looking forward to continuing to drive it towards to the clinic.”
Much of the funding for this novel treatment for MS, which Dr. Fang and her team have been investigating for over a decade, has come from the Multiple Sclerosis Society of Canada and the National Multiple Sclerosis Society USA’s Fast Forward commercial research program.
“We are pleased to have helped enable the early development of a novel neuroprotective strategy for MS, and look forward to seeing it progress through the critical next stages needed to determine its potential benefits for people living with MS,” said Walt Kostich, PhD, head of the National MS Society (USA)’s Fast Forward commercial research programme.
Dr. Liu believes that the evidence of efficacy and tolerability generated in this study for the small molecule drug makes it a good candidate to be developed for human trials. The next steps in drug development will involve some further pre-clinical research, including investigating safety and stability of the compound. CAMH and the University of Aberdeen have already filed patent applications to protect this research and are actively seeking industry partners to further advance this work towards clinical trials over the next few years.
