Magnetic resonance imaging shows the combined presence of astrogliosis and axonal damage in white matter, which has cardinal importance in multiple sclerosis (MS) severity, according to an article published in JAMA Neurology.
Researchers from the U.S. and Spain performed a study to evaluate the potential of MR markers of central nervous system injury to predict brain-volume loss and clinical disability among patients with MS.
A total of 59 patients with MS and 43 healthy controls participated in the study. There was also a confirmatory data set that included 220 patients from an independent, large genotype-phenotype research project. Participants were assessed annually over four years for outcomes, which were based on baseline N-acetylaspartate (NAA) level, myo-inositol (mI) in normal-appearing white and gray matter, myelin water fraction in normal-appearing white matter, markers of axonal damage, astrogliosis, and demyelination.
The results showed that mI:NAA could be used as a predictor, based on NAA and mI having significant effects on brain volume. “The ratio was a predictor of brain-volume change in both cohorts (annual slope in the percentage of brain-volume change/unit of increase in the ratio: −1.68; 95 percent CI, −3.05 to −0.30; P = .02 in the preliminary study cohort and −1.08; 95 percent CI, −1.95 to −0.20; P = .02 in the confirmatory study cohort),” the authors wrote.
The mI:NAA ratio predicted clinical disability in the preliminary data set as well, they noted. Also predicted were Multiple Sclerosis Functional Composite evolution, Expanded Disability Status Scale evolution, and Expanded Disability Status Scale sustained progression in the confirmatory data set. However, there was no predictive value shown with myelin water fraction.
The authors concluded that “the mI:NAA ratio in normal-appearing white matter has consistent predictive power on brain atrophy and neurological disability evolution. The combined presence of astrogliosis and axonal damage in white matter has cardinal importance in disease severity.”
Source: Diagnostic Imaging © 1996 – 2014 UBM Medica, LLC (16/07/14)
Sub-Millimeter Imaging of Brain-Free Water for Rapid Volume Assessment in Atrophic Brains.
Gao KC, Nair G, Cortese IC, Koretsky A, Reich DS.
INTRODUCTION: Cerebral atrophy occurs in healthy aging, and in disease processes such as multiple sclerosis (MS), it correlates with disability accumulation. Imaging measurements of brain atrophy are commonly based on tissue segmentation, which is susceptible to classification errors and inconsistencies. High-resolution imaging techniques with strong contrast between brain parenchyma and cerebrospinal fluid (CSF) might allow fully automated, rapid, threshold-based determination of the free water in the brain. We hypothesized that total brain-free-water (BFW) volume and BFW volume expressed as a normalized fraction of the intracranial volume ("BFW fraction"), determined from heavily T2-weighted images, would be useful surrogates for cerebral atrophy and therefore would correlate with clinical measures of disability in MS.
METHODS: Whole brains of 83 MS cases and 7 healthy volunteers were imaged with a 4.7-min, heavily T2-weighted sequence on a 3T MRI scanner, acquiring 650-μm isotropic voxels. MS cases were clinically assessed on Expanded Disability Status Scale (EDSS), Scripps Neurological Rating Scale (SNRS), Paced Auditory Serial Addition Test (PASAT), 9-Hole Peg Test (9HP), Symbol Digit Modalities Test (SDMT), and 25-Foot Walk. Twelve of the MS cases were rescanned within an average of 1.8months to assess reproducibility. Automated calculations of BFW volume and BFW fraction were correlated with clinical measures of disability upon adjusting for age and sex. Results were compared to data from T1-based approaches (SIENAX and Lesion-TOADS).
RESULTS AND DISCUSSION: BFW volume was automatically derived from heavily T2-weighted images with no need for separate skull stripping. BFW volume and fraction had mean scan-rescan coefficients of variation of 1.5% and 1.9%, respectively, similar to the T1-based approaches tested here. BFW fraction more strongly correlated with clinical measures than T1-derived results. Among those clinical measures, modality-specific disability scores, such as SDMT and 9HPT, were more strongly associated with BFW fraction than composite measures, such as EDSS and SNRS.
CONCLUSION: The BFW method robustly estimates cerebral atrophy in an automated, fast, and reliable manner, and as such may prove a useful addition to imaging protocols for clinical practice and trials.
Sources: Neuroimage. 2014 Jun 16. pii: S1053-8119(14)00491-1. doi: 10.1016/j.neuroimage.2014.06.014. [Epub ahead of print] & Pubmed PMID: 24945671 (23/06/14)
Magnetic resonance imaging (MRI) can predict responses to depression treatment in patients with multiple sclerosis (MS), according to Anthony Feinstein, Professor at the Department of Psychiatry of the Sunnybrook Health Sciences Centre & the University of Toronto. In the presentation “Depression in MS: Is brain imaging helpful?” at this year’s 2014 CMSC ACTRIMS Annual Meeting in Dallas, the researcher argued that continuing to image and document brain function will help in the diagnosis and treatment of depression associated with the disease.
Feinstein believes that imaging the brain enables clinicians “to appreciate the structural brain changes” that occur in depressed MS patients in order to study the links between these changes and alterations in mood. In addition to improving diagnosis and treatment by observing lesion changes in the brain over time, Feinstein also stated the importance of MRI in determining “how the structural brain changes linked to depression differ from those seen in pseudobulbar affect.”
The pseudobulbar affect is a neurologic disorder characterized by involuntary and uncontrolled episodes of crying, without sadness, or laughing, without happiness. Although it affects up to 10% of MS patients, imaging the variance and location of the lesions in the brain can determine the pattern of the affect. The lifetime prevalence of the disease in patients with MS may be as high as 50 percent. During the annual meeting, Dr. Feinstein presented a study that analysed 115,071 Canadians that revealed a 12-month prevalence of depression in MS patients higher that in healthy subjects. Between the ages of 18 and 45 years old, the 12 month prevalence was 25.7%. Moreover, the rates have increased in relation to other neurological disorders.
“Feeling depressed mood most of the day, markedly diminished interest or pleasure in all activities, appetite change with significant weight loss or gain, psychomotor agitation or retardation, fatigue or loss of energy nearly every day, worthlessness, excessive, inappropriate guilt, having insomnia or hypersomnia nearly every day, diminished ability to think or concentrate or recurrent thoughts of death five or more times during the same two week period” may be evidence of depression, according to Dr. Feinstein.
Dr. Feinstein believes that adequately managing depression in disorders like MS cannot be overstated, since it not only impacts the clinical condition of the patient, but also the quality of life and cognitive function. A quarter of MS patients contemplate suicide, and the major factors for it include depression, social isolation, and alcohol abuse.
A new automated imaging technique was recently successfully used in a trial with women who suffered both from MS and depression. The study, led by Cedars-Sinai neurologist Nancy Sicotte‘s multicenter research team, was able to identify shrinkage of a mood-regulating brain structure. The results revealed that patients with MS and symptoms of “depressive affect” – such as depressed mood and loss of interest — feature a reduced size of the right hippocampus.
At the University of Calgary’s Hotchkiss Brain Institute, new techniques are also being studied to improve diagnosis and treatment using MRI by sensing small changes in patterns of the MS patients’ brains. Using an algorithm, the researchers hope to find a parameter called MRI texture heterogeneity and clearly identify patterns and changes in the tissue.
Source: Multiple Sclerosis News Today © Copyright 2014 BioNews Services, LLC (17/06/14)
What if an MRI scan could detect damage caused by Multiple Sclerosis at an early stage?
Researchers at Western University have developed a way to better track MS progression in patients by looking at damage in brain areas common to all MS patients.
The technique is called Quantitative Susceptibility Magnetic Resonance Imaging (MRI).
While MRI scans are a vital part of diagnosing Multiple Sclerosis, they are often not conclusive until a patient is relatively late in the progression of the disease. However, the brain changes long before symptoms begin.
MRIs are able to detect spots on the brain, but using Quantitative Susceptibility MRI data, doctors can see damage areas of the brain that otherwise would go unnoticed until symptoms were farther advanced.
Currently a standard MRI will detect lesions in the brain but, until now, there was no correlation between lesions and the extent of a patient's disability. While lesions can appear or disappear over time, the damage caused is still apparent in QS image testing even after the patient's first episode.
Research leader at UWO, Ravi Menon, noted the changes are subtle – on the parts per billion level – but by using QS they are able to measure when tissues begin to degenerate or as iron accumulates in the brain. Iron accumulation happens naturally as a person ages, however, Menon explained that for an MS patient, they have levels that are likened to that of a person three years older.
Early detection and treatment can stop or slow down the disease.
Menon said if every current MS patient were diagnosed early and treated with low doses of prescription drugs the number of cases would drop four to five fold. He estimated about $100 billion dollars would be saved in drug costs alone.
The next stage, he said, is to have QS work on a single subject.
The university is equipped with a 7T MRI machine – the only one in Canada - but the tests were performed on the less sensitive 3T machine, meaning they can be reproduced in any hospital in the country.
That, Menon said, is a sign of hope.
The QS test group consisted of 25 patients with recurring or remitted MS or clinically isolated syndrome, which leads to the disease, as well as 15 age and sex-matched participants. The QS mapping showed the same damage areas in brains of all MS patients.
The progression of Multiple Sclerosis is measured using an Extended Disability Status Score, and QS results from the MS patients correlated to individual scores very well.
The diagnostic benefits of QS imaging has great potential, as some patients have to wait between six months to twenty years for their MS to become apparent.
For those with low disability scores or those who have not been diagnosed, the difference is life-changing. The wait, Menon said, is the hardest part for many patients. Early detection and treatment of MS can save much heartache for patients waiting on diagnosis, as well as save lives and long term healthcare costs.
Source: thelondoner.ca © 2014 Londoner (10/06/14)
Mean upper cervical cord area (MUCCA) measurement in long-standing multiple sclerosis: Relation to brain findings and clinical disability.
BACKGROUND: The majority of patients with multiple sclerosis (MS) present with spinal cord pathology. Spinal cord atrophy is thought to be a marker of disease severity, but in long-disease duration its relation to brain pathology and clinical disability is largely unknown.
OBJECTIVE:Our aim was to investigate mean upper cervical cord area (MUCCA) in patients with long-standing MS and assess its relation to brain magnetic resonance imaging (MRI) measures and clinical disability.
METHODS: MUCCA was measured in 196 MS patients and 55 healthy controls using 3DT1-weighted cervical images obtained at 3T MRI. Clinical disability was measured using the Expanded Disability Status Scale (EDSS), Nine-Hole-Peg test (9-HPT), and 25 feet Timed Walk Test (TWT). Stepwise linear regression was performed to assess the association between MUCCA and MRI measures, and between MUCCA and clinical disability.
RESULTS: MUCCA was smaller (mean 11.7%) in MS patients compared with healthy controls (72.56±9.82 and 82.24±7.80 mm2 respectively; p<0.001), most prominently in male patients. MUCCA was associated with normalized brain volume, and number of cervical cord lesions. MUCCA was independently associated with EDSS, TWT, and 9-HPT.
CONCLUSION: MUCCA was reduced in MS patients compared with healthy controls. It provides a relevant marker for clinical disability in long-standing disease, independent of other MRI measures.
Daams M, Weiler F, Steenwijk MD, Hahn HK, Geurts JJ, Vrenken H, van Schijndel RA, Balk LJ, Tewarie PK, Tillema JM, Killestein J, Uitdehaag BM, Barkhof F.
Source: Mult Scler. 2014 May 8. [Epub ahead of print] & Pubmed PMID: 24812042 (12/05/14)
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)
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)
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.
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)