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Neuroimaging study sheds light on mechanisms of cognitive fatigue in MS(04/11/13)

A new study by Kessler Foundation scientists sheds light on the mechanisms underlying cognitive fatigue in individuals with multiple sclerosis. Cognitive fatigue is fatigue resulting from mental work rather than from physical labor. Genova H et al: Examination of cognitive fatigue in multiple sclerosis using functional magnetic resonance imaging and diffusion tensor imaging" was published on Nov. 1 in PlosOne. This is the first study to use neuroimaging to investigate aspects of cognitive fatigue. The study was funded by grants from the National MS Society and Kessler Foundation.

The study investigated the neural correlates of cognitive fatigue in MS utilizing three neuroimaging approaches: functional magnetic resonance imaging (fMRI), which allows researchers to look at where in the brain activation is associated with a task or an experience; diffusion tensor imaging (DTI), which allows researchers to look at the health of the brain's white matter; and voxel-based morphometry (VBM), which allows researchers to investigate structural changes in the brain. These three approaches were used to examine how likely it is for an individual to report fatigue ("trait" fatigue), as well as the fatigue an individual feels in the moment ("state" fatigue). This study is the first to use neuroimaging to investigate these two, separable aspects of fatigue.

"We looked specifically at the relationship between individuals 'self-reported fatigue and objective measures of cognitive fatigue using state-of-the-art neuroimaging," explained Helen M. Genova, Ph.D., research scientist in Neuropsychology & Neuroscience Research at Kessler Foundation. "The importance of this work lies in the fact that it demonstrates that the subjective feeling of fatigue can be related to brain activation in specific brain regions. This provides us with an objective measure of fatigue, which will have incalculable value as we begin to test interventions designed to alleviate fatigue."

In Experiment 1, patients were scanned during performance of a task designed to induce cognitive fatigue. Investigators looked at the brain activation associated with "state" fatigue. In Experiment 2, DTI was used to examine where in the brain white matter damage correlated with increased "trait" fatigue in individuals with MS, as assessed by the Fatigue Severity Scale (FSS). The findings of Experiments 1 and 2 support the role of a striato-thalamic-frontal cortical system in fatigue, suggesting a "fatigue-network" in MS.

"Identifying a network of fatigue-related brain regions could reframe the current construct of cognitive fatigue and help define the pathophysiology of this multifaceted yet elusive symptom of MS," said John DeLuca, Ph.D., VP of Research & Training at Kessler Foundation. "Replication of these findings with larger sample sizes will be an important next step."

Source: Science Codex (04/11/13)

New imaging test could diagnose MS(03/10/13)

A brand new biomarker that helps visualize multiple sclerosis could one day do for MS what Amyvid has done for Alzheimer's disease.

Associate professor of radiology, chemistry, and biomedical engineering Yanming Wang and his team at Case Western Reserve University developed the biomarker to fill a void in the market.

Physicians currently lack an imaging technique that detects and quantifies myelin sheath damage in the central nervous system — one of the key symptoms of the disease. Myelin damage disrupts nerve signals, resulting in mobility and cognitive dysfunction.

Though MRI can detect brain lesions associated with MS, the lesions could also indicate other unrelated conditions such as edema or inflammation. Doctors rely primarily on behavioral tests to diagnose people with MS.

Multiple sclerosis is the second most common neurodegenerative disease after Alzheimer's.

Experts estimate that between 250,000 to 350,000 people in the United States suffer from the disease. Unlike Alzheimer's, the disease affects young people as well.

Since PET is particularly suited to highlight intact myelin, over the past 10 years researchers have attempted to develop a PET tracer that can visualize myelin damage. With the biotracer, doctors can measure how much myelin remains intact and how much is damaged — an industry first.

Researchers were interested to note that myelin was particularly good for imaging the myelin sheath in the spinal cord — a notoriously hard organ to image.

The test can be used to monitor the progression of the disease over time. But could the scan also be used for diagnosis? "If you have a cohort of patients [cpmprising] normal, healthy subjects, you can get the average outtake and use that as a guideline," Wang said.

In the future, Wang sees two major applications for the probe.

One is to aid researchers in developing a drug to treat MS. Currently MS is treated with symptom-modifying therapy, but to really cure the disease, researchers need an imaging tool that allows them to develop a drug that repairs myelin.

The tool could also potentially be used to monitor the progression of the disease in high-risk individuals so that doctors can treat them before they develop symptoms. "Early treatment is key to treating the disease efficiently," said Wang.

PET is a widely used imaging technique, but its uses are currently limited due to a lack of probes. "This is another step forward to enhance the potential to use PET in routine clinical settings," said Wang.

Researchers are currently initiating clinical trials to get the ball rolling on making the probe available for wider use.

Source: DOTmed Daily News Copyright ©2001-2013 DOTmed.com, Inc (03/10/13)

Brain atrophy can precede MS symptoms(03/10/13)

Patients with radiological signs of multiple sclerosis, even before showing MS-specific symptoms, already had significant brain atrophy relative to healthy controls, a researcher said here.

Mean normalized total brain volume in 12 patients with "radiologically isolated syndrome" (RIS) -- MS-like brain lesions in patients who have not experienced a clear MS-like clinical attack -- was measured via MRI scans at 1.53 L (SD 0.07), compared with 1.64 L (SD 0.03) in 29 neurologically healthy individuals (P=0.003), reported Juan Ignacio Rojas, MD, of Hospital Italiano in Buenos Aires, Argentina.

Gray matter volume after normalization was also significantly lower in the RIS patients relative to controls, with means of 0.56 L (SD 0.07) versus 0.71 L (SD 0.08) and a P value of 0.003 for the difference, Rojas told attendees at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) annual meeting.

Both brain volume measures in RIS patients were very similar to those found in a third group of 43 patients with clinically isolated syndrome (CIS), the diagnosis for individuals who have recently experienced a first MS-like attack. Patients must have a second attack or show progressive symptoms to receive a diagnosis of clinically definite MS.

Rojas said that measurements of brain volume "might be a useful tool to identify RIS subjects that might be at risk of developing MS," and who therefore could benefit from early treatment with disease-modifying MS agents.

Further analysis of the 12 RIS patients indicated that 42% were eventually diagnosed with CIS, after a mean of 33 months of follow-up, according to an abstract to be presented later in the ECTRIMS meeting.

Because RIS is defined as lacking clear MS-like symptoms, it is identified only as an incidental finding from MRI scans conducted in patients with nonspecific clinical presentations. Among the 12 patients included in the study, six had undergone scans because of unexplained headache, four because of minor trauma, and two because of anxiety, Rojas explained.

But although the lesions in RIS strongly resemble those seen with CIS and full-blown MS, that does not guarantee that the condition always represents a prodromal form of MS. RIS has only been recognized since 2008 and much remains unknown about its relationship to MS, he said.

Approximately half of all three groups in the study were women. Mean age in the RIS patients was 30 (SD 5.4); it was 34 in both the healthy controls and CIS patients (SD 9 and SD 7, respectively).

The MRI measurements in the study also included normalized white matter volume. The means for this parameter were also lower in the RIS and CIS patients relative to controls, but the differences failed to reach statistical significance. Most of the increased atrophy in the RIS group relative to controls was concentrated in the gray matter, Rojas concluded.

None of the slight differences between the RIS and CIS groups approached statistical significance, he reported.

The study was supported by Genzyme.

Ignacio Rojas reported honoraria from Novartis. Other investigators reported relationships with Novartis, Merck Serono, Biogen Idec, Genzyme, and Bayer.

Primary source: European Committee for Treatment and Research in Multiple Sclerosis
Source reference: Rojas J, et al "Brain atrophy in radiologically isolated syndrome (RIS)" ECTRIMS 2013; Abstract 62.

Source: Medpage Today © 2013 MedPage Today, LLC (03/10/13)

Breakthrough offers first direct measurement of spinal cord myelin in Multiple Sclerosis(24/09/13)

Real-time imaging technique provides essential molecular picture of protective nerve sheath.

Researchers have made an exciting breakthrough – developing a first-of-its-kind imaging tool to examine myelin damage in multiple sclerosis (MS). An extremely difficult disease to diagnose, the tool will help physicians diagnose patients earlier, monitor the disease’s progression, and evaluate therapy efficacy.

Case Western Reserve University School of Medicine scientists have developed a novel molecular probe detectable by positron emission tomography (PET) imaging. The new molecular marker, MeDAS, offers the first non-invasive visualization of myelin integrity of the entire spinal cord at the same time, as published today in an article in the Annals of Neurology.

“While MS originates in the immune system, the damage occurs to the myelin structure of the central nervous system. Our discovery brings new hope to clinicians who may be able to make an accurate diagnosis and prognosis in as little as a few hours compared to months or even years,” said Yanming Wang, PhD, senior author of study and associate professor of radiology at Case Western Reserve University School of Medicine. “Because of its shape and size, it is particularly difficult to directly detect myelin damage in the spinal cord; this is the first time we have been able to image its function at the molecular level.”

As the most common acquired autoimmune disease currently affecting more than two million people worldwide, MS is characterized by destruction of myelin, the membrane that protects nerves. Once damaged, it inhibits the nerves’ ability to transmit electrical impulses, causing cognitive impairment and mobility dysfunction. So far, there is no cure for MS, therapies are only available that modify the symptoms.

In addition to its role in monitoring the effects of myelin-repair drugs currently under development, the new imaging tool offers a real-time quantitative clinical diagnosis of MS. A long lag exists between the onset of disease, physical symptoms in the patient and diagnosis via behavioral testing and magnetic resonance imaging (MRI). The lesions, or plaques, as detected by a MRI in the brain and spinal cord are not myelin specific and thus poorly associated with a patient’s disease severity or progression. There is an urgent need to find a new imaging marker that correlates with a patient’s pathology.

“This discovery has open the door to develop new drugs that can truly restore nerve function, not just modify the symptoms,” said Robert Miller, PhD, co-author on the study, vice president for research for Case Western Reserve and the Allen C. Holmes Professor of Neurological Diseases at the School of Medicine. “A cure for MS requires both repairing myelin and a tool to measure the mechanism.”

For the past 20 years, Miller’s lab has been working tirelessly to create new myelin-repair therapies that would restore nerve function. Successful translation of new drugs from animal studies to human clinical trials is contingent upon researchers’ ability to measure and evaluate the effectiveness of a therapy.

Created by Wang’s laboratory, the MeDAS molecular probe works like a homing device. Injected into the body intravenously, it is programmed to seek out and bind only to myelin in the central nervous system, i.e., the brain, spinal cord and optic nerves. A positron-emitting radioisotope label on the molecule allows a PET scanner to detect the targets and quantify their intensity and location. The data can then be reconstructed into an image as shown in the article: http://onlinelibrary.wiley.com/doi/10.1002/ana.23965/abstract.

“This is an indispensable tool to help find a new way to treat MS down the road” said Chunying Wu, PhD, first author of the study and instructor of radiology at Case Western Reserve. “It can also be used as a platform technology to unlock the mysteries of other myelin related diseases such as spinal cord injury.”

The Case Western Reserve research team has completed preclinical studies in animals and has begun the process of initiating human trials.

This study was supported by grants from the Department of Defense, National Multiple Sclerosis Society, and the National Institutes of Health.

Source: Health Canal (24/09/13)

Clinical and magnetic resonance imaging predictors of disease progression in MS(22/07/13)

This nine-year follow-up study aimed to identify clinical and/or MRI predictors of long-term progression in a large group of people with MS. 241 people with relapsing remitting MS (RRMS) were included in the study.

The researchers used a fully-automated, operator-independent, multi-parameter segmentation method for the volumetric MRI metrics. Clinical progression was evaluated as defined by conversion from RR to a secondary progressive (SP) disease course, progression of EDSS and time to reach EDSS 4.

The results demonstrated that conversion from RR to SP, progression of EDSS, achievement of EDSS 4 and time to reach EDSS 4 were all predicted by baseline grey matter (GM) volume, and except for progression of EDSS, by baseline EDSS. Therefore, grey matter volume and EDSS are the best long-term predictors of disease progression in people with RRMS with a relatively long and mild disease.

Abstract

OBJECTIVE: The objective of this paper is to identify clinical or magnetic resonance imaging (MRI) predictors of long-term clinical progression in a large cohort of multiple sclerosis (MS) patients.

METHODS: A total of 241 relapsing-remitting (RR) MS patients were included in a nine-year follow-up (FU) study. The reference MRIs were acquired at baseline (BL) as part of a multicenter, cross-sectional, clinical-MRI study. Volumetric MRI metrics were measured by a fully automated, operator-independent, multi-parametric segmentation method. Clinical progression was evaluated as defined by: conversion from RR to secondary progressive (SP) disease course; progression of Expanded Disability Status Scale (EDSS); achievement and time to reach EDSS 4.

RESULTS: We concluded that conversion from RR to SP (OR 0.79; CI 0.7-0.9), progression of EDSS (OR 0.85; CI 0.77-0.93), achievement of EDSS 4 (OR 0.8; CI 0.7-0.9), and time to reach EDSS 4 (HR 0.88; CI 0.82-0.94) were all predicted by BL gray matter (GM) volume and, except for progression of EDSS, by BL EDSS (respectively: (OR 2.88; CI 1.9-4.36), (OR 2.7; CI 1.7-4.2), (HR 3.86; CI 1.94-7.70)).

CONCLUSIONS: BL GM volume and EDSS are the best long-term predictors of disease progression in RRMS patients with a relatively long and mild disease.

Lavorgna L, Bonavita S, Ippolito D, Lanzillo R, Salemi G, Patti F, Valentino P, Coniglio G, Buccafusca M, Paolicelli D, d'Ambrosio A, Bresciamorra V, Savettieri G, Zappia M, Alfano B, Gallo A, Simone I, Tedeschi G.

Source: Mult Scler. 2013 Jul 9 & Pubmed PMID: 23838177 (22/07/13)

Atrophy in key region of brain associated with multiple sclerosis(23/04/13)

Magnetic resonance imaging (MRI) measurements of atrophy in an important area of the brain are an accurate predictor of multiple sclerosis (MS), according to a new study published online in the journal Radiology. According to the researchers, these atrophy measurements offer an improvement over current methods for evaluating patients at risk for MS.

MS develops as the body's immune system attacks and damages myelin, the protective layer of fatty tissue that surrounds nerve cells within the brain and spinal cord. Symptoms include visual disturbances, muscle weakness and trouble with coordination and balance. People with severe cases can lose the ability to speak or walk. Approximately 85 percent of people with MS suffer an initial, short-term neurological episode known as clinically isolated syndrome (CIS). A definitive MS diagnosis is based on a combination of factors, including medical history, neurological exams, development of a second clinical attack and detection of new and enlarging lesions with contrast-enhanced or T2-weighted MRI.

"For some time we've been trying to understand MRI biomarkers that predict MS development from the first onset of the disease," said Robert Zivadinov, M.D., Ph.D., FAAN, from the Buffalo Neuroimaging Analysis Center of the University at Buffalo in Buffalo, N.Y. "In the last couple of years, research has become much more focused on the thalamus."

The thalamus is a structure of gray matter deep within the brain that acts as a kind of relay center for nervous impulses. Recent studies found atrophy of the thalamus in all different MS disease types and detected thalamic volume loss in pediatric MS patients. "Thalamic atrophy may become a hallmark of how we look at the disease and how we develop drugs to treat it," Dr. Zivadinov said. For this study, Dr. Zivadinov and colleagues investigated the association between the development of thalamic atrophy and conversion to clinically definite MS.

"One of the most important reasons for the study was to understand which regions of the brain are most predictive of a second clinical attack," he said. "No one has really looked at this over the long term in a clinical trial." The researchers used contrast-enhanced MRI for initial assessment of 216 CIS patients. They performed follow-up scans at six months, one year and two years. Over two years, 92 of 216 patients, or 42.6 percent, converted to clinically definite MS. Decreases in thalamic volume and increase in lateral ventricle volumes were the only MRI measures independently associated with the development of clinically definite MS.

"First, these results show that atrophy of the thalamus is associated with MS," Dr. Zivadinov said. "Second, they show that thalamic atrophy is a better predictor of clinically definite MS than accumulation of T2-weighted and contrast-enhanced lesions." The findings suggest that measurement of thalamic atrophy and increase in ventricular size may help identify patients at high risk for conversion to clinically definite MS in future clinical trials involving CIS patients. "Thalamic atrophy is an ideal MRI biomarker because it's detectable at very early stage," Dr. Zivadinov said.

"It has very good predictive value, and you will see it used more and more in the future."

The research team continues to follow the study group, with plans to publish results from the four-year follow-up next summer. They are also trying to learn more about the physiology of the thalamic involvement in MS. "The next step is to look at where the lesions develop over two years with respect to the location of the atrophy," Dr. Zivadinov said. "Thalamic atrophy cannot be explained entirely by accumulation of lesions; there must be an independent component that leads to loss of thalamus." MS affects more than 2 million people worldwide, according to the Multiple Sclerosis International Foundation. There is no cure, but early diagnosis and treatment can slow development of the disease.

Source: MedicalXpress © Medical Xpress 2011-2013 (23/04/13)

Early Identification Of Disease Via New MRI Fingerprint Method(18/03/13)

A new method of magnetic resonance imaging (MRI) could routinely spot specific cancers, multiple sclerosis, heart disease and other maladies early, when they're most treatable, researchers at Case Western Reserve University and University Hospitals (UH) Case Medical Center suggest in the journal Nature.

Each body tissue and disease has a unique fingerprint that can be used to quickly diagnose problems, the scientists say.

By using new MRI technologies to scan for different physical properties simultaneously, the team differentiated white matter from gray matter from cerebrospinal fluid in the brain in about 12 seconds, with the promise of doing this much faster in the near future.

The technology has the potential to make an MRI scan standard procedure in annual check-ups, the authors believe. A full-body scan lasting just minutes would provide far more information and require no radiologist to interpret the data, making diagnostics cheap, compared to today's scans, they contend.

"The overall goal is to specifically identify individual tissues and diseases, to hopefully see things and quantify things before they become a problem," said Mark Griswold, a radiology professor at Case Western Reserve School of Medicine and UH Case Medical Center. "But to try to get there, we've had to give up everything we knew about the MRI and start over."

Griswold has been working on this goal with Case Western Reserve's Vikas Gulani, MD, an assistant professor of radiology, and Nicole Seiberlich, assistant professor of biomedical engineering, for a decade. During the last three years, they developed the technology and proved the concept with graduate student Dan Ma; Kecheng Liu, PhD, collaborations manager from Siemens Medical Solutions Inc.; Jeffrey L. Sunshine, MD, professor of radiology and a radiologist at UH Case Medical Center; and Jeffrey L. Duerk, dean of Case School of Engineering and professor of biomedical engineering.

A magnetic resonance imager uses a magnetic field and pulses of radio waves to create images of the body's tissues and structures. Magnetic resonance fingerprinting, MRF for short, can obtain much more information with each measurement than a traditional MRI.

Griswold likens the difference in technologies to a pair of choirs.

"In the traditional MRI, everyone is singing the same song and you can tell who is singing louder, who is off-pitch, who is singing softer," he said. "But that's about it."

The louder, softer and off-pitch singing is represented by dark, light or bright spots in the scan that a radiologist must interpret. For example, an MRI would show swelling as a bright area in an image. But brightness doesn't necessarily equate with severity or cause.

"With an MRF," Griswold said, "we hope that with one step we can tell the severity and exactly what's happening in that area."

The fingerprint of each tissue, each disease and each material inside the body is therefore a different song. In an MRF, each member of the choir sings a different song simultaneously, Griswold said. "What it sounds like in total is a randomized mess."

The researchers generate unique songs by simultaneously varying different parts of the input electromagnetic fields that probe the tissues. These variations make the received signal sensitive to four physical properties that vary from tissue to tissue. These differences - the different notes and lyrics of their songs - become evident when applying pattern recognition programs using the same math in facial recognition software.

The patterns are then charted. Instead of looking at relative measurements from an image, Griswold said quantitative estimates told one tissue from another. As the technology progresses, these results will determine whether tissue is healthy or diseased, how badly and by what.

The scientists believe that they will be able to interrogate a total of eight or nine physical properties which will allow them to elicit the songs from a vast array of tissues, diseases and materials.

For a patient, an MRF would seem like a quick MRI. When the scan is done, all of the patient's songs would be compared with the songbook, which will provide doctors with a suite of diagnostic information.

"If colon cancer is 'Happy Birthday' and we don't hear 'Happy Birthday,' the patient doesn't have colon cancer," Griswold said.

Other researchers have tried to use multiple parameters in MRI's, but this group was able to scan fast and with higher sensitivity than in previous attempts, he continued. "This research gives us hope. We can see that it's possible the MRI can see all sorts of things."

The group expects to reduce scanning time and continue to build the songbook, or library of fingerprints, over the next few years.

Source: Medical News Today © MediLexicon International Ltd 2004-2013 (18/03/13)