Nerves, brain cells and spinal cord
In a discovery that could overturn decades of textbook teaching, researchers at the University of Virginia School of Medicine have determined that the brain is directly connected to the immune system by vessels previously thought not to exist.
That such vessels could have escaped detection when the lymphatic system has been so thoroughly mapped throughout the body is surprising on its own, but the true significance of the discovery lies in the effects it could have on the study and treatment of neurological diseases ranging from autism to Alzheimer's disease to multiple sclerosis.
"Instead of asking, 'How do we study the immune response of the brain?' 'Why do multiple sclerosis patients have the immune attacks?' now we can approach this mechanistically. Because the brain is like every other tissue connected to the peripheral immune system through meningeal lymphatic vessels," said Jonathan Kipnis, PhD, professor in the UVA Department of Neuroscience and director of UVA's Center for Brain Immunology and Glia (BIG).
"It changes entirely the way we perceive the neuro-immune interaction. We always perceived it before as something esoteric that can't be studied. But now we can ask mechanistic questions.
"We believe that for every neurological disease that has an immune component to it, these vessels may play a major role. Hard to imagine that these vessels would not be involved in a [neurological] disease with an immune component."
Kevin Lee, PhD, chairman of the UVA Department of Neuroscience, described his reaction to the discovery by Kipnis' lab: "The first time these guys showed me the basic result, I just said one sentence: 'They'll have to change the textbooks.' There has never been a lymphatic system for the central nervous system, and it was very clear from that first singular observation - and they've done many studies since then to bolster the finding - that it will fundamentally change the way people look at the central nervous system's relationship with the immune system."
The discovery was made possible by the work of Antoine Louveau, PhD, a postdoctoral fellow in Kipnis' lab. The vessels were detected after Louveau developed a method to mount a mouse's meninges - the membranes covering the brain - on a single slide so that they could be examined as a whole. "It was fairly easy, actually," he said. "There was one trick: We fixed the meninges within the skullcap, so that the tissue is secured in its physiological condition, and then we dissected it. If we had done it the other way around, it wouldn't have worked."
After noticing vessel-like patterns in the distribution of immune cells on his slides, he tested for lymphatic vessels and there they were. The impossible existed. The soft-spoken Louveau recalled the moment: "I called Jony [Kipnis] to the microscope and I said, 'I think we have something.'" As to how the brain's lymphatic vessels managed to escape notice all this time, Kipnis described them as "very well hidden" and noted that they follow a major blood vessel down into the sinuses, an area difficult to image. "It's so close to the blood vessel, you just miss it," he said. "If you don't know what you're after, you just miss it."
"Live imaging of these vessels was crucial to demonstrate their function, and it would not be possible without collaboration with Tajie Harris," Kipnis noted. Harris, a PhD, is an assistant professor of neuroscience and a member of the BIG center. Kipnis also saluted the "phenomenal" surgical skills of Igor Smirnov, a research associate in the Kipnis lab whose work was critical to the imaging success of the study.
The unexpected presence of the lymphatic vessels raises a tremendous number of questions that now need answers, both about the workings of the brain and the diseases that plague it. For example, take Alzheimer's disease. "In Alzheimer's, there are accumulations of big protein chunks in the brain," Kipnis said. "We think they may be accumulating in the brain because they're not being efficiently removed by these vessels." He noted that the vessels look different with age, so the role they play in aging is another avenue to explore. And there's an enormous array of other neurological diseases, from autism to multiple sclerosis, that must be reconsidered in light of the presence of something science insisted did not exist.
Source: Medical Xpress © Medical Xpress 2011-2015, Science X network (02/06/15)
Exploratory research conducted at Virginia Commonwealth University and the University of Illinois at Chicago may translate into a new therapeutic agent to treat progressive multiple sclerosis, reports Multiple Sclerosis News Today.
Researchers in the laboratories of Dr Jefferey L. Dupree and Dr Douglas L. Feinstein tested a new compound in mice with induced multiple sclerosis and found the compound reduced neurodegeneration and helped improve symptoms.
The compound, lanthionine ketimine, is a naturally occurring molecule that binds to collapsin response mediator protein-2 (CRMP2), which is a protein found in the brain that helps regulate vital neuronal activities. In order to use this compound to treat mice with induced multiple sclerosis, the researchers needed to chemically modify it into a cell-permeable state. The resulting molecule was lanthionine ketimine ethyl-ester (LKE), which was shown to promote neurogenesis and healthy nervous system function.
As explained in the journal article, “Lanthionine Ketimine Ester Provides Benefit in a Mouse Model of Multiple Sclerosis,” which was published in Journal of Neurochemistry, the authors induced multiple sclerosis in mice using the well-accepted model of experimental autoimmune encephalomyelitis (EAE). After mice began to show moderate clinical symptoms of multiple sclerosis, the researchers mixed LKE into the animals’ food so that mice were treated whenever they decided to eat.
After four weeks of ingesting LKE, mice had lower levels of inflammation than those that did not receive LKE but were induced with EAE. LKE-treated mice also showed lower degeneration of the optic nerve and spinal cord, showing only minimal damage to the myelin sheath around the axons. The protective effect was more pronounced in the optic nerve, but the spinal cord also showed great benefit from LKE treatment.
If the researchers continue to pursue LKE and design a well-controlled dosing study in other animal models of multiple sclerosis, the compound may be a potential candidate for clinical trials in patients with progressive multiple sclerosis.
“Only few drugs have been shown to reduce neurodegeneration in multiple sclerosis,” stated the authors. By identifying neuronal protection in the spinal cord and optic nerve, the researchers showed that LKE is a novel and strong candidate for testing in progressive multiple sclerosis.
Source: Multiple Sclerosis News Today © BioNews Services 2015 (26/05/15)
A team of Canadian scientists has found a way to break the barrier of the human body that keeps the nervous and circulatory systems apart, and inject the drugs directly into the brain using “carrier” antibodies.
That system known as the blood-brain barrier (BBB) protects the human skull from any microbes or chemicals, thus keeping the brain clean.
But this barrier also filters good things, such as disease fighting drugs from entering the nervous system. It only allows a selected few types of molecules to cross including water, some gases and lipid soluble molecules.
Scientists from the Canadian National Research Council have been battling for years to find a way to trick it and get the drugs to where they are most needed - to the human brain.
Currently, researchers say they have found a way based on the so-called “single domain antibodies” (SDA). It includes using special molecular fragments that are capable of tricking the blood-brain barrier (BBB) and making it believe they should be let through to the brain. The antibodies are able to squeeze past the barrier not just because of their size (these are fragments that consist of one molecule) but also due to being familiar to some of the receptors along the blood-brain barrier.
The single domain antibodies are exploiting the same mechanism that allows nutrients into the brain, and are able to bind chemically to other molecules.
The scientists add that the method allows them to target multiple types of diseases by producing different carrier molecules.
The method is part of the NRC's Therapeutics Beyond Brain Barriers (TBBB) program, which has been developing special carrier molecules for the past six years.
"It really opens the possibilities to use many different types of therapeutics for different diseases that we couldn't really use before unless we inject them directly into the brain which is highly invasive,” Dr. Danica Stanimirovic, the project`s scientific head,said.
Scientists add that it could become a significant step towards slowing the spread of brain diseases like Alzheimer’s, multiple sclerosis and Parkinson’s.
The discovery follows years of scientific work. At the moment drugs are usually placed into the blood and there they find a way around the body.
Still, researchers say it will take over a decade to finalise clinical trials.
Source: RT © Autonomous Nonprofit Organization “TV-Novosti”, 2005–2015. (15/05/15)
In a new study, researchers have made insights into how the blood-brain barrier (BBB) - which allows only selected molecules to pass through - is maintained, identifying a protein key to the process. Delivering this protein to mice with the rodent equivalent of MS improved their symptoms.
In certain diseases, however, such as multiple sclerosis, the barrier can be improperly breached. These "leaks" can allow immune cells and inflammatory molecules to pass through, causing inflammation that leads to neuronal damage.
The research, led by the University of Pennsylvania's Jorge Ivan Álvarez and Cornelia Podjaski of McGill University and Alexandre Prat of the University of Montreal, will appear in the journal Brain.
Alvarez, an assistant professor in Penn's School of Veterinary Medicine, conducted the study with Podjaski and Prat and colleagues from McGill University and from the University of Montreal.
In 2011, Alvarez and Prat published a study in Science that showed that the protein sonic hedgehog, or Shh, is secreted by central nervous system cells called astrocytes and plays a key role in blood-brain barrier maintenance, in part by preventing immune cells from entering the brain. But the researchers still didn't have a complete picture of the signaling events downstream of Shh that mediated this effect. To learn more, they first used human cells in culture from the blood-brain barrier, called endothelial cells. They found that applying Shh to the cells caused levels of a protein called netrin-1 to rise.
In mice bred to lack the molecular receptor for Shh, netrin-1 expression was reduced, indicating that netrin-1 expression depends on Shh.
"Netrins are best known to play a role in guiding the direction of axon growth as well as morphogenesis and tissue formation," Álvarez said. "But our work suggested a new role for netrin-1 in the blood brain barrier."
Curious as to whether this might influence MS, they examined BBB cells from the brains of people who had died from the disease. Normal tissue from these individuals contained low levels of netrin-1, while the diseased lesions in the brain had higher levels. The researchers found similar results in a mouse model of MS called experimental autoimmune encephalomyelitis, or EAE.
Next, the team directly measured netrin-1's effect on BBB permeability by labeling tracer molecules and found that netrin-1 significantly reduced the movement of molecules across cultures of human BBB endothelial cells. Further experiments showed that netrin regulates this process by promoting the expression of the so-called "tight junction" proteins, which are located between BBB endothelial cells and are responsible for controlling barrier function. The team also found that, when in an environment rife with inflammatory signaling molecules, which would normally compromise the integrity of the BBB, netrin-1 had a counteracting effect, preventing disruption to the BBB.
"In mice bred to lack netrin-1, we observed that proteins normally found in the blood accumulated in the animals' brain, another sign that netrin-1 ensured the integrity of the BBB," Podjaski said.
Armed with these findings suggesting netrin-1 protects the BBB, the team tested the potential of netrin-1 in ameliorating EAE symptoms, which are similar to those of people with MS.
"By administering netrin-1 to mice before the EAE disease was induced, we found that animals had less severe disease, delayed disease onset, fewer lesions in their brain, fewer markers of inflammation and better maintenance of body weight compared to mice given a sham treatment," Podjaski said.
"In mice, we found the disease outcome is better when they're treated with netrin-1, even when delivered after disease processes had begun," Alvarez said. "And all those observations held up in vitro as well."
Moving forward, the researchers hope to further elucidate the pathway through which Shh and netrin-1 operate, with an aim toward finding more effective ways to uphold the barrier and perhaps one day treat diseases like MS.
"We now know that Sonic is above netrin-1 in the signaling pathway, but what else is Sonic hedgehog doing?" Prat said. "We need to complete the puzzle with Sonic first to give us better therapeutic strategies."
Source: Source: Medical Xpress © Medical Xpress 2011-2015, Science X network (23/04/15)
Patients could benefit from brain boost(07/04/15)
Multiple sclerosis patients could one day benefit from treatments that boost their brain function, a study has suggested.
Increasing the activity of neurons could be beneficial in people with the condition, researchers say. It could stimulate the production of a substance that protects nerve fibres.
The finding could pave the way for new treatments, researchers say. MS affects the brain and spinal cord and can cause problems with balance, movement and vision.
Information in the brain is transmitted along nerve fibres known as axons. A material - called myelin - forms a layer around axons, which keeps them healthy and helps speed up the transfer of information.
Damage to myelin contributes to diseases of the brain such as multiple sclerosis.
Until now, it was not known how brain activity controls production of myelin by specialist cells, researchers say.
Researchers examined how changes in the activity of neurons affects how much myelin is produced in the brains of zebrafish. Decreased brain function reduced the amount of myelin made, while production was increased by around 40 per cent when the neuronal activity of fish was increased, the team says.
Before they can develop new therapies, the team says it needs to learn more about how brain function controls the complex processes by which axons are coated with myelin.
The study, published in the journal Nature Neuroscience, was funded by The Wellcome Trust, the Biotechnology and Biological Sciences Research Council, and the Lister Research Prize.
Dr David Lyons, of the University of Edinburgh's Centre for Neuroregeneration, who led the study, said: "We have a long way to go before we fully understand how our brain activity regulates myelin production, but the fact that this is even something that the brain can do is a good news story. We are hopeful that one day in the future we may be able to translate this type of discovery to help treat disease and to maintain a healthy nervous system through life."
Source: Medical Xpress © Medical Xpress 2011-2015, Science X network (07/04/15)
A recent study led by researchers at the Centre for Addiction and Mental Health (CAMH) in Toronto, Canada, revealed a promising new method for MS treatment. The study was published in the journal Annals of Clinical and Translational Neurology and is entitled “Blocking GluR2–GAPDH ameliorates experimental autoimmune encephalomyelitis.”
MS is a progressive, immune-mediated disorder in which the body’s own immune system attacks the central nervous system (brain and spinal cord nerves). The exact causes for MS are not clear but the fact that the immune system is involved makes it a target for current therapies that address immune system responses. While the medications used in these therapies are not curative, they can help relieve the disease symptoms and slow its progression.
Researchers have identified a previously unknown spinal cord alteration linked to MS related to a protein called GAPDH (glyceraldehyde 3-phosphate dehydrogenase, a protein important in glucose metabolism) and a specific cell receptor for the glutamate neurotransmitter (the major excitatory neurotransmitter in the brain, critical for normal brain function). GAPDH was found to interact with this glutamate receptor, called the AMPA receptor, at higher levels in post mortem spinal cord tissues of MS patients and also in MS animal models. The AMPA receptor has been previously suggested as being able to mediate the cytotoxicity linked to the loss of neurons. Researchers therefore hypothesized that blocking AMPA-GAPDH interactions could be therapeutic for MS.
“We’ve identified a new biological target for MS therapy,” said the study’s senior author Dr. Fang Liu in a news release. The team discovered an approach to changing this alteration in order to stop nerve cell damage and also improve motor problems usually linked to the disorder. They developed a new peptide (a small piece of protein) to block the interaction between GAPDH and the AMPA receptor, more specifically GAPDH -GluR2 subunit of the AMPA receptor, and tested it in MS animal models.
“We found that our peptide disrupted this linkage, and led to major improvements in neurological functioning,” explained Dr. Liu. Mice treated with the peptide had their motor function significantly improved and a lower rate of neuron death along with myelin restoration, the protective coating of neurons important for the normal transmission of nerve impulses. More importantly, the peptide developed was found to be different from drugs targeting the glutamate system as it did not directly suppress the immune response of the body, which is a common side effect of many glutamate drugs.
The team believes that the GluR2-GAPDH complex could be a novel target for the development of new types of MS therapies that exploit a different mechanism from those currently used in treatments. “Our priority now would be to extend this research and determine how this discovery can be translated into treatment for patients,” concluded Dr. Liu.
Source: Multiple Sclerosis News Today © BioNews-tx.com 2015 (23/02/15)
Due to its complex nature, scientists have only really been unravelling the mysteries of the brain over the last few decades, and now researchers have discovered that the brains of mice contain at least seven unknown types of cells, including a nerve cell.
These findings could shed light on conditions such as multiple sclerosis.
Using a process called single cell sequencing, scientists at the Karolinska Institute in Sweden produced a detailed map of brain cell types and the genes active within them.
It is the first time the method has been used on such a large scale and on such a complex tissue.
Researchers studied more than 3,000 cells, one at a time, to identify a number of previously unknown types.
‘If you compare the brain to a fruit salad, you could say that previous methods were like running the fruit through a blender and seeing what colour juice you got from different parts of the brain,’ said Sten Linnarsson, senior researcher at the Department of Medical Biochemistry and Biophysics.
‘But in recent years we've developed much more sensitive methods of analysis that allow us to see which genes are active in individual cells.
‘This is like taking pieces of the fruit salad, examining them one by one and then sorting them into piles to see how many different kinds of fruit it contains, what they're made up of and how they interrelate.’
After the scientist analysed the 3,000 cells from the cerebral cortex in mice, they compared which of the 20,000 genes were active in each one, enabling them to sort the cells into virtual piles.
They identified 47 different kinds of cell, including a large proportion of specialised neurons, as well as blood vessel cells and glial cells, which take care of waste products, protect against infection and supply nerve cells with nutrients.
Then, they identified unknown cell types, including a nerve cell in the outermost layer of the cortex plus six different types of oligodendrocyte.
These are cells that form the electrically insulating myelin sheath around the nerve cells.
The study, published in the journal Science, could shed more light on things that affect the myelin.
Co-leader of the study, Jens Hjerling-Leffler, said: ‘We have created a much more detailed map of the cells of the brain that describes each cell type in detail and shows which genes are active in it.
‘This gives science a new tool for studying these cell types in disease models and helps us to understand better how brain cell respond to disease and injury.’
Source: Daily Mail Online © Associated Newspapers Ltd 2015 (20/02/15)
A drug that can encourage nerves in the spinal cord to grow and repair injuries has been developed by US scientists.
The study on rats, published in the journal Nature, showed some degree of movement and bladder control could be restored.
The drug works by disrupting the "sticky glue" that prevents nerve cells from growing during an injury.
Further tests still need to take place, but the charity Spinal Research said "real progress" was being made.
Damage to the spinal cord interrupts the constant stream of electrical signals from the brain to the body.
It can lead to paralysis below an injury.
The team at Case Western Reserve University School of Medicine, in Ohio, said scar tissue that formed after an injury prevented spinal cord repair.
Sugary proteins are released by the scar tissue which act like glue.
The long spindly part of the nerve - the axon - gets trapped in the glue if it tries to cross the site of the injury.
The research team injected a chemical under the skin which crossed into the spinal cord and disrupted the activity of the glue.
"It was amazing - the axons kept growing and growing," said lead researcher Prof Jerry Silver.
In the tests, 21 out of 26 rats showed some degree of recovery either in their ability to move or in bladder function.
Prof Silver told the BBC: "What we could see was really remarkable. Some recovered to a fantastic extent and so well you could hardly tell there was an injury."
He says further testing in larger animals is needed before human trials can take place.
But he sees any future therapy resulting from the research as working in conjunction with other treatments being pioneered such as nerve transplants and electrical stimulation.
Dr Mark Bacon, from the charity Spinal Research, said: "I like Prof Silver's work.
"We believe plasticity - the reorganisation and rerouting of signal pathways - is the major mechanism responsible for the spontaneous recovery we see in patients with spinal cord injury, but is very limited.
"Enhancing plasticity is therefore a major goal for the field.
"Preliminary data here suggests that real progress is being made towards this."
Dr Lyn Jakeman, from the US National Institute of Neurological Disorders and Stroke, said: "There are currently no drug therapies available that improve the very limited natural recovery from spinal cord injuries that patients experience.
"This is a great step towards identifying a novel agent for helping people recover."
Source: BBC News © British Broadcasting Corporation 2014 (04/12/14)
A study published in the October, 2014 issue of Nature Medicine points to a new target for the treatment of multiple sclerosis (M.S.). Inhibiting this target, in a mouse model of the disease, was shown to inhibit the disease in its most advanced stages.
The landmark paper, “B4GALT6 regulates astrocyte activation during CNS inflammation,” was authored by Lior Mayo, Francisco J. Quinta et al. at Harvard Medical School. Abdolmohamad Rostami, M.D. Ph.D., professor and chair of the department of neurology at Thomas Jefferson University, together with Assistant Professor of Neurology Bogoljub Ciric, Ph.D., authored a commentary article, “Astrocyte-derived lactosylceramide implicated in multiple sclerosis,” about the research for Nature Medicine.
“These findings provide a basis for targeting astrocytes, in particular LacCer signaling, as an alternative to most existing M.S. therapies, which modulate the immune system,” said Dr. Rostami. Patients and researchers have been frustrated by the limited effectiveness of available therapies for M.S., especially for “progressive” M.S., a devastating form of the disease that continues to progress with no interruption.
As Rostami and Ciric write in their commentary, the researchers started by investigating a puzzle in M.S. biology. M.S. is thought of as a disease in which the immune cells attack the neuron’s “insulating” tissue, myelin, which helps speed the signals passing from one cell to the next. A type of brain cell, called an astrocyte, appears to play two roles in the disease – protecting and re-myleninating cells early on, and then later, it appears to participate in the inflammatory reaction that fuels the disease.
Exploring this question, the researchers found that the gene B4GALT6 encodes an enzyme that makes LaCer (latosylceramide) — a lipid-signaling molecule. Increasing LaCer production worsens the disease, while inhibiting LaCer halts progression in a mouse model of late-stage disease, suggesting that this enzyme could be a potent target for developing a novel class of therapies against M.S.
Rostami and Ciric write that LaCer appears to contribute to disease progression by activating astrocytes, which in turn activate inflammatory signals that damage nerve cells; it also contributes to the repression of genes associated with remyelinization.
Drs. Rostami and Ciric were particularly impressed with the studies that bridged the finding to human disease. The Harvard team also showed that in samples taken from humans with M.S., B4GALT6 expression levels were increased, as were markers of astrocyte activation, suggesting that a similar pathway may be at play in humans.
Source: Thomas Jefferson University Copyright © 2014 Thomas Jefferson University (15/10/14)
A spice commonly found in curries may boost the brain's ability to heal itself, according to a report in the journal Stem Cell Research and Therapy.
The German study suggests a compound found in turmeric could encourage the growth of nerve cells thought to be part of the brain's repair kit.
Scientists say this work, based in rats, may pave the way for future drugs for strokes and Alzheimer's disease.
But they say more trials are needed to see whether this applies to humans.
Researchers from the Institute of Neuroscience and Medicine in Julich, Germany, studied the effects of aromatic-turmerone - a compound found naturally in turmeric.
Rats were injected with the compound and their brains were then scanned.
Particular parts of the brain, known to be involved in nerve cell growth, were seen to be more active after the aromatic-turmerone infusion.
Scientists say the compound may encourage a proliferation of brain cells.
In a separate part of the trial, researchers bathed rodent neural stem cells (NSCs) in different concentrations of aromatic-tumerone extract.
NSCs have the ability to transform into any type of brain cell and scientists suggest they could have a role in repair after damage or disease.
Dr Maria Adele Rueger, who was part of the research team, said: "In humans and higher developed animals their abilities do not seem to be sufficient to repair the brain but in fish and smaller animals they seem to work well."
The research found the higher the concentration of aromatic-turmerone, the greater the growth of the NSCs.
And the cells bathed in the turmeric compound seemed to specialise into certain types of brain cells more rapidly too.
Dr Rueger added: "It is interesting that it might be possible to boost the effectiveness of the stem cells with aromatic-turmerone.
"And it is possible this in turn can help boost repair in the brain."
She is now considering whether human trials may be feasible.
Dr Laura Phipps at the charity, Alzheimer's Research UK, said: "It is not clear whether the results of this research would translate to people, or whether the ability to generate new brain cells in this way would benefit people with Alzheimer's disease.
"We'd need to see further studies to fully understand this compound's effects in the context of a complex disease like Alzheimer's, and until then people shouldn't take this as a sign to stock up on supplies of turmeric for the spice rack."
Aromatic-turmerone is the lesser-studied of two major compounds in turmeric that may have an effect on the human body.
Previous studies suggest the other compound, curcumin, could reduce inflammation in the body and have anti-cancer benefits.
Source: BBC News © British Broadcasting Corporation 2014 (26/09/14)
Dock3 protects myelin in the cuprizone model for demyelination.
Namekata K, Kimura A, Harada C, Yoshida H, Matsumoto Y, Harada T.
Dedicator of cytokinesis 3 (Dock3) belongs to an atypical family of the guanine nucleotide exchange factors. It is predominantly expressed in the neural tissues and causes cellular morphological changes by activating the small GTPase Rac1.
We previously reported that Dock3 overexpression protects retinal ganglion cells from excitotoxic cell death. Oligodendrocytes are the myelinating cells of axons in the central nervous system and these cells are damaged in demyelinating disorders including multiple sclerosis (MS) and optic neuritis.
In this study, we examined if Dock3 is expressed in oligodendrocytes and if increasing Dock3 signals can suppress demyelination in a cuprizone-induced demyelination model, an animal model of MS.
We demonstrate that Dock3 is expressed in oligodendrocytes and Dock3 overexpression protects myelin in the corpus callosum following cuprizone treatment. Furthermore, we show that cuprizone demyelinates optic nerves and the extent of demyelination is ameliorated in mice overexpressing Dock3.
Cuprizone treatment impairs visual function, which was demonstrated by multifocal electroretinograms, an established non-invasive method, and Dock3 overexpression prevented this effect.
In mice overexpressing Dock3, Erk activation is increased, suggesting this may at least partly explain the observed protective effects.
Our findings suggest that Dock3 may be a therapeutic target for demyelinating disorders including optic neuritis.
Source: Cell Death and Disease (2014) 5, e1395; doi:10.1038/cddis.2014.357 & Pubmed PMID: 25165881 (09/09/14)
Axonal degeneration in multiple sclerosis: can we predict and prevent permanent disability?
Lee J, Taghian K, Petratos S.
Axonal degeneration is a major determinant of permanent neurological impairment during multiple sclerosis (MS). Due to the variable course of clinical disease and the heterogeneity of MS lesions, the mechanisms governing axonal degeneration may differ between disease stages.
While the etiology of MS remains elusive, there now exist potential prognostic biomarkers that can predict the conversion to clinically definite MS.
Specialised imaging techniques identifying axonal injury and drop-out are becoming established in clinical practice as a predictive measure of MS progression, such as optical coherence tomography (OCT) or diffusion tensor imaging (DTI). However, these imaging techniques are still being debated as predictive biomarkers since controversy surrounds their lesion-specific association with expanded disability status scale (EDSS).
A more promising diagnostic measure of axonal degeneration has been argued for the detection of reduced N-acetyl aspartate (NAA) and Creatine ratios via magnetic resonance spectroscopic (MRS) imaging, but again fail with its specificity for predicting actual axonal degeneration. Greater accuracy of predictive biomarkers is therefore warranted and may include CSF neurofilament light chain (NF-L) and neurofilament heavy chain (NF-H) levels, for progressive MS. Furthermore, defining the molecular mechanisms that occur during the neurodegenerative changes in the various subgroups of MS may in fact prove vital for the future development of efficacious neuroprotective therapies.
The clinical translation of a combined Na+ and Ca2+ channel blocker may lead to the establishment of a bona fide neuroprotective agent for the treatment of progressive MS. However, more specific therapeutic targets to limit axonal damage in MS need investigation and may include such integral axonal proteins such as the collapsin response mediator protein-2 (CRMP-2), a molecule which upon post-translational modification may propagate axonal degeneration in MS.
In this review, we discuss the current clinical determinants of axonal damage in MS and consider the cellular and molecular mechanisms that may initiate these neurodegenerative changes. In particular we highlight the therapeutic candidates that may formulate novel therapeutic strategies to limit axonal degeneration and EDSS during progressive MS.
Source: Acta Neuropathol Commun. 2014 Aug 27;2(1):97. [Epub ahead of print] & Pubmed PMID: 25159125 (02/09/14)
Atrophy and structural variability of the upper cervical cord in early multiple sclerosis.
Biberacher V, Boucard CC, Schmidt P, Engl C, Buck D, Berthele A, Hoshi MM, Zimmer C, Hemmer B, Mühlau M.
BACKGROUND: Despite agreement about spinal cord atrophy in progressive forms of multiple sclerosis (MS), data on clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS) are conflicting.
OBJECTIVE: To determine the onset of spinal cord atrophy in the disease course of MS.
METHODS: Structural brain magnetic resonance imaging (MRI) was acquired from 267 patients with CIS (85) or RRMS (182) and 64 healthy controls (HCs). The upper cervical cord cross-sectional area (UCCA) was determined at the level of C2/C3 by a segmentation tool and adjusted for focal MS lesions. The coefficient of variation (CV) was calculated from all measurements between C2/C3 and 13 mm above as a measure of structural variability.
RESULTS: Compared to HCs (76.1±6.9 mm2), UCCA was significantly reduced in CIS patients (73.5±5.8 mm2, p=0.018) and RRMS patients (72.4±7.0 mm2, p<0.001). Structural variability was higher in patients than in HCs, particularly but not exclusively in case of focal lesions (mean CV HCs/patients without/with lesions: 2.13%/2.55%/3.32%, all p-values<0.007). UCCA and CV correlated with Expanded Disability Status Scale (EDSS) scores (r =-0.131/0.192, p=0.044/<0.001) and disease duration (r=-0.134/0.300, p=0.039/< 0.001). CV additionally correlated with hand and arm function (r=0.180, p=0.014).
CONCLUSION: In MS, cervical cord atrophy already occurs in CIS. In early stages, structural variability may be a more meaningful marker of spinal cord pathology than atrophy.
Source: Mult Scler. 2014 Aug 19. pii: 1352458514546514 & Pubmed PMID: 25139943 (27/08/14)