Multiple Sclerosis (etiology)
Introduction: B cells are attracting increasing attention in the pathogenesis of multiple sclerosis (MS). B cell-targeted therapies with monoclonal antibodies or plasmapheresis have been shown to be successful in a subset of patients.
Here, patients with either relapsing-remitting (n = 24) or secondary progressive (n = 6) MS presenting with an acute clinical relapse were screened for their B cell reactivity to brain antigens and were re-tested three to nine months later. Enzyme-linked immunospot technique (ELISPOT) was used to identify brain-reactive B cells in peripheral blood mononuclear cells (PBMC) directly ex vivo and after 96 h of polyclonal stimulation.
Clinical severity of symptoms was determined using the Expanded Disability Status Scale (EDSS).
Results: Nine patients displayed B cells in the blood producing brain-specific antibodies directly ex vivo. Six patients were classified as B cell positive donors only after polyclonal B cell stimulation.
In 15 patients a B cell response to brain antigens was absent. Based on the autoreactive B cell response we categorised MS relapses into three different patterns.
Patients who displayed brain-reactive B cell responses both directly ex vivo and after polyclonal stimulation (pattern I) were significantly younger than patients in whom only memory B cell responses were detectable or entirely absent (patterns II and III; pâ€‰=â€‰0.003). In one patient a conversion to a positive B cell response as measured directly ex vivo and subsequently also after polyclonal stimulation was associated with the development of a clinical relapse.
The evaluation of the predictive value of a brain antigen-specific B cell response showed that seven of eight patients (87.5%) with a pattern I response encountered a clinical relapse during the observation period of 10 months, compared to two of five patients (40%) with a pattern II and three of 14 patients (21.4%) with a pattern III response (pâ€‰=â€‰0.0005; hazard ratio 6.08 (95% confidence interval 1.87-19.77).
Conclusions: Our data indicate actively ongoing B cell-mediated immunity against brain antigens in a subset of MS patients that may be causative of clinical relapses and provide new diagnostic and therapeutic options for a subset of patients.
Author: Christopher HohmannBianca MillesMichael SchinkeMichael SchroeterJochen UlzheimerPeter KraftChristoph KleinschnitzPaul V LehmannStefanie Kuerten Credits/Source: Acta Neuropathologica Communications 2014, 2:138
Source: 7thSpace Interactive © 2014 7thSpace Interactive (25/09/14)
The thinning of the retina that occurs during the course of multiple sclerosis (MS) closely parallels brain atrophy and may be used to measure neurodegeneration, a new study has shown.
Presenting the data here at MSBoston 2014, the 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS) meeting, Shiv Saidha, MD, Johns Hopkins Hospital, Baltimore, Maryland, explained that previous studies had correlated retinal thinning with global disability and brain atrophy, but these studies were primarily cross-sectional in design.
"Our study is groundbreaking in that it is the first ever longitudinal study to look at how retinal changes measured by optical coherence tomography (OCT) track with MRI measures of brain atrophy," he said. "These results could have far-reaching implications for the field of neurodegeneration."
"We showed clearly that the degree of retinal layer thinning predicts the loss of brain tissue. Patients who lost the most neurons in the retina had the highest amount of brain loss on MRI."
He added: "It was particularly effective in patients with progressive MS, but it can be used from the very beginning to identify which patients are deteriorating the fastest."
The MS field has suffered from a lack of tools to track neurodegeneration, and much work is underway to identify such markers, Dr. Saidha added. "Our data shows that measuring changes in the retina with OCT is one of the most promising techniques for this purpose."
"It is easy to do — it takes just 5 minutes to assay the retina," he commented to Medscape Medical News. "It is cheap and easily reproducible. In my view, it is very encouraging."
Validation for Use in Clinical Trials
These opinions were echoed by the chair of the Young Investigators session at which Dr. Saidha presented the study, Patrick Vermersch, MD, Centre Hospitalier Régional Universitaire de Lille, France.
"This study is really interesting," he told Medscape Medical News. "This methodology adds complementary information to explain the neurodegenerative process in MS. Measuring retinal thinning with OCT is much easier than trying to assess brain atrophy with MRI. It is already being used as a marker of treatment response in therapeutic trials, but this study gives validation that this is an appropriate marker to measure."
Dr. Vermersch suggested that OCT may not be as sensitive as measuring brain atrophy with MRI, but it is far more convenient. "I would think MRI will be superior, but it is not widely available," he added. "It is not possible to measure brain atrophy in routine clinical practice — the specific software is only available in specialist centers for research use at present. But OCT is widely available and easy to use."
For the study, 108 MS patients underwent OCT every 6 months (average follow-up duration, 42 months) and annual MRI (3T) of the brain (average follow-up duration, 39 months). Patients with optic neuritis during the study were excluded. Individual-specific rates of change in retinal and brain measures were correlated after adjustment for age, sex, disease duration, and optic neuritis history.
Results showed that the thickness of the ganglion cell layer plus inner plexiform layer of the retina together (GCIP) had the best correlation to whole brain atrophy, with a correlation coefficient of 0.449. GCIP loss was also correlated to atrophy in gray matter (r = 0.371), white matter (r = 0.285), and thalamic (r = 0.379) regions of the brain over time.
Best in Secondary Progressive Disease
The correlation between GCIP and brain atrophy rates was stronger in secondary progressive MS (r = 0.730) and primary progressive MS (r = 0.542) than in relapsing-remitting MS (r = 0.328).
"Although the association between GCIP and brain atrophy in relapsing-remitting MS is impressive, the association in progressive MS, particularly secondary progressive MS, appears to be exceptional," Dr. Saidha stated.
The relationship between GCIP and brain atrophy was affected by history of optic neuritis, which reduced the strength of the correlation, especially in the relapsing-remitting population.
Dr. Saidha reported that for every yearly change of 1 micron in GCIP thickness there was a 0.45% yearly brain loss in eyes without a history of optic neuritis. GCIP atrophy also mirrored lesion accumulation in MS, although this was not as strong as the relationship with brain atrophy.
"Our findings confirm the utility of OCT for tracking subclinical as well as clinical disease progression in MS and establish a role for OCT in clinical trials for the objective investigation of neuroprotection," Dr. Saidha concluded.
Primary Source: MSBoston 2014: 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS). Abstract Y12.2. Presented September 10, 2014.
Source: Medscape Multispeciality © 1994-2014 by WebMD LLC (12/09/14)
Evaluation of visual structural and functional factors that predict the development of multiple sclerosis in clinically isolated syndrome patients.
Perez-Rico C, Ayuso-Peralta L, Rubio-Pérez L, Roldán-Díaz I, Arévalo-Serrano J, Jiménez Jurado D, Blanco R.
PURPOSE. To evaluate visual pathway structure and function in patients with clinical isolated syndrome (CIS) using spectral domain optical coherence tomography (OCT) and multifocal visual evoked potentials (mfVEP), predicting CIS conversion to clinically definite multiple sclerosis (MS).
METHODS. This observational, longitudinal study assessed the eyes with no prior history of optic neuritis of twenty-nine consecutive patients with CIS according to the McDonald criteria. The relationships of the mfVEP results with the clinical findings, psychophysical (Humphrey perimetry) and structural (OCT) diagnostic test data were investigated.
RESULTS. The mfVEP amplitude responses (interocular and monocular probability analysis) showed abnormal cluster visual field defects in 48.3% of the CIS eyes, while mfVEP latency analysis showed significant delays in 20.7%. OCT average RNFLT (retinal nerve fiber layer thickness) was significantly reduced compared to the control group (P = 0.02). Significant differences between CIS eyes with abnormal and normal mfVEP latencies were found for the OCT RNFLT (P < 0.001) with a longer latency being linked to more severe axonal damage. Using multivariate logistic regression analysis, OCT average RNFLT was found to be independent predictor of clinically definitive MS diagnosis at twelve months.
CONCLUSIONS. The combined use of OCT and mfVEP is helpful to detect significant subclinical visual pathways abnormalities and axonal loss in CIS patients. Retinal axonal loss measured by OCT is an important prognosis factor of conversion to MS in patients with clinically isolated syndrome in absence of symptomatic optic neuritis.
Source: Invest Ophthalmol Vis Sci. 2014 Sep 4. pii: IOVS-14-14807. doi: 10.1167/iovs.14-14807 © 2014 by Association for Research in Vision and Ophthalmology & Pubmed PMID: 25190654 (10/09/14)
Is the intestinal barrier damaged in MS?(05/09/14)
Researchers at Lund University in Sweden have published new research findings on the role of the intestinal barrier in the autoimmune disease multiple sclerosis (MS).
Within medical science, it is not known for certain how MS develops or why the body’s immune system attacks cells in the central nervous system. Inflammation develops for an unknown reason, which hinders transport of neural impulses. This can produce various physical and mental symptoms, including a loss of sensation, motor difficulties, blurred vision, dizziness and tiredness.
The present study investigates whether the function of the intestines is also attacked in MS. The results, obtained from a disease model of MS in mice, shows inflammation and changes in the barrier function of the intestines early in the course of the disease. The study has been published in the scientific journal PLOS ONE.
“We know that the permeability of the intestines to harmful substances is raised in inflammatory bowel diseases such as Crohn’s disease and ulcerous colitis, as well as in some other autoimmune diseases such as type 1 diabetes. The condition is called ‘leaky gut syndrome’. Our studies indicate a leaky gut and increased inflammation in the intestinal mucous membrane and related lymphoid tissue before clinical symptoms of MS are discernible. It also appears that the inflammation increases as the disease develops”, said Shahram Lavasani, one of the authors of the study.
Dr Lavasani and his colleagues at Lund University have previously shown that probiotic bacteria could give a certain amount of protection against MS. They therefore wondered whether the intestinal barrier is affected and decided to investigate inflammatory cells and processes in the intestine. The hypothesis was tested in a research project in collaboration with Professor Björn Weström, doctoral student Mehrnaz Nouri and reader Anders Bredberg.
“To our surprise, we saw structural changes in the mucous membrane of the small intestine and an increase in inflammatory T-cells, known as Th1 and Th17. At the same time, we saw a reduction in immunosuppressive cells, known as regulatory T-cells. These changes are often linked to inflammatory bowel diseases, and biologically active molecules produced by Th1 and Th17 are believed to be behind this damage to the intestines.”
Neuroinflammatory processes in MS are believed to lead to damage and leakage in the blood-brain barrier that protects the central nervous system and regulates the transport of cells. The researchers have now observed similar damage in the intestinal barrier, especially to the ‘tight junctions’ that bind the cells together in the mucous membrane of the intestine, and have demonstrated that these are connected to disease-specific T-cells.
“In most cases, we don’t know what triggers autoimmune diseases, but we know that pathogenic cells frequent and disrupt the intestines. A leaky gut enables harmful bacteria and toxic substances in the body to enter the intestine, which creates even more inflammation. Our findings provide support for the idea that a damaged intestinal barrier can prevent the body ending an autoimmune reaction in the normal manner, leading to a chronic disease such as MS”, said Dr Lavasani.
Shahram Lavasani and his colleagues believe that future drugs to treat this type of disease should perhaps not only focus on the central nervous system, but also on the intestines by repairing and restoring the intestinal barrier.
“In the long run, we hope that our findings will lead to better understanding of what actually happens in the development of MS. Looking even further to the future, we hope for the development of a better treatment that aims at the intestinal barrier as a new therapeutic target.”
The research group is now studying other inflammatory parameters in the gut that could affect the development of MS. Their aim is to draw up treatment methods that can heal the mucous membrane in the intestine in the hope of preventing the development of the disease. Some of this work forms part of Mehrnaz Nouri’s thesis, which will be defended later in the year.
Full Article - ‘Intestinal barrier dysfunction develops at the onset of experimental autoimmune encephalomyelitis, and can be induced by adoptive transfer of auto-reactive T cells.’
Source: Lund University (05/09/14)
EAE is not a useful model for demyelinating disease
Peter O. Behanemail, Abhijit Chaudhuri
Experimental allergic encephalomyelitis (EAE) is the commonest, readily induced, organspecific, autoimmune disorder of laboratory animals of its kind.
It is an artificial disorder brought about by the immunisation of susceptible animals with brain antigens in complete Freund?s adjuvant (CFA).
Variations can be induced by altering the nature of the antigen and the conditions involving immunisation.
Whilst it is often described as a demyelinating disease, in strict terms it is not, since the primary pathologic process is not demyelination but rather an encephalomyelitis that is immunologically induced. Rather, the prototype demyelinating disease is multiple sclerosis and its variants.
In this paper, the central question we ask is whether the data gleaned from the EAE model contributes to our understanding of the pathological events in MS.
Towards answering this, we describe the historical development of EAE and its hyperacute form, and discuss the findings studied extensively in the non-human primate which show that ordinary EAE is an exact model for ADEM in the human, and that the hyperacute form of EAE is represented by AHLE in the human. Additionally, we shall comment on the latest research on new variants of EAE, and explain our opinion regarding the use of EAE models in research aiming to understand the pathogenesis of multiple sclerosis.
Source: Multiple Sclerosis and related disorders Copyright © 2014 Elsevier Inc (19/08/14)
Understanding the human brain could provide the foundation to explore new ways to treat and eventually prevent diseases such as multiple sclerosis, Parkinson's or Alzheimer's disease, according to the European Brain Council (EBC).
The brain is at the centre of exciting but challenging new times in neuroscience research.
“We have already identified a lot of gaps in knowledge about treatments of brain diseases,” said Gordon Francis, head of the NeuroInflammation Clinical Science Unit within the NeuroScience Franchise at the Swiss pharmaceutical company Novartis.
Francis was addressing a conference on Friday (14 February) focusing on brain-related issues in Barcelona, Spain, which advocated for a "brain-political road map" under the motto 'Understanding the brain: Where are we in 2014?'
Among the challenges that scientists are looking into are the loss of brain tissues which for example occur at very early stages of multiple sclerosis and dealing with the changes of brain volume, said Frederik Barkhof, professor of Neuroradiology at the VU University Medical Centre in Amsterdam.
According to data by the European Multiple Sclerosis Platform, at least 600,000 people in Europe are affected by multiple sclerosis, an autoimmune disease of the central nervous system.
The crippling disease, which strikes the white matter of the brain and spinal cord and affects the rest of the nervous system, has far-reaching consequences for society as more than one million people are affected indirectly through their role as carers and family members, the EMPS said.
However, despite its importance, knowledge on how the brain works is still very limited. According to researchers, understanding the complex brain could provide the foundation to explore new ways to treat, cure and eventually prevent brain diseases such as multiple sclerosis, Parkinson's or Alzheimer's disease.
“We don't want this to be a race or competition against cancer, cardiovascular diseases or diabetes," Mary Baker, president of the European Brain Council, told EurActiv.
“But it is the brain that manages cancer, cardiovascular diseases and diabetes. The brain is a very special organ, we must take care of it," Baker added.
A disease like multiple sclerosis significantly impacts on the quality of life of patients and their families. For example, less than 50% of people with multiple sclerosis will be employed 10 years after receiving their diagnosis. About one-third of people will also need a wheelchair within 20 years of developing multiple sclerosis, according to data published by the Multiple Sclerosis Foundation.
“We try to mobilise the key actors, among them the European Commission's DG Research, on the need for innovation (with news drugs), but also on the social impact of multiple sclerosis," Baker stressed.
Economic and social costs of brain diseases
According to the EBC, the direct cost of healthcare related to brain diseases has increased from €386 billion in 2004 to €798 billion in 2010, measured across 30 European countries.
This means “more money is spent into brain diseases than cancer or cardiovascular diseases”, according to Baker.
The EBC wants to put the emphasis on the economic burden of brain diseases, in particular on multiple sclerosis. Up to 2.5 million people worldwide are affected by multiple sclerosis. It's more often younger people between between 20 and 40 who are diagnosed with multiple sclerosis, and women are diagnosed three times as often as men.
In the UK alone, the direct healthcare costs of brain diseases are estimated at 37% of the overall health budget which Baker called "an enormous amount of money, simply not sustainable”.
A part from the economic burden on society, a multiple sclerosis diagnosis can be devastating for the individual young adult who may be starting careers and making plans for the future. Early adulthood is also a time when young people may be pursuing higher education, making new relationships or considering starting a family.
“They are the brains of the future,” Baker said.
More attention to research
The EBC advocates for more and better funding for brain research, for example a combination of public and private sector resources. The EBC is currently working with the Commission's DG Research and the Innovative Medicines Initiative (IMI) on one of Europe's largest public-private initiatives aiming at speeding up the development of better and safer medicines. The second project, IMI2, has a budget of €3.45 billion.
"The attention paid to brain diseases is still relatively low when you compare it to cancer or diabetes. In order to raise awareness on multiple sclerosis, you need to make clear what the implications of the conditions are, what the impact they have for a condition like multiple sclerosis which hits people it their 20s. It has a huge impact," Alan Thompson, chair of the International Progressive MS Alliance, told EurActiv.
"The problem with the pharmaceutical industry is that people think they are just raising the profile in order to sell more drugs, but a combined approach should be better," he said.
According to a survey conducted in 124 countries by the Atlas of MS, access to drugs (Disease-Modifying Therapies, DMTs, or Symptomatic treatments) is very limited in low or medium-income parts of the world. Only 40% in developing countries have access as opposed to 90% in high-income countries.
“Unfortunately, inequalities remain," Thompson stated.
Source: EurActiv © 1999-2014 EurActiv.com PLC (17/02/14)
Rutgers professor’s advanced analysis could let therapy start earlier and lead MS research in new directions.
The search for the cause of multiple sclerosis, a debilitating disease that affects up to a half million people in the United States, has confounded researchers and medical professionals for generations. But Steven Schutzer, a physician and scientist at Rutgers New Jersey Medical School, has now found an important clue why progress has been slow – it appears that most research on the origins of MS has focused on the wrong part of the brain.
Look more to the gray matter, the new findings published in the journal PLOS ONE suggest, and less to the white. That change of approach could give physicians effective tools to treat MS far earlier than ever before.
Until recently, most MS research has focused on the brain’s white matter, which contains the nerve fibers. And for good reason: Symptoms of the disease, which include muscle weakness and vision loss, occur when there is deterioration of a fatty substance called myelin, which coats nerves contained in the white matter and acts as insulation for them. When myelin in the brain is degraded, apparently by the body’s own immune system, and the nerve fiber is exposed, transmission of nerve impulses can be slowed or interrupted. So when patients’ symptoms flare up, the white matter is where the action in the brain appears to be.
But Schutzer attacked the problem from a different direction. He is one of the first scientists to analyze patients’ cerebrospinal fluid (CSF) by taking full advantage of a combination of technologies called proteomics and high-resolution mass spectrometry. “Proteins present in the clear liquid that bathes the central nervous system can be a window to physical changes that accompany neurological disease,” says Schutzer, “and the latest mass spectrometry techniques allow us to see them as never before.” In this study, he used that novel approach to compare the cerebrospinal fluid of newly diagnosed MS patients with that of longer term patients, as well as fluid taken from people with no signs of neurological disease.
What Schutzer found startled one of his co-investigators, Patricia K. Coyle of Stony Brook University in New York, one of the leading MS clinicians and researchers in the country. The proteins in the CSF of the new MS patients suggested physiological disruptions not only in the white matter of the brain where the myelin damage eventually shows up. They also pointed to substantial disruptions in the gray matter, a different part of the brain that contains the axons and dendrites and synapses that transfer signals between nerves.
Several scientists had in fact hypothesized that there might be gray matter involvement in early MS, but the technology needed to test their theories did not yet exist. Schutzer’s analysis, which Coyle calls “exquisitely sensitive,” provides the solid physical evidence for the very first time. It includes a finding that nine specific proteins associated with gray matter were far more abundant in patients who had just suffered their first attack than in longer term MS patients or in the healthy controls. “This evidence indicates gray matter may be the critical initial target in MS rather than white matter,” says Coyle. “We may have been looking in the wrong area.”
According to Coyle, that realization presents exciting possibilities. One, she says, is that patients who suffer attacks that appear related to MS could have their cerebrospinal fluid tested quickly. If proteins that point to early MS are found, helpful therapy could begin at once, before the disease can progress further.
Coyle says Schutzer’s findings may also lead one day to more effective treatments for MS with far fewer side effects. Without specific knowledge of what causes multiple sclerosis, patients now need to take medications that can broadly weaken their immune systems. These drugs slow the body’s destruction of myelin in the brain, but also degrade the immune system’s ability to keep the body healthy in other ways. By suggesting an exciting new direction for MS research, Schutzer and his team may have set the stage for more targeted treatments that attack MS while preserving other important immune functions.
Schutzer sees an even broader future for the work he is now doing. He also has used advanced analysis of cerebrospinal fluid to identify physical markers for neurological ailments that include Lyme disease, in which he has been a world leader in research for many years, as well as chronic fatigue syndrome. He says, “When techniques are refined, more medical conditions are examined, and costs per patient come down, one day there could be a broad panel of tests through which patients and their doctors can get early evidence of a variety of disorders, and use that knowledge to treat them both more quickly and far more effectively than is possible now.“
This research was funded by the National Institutes of Health.
Source: Rutgers Today Copyright 2013, Rutgers, The State University of New Jersey (11/09/13)