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Biomarkers and microRNA









The effects of microparticles on endothelial barrier function in MS and clinically isolated syndrome highlighted(22/09/14)

Microparticles in multiple sclerosis and clinically isolated syndrome: effect on endothelial barrier function.

Cell-derived microparticles are secreted in response to cell damage or dysfunction. Endothelial and platelet dysfunction are thought to contribute to the development of multiple sclerosis (MS).

Our aim here is, first, to compare the presence of microparticles of endothelial and platelet origin in plasma from patients with different clinical forms of MS and with clinically isolated syndrome. Second, to investigate the effect of microparticles on endothelial barrier function.

Results: Platelet-poor plasma from 95 patients (12 with clinically isolated syndrome, 51 relapsing-remitting, 23 secondary progressive, 9 primary progressive) and 49 healthy controls were analyzed for the presence of platelet-derived and endothelium-derived microparticles by flow cytometry.

The plasma concentration of platelet-derived and endothelium-derived microparticles increased in all clinical forms of MS and in clinically isolated syndrome versus controls. The response of endothelial barriers to purified microparticles was measured by electric cell-substrate impedance sensing.

Microparticles from relapsing-remitting MS patients induced, at equivalent concentrations, a stronger disruption of endothelial barriers than those from healthy donors or from patients with clinically isolated syndrome. MS microparticles acted synergistically with the inflammatory mediator thrombin to disrupt the endothelial barrier function.

Conclusions: Plasma microparticles should be considered not only as markers of early stages of MS, but also as pathological factors with the potential to increase endothelial permeability and leukocyte infiltration.

Source: 7thSpace Interactive © 2014 7thSpace Interactive (22/09/14)

Molecule linked to neurological dysfunctions identified(06/08/14)

A team of researchers has pinpointed a small molecule responsible for nerve cell damage and other symptoms tied to neurological diseases, including multiple sclerosis (MS).

In a study published in the June 2014 issue of The Federation of American Societies for Experimental Biology Journal, investigators at The Open University (OU) in the United Kingdom and colleagues from Sheffield, London, and Amsterdam highlighted the behavior of MicroRNA-155 (miR-155) and its activity during inflammation.

According to a statement released by the OU, inflammation in the molecule creates gaps in tissue cells, leading to toxins entering the brain from the bloodstream. In comparison, unaffected individuals’ cells create a barrier that prevents molecules from invading the brain.

“We have identified miR-155 as a critical miRNA in neuroinflammation at the blood-brain barrier (BBB),” the authors noted. “miR-155 is expressed at the neurovascular unit of individuals with MS and of mice with experimental autoimmune encephalomyelitis.”

The statement also noted that cells that line blood vessels and control molecules’ brain access when inflamed become “leaky” due to neurological immunity. This inflammation, the study noted, has been observed with several conditions such as MS, HIV, dementia, and bacterial infections of the blood.

The investigators said that while BBB dysfunction was recognised in MS and stroke patients, molecular activity behind the dysfunction is still a mystery.

"This research has helped us to gain a better understanding of how toxins and other blood-borne molecules are leaked into the brain in inflammatory conditions,” lead author Ignacio Romero, MD, senior lecturer in Cellular Neuroscience in Open University’s Department of Life, Health and Chemical Sciences, said in a statement.“This is crucial, not only for helping to explain the molecular underpinnings of neurological diseases such as Alzheimer’s and MS, but also for opening up new possibilities for developing treatments to reduce the flow of these unwanted molecules to the brain and also for delivering life-saving drugs.”

Source: HCP Live Copyright HCPLive 2006-2014 (06/08/14)

KIR4.1 ruled out as possible antigen for MS(15/07/14)

Investigation of the KIR4.1 potassium channel as a putative antigen in patients with multiple sclerosis: a comparative study.

Brickshawana A, Hinson SR, Romero MF, Lucchinetti CF, Guo Y, Buttmann M, McKeon A, Pittock SJ, Chang MH, Chen AP, Kryzer TJ, Fryer JP, Jenkins SM, Cabre P, Lennon VA.


BACKGROUND: Antibodies have been implicated in the pathogenicity of multiple sclerosis by findings of immunoglobulins in patients' CSF and often IgG and complement in lesions, and by a 2012 report that nearly half of patients' serum samples contain IgG specific for a glial potassium-channel, KIR4.1. We aimed to establish the frequency of KIR4.1-binding IgG in serum and CSF of patients with multiple sclerosis, and whether KIR4.1 immunoreactivity is retained or lost in demyelinating lesions.

METHODS: Using ELISA with a KIR4.1 peptide, we tested archival serum from 229 population-based and 57 clinic-based patients with multiple sclerosis, 99 healthy controls, and 109 disease controls, and CSF from 25 patients with multiple sclerosis and 22 disease controls. We tested all CSF and serum samples from 50 of the clinic-based patients with multiple sclerosis on cells expressing functional KIR4.1, using cell-based immunofluorescence and immunoprecipitation (solubilised recombinant human KIR4.1). We assessed KIR4.1 immunoreactivity in archival brain samples from 15 patients with histopathologically confirmed multiple sclerosis (22 plaques [eight early active, eight inactive, and six remyelinated], 13 periplaque regions and eight normal-appearing white-matter and grey-matter regions) and from three controls with non-neurological diseases.

FINDINGS: Three of 286 serum samples from patients with multiple sclerosis and two of 208 serum samples from controls showed KIR4.1 reactivity on ELISA; none of the CSF samples from patients or controls showed KIR4.1 reactivity. IgG in none of the 50 serum samples from clinic-based patients immunoprecipitated KIR4.1, but a commercial KIR4.1-specific control IgG did. By immunofluorescence, one of 50 serum samples from patients with multiple sclerosis yielded faint plasmalemmal staining on both KIR4.1-expressing and non-expressing cells; 16 bound faintly to intracellular components. In all cases, IgG binding was quenched by absorption with liver powder or lysates from non-transfected cells. Binding by the KIR4.1-specific control IgG was quenched only by lysates containing KIR4.1. IgG in none of the 25 CSF samples from patients with multiple sclerosis bound to KIR4.1-transfected cells. Glial KIR4.1 immunoreactivity was increased relative to expression in healthy control brain in all active demyelinating lesions, remyelinated lesions, and periplaque white matter regions.

INTERPRETATION: We did not detect KIR4.1-specific IgG in serum or CSF from patients with multiple sclerosis or KIR4.1 loss from glia in multiple sclerosis lesions. Serological testing for KIR4.1-specific IgG is unlikely to aid diagnosis of multiple sclerosis. The target antigen of multiple sclerosis remains elusive.

FUNDING: The National Institutes of Health, the National Multiple Sclerosis Society, and the Mayo Clinic Robert and Arlene Kogod Center on Aging.

Source: Lancet Neurol. 2014 Jul 4. pii: S1474-4422(14)70141-3. doi: 10.1016/S1474-4422(14)70141-3. [Epub ahead of print] & Pubmed PMID: 25008548 (15/07/14)

Cytokine signature patterns provide insights into immunomodulatory drug effects(07/07/14)

The use of cytokine signature patterns: separating drug naïve, interferon and natalizumab-treated multiple sclerosis patients.

O'Connell KE1, Mok T, Sweeney B, Ryan AM, Dev KK.


Multiple sclerosis (MS) is an inflammatory illness characterised by demyelination and axonal neurodegeneration. Here, we used serum samples from MS patients to demonstrate if "cytokine signature" patterns can separate different patient groups better than using single cytokines.

In this case, we used cytokine profiling to demonstrate if "cytokine signature" patterns can separate MS patients treated with interferon or natalizumab from drug naïve patients.

Serum levels of eight individual cytokines (TNFα, IFNγ, S100B, IL-1β, IL-6, IL-8, IL-17 and IL-23) in MS patients treated with interferons (n = 11) and natalizumab (n = 14) were measured and, in general, showed reduced levels compared to drug naïve MS patients (n = 12).

More evident changes were seen when analyzing "cytokine signatures" (i.e. summed value of all eight cytokines), which showed that patients treated with natalizumab and interferons showed significantly reduced cytokine signature levels than drug naïve MS patients.

Moreover, patients treated with natalizumab were separated from drug naïve patients by almost 100% fidelity and that patients treated with natalizumab also had reduced levels of pro-inflammatory cytokines compared to patients treated with interferon.

Overall, this study provides an example showing that the use of "cytokine signatures" may provide benefits over the analysis of single cytokines for the development of potential biomarkers.

Source: Autoimmunity. 2014 Jun 30:1-7. [Epub ahead of print] & Pubmed PMID: 24974887 (07/07/14)

Molecular sensor detects early signs of Multiple Sclerosis(05/12/13)

For some, the disease multiple sclerosis (MS) attacks its victims slowly and progressively over a period of many years. For others, it strikes without warning in fits and starts. But all patients share one thing in common: the disease had long been present in their nervous systems, hiding under the radar from even the most sophisticated detection methods. But now, scientists at the Gladstone Institutes have devised a new molecular sensor that can detect MS at its earliest stages -- even before the onset of physical signs.

In a new study from the laboratory of Gladstone Investigator Katerina Akassoglou, PhD, scientists reveal in animal models that the heightened activity of a protein called thrombin in the brain could serve as an early indicator of MS. By developing a fluorescently labeled probe specifically designed to track thrombin, the team found that active thrombin could be detected at the earliest phases of MS -- and that this active thrombin correlates with disease severity. These findings, reported online in Annals of Neurology, could spur the development of a much-needed early-detection method for this devastating disease.

MS, which afflicts millions of people worldwide, develops when the body's immune system attacks the protective myelin sheath that surrounds nerve cells. This attack damages the nerve cells, leading to a host of symptoms that include numbness, fatigue, difficulty walking, paralysis and loss of vision. While some drugs can delay these symptoms, they do not treat the disease's underlying causes -- causes that researchers are only just beginning to understand.

Last year, Dr. Akassoglou and her team found that a key step in the progression of MS is the disruption of the blood brain barrier (BBB). This barrier physically separates the brain from the blood circulation and if it breaks down, a blood protein called fibrinogen seeps into the brain. When this happens, thrombin responds by converting fibrinogen into fibrin -- a protein that should normally not be present in the brain. As fibrin builds up in the brain, it triggers an immune response that leads to the degradation of the nerve cells' myelin sheath, over time contributing to the progression of MS.

"We already knew that the buildup of fibrin appears early in the development of MS -- both in animal models and in human patients, so we wondered whether thrombin activity could in turn serve as an early marker of disease." said Dr. Akassoglou, who directs the Gladstone Center for In Vivo Imaging Research (CIVIR). She is also a professor of neurology at the University of California, San Francisco, with which Gladstone is affiliated. "In fact, we were able to detect thrombin activity even in our animal models -- before they exhibited any of the disease's neurological signs."

In laboratory experiments on mice modified to mimic the signs of MS, the team employed an Activatable Cell-Penetrating Peptide (ACPP), a special type of molecular probe that delivers fluorescent agents to a region of interest. For this study, they developed a thrombin-specific ACPP that could track thrombin activity in mice as the disease progressed. They then carefully analyzed where -- and at what stage of disease -- thrombin activity was found.

"We detected heightened thrombin activity at specific disease 'hot-spots,' regions where neuronal damage developed over time," said Gladstone Staff Research Scientist Dimitrios Davalos, PhD, associate director of the CIVIR and one of the paper's lead authors. "And when we compared those results to those of a separate, healthy control group of mice, we saw that thrombin activity in the control group was wholly absent."

"Our results are proof of principle that a thrombin-specific molecular probe could be used as an early-detection method," added former Gladstone Postdoctoral Researcher Kim Baeten, PhD, the paper's other lead author.

The team's results offered significant support for the notion that thrombin activity is directly tied to the degradation of nerve cell's myelin sheath -- and the subsequent destruction of nerve cells -- that characterizes MS. But they also shed light on what has been a long-standing mystery: the underlying molecular processes that kick-start the progression of MS.

"In the future," said Dr. Akassoglou, "this thrombin-specific ACPP could be developed to one day allow for early patient diagnosis and therapeutic intervention -- including a way to effectively monitor how patients are responding to the latest treatments."

Journal Reference:
Dimitrios Davalos, Kim M. Baeten, Michael A. Whitney, Eric S. Mullins, Beth Friedman, Emilia S. Olson, Jae Kyu Ryu, Dimitri S. Smirnoff, Mark A. Petersen, Catherine Bedard, Jay L. Degen, Roger Y. Tsien, Katerina Akassoglou. Early detection of thrombin activity in neuroinflammatory disease. Annals of Neurology, 2013; DOI: 10.1002/ana.24078

Source: ScienceDaily Copyright 2013 by ScienceDaily, LLC (05/12/13)

Blood-clotting protein may offer early detection of Multiple Sclerosis(11/11/13)

A protein involved in blood clotting may be a new indicator to help detect multiple sclerosis (MS) lesions before symptoms arise. The presence of the clotting protein, thrombin, signals an early stage of the disease when the blood-brain barrier is breached and the brain’s immune response is set into motion. The research was presented at Neuroscience 2013, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health.

30,000 scientists are attending this meeting.

“Our research shows this indicator is a promising approach for detecting MS-like lesions early, even before major symptoms appear,” said senior author Katerina Akassoglou, Ph.D., of the Gladstone Institutes and the University of California, San Francisco. “Such sensitive indicators could act as red flags that signal neuroinflammatory changes in the brain not only in MS, but also in other diseases such as Alzheimer’s.”

MS is a debilitating disorder that can be intermittent or progressive, and causes numbness, fatigue, difficulty walking, paralysis, and loss of vision in 2 million people worldwide. MS arises when the body’s immune system attacks its own myelin sheaths, the protective coverings that surround neurons and allow signals to move from one cell to the next.

The researchers found that thrombin, usually a beneficial protein involved in blood clotting, builds up in the central nervous system as MS progresses. Thrombin enters in the brain together with fibrinogen, another clotting protein when the protective barrier between the blood and brain becomes leaky. Thrombin converts the fibrinogen to fibrin which activates brain’s immune cells that break down the protective myelin sheath that surrounds neurons in the central nervous system. Because thrombin levels increase as the disease progresses, the researchers conclude that it could be used as an early detector of the disease.

In their studies, the researchers used a mouse model and demonstrated that MS symptoms increased as thrombin levels rose. Early detection of MS could result in more successful treatment of the disease.

Research was supported with funds from the National Multiple Sclerosis Society, the Nancy Davis Foundation for Multiple Sclerosis, and the National Institutes of Health. Dr. Akassoglou outlined her findings in a press conference held on Sunday, November 10, and this summary was distributed with the press release. The scientific presentation of Dr. Akassoglou’s work will be delivered on Monday, Novermber 11.

Source: Bioquick News (11/11/13)

Biomarkers predict second MS attack(07/10/13)

In patients who experienced a first attack of multiple sclerosis (MS) symptoms, risk of a second attack was associated with a variety of baseline factors, researchers said here.

Measurements of brain lesions with MRI, oligoclonal bands in cerebrospinal fluid (CSF), and visual and sensorimotor evoked potentials were, collectively, indicators for patients at relatively high risk of a second attack within 12 months, reported Vittorio Martinelli, MD, of San Raffaele Hospital in Milan.

And, in a separate pan-European study, levels of the chitinase 3-like 1 (CHI3L1) CSF protein were a moderately strong predictor of second attacks in a similar patient population, said Ester Cantó, a PhD student a Vall d'Hebron University in Barcelona.

Using a cutoff value of 190 ng/mL, patients with higher CHI3L1 values showed a median time to develop clinically definite MS by 2005 McDonald criteria of 12.4 months (95% CI 11.8-13.0), compared with 39.5 months in patients with lower CHI3L1 values (95% CI 29.5-50.4), she said.

Both studies were reported at the European Committee for Treatment and Research in Multiple Sclerosis annual meeting, where attention has been particularly focused on the earliest stages of MS.

To qualify for a diagnosis, patients must have experienced two bouts of symptoms separated in time. A first attack is called clinically isolated syndrome (CIS).

In some patients, years may pass until they experience a second attack and are diagnosed with MS -- or never. Others may experience renewed symptoms in as little as 6 months.

Physicians now want to initiate disease-modifying therapies right away in patients with such aggressive pathology, but currently there are no standards for identifying them.

Martinelli noted that previous studies, using different criteria to stratify patients, have found very different rates of conversion from CIS to MS.

Those studies had established some risk factors for conversion: young age, presence of oligoclonal bands in CSF, past steroid treatment, and large MRI lesion burdens.

But narrowing them to establish a reliable predictive model would be useful, he suggested.

Improved Prediction with Conventional Tests

In a step toward that goal, he and colleagues at San Raffaele examined data collected prospectively from 227 CIS patients seen from 2000 through 2010. The data represented results of standard tests for patients with suspected CIS including MRI scans, CSF analysis for oligoclonal bands, and multimodal (visual and sensorimotor) evoked potential testing.

Mean follow-up was 6.8 years (standard deviation 2.8). Mean time from symptom onset to hospitalization and CIS diagnosis was 1.7 months (SD 1.4).

MRI findings at baseline indicated three-quarters of patients had monofocal lesions, with the remainder showing a multifocal distribution. Total T2 lesion counts were zero or one in 12% of patients, from two to nine in 59%, and 10 or more in 29%. Half the patients had gadolinium-enhancing lesions and 74% had oligoclonal bands in CSF.

Just over 30% converted to clinically definite MS within 2 years; through the entire follow-up, 53% converted.

Statistical analysis showed that three factors were most strongly associated with early conversion to MS:

Having more than two T2 lesions
A positive test for oligoclonal bands in CSF
Being in the top quartile of multimodal evoked potentials (indicating impaired peripheral nerve function)
Among patients lacking these three factors, some 15% converted to MS within 12 months, whereas 40% of those showing all three converted.

"Integration of MRI, CSF, and multimodal evoked potential data is essential for an accurate and personalized risk management in patients with CIS," Martinelli said.

CSF Protein Marker

The study reported by Cantó involved CSF samples and clinical data from 813 CIS patients and 559 controls recruited from 15 centers across Europe. Controls included 121 patients with inflammatory neurological diseases that were not CIS or MS.

Her team focused on CHI3L1 due to its appearance in an earlier proteomics discovery project aimed at finding CSF biomarkers that could distinguish early converters from CIS to MS. The current study was designed to validate those findings in a larger, well controlled sample from multiple centers.

In addition, Cantó said, the researchers wanted to understand more about the origins of CHI3L1 within the nervous system.

CIS patients in the study had provided CSF samples during their diagnostic workups. With mean follow-up of 5.4 years, a total of 60% eventually received an MS diagnosis according to 2005 McDonald criteria and 51.5% by the more restrictive Poser criteria.

Across the entire cohort of CIS patients (irrespective of conversion), mean CHI3L1 levels were higher than those in non-inflammatory neurological disease controls by 70 ng/mL, but lower than those in the controls with inflammatory neurological disease by 329 ng/mL (both P<0.0001).

Levels were higher by 40 ng/mL (95% CI 25-56) in patients who converted to MS during follow-up than in those who didn't (P<0.00001), Cantó said.

CHI3L1 levels remained an independent risk factor (P<0.00001) for early conversion when analyzed in a model that also included age at CIS onset, presence of oligoclonal bands, and so-called Barkhof criteria based on MRI findings.

In addition to predicting early conversion to MS, CHI3L1 levels above 190 ng/mL also predicted more rapid disability progression, Cantó said.

Mean time to expanded disability status scale (EDSS) scores of 3.0 was 156 months in those with high values compared with 215 months in those with low values (P=1×10-9).

A histopathology study, using cells from CSF obtained from five CIS patients and five controls with non-inflammatory neurological disease, showed that CHI3L1 expression was localized in MS-type lesions and reactive astrocytes and other activated immune cells.

Cantó said these latter results suggested that elevations in the marker "reflect the degree of astrocyte activation secondary to inflammation."

Both studies had no commercial funding. Quidel provided assays for CHI3L1 but otherwise played no role in the study by Cantó and colleagues.

Martinelli reported relationships with Biogen Dompe, Merck Serono, Bayer Schering, Teva, and Sanofi. Other investigators in his study had relationships with these firms and Genmab.

Cantó reported no conflicts of interest. Other investigators in her study reported relationships with Bayer Schering, Merck Serono, Biogen Idec, Teva, Sanofi, Novartis, Roche, Elan, Genmab, UCB, Wyeth, and others.

Primary source: European Committee for Treatment and Research in Multiple Sclerosis
Source reference: Martinelli V, et al. "Predicting early conversion to multiple sclerosis in patients with clinically isolated syndromes: the importance of an integrated modeling of risk factors" ECTRIMS 2013; Abstract 155.

Additional source: European Committee for Treatment and Research in Multiple Sclerosis
Source reference:Canto E, et al. "Validation of cerebrospinal fluid chitinase 3-like 1 as a prognostic biomarker of conversion to multiple sclerosis and disease severity in patients with clinically isolated syndromes" ECTRIMS 2013; Abstract 156.

Source: MedPage Today © 2013 MedPage Today, LLC (07/10/13)