Posts tagged MS
Posts tagged MS
A medical test previously developed to measure a toxin found in tobacco smokers has been adapted to measure the same toxin in people suffering from spinal cord injuries and multiple sclerosis, offering a potential tool to reduce symptoms.
The toxin, called acrolein, is produced in the body after nerve cells are injured, triggering a cascade of biochemical events thought to worsen the injury’s severity. Acrolein (pronounced a-KRO-le-an) also may play an important role in multiple sclerosis and other conditions.
Because drugs already exist to reduce the concentration of acrolein in the body, being able to detect and measure it non-invasively represents a potential treatment advance, said Riyi Shi (pronounced Ree Shee), a professor of neuroscience and biomedical engineering in Purdue University’s Department of Basic Medical Sciences, School of Veterinary Medicine, Center for Paralysis Research and Weldon School of Biomedical Engineering.
“If the acrolein level is high it needs to be reduced, and we already have effective acrolein removers to do so,” Shi said. “Reducing or removing acrolein may lessen the severity of symptoms in people who have nerve damage, but there has not been a practical way to monitor acrolein levels in nervous system trauma and diseases.”
The toxin is present in tobacco smoke and air pollutants. A method had been developed previously to detect and measure acrolein in the urine of smokers, but it has not been used in people suffering from conditions in which the body produces acrolein internally.
“Based on this method, it was revealed that acrolein is significantly elevated in smokers and decreases following the cessation of cigarette smoke,” Shi said. “However, such a method has not been widely used for conditions in which acrolein is elevated due to central nervous system damage or disease.”
The researchers tested the method in laboratory animals.
“We wanted to see if higher levels of acrolein corresponds to greater severity of spinal cord injury, and the answer is yes,” said Shi, who is working with Bruce Cooper, director of the Metabolite Profiling Facility in the Bindley Bioscience Center of Purdue’s Discovery Park. “This means reducing acrolein may help to control symptoms.”
New findings are detailed in a research paper that recently appeared online in the Journal of Neurotrauma. The paper, which also will appear in an upcoming print edition of the journal, was authored by doctoral students Lingxing Zheng, Jonghyuck Park, Michael Walls and Melissa Tully; Amber Jannasch, laboratory manager of the Metabolite Profiling Facility; and Cooper and Shi.
The method does not detect acrolein directly but determines the presence of a byproduct, or metabolite, of acrolein in the urine. The metabolite is a chemical compound called N-acetyl-S-3-Hydroxypropylcysteine, or 3-HPMA.
“Acrolein is very volatile, so it doesn’t remain stable long enough to monitor, but one molecule of acrolein will make one molecule of 3-HPMA, which is very stable in urine,” Shi said.
Laboratory rats were injected with different doses of acrolein, and findings showed that the detection technique is able to accurately measure these differences in acrolein concentration in the urine. The technique might one day be performed routinely in a doctor’s office.
“The non-invasive nature of measuring 3-HPMA concentrations in urine allows for long-term monitoring of acrolein in the same animal and ultimately in human clinical studies,” Shi said.
Two drugs have been shown to be effective in reducing acrolein levels in the body: hydralazine and phenelzine, which have been approved by the U.S. Food and Drug Administration for hypertension and depression, respectively.
The testing method could be used in conjunction with other measures to test patients for the progress of spinal cord disease.
“Nervous system trauma and diseases are like many other illnesses: A disease-associated marker can be critical for making a diagnosis, a therapeutic selection and a treatment evaluation,” Shi said. “Therefore, determination of acrolein levels gives you more assurance that you have an intense biochemical imbalance and biochemical damage and that you should use an acrolein scavenger as a treatment. We used different levels of hydralazine to see if it causes a dose-dependent reduction of 3-HPMA and found that, in fact, it did. This shows that this method is capable of monitoring the decrease of acrolein through treatment with acrolein-removing medications.”
Acrolein damages mitochondria, which provide energy for cells, and in multiple sclerosis compromises the myelin sheath surrounding a nerve cell’s axon, preventing nerves from properly conducting electrical impulses. The toxin has a possible role in other diseases, including Alzheimer’s disease, cancer and atherosclerosis.
“Due to widespread involvement of acrolein in the body, the benefits of this study have the potential to significantly enhance human health,” Shi said. “For example, there is evidence that heightened levels of acrolein could diminish an individual’s ability to recover fully from stroke and cancer.”
In laboratory animals, hydralazine has been shown to delay onset of multiple sclerosis for several days, which could mean several years in humans. Tests with animals also suggests the drug could help to reduce the most severe symptoms once the disease has progressed.
Acrolein has been found to be elevated by about 60 percent in the spinal cord tissues of mice with a disease similar to multiple sclerosis. The toxin causes harm by reacting with the proteins and lipids that make up cells, including neurons.
Researchers at the University of British Columbia have developed a new magnetic resonance imaging (MRI) technique that detects the telltale signs of multiple sclerosis in finer detail than ever before – providing a more powerful tool for evaluating new treatments.
The technique analyzes the frequency of electro-magnetic waves collected by an MRI scanner, instead of the size of those waves. Although analyzing the number of waves per second had long been considered a more sensitive way of detecting changes in tissue structure, the math needed to create usable images had proved daunting.
Multiple sclerosis (MS) occurs when a person’s immune cells attack the protective insulation, known as myelin, that surrounds nerve fibres. The breakdown of myelin impedes the electrical signals transmitted between neurons, leading to a range of symptoms, including numbness or weakness, vision loss, tremors, dizziness and fatigue.
Alexander Rauscher, an assistant professor of radiology, and graduate student Vanessa Wiggermann in the UBC MRI Research Centre, analyzed the frequency of MRI brain scans. With Dr. Anthony Traboulsee, an associate professor of neurology and director of the UBC Hospital MS Clinic, they applied their method to 20 MS patients, who were scanned once a month for six months using both conventional MRI and the new frequency-based method.
Once scars in the myelin, known as lesions, appeared in conventional MRI scans, Rauscher and his colleagues went back to earlier frequency-based images of those patients. Looking in the precise areas of those lesions, they found frequency changes – indicating tissue damage – at least two months before any sign of damage appeared on conventional scans. The results were published in the June 12 issue of Neurology.
“This technique teases out the subtle differences in the development of MS lesions over time,” Rauscher says. “Because this technique is more sensitive to those changes, researchers could use much smaller studies to determine whether a treatment – such as a new drug – is slowing or even stopping the myelin breakdown.”
Phase 1 trial safely resets patients’ immune systems, reduces attack on myelin protein
A phase 1 clinical trial for the first treatment to reset the immune system of multiple sclerosis (MS) patients showed the therapy was safe and dramatically reduced patients’ immune systems’ reactivity to myelin by 50 to 75 percent, according to new Northwestern Medicine research.
In MS, the immune system attacks and destroys myelin, the insulating layer that forms around nerves in the spinal cord, brain and optic nerve. When the insulation is destroyed, electrical signals can’t be effectively conducted, resulting in symptoms that range from mild limb numbness to paralysis or blindness.
“The therapy stops autoimmune responses that are already activated and prevents the activation of new autoimmune cells,” said Stephen Miller, the Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine. “Our approach leaves the function of the normal immune system intact. That’s the holy grail.”
Miller is the co-senior author of a paper on the study, which was published June 5 in the journal Science Translational Medicine. The study is a collaboration between Northwestern’s Feinberg School, University Hospital Zurich in Switzerland and University Medical Center Hamburg-Eppendorf in Germany.
The human trial is the translation of more than 30 years of preclinical research in Miller’s lab.
In the trial, the MS patients’ own specially processed white blood cells were used to stealthily deliver billions of myelin antigens into their bodies so their immune systems would recognize them as harmless and develop tolerance to them.
Current therapies for MS suppress the entire immune system, making patients more susceptible to everyday infections and higher rates of cancer.
While the trial’s nine patients — who were treated in Hamburg, Germany — were too few to statistically determine the treatment’s ability to prevent the progression of MS, the study did show patients who received the highest dose of white blood cells had the greatest reduction in myelin reactivity.
The primary aim of the study was to demonstrate the treatment’s safety and tolerability. It showed the intravenous injection of up to 3 billion white blood cells with myelin antigens caused no adverse affects in MS patients. Most importantly, it did not reactivate the patients’ disease and did not affect their healthy immunity to real pathogens.
As part of the study, researchers tested patients’ immunity to tetanus because all had received tetanus shots in their lifetime. One month after the treatment, their immune responses to tetanus remained strong, showing the treatment’s immune effect was specific only to myelin.
The human safety study sets the stage for a phase 2 trial to see if the new treatment can prevent the progression of MS in humans. Scientists are currently trying to raise $1.5 million to launch the trial, which has already been approved in Switzerland. Miller’s preclinical research demonstrated the treatment stopped the progression of relapsing-remitting MS in mice.
“In the phase 2 trial we want to treat patients as early as possible in the disease before they have paralysis due to myelin damage.” Miller said. “Once the myelin is destroyed, it’s hard to repair that.”
In the trial, patients’ white blood cells were filtered out, specially processed and coupled with myelin antigens by a complex GMP manufacturing process developed by the study co-senior authors, Roland Martin, Mireia Sospedra, and Andreas Lutterotti and their team at the University Medical Center Hamburg-Eppendorf. Then billions of these dead cells secretly carrying the myelin antigens were injected intravenously into the patients. The cells entered the spleen, which filters the blood and helps the body dispose of aging and dying blood cells. During this process, the immune cells start to recognize myelin as a harmless and immune tolerance quickly develops. This was confirmed in the patients by immune assays developed and carried out by the research team in Hamburg.
This therapy, with further testing, may be useful for treating not only MS but also a host of other autoimmune and allergic diseases simply by switching the antigens attached to the cells. Previously published preclinical research by Miller showed the therapy’s effectiveness for type 1 diabetes and airway allergy (asthma) and peanut allergy.
The MS human trial relates directly to Miller’s recently published research in mice in which he used nanoparticles — rather than a patient’s white blood cells — to deliver the myelin antigen. Using a patient’s white blood cells is a costly and labor-intensive procedure. Miller’s study showed the nanoparticles, which are potentially cheaper and more accessible to a general population, could be as effective as the white blood cells as delivery vehicles. This nanoparticle technology has been licensed to Cour Pharmaceutical Development Company and is in preclinical development.
Miller’s research represents several pillars of Northwestern’s Strategic Plan by discovering new ways to treat disease in the biomedical sciences and translating those discoveries into ideas and products that make the world a better place for everyone.
Biological processes are generally based on events at the molecular and cellular level. To understand what happens in the course of infections, diseases or normal bodily functions, scientists would need to examine individual cells and their activity directly in the tissue. The development of new microscopes and fluorescent dyes in recent years has brought this scientific dream tantalisingly close. Scientists from the Max Planck Institute of Neurobiology in Martinsried have now presented not one, but two studies introducing new indicator molecules which can visualise the activation of T cells. Their findings provide new insight into the role of these cells in the autoimmune disease multiple sclerosis (MS). The new indicators are set to be an important tool in the study of other immune reactions as well.
Inflammation is the body’s defence response to a potentially harmful stimulus. The purpose of an inflammation is to fight and remove the stimulus – whether it be disease-causing pathogens or tissue. As an inflammation progresses, significant steps that occur thus include the recruitment of immune cells, the interactions of these cells in the affected tissue and the resulting activation pattern of the immune cells. The more scientists understand about these steps, the better they can develop more effective drugs and treatments to support them. This is particularly true for diseases like multiple sclerosis. In this autoimmune disorder cells from the body’s immune system penetrate into the central nervous system where they cause massive damage in the course of an inflammation.
In order to truly understand the cellular processes involved in MS, scientists ideally need to study them in real time at the exact location where they take place – directly in the affected tissue. In recent years, new microscopic techniques and fluorescent dyes have been developed to make this possible for the first time. These coloured indicators make individual cells, their components or certain cell processes visible under the microscope. For example, scientists from the Max Planck Institute of Neurobiology have developed a genetic calcium indicator, TN-XXL, which the cells themselves form, and which highlights the activity of individual nerve cells reliably and for an unlimited time. However, the gene for the indicator was not expressed by immune cells. That is why it was previously impossible to track where in the body and when a contact between immune cells and other cells led to the immune cell’s activation.
Now the Martinsried-based neuroimmunologists report two major advances in this field simultaneously. One is their development of a new indicator which visualises the activation of T cells. These cells, which are important components of the immune system, detect and fight pathogens or substances classified as foreign (antigens). Multiple sclerosis, for example, is one of the diseases in which T cells play an important role: here, however, they detect and attack the body’s brain tissue. If a T cell detects “its own” antigen, the NFAT signal protein migrates from the cell plasma to the nucleus of the T cell. “This movement of the NFAT shows us that the cell has been activated, in other words it has been ‘armed’,” explains Marija Pesic, lead author of the study published in the Journal of Clinical Investigation. “We took advantage of this to bind the fluorescent dye called GFP to the NFAT, thereby visualising the activation of these cells.” The scientists are thus now able to conclusively show in the organism whether an antigen leads to the activation of a T cell. The new indicator is an important new tool for researching autoimmune diseases and also for studying immune cells during their development, during infections or in the course of tumour reactions.
In parallel to these studies, the neuroimmunologists in Martinsried developed a slightly different, complementary method. They modified the calcium indicator TN-XXL to enable, for the first time, T cell activation patterns to be observed live under the microscope, even while the cells are wandering about the body. When a T cell detects an antigen, a rapid rise in the calcium concentration within the cell ensues. The TN-XXL makes this alteration in the calcium level apparent by changing colour, giving the scientists a direct view of when and where the T cells are being activated.
“This method has enabled us to demonstrate that these cells really can be activated in the brain,” says a pleased Marsilius Mues, lead author of the study which has just been published in Nature Medicine. Until now, scientists had only suspected this to be the case. In the animal model of multiple sclerosis, scientists are now able to track not only the migration of the T cells, but also their activation pattern in the course of the disease. Initial investigations have already shown, besides the expected activation by antigen detection, that numerous fluctuations in calcium levels also take place which bear no relation to an antigen. “These fluctuations can tell us something about how potent the T cell is, how strong the antigen is, or it may have something to do with the environment,” speculates Marsilius Mues. These observations could indicate new research approaches for drugs – or they could even show whether a drug actually has an effect on T cell activation.
Working with lab mice models of multiple sclerosis (MS), UC Davis scientists have detected a novel molecular target for the design of drugs that could be safer and more effective than current FDA-approved medications against MS.
The findings of the research study, published online today in the journal EMBO Molecular Medicine could have therapeutic applications for MS as well as cerebral palsy and leukodystrophies, all disorders associated with loss of white matter, which is the brain tissue that carries information between nerve cells in the brain and the spinal cord.
The target, a protein referred to as mitochondrial translocator protein (TSPO), had been previously identified but not linked to MS, an autoimmune disease that strips the protective fatty coating off nerve fibers of the brain and spinal cord. The mitrochronical TSPO is located on the outer surface of mitochondria, cellular structures that supply energy to the cells. Damage to the fatty coating, or myelin, slows the transmission of the nerve signals that enable body movement as well as sensory and cognitive functioning.
The scientists identified mitochondrial TSPO as a potential therapeutic target when mice that had symptoms of MS improved after being treated with the anti-anxiety drug etifoxine, which interacts with mitochondrial TSPO. When etifoxine, a drug clinically available in Europe, was administered to the MS mice before they had clinical signs of disease, the severity of the disease was reduced when compared to the untreated lab animals. When treated at the peak of disease severity, the animals’ MS symptoms improved.
“Etifoxine has a novel protective effect against the loss of the sheath that insulates the nerve fibers that transmit the signals from brain cells,” said Wenbin Deng, principal investigator of the study and associate professor of biochemistry and molecular medicine at UC Davis.
“Our discovery of etifoxine’s effects on an MS animal model suggests that mitochondrial TSPO represents a potential therapeutic target for MS drug development,” said Deng.
“Drugs designed to more precisely bind to mitochondrial TSPO may help repair the myelin sheath of MS patients and thereby even help restore the transmission of signals in the central nervous system that enable normal motor, sensory and cognitive functions,” he said.
Deng added that better treatments for MS and other demyelinating diseases are needed, especially since current FDA-approved therapies do not repair the damage of immune attacks on the myelin sheath.
The UC Davis research team hopes to further investigate the therapeutic applications of mitochondrial TSPO in drug development for MS and other autoimmune diseases. To identify more efficacious and safer drug candidates, they plan to pursue research grants that will enable them to test a variety of pharmacological compounds that bind to mitochondrial TSPO and other molecular targets in experimental models of MS and other myelin diseases.
Magnetic resonance imaging (MRI) measurements of atrophy in an important area of the brain are an accurate predictor of multiple sclerosis (MS), according to a new study published online in the journal Radiology. According to the researchers, these atrophy measurements offer an improvement over current methods for evaluating patients at risk for MS.
MS develops as the body’s immune system attacks and damages myelin, the protective layer of fatty tissue that surrounds nerve cells within the brain and spinal cord. Symptoms include visual disturbances, muscle weakness and trouble with coordination and balance. People with severe cases can lose the ability to speak or walk.
Approximately 85 percent of people with MS suffer an initial, short-term neurological episode known as clinically isolated syndrome (CIS). A definitive MS diagnosis is based on a combination of factors, including medical history, neurological exams, development of a second clinical attack and detection of new and enlarging lesions with contrast-enhanced or T2-weighted MRI.
“For some time we’ve been trying to understand MRI biomarkers that predict MS development from the first onset of the disease,” said Robert Zivadinov, M.D., Ph.D., FAAN, from the Buffalo Neuroimaging Analysis Center of the University at Buffalo in Buffalo, N.Y. “In the last couple of years, research has become much more focused on the thalamus.”
The thalamus is a structure of gray matter deep within the brain that acts as a kind of relay center for nervous impulses. Recent studies found atrophy of the thalamus in all different MS disease types and detected thalamic volume loss in pediatric MS patients.
“Thalamic atrophy may become a hallmark of how we look at the disease and how we develop drugs to treat it,” Dr. Zivadinov said.
For this study, Dr. Zivadinov and colleagues investigated the association between the development of thalamic atrophy and conversion to clinically definite MS.
“One of the most important reasons for the study was to understand which regions of the brain are most predictive of a second clinical attack,” he said. “No one has really looked at this over the long term in a clinical trial.”
The researchers used contrast-enhanced MRI for initial assessment of 216 CIS patients. They performed follow-up scans at six months, one year and two years. Over two years, 92 of 216 patients, or 42.6 percent, converted to clinically definite MS. Decreases in thalamic volume and increase in lateral ventricle volumes were the only MRI measures independently associated with the development of clinically definite MS.
“First, these results show that atrophy of the thalamus is associated with MS,” Dr. Zivadinov said. “Second, they show that thalamic atrophy is a better predictor of clinically definite MS than accumulation of T2-weighted and contrast-enhanced lesions.”
The findings suggest that measurement of thalamic atrophy and increase in ventricular size may help identify patients at high risk for conversion to clinically definite MS in future clinical trials involving CIS patients.
“Thalamic atrophy is an ideal MRI biomarker because it’s detectable at very early stage,” Dr. Zivadinov said. “It has very good predictive value, and you will see it used more and more in the future.”
The research team continues to follow the study group, with plans to publish results from the four-year follow-up next summer. They are also trying to learn more about the physiology of the thalamic involvement in MS.
“The next step is to look at where the lesions develop over two years with respect to the location of the atrophy,” Dr. Zivadinov said. “Thalamic atrophy cannot be explained entirely by accumulation of lesions; there must be an independent component that leads to loss of thalamus.”
MS affects more than 2 million people worldwide, according to the Multiple Sclerosis International Foundation. There is no cure, but early diagnosis and treatment can slow development of the disease.
Newborn babies’ immune system development and levels of vitamin D have been found to vary according to their month of birth, according to new research.
The research, from scientists at Queen Mary, University of London and the University of Oxford, provides a potential biological basis as to why an individual’s risk of developing the neurological condition multiple sclerosis (MS) is influenced by their month of birth. It also supports the need for further research into the potential benefits of vitamin D supplementation during pregnancy.
Around 100,000 people in the UK have MS, a disabling neurological condition which results from the body’s own immune system damaging the central nervous system. This interferes with the transmission of messages between the brain and other parts of the body and leads to problems with vision, muscle control, hearing and memory.
The development of MS is believed to be a result of a complex interaction between genes and the environment.
A number of population studies have suggested that the month you are born in can influence your risk of developing MS. This ‘month of birth’ effect is particularly evident in England, where the risk of MS peaks in individuals born in May and drops in those delivered in November. As vitamin D is formed by the skin when it is exposed to sunlight, the ‘month of birth’ effect has been interpreted as evidence of a prenatal role for vitamin D in MS risk.
In this study, samples of cord blood – blood extracted from a newborn baby’s umbilical cord – were taken from 50 babies born in November and 50 born in May between 2009 and 2010 in London.
The blood was analysed to measure levels of vitamin D and levels of autoreactive T-cells. T-cells are white blood cells which play a crucial role in the body’s immune response by identifying and destroying infectious agents, such as viruses. However some T-cells are ‘autoreactive’ and capable of attacking the body’s own cells, triggering autoimmune diseases, and should be eliminated by the immune system during its development. This job of processing T-cells is carried out by the thymus , a specialised organ in the immune system located in the upper chest cavity.
The results showed that the May babies had significantly lower levels of vitamin D (around 20 per cent lower than those born in November) and significantly higher levels (approximately double) of these autoreactive T-cells, compared to the sample of November babies.
Co-author Dr Sreeram Ramagopalan, a lecturer in neuroscience at Barts and The London School of Medicine and Dentistry, part of Queen Mary, said: “By showing that month of birth has a measurable impact on in utero immune system development, this study provides a potential biological explanation for the widely observed “month of birth” effect in MS. Higher levels of autoreactive T-cells, which have the ability to turn on the body, could explain why babies born in May are at a higher risk of developing MS.
“The correlation with vitamin D suggests this could be the driver of this effect. There is a need for long-term studies to assess the effect of vitamin D supplementation in pregnant women and the subsequent impact on immune system development and risk of MS and other autoimmune diseases.”
The research letter is published today in the journal JAMA Neurology.
Amyloids — clumps of misfolded proteins found in the brains of people with Alzheimer’s disease and other neurodegenerative disorders — are the quintessential bad boys of neurobiology. They’re thought to muck up the seamless workings of the neurons responsible for memory and movement, and researchers around the world have devoted themselves to devising ways of blocking their production or accumulation in humans.
But now a pair of recent research studies from the Stanford University School of Medicine sets a solid course toward rehabilitating the reputation of the proteins that form these amyloid tangles, or plaques. In the process, they appear poised to turn the field of neurobiology on its head.
The first study, published in August, showed that an amyloid-forming protein called beta amyloid, which is strongly implicated in Alzheimer’s disease, could reverse the symptoms of a multiple-sclerosis-like neurodegenerative disease in laboratory mice.
The second study, published April 3 in Science Translational Medicine, extends the finding to show that small portions of several notorious amyloid-forming proteins (including well-known culprits like tau and prion proteins) can also quickly alleviate symptoms in mice with the condition — despite the fact that the fragments can and do form the long tendrils, or fibrils, previously thought harmful to nerve health.
“What we’re finding is that, at least under certain circumstances, these amyloid peptides actually help the brain,” said Lawrence Steinman, MD, professor of neurology and neurological sciences and of pediatrics. “This really turns the ‘amyloid-is-bad’ dogma upside down. It will require a shift in people’s fundamental beliefs about neurodegeneration and diseases like multiple sclerosis, Alzheimer’s and Parkinson’s.”
Steinman is a noted expert in multiple sclerosis whose research led to the development of natalizumab (marketed as Tysabri), a potent treatment for the disease.
Taken together, the studies begin to suggest the radical new idea that full-length, amyloid-forming proteins may in fact be produced by the body as a protective, rather than destructive, force. In particular, Steinman’s study shows that these proteins may function as molecular chaperones, escorting and removing from sites of injury specific molecules involved in inflammation and inappropriate immune responses.
Steinman, who is also the medical school’s George A. Zimmermann Professor, is the corresponding author of the research. Jonathan Rothbard, PhD, a senior research scientist in the Steinman laboratory, is the senior author; postdoctoral scholar Michael Kurnellas, PhD, is the lead author.
Although the specific findings of Steinman’s two studies are surprising, there have been inklings from previous research that amyloid-forming proteins may not be all bad. In particular, inhibiting, or knocking out, the expression of several of the proteins in the mouse models of multiple sclerosis — a technique that should block the course of the disease if these proteins are the cause — instead worsened the animals’ symptoms.
And there’s the fact that these so-called dangerous amyloid-forming molecules are surprisingly prevalent. “We know the body makes a lot of amyloid-forming proteins in response to injury,” said Steinman. “I’m doubtful that that’s done to produce more harm. For example, the prion protein is found in every cell in our bodies. What is it doing? It’s possible that any therapeutic maneuver to remove all of these proteins could interfere with their natural function.”
Understanding how amyloids form requires an understanding of the biology of proteins, which are essentially strings of smaller components called amino acids attached end to end. Once they’re made, these protein strings twist and fold into specific three-dimensional shapes that fit together like keys and locks to do the work of the cell.
A misfolded protein is likely to be unable to carry out its duties and must be disposed of by the body’s cellular waste-management system. Amyloid-forming proteins (of which there are around 20), however, don’t go quietly, if at all. Instead, they initiate a chain reaction with other misfolded proteins — forming long, insoluble strands called fibrils that mat together to form amyloid clumps. These clumps appear consistently in the brains of people with neurodegenerative diseases like Alzheimer’s and multiple sclerosis, but not in the brains of healthy people.
Although these clumps are thought to be detrimental to nerve cells, it’s not entirely clear how they cause harm. One possibility is the ability of the fibrils to form cylindrical pores that could disrupt the cellular membrane and interfere with the orderly flow of ions and molecules used by the cells to communicate and transmit nerve signals. Regardless, their very presence suggests a diagnosis of neurodegeneration to many clinicians, including — until recently — Steinman.
“We began this research because these molecules are present in the brains of people with multiple sclerosis,” said Steinman. “We expected to show that the presence of beta amyloid made the disease worse in laboratory animals. Instead, we saw a great deal of benefit.”
Intrigued by the results of their first study, the researchers next tested the effect of small, six-amino-acid portions of several amyloid-forming proteins, including beta amyloid, which appeared likely to share a three-dimensional structure. They found that nearly all of the tiny protein molecules, or hexamers, were also able to temporarily reverse the symptoms of multiple sclerosis in the mice (when the treatment was stopped, the mice developed signs of the condition within a few days).
The researchers noted, however, that the curative effect of the hexamers was linked to their ability to form fibrils similar, but not identical, to their longer parent molecules. For example, these simplified hexamer fibrils are more easily formed and broken apart than those composed of whole proteins. They are also thought not to be able to form the cylindrical pores that might damage cell membranes. Finally, the hexamer fibrils appear to inhibit the formation of fibrils from full-length proteins — perhaps by blocking, or failing to promote, the chain reaction that initiates fibril formation.
When Steinman and his colleagues mixed the fibril-forming hexamers with blood plasma from three people with multiple sclerosis, they found that the fibrils bound to and removed from solution many potentially damaging molecules involved in inflammation and the immune response.
“These hexamer fibrils appear to be working to remove dangerous chemicals from the vicinity of the injury,” said Steinman.
The researchers are eager to pursue the use of these small hexamers as therapies for neurodegenerative diseases like multiple sclerosis. Much research is still needed, but Steinman is hopeful.
“The lessons we learn from our study of amyloid-forming proteins in multiple sclerosis could be helpful for stroke and brain trauma, as well as for Alzheimer’s,” said Steinman. “We’re gaining insight into how current therapeutic approaches may be affecting the body, and beginning to understand the nuances necessary to design a successful treatment. Although it will take time, we’re determined to move promising results out of the laboratory and into the clinic as quickly as possible.”
(Image: Wikimedia Commons)
A growing body of research by multiple sclerosis (MS) investigators at the University at Buffalo and international partners is providing powerful new evidence that the brain’s gray matter reflects important changes in the disease that could allow clinicians to diagnose earlier and to better monitor and predict how the disease will progress.
Over the past three years, the UB researchers and their partners around the world, supported by an active fellowship program at UB’s Buffalo Neuroimaging Analysis Center (BNAC), have published journal papers and given presentations demonstrating that the thalamus region, in particular, is key to a host of issues involving MS.
“The thalamus is providing us with a new window on MS,” says Robert Zivadinov, MD, PhD, UB professor of neurology, BNAC director and leader of the research team. “In our recent studies, we have used large datasets to investigate the evolution of atrophy of the thalamus and its association with clinical impairment in MS, starting with the earliest stages of the disease. The location of the thalamus in the brain, its unique function and its vulnerability to changes wrought by the disease make the thalamus a critical barometer of the damage that MS causes to the brain.”
Zivadinov and UB professor of neurology Ralph Benedict discuss the new research in a video.
At the annual meeting of the American Academy of Neurology today, Zivadinov will discuss a study he performed in collaboration with colleagues from Charles University in Prague. The study found that atrophy of the thalamus, determined with MRI, can help identify which patients with clinically isolated syndrome (CIS), a patient’s first episode of MS, are at risk for developing clinically definite MS. Such a tool would be immensely helpful to clinicians, Zivadinov notes.
“This study, which included more than 200 patients, shows that thalamic atrophy is one of the most important predictors of clinically definite MS,” says Dana Horakova, MD, PhD, the principal investigator at Charles University.
“Therefore, based on these findings, we think MRI should be used to determine which patients are at highest risk for a second attack,” explains Zivadinov.
Results of a study using several imaging methods showed that CCSVI (chronic cerebrospinal venous insufficiency) occurs at a low rate in both people with multiple sclerosis (MS) and non-MS volunteers, contrary to some previous studies. The research by an interdisciplinary team at The University of Texas Health Science Center at Houston (UTHealth) was published in a recent early online edition of the Annals of Neurology.
“Our results in this phase of the study suggest that findings in the major veins that drain the brain consistent with CCSVI are uncommon in individuals with MS and quite similar to those found in our non-MS volunteers,” said Jerry Wolinsky, M.D., principal investigator and the Bartels Family and Opal C. Rankin Professor of Neurology at The UTHealth Medical School. “This makes it very unlikely that CCSVI could be the cause of MS, or contribute in an important manner to how the disease can worsen over time.” Wolinsky is also a member of the faculty of The University of Texas Graduate School of Biomedical Sciences at Houston and director of the UTHealth MS Research Group.
CCSVI has been described by Italian neurosurgeon Paolo Zamboni, M.D., as a new disorder in which veins draining the central nervous system are abnormal. Zamboni’s published research linked CCSVI to MS. Not all researchers have been able to duplicate his results.
UTHealth was one of three institutions in the United States to receive an initial grant to study CCSVI in multiple sclerosis (MS). The grant was part of a $2.3 million joint commitment from the National MS Society and the MS Society of Canada.
The UTHealth team tested several imaging methods including ultrasound, magnetic resonance imaging with an intravenous contrast agent, and direct radiologic investigation of the major veins by direct injection of veins with radio-opaque contrast. The goal was to validate a consistent, reliable diagnostic approach for CCSVI, determine whether CCSVI was specific to MS and if CCSVI contributed to disease activity.
The team was blinded to the participant’s diagnosis throughout the study. Doppler ultrasound was used to investigate venous drainage in 276 people with and without MS. Using the criteria described by Zamboni for the diagnosis of CCVSI, UTHealth researchers found less prevalence of CCVSI than in some previous studies and no statistical difference between those with MS and those without MS. Detailed experience with the other imaging approaches are being readied for publication.
Multiple sclerosis is an unpredictable, often disabling disease of the central nervous system, interrupting the flow of information within the brain and from the brain to the body. It affects more than 400,000 people in the United States and 2.1 million in the world.