Nerves, brain cells and spinal cord
Cervical spinal cord volume loss is related to clinical disability progression in multiple sclerosis.
Lukas C, Knol DL, Sombekke MH, Bellenberg B, Hahn HK, Popescu V, Weier K, Radue EW, Gass A, Kappos L, Naegelin Y, Uitdehaag BM, Geurts JJ, Barkhof F, Vrenken H.
OBJECTIVE: To examine the temporal evolution of spinal cord (SC) atrophy in multiple sclerosis (MS), and its association with clinical progression in a large MS cohort.
METHODS: A total of 352 patients from two centres with MS (relapsing remitting MS (RRMS): 256, secondary progressive MS (SPMS): 73, primary progressive MS (PPMS): 23) were included. Clinical and MRI parameters were obtained at baseline, after 12 months and 24?months of follow-up. In addition to conventional brain and SC MRI parameters, the annualised percentage brain volume change and the annualised percentage upper cervical cord cross-sectional area change (aUCCA) were quantified. Main outcome measure was disease progression, defined by expanded disability status scale increase after 24?months.
RESULTS: UCCA was lower in SPMS and PPMS compared with RRMS for all time points. aUCCA over 24?months was highest in patients with SPMS (-2.2% per year) and was significantly higher in patients with disease progression (-2.3% per year) than in stable patients (-1.2% per year; p=0.003), while annualised percentage brain volume change did not differ between subtypes (RRMS: -0.42% per year; SPMS -0.6% per year; PPMS: -0.46% per year) nor between progressive and stable patients (p=0.055). Baseline UCCA and aUCCA over 24?months were found to be relevant contributors of expanded disability status scale at month-24, while baseline UCCA as well as number of SC segments involved by lesions at baseline but not aUCCA were relevant contributors of disease progression.
CONCLUSIONS: SC MRI parameters including baseline UCCA and SC lesions were significant MRI predictors of disease progression. Progressive 24-month upper SC atrophy occurred in all MS subtypes, and was faster in patients exhibiting disease progression at month-24.
Source : J Neurol Neurosurg Psychiatry. 2014 Jun 27. pii: jnnp-2014-308021. doi: 10.1136/jnnp-2014-308021. [Epub ahead of print] & Pubmed PMID: 24973341 (30/06/14)
Researchers at VIB and Ghent University have unraveled the mechanism of necroptosis. This is a type of cell death that plays a crucial role in numerous diseases, from viral infections and loss of auditory nerve cells to multiple sclerosis, acute heart failure and organ transplantation. Having detailed knowledge of the cell death process enables a targeted search for new drugs.
Peter Vandenabeele (VIB/UGent): "The molecular mechanism of necroptosis was a complete mystery for a long time. Cells explode. But exactly how they do this was unclear. Now we have found that cells activate pore-forming molecules that make holes in the membrane. This basic research provides entirely new perspectives for the treatment of numerous chronic and acute inflammatory and degenerative diseases where necroptosis needs to be blocked. But it can also be useful to stimulate necroptosis in a controlled way, for example to circumvent the resistance of cancer cells to chemotherapy or to resensitize cancer cells to cell death."
Inflammatory reactions due to cell death
Many diseases are associated with dying cells. That is why understanding the cell death process is essential for the search for new medications. Peter Vandenabeele has many years of expertise in researching cell death, including with 'necroptosis'. In this type of cell death the cell explodes, as it were, and the cell content is released. This causes inflammatory reactions in the surrounding tissue.
Prior research shows that necroptosis occurs with a number of diseases, including viral infections, septic shock, detached retina, loss of auditory nerve cells, multiple sclerosis, acute heart failure, stroke, kidney failure and organ transplant complications. It also occurs in the presence of bad blood circulation and oxygen deficiency in the extremities or organs such as with atherosclerosis or type II diabetes.
A new therapeutic strategy: counteracting pore formation
Yves Dondelinger and Peter Vandenabeele discovered that the cellular explosion during necroptosis is paired with the formation of pores consisting of MLKL proteins. These MLKL pores are formed on the cell surface and cause the cells to absorb too much water. Because of this the cells ultimately explode. Detailed knowledge about how MLKL proteins create pores offers possibilities for developing medications for combatting or tolerating cell death by preventing or temporarily blocking this process.
Source: Medical Xpress © Medical Xpress 2011-2014 (05/06/14)
A $500,000 drug development grant from the National Multiple Sclerosis Society (NMSS) was awarded to a partnership between a multiple sclerosis research team at the Icahn School of Medicine at Mount Sinai and Karyopharm Therapeutics Inc., a clinical stage pharmaceutical company. Dr. Patrizia Casaccia, MD, PhD, Professor in the Departments of Neuroscience and Genetics and Genomics, at Icahn School of Medicine at Mount Sinai, will be the academic lead. She will test the effectiveness of a novel Karyopharm compound that can be orally administered and aimed at stopping the progressive phase of the disease. With the 14-month grant, Dr. Casaccia also hopes to gather information that will help design future clinical trials for MS treatments.
Karyopharm specializes in the synthesis of Selective Inhibitors of Nuclear Export, also known as SINE compounds. These compounds are thought to prevent the cause of irreversible damage to neurons, by blocking the early stages of neurodegeneration. Dr. Casaccia's laboratory first identified nuclear export as an important mechanism related to the initial events occurring in neurons and eventually leading to neurodegeneration. As inhibitors, these novel compounds target the nucleus in neurons, and block the accumulation of toxic substances in the axons. Axons are coated with myelin, and they can be damaged because myelin is destroyed or because they can be directly attacked by toxic factors that accumulate during the MS disease process. Neurodegenerative symptoms result from loss of myelin. Electrical signals are transmitted from the cell body of the neuron down an axon to other nerve cells, muscles, and other cells. Signal transmission slows down and progressive disability results from damage to the axons and loss of neurons, due to neurodegeneration.
Dr. Casaccia underscored the new strategy in MS drug development. "What's unique about this work is that SINE compounds target and prevent nuclear export, which is critically important for the neurodegenerative phase of the disease," she said. Preliminary experiments in Dr. Casaccia's laboratory have been encouraging. In mouse models, oral administration of the new compound to mice with paralysis of the tail and hindlimb, allowed them to walk again.
"The idea of rebuilding the nervous system and protecting it from ongoing MS damage was just a dream a few years ago," said Timothy Coetzee, Chief Advocacy, Services and Research Officer at the National MS Society. "Now, because of efforts by the research community as well as focused investments by the Society, we can see a future where people with MS will have treatments that could restore what's been lost."
In partnering with Karyopharm Therapeutics Inc., Dr. Casaccia will test these oral compounds in preclinical models and unravel their mechanism of action. The work would not be possible if the National MS Society did not invest $500,000 with Karyopharm through Fast Forward, as part of a comprehensive approach to MS research and treatment focusing on accelerating commercial development of promising research discoveries.
"We look forward to collaborating with Dr. Casaccia, who has dedicated herself to advancing research in multiple sclerosis and other important diseases," said Karyopharm Founder, Chief Scientific Officer, and President of Research and Development, Sharon Shacham, PhD, MBA.
Fred Lublin, MD, Saunders Family Professor of Neurology and the Director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Medical Center also applauded this research. "Developing novel approaches to treating the neurodegenerative component of MS is critically important for our efforts at halting this disease and then reversing the damage. Existing medications for MS only aim to reduce the number of relapses. They are not restorative to the nervous system."
Source: The Mount Sinai Hospital (22/11/13)
Sodium “overload” in the brain is one of the major factors to blame for the disabling symptoms of multiple sclerosis, researchers have found.
Pioneering work by scientists at University College London Hospitals shows high sodium levels are a major trigger for nerve cell damage. This damage is a key factor in devastating long-term effects of MS, such as walking difficulties and vision problems.
Experts predict the findings, published today, will lead to new treatments aimed at halting the progression of the disease.
The study, the first of its kind, will bring hope to thousands of people. In particular, it could benefit those with progressive forms of the illness where there is more disability.
Healthy people have normal levels of sodium in their nerve cells. However, the researchers discovered MS patients had above-average levels. This is because the cells are too weak to pump it out quickly enough, leading to a build-up of sodium which then causes long-term damage.
The study was funded by the MS Society and NIHR University College London Hospitals Biomedical Research Centre. Dr Susan Kohlhaas, the charity’s head of biomedical research, said: “We urgently need treatments for people with progressive forms of multiple sclerosis and the results of this study, and others funded by the MS Society, open up more options for researchers to investigate potential medicines that could slow or even stop the accumulation of disability.”
Multiple sclerosis affects at least 100,000 people in Britain. It is a condition of the central nervous system, in which the coating around nerve fibres is damaged, causing a range of symptoms. There is no cure. It is normally diagnosed in people between the ages of 20 and 40 and affects almost three times as many women as men.
The researchers used an MRI scanner to assess salt levels in the brains of patients. Ninety-seven people with MS took part in the study.
Dr David Paling, lead author of the study, said scientists would investigate ways of blocking the sodium build-up. “The study is important because it proves sodium accumulation in the nerves affects the progressive nature of the disease,” he said. “We can now move forward to plan trials with medications that prevent sodium from getting into cells and causing damage.
“In addition, we now have an effective test to check if these treatments are working for MS patients, instead of waiting five to 10 years.”
One MS sufferer who took part in the research was Dominic Weaver, 46, from west London. The sound engineer and dubbing mixer for television and film was diagnosed in 2011 and now walks using a stick. He said: “I can still walk but I don’t know if tomorrow I may not be able to get out of bed again. Any treatment which could halt the progression of the disease is a step forward.”
The findings are published this month in the journal Brain.
Source: The Evening Standard © Evening Standard Limited 2013 (12/07/13)