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    You are here : Home » MS Research News » New Discoveries » Brain Atrophy, Lesion Loads, White and Grey Matter

    Brain Atrophy, Lesion Loads, White and Grey Matter

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    Multiple sclerosis often starts in brain’s outer layers

    MS MRIMultiple sclerosis (MS) may progress from the outermost layers of the brain to its deep parts, and isn’t always an “inside-out” process as previously thought, reported a new collaborative study from researchers at the Mayo Clinic and the Cleveland Clinic.

    The traditional understanding is that the disease begins in the white matter that forms the bulk of the brain’s inside, and extends to involve the brain’s superficial layers, the cortex. Study findings support an opposite, outside-in process: from the cerebrospinal fluid-filled subarachnoid space, that cushions the outside of the brain and the cortex, into the white matter. The new findings will guide researchers as they seek to further understand and treat the disease.

    The study was published in the New England Journal of Medicine in December, 2011.

    Researchers do not know precisely what causes MS, but it is thought to be an autoimmune disease in which the body’s immune system attacks and destroys its own myelin. This fatty substance surrounds and protects axons, nerve cell projections that carry information, and its damage slows down or blocks messages between the brain and body, leading to MS symptoms, which can include blindness, numbness, paralysis, and thinking and memory problems.

    “Our study shows the cortex is involved early in MS and may even be the initial target of disease,” says Claudia F. Lucchinetti, M.D., co-lead author of the study and Mayo Clinic neurologist. “Inflammation in the cortex must be considered when investigating the causes and progression of MS,” she says.

    Study authors say current therapeutic options may not even address issues associated with the cortex. Understanding how the cortex is involved, therefore, is critical to creating new therapies for MS. “Measures of cortical damage will enhance enormously the power of clinical trials to determine if new medications address tissue changes of MS in all regions of the brain,” says co-lead author Richard Ransohoff, M.D., a Cleveland Clinic neurologist.

    These measures are important because disease accumulates in the cortex over time, and inflammation in the cortex is a sign the disease has progressed.

    The research is distinct because it studied brain tissues from patients in the earliest stages of MS. “What’s unique about the study is, and the reason the National MS Society funded this international team of researchers, is that it offers a rare view of MS early in the disease,” says Timothy Coetzee, Ph.D., Chief Research Officer at the National Multiple Sclerosis Society. “Collaborative studies like this, that deepen our understanding of the sequence of nervous system-damaging events, should offer new opportunities for stopping MS disease progression and improving quality of life for people with MS.”

    The findings support the understanding that MS is primarily a disease of inflammation, not neurodegeneration, as some studies have recently suggested. Co-lead authors Drs. Lucchinetti and Ransohoff conclude that it is “overwhelmingly likely” that MS is fundamentally an inflammatory disease, and not a neurodegenerative Alzheimer-like disease.

    How They Did It The research did not at first focus on the ‘outside-in’ question, says Dr. Lucchinetti. Instead, the team initially wondered what tissue changes in the cortex of MS patients gave rise to indicators of cortical damage. For the last several years, researchers knew from MRI studies that the cortex was damaged very early after onset of MS, and they knew from autopsy studies that the cortex was demyelinated, as was white matter. What researchers were unable to determine, until completion of the present study, was whether findings at autopsy (usually after 30-50 years of disease) accurately reflected the indicators of cortical damage from MRI images taken after only a few months of disease. In autopsy MS tissues, cortical lesions show demyelination, but without inflammation-raising the possibility that MS cortex degenerates due to intrinsic tissue defects. Such a process would not be treatable by current MS therapies and could not be explained by present concepts of the causes of MS.

    Drs. Lucchinetti and Ransohoff determined to see if early-MS cortical lesions were, or were not, inflammatory. To do so, they studied the Mayo resource of white-matter biopsies taken largely from patients with suspected tumors, but eventually proving to have MS. About one-fourth of the biopsies also included tiny fragments of cortex, which formed the focus of study. The primary question was quickly answered: cortical demyelinating lesions of early-MS patients resembled those found at autopsy in every way but one — the early lesions were highly inflammatory. These findings were reassuring because they indicated that treatments targeting inflammation in the disease may ameliorate MS effects on both the cortex as well as the white matter.

    While investigating the cortical changes in the biopsies, researchers were struck by the high frequency of cortical demyelinating lesions. Furthermore, in the white matter biopsies, which contained miniscule cortical fragments, about 20% showed inflammatory demyelination was contained entirely in the cortex.

    Researchers also noted inflammation was present in the meninges, the protective membranes that cover the surface of the brain and demarcate the subarachnoid space. Meningeal inflammation and cortical demyelination were highly-associated. Looking at implications of their data, Drs. Lucchinetti and Ransohoff could weave together a proposed pathway for lesion initiation, along with known experimental data from MS animal models, and term this pathway the “outside-in” theory. The research findings also lend urgency to efforts to use MRI to “see” more deeply into the cortical lesions of MS, particularly given that cortical damage is an important correlate of progressive disability and cognitive dysfunction in MS.

    This study was funded by the National MS Society’s MS Lesion Project, led by Dr. Lucchinetti, as well as the National Institutes of Health.

    Other Mayo Clinic study authors include: Bogdan Popescu, M.D.; Reem Bunyan, M.D.; Shanu Roemer, M.D.; Joseph Parisi, M.D.; Bernd Scheithauer, M.D.; Caterina Giannini, M.D.; Stephen Weigand, M.S.; Jay Mandrekar, Ph.D.

    Additional authors included Hans Lassmann, M.D. from the Center for Brain Research, Medical University of Vienna, Austria; Wolfgang Bruck, M.D. from the Department of Neuropathology, University Medical Center and Institute for MS Research in Gottingen, Germany; and Natalia Moll, M.D, Ph.D. from the Neuroinflammation Research Center and Department of Neurosciences Lerner Research Institute, Cleveland Clinic.

    Source: H H & S © 2011 Human Health and Science. (08/12/11)

    Cortical demyelination, inflammation found in early MS

    MyelinCortical demyelination is common early in the course of multiple sclerosis and is inflammatory in nature, according to an analysis of brain biopsy samples containing cortical tissue.

    "These findings do not support a primary (noninflammatory) neurodegenerative process during early-stage multiple sclerosis," Dr. Claudia F. Lucchinetti of the Mayo Clinic, Rochester, Minn., and her associates wrote in the Dec. 8 issue of the New England Journal of Medicine.

    Most previous studies of cortical lesions have focused on autopsy findings in patients with longstanding multiple sclerosis and "have suggested that neurodegeneration proceeds independently of parenchymal inflammation," the investigators noted.

    They chose instead to study the prevalence and histopathologic features of cortical demyelination in brain biopsy samples from 563 patients who underwent the procedure to rule out other possible causes of their neurological symptoms, such as brain tumors. The cortical matter was obtained "in passing," in samples that were targeting white-matter lesions. The samples were obtained within a median of 27 days from the onset of symptoms.

    A total of 138 patients’ samples contained a sufficient amount of cortex for analysis. Of these 138 patients, 77 had clinical follow-up for a median of 3.5 years. MS was eventually diagnosed in 58 (75%), and a clinically isolated syndrome was diagnosed in the remaining 19 (25%).

    In all, 53 of the 138 samples (38%) showed cortical demyelination, Dr. Lucchinetti and her colleagues reported (N. Engl. J. Med. 2011;365:2188-97).

    The lesions were highly inflammatory and had a high prevalence of CD3-positive and CD8-positive T-cell infiltrates as well as myelin-laden macrophages.

    In addition, among patients who had sufficient meningeal tissue for analysis, meningeal inflammation was topographically adjacent to the cortical demyelination.

    The researchers also found concurrent subpial and leukocortical lesions within individual tissue sections, "suggesting that superficial demyelinating disease may contribute to the generation of deeper lesions by means of cytokine diffusion."

    In addition, "our findings of microglial activation, neuritic injury, pyknotic neurons, and reduced oligodendrocyte density ... are consonant with the findings in patients with progressive MS, underscoring the potential of cortical demyelination to cause irreversible injury, although inflammation may resolve rapidly."

    They speculated that the mechanism of MS progression might involve "myelin-laden macrophages leaving the cortex, entering the cerebrospinal fluid, and gaining access to deep cervical lymph nodes to promote epitope spreading."

    This study was supported by the National Multiple Sclerosis Society and the National Institutes of Health. Dr. Lucchinetti’s associates reported ties to numerous companies that market and develop drugs for MS, as well as receiving research funding or travel awards from research institutions or patient advocacy organizations.

    View on the News

    First Definitive Evidence

    The "provocative" findings of Dr. Lucchinetti and her colleagues "provide definitive evidence that inflammatory disease of the gray matter commences early in the pathogenesis of some cases of multiple sclerosis," wrote Dr. Peter A. Calabresi.

    Before now, macrophages laden with myelin – the hallmark of an active plaque – have not been seen in cortical tissue, and gray-matter lesions have been "routinely underestimated" because conventional MRI doesn’t pick up MS plaques in the cortical and deep gray structures, he said.

    This study suggests that cortical neuronal loss "is directly associated with inflammatory demyelination, and therefore early therapeutic efforts to suppress inflammation may be neuroprotective in both gray-matter and white-matter compartments," Dr. Calabresi added.

    Dr. Calabresi is in the department of neurology at Johns Hopkins Hospital, Baltimore. He reported ties to numerous companies that market and develop drugs for MS. These remarks were adapted from his editorial comment accompanying Dr. Lucchinetti’s report (N. Engl. J. Med. 2011;365:2231-3).

    Source: Clinical Psychiatry News Copyright © 2011 International Medical News Group, LLC (08/12/11)

    Early central atrophy rate predicts 5 year clinical outcome in MS


    MS MRIObjective: To examine the predictive value of central atrophy in early multiple sclerosis (MS) patients, for medium term clinical outcome.

    Methods: In 54 patients with recently diagnosed MS, clinical and MRI parameters were obtained at baseline, and after 2 and 5.5 years of follow-up.

    In addition to conventional MRI parameters and the annualised percentage brain volume change (aPBVC), the annualised percentage ventricular volume change (aPVVC) was quantified. Main outcome measure was disease progression, defined by an increase in Expanded Disability Status Scale of ≥1 after 5.5 years.

    Results: Disease progression occurred in 29 patients. aPVVC within the first two years was significantly higher in these progressing patients (median 4.76%; IQR 3.05-9.17) compared with stable patients (median 3.23%; IQR -0.1-6.02) (p=0.02).

    A logistic regression model selected aPVVC within the first 2 years as the only MRI marker predicting progression after 5.5 years (OR 1.17, 95% CI 1.02 to 1.35). When entering all MRI and clinical markers, again aPVVC within the first 2 years was the only MRI marker selected. While aPVVC was correlated between the two consecutive time intervals (ρ=0.41, p<0.01), aPBVC was not.

    Furthermore, baseline T2 lesion load and gadolinium enhancing lesion load were correlated with aPVVC in the second time interval (2-5.5 years) but not with aPBVC.

    Conclusion: The rate of ventricular enlargement seems to be even more strongly predictive of disease progression after medium term follow-up than whole brain atrophy rate, and also outperforms lesion measures. Central atrophy rate could therefore be an important prognostic marker, especially in the early stages of MS.

    Authors: Lukas C, Minneboo A, de Groot V, Moraal B, Knol DL, Polman CH, Barkhof F, Vrenken H

    Source J Neurol Neurosurg Psychiatry. 2010 Sep 8 & Pubmed PMID: 20826873 (13/09/10)

    T2 lesion location really matters: a 10 year follow-up study in PPMS

    MS MRIAbstract
    Objectives: Prediction of long term clinical outcome in patients with primary progressive multiple sclerosis (PPMS) using imaging has important clinical implications, but remains challenging.

    We aimed to determine whether spatial location of T2 and T1 brain lesions predicts clinical progression during a 10-year follow-up in PPMS.

    Methods: Lesion probability maps of the T2 and T1 brain lesions were generated using the baseline scans of 80 patients with PPMS who were clinically assessed at baseline and then after 1, 2, 5 and 10 years. For each patient, the time (in years) taken before bilateral support was required to walk (time to event (TTE)) was used as a measure of progression rate. The probability of each voxel being 'lesional' was correlated with TTE, adjusting for age, gender, disease duration, centre and spinal cord cross sectional area, using a multiple linear regression model. To identify the best, independent predictor of progression, a Cox regression model was used.

    Results: A significant correlation between a shorter TTE and a higher probability of a voxel being lesional on T2 scans was found in the bilateral corticospinal tract and superior longitudinal fasciculus, and in the right inferior fronto-occipital fasciculus (p<0.05). The best predictor of progression rate was the T2 lesion load measured along the right inferior fronto-occipital fasciculus (p=0.016, hazard ratio 1.00652, 95% CI 1.00121 to 1.01186).

    Conclusion: Our results suggest that the location of T2 brain lesions in the motor and associative tracts is an important contributor to the progression of disability in PPMS, and is independent of spinal cord involvement.

    Bodini B, Battaglini M, De Stefano N, Khaleeli Z, Barkhof F, Chard D, Filippi M, Montalban X, Polman C, Rovaris M, Rovira A, Samson R, Miller D, Thompson A, Ciccarelli O.

    Department of Brain Repair and Rehabilitation, Institute of Neurology, University College London, London, UK.

    Source: J Neurol Neurosurg Psychiatry. 2010 Jul 13. & Pubmed PMID: 20627965 (21/07/10)

    Reduced creatine kinase B activity in MS normal appearing white matter


    Two studies using 31P-magnetic resonance spectroscopy (MRS) reported enhanced phosphocreatine (PCr) levels in normal appearing white matter (NAWM) of subjects with multiple sclerosis (MS), but this finding could not be properly explained.

    Methodology/Principal Findings
    We performed 31P-MRS and 1H-MRS in the NAWM in 36 subjects, including 17 with progressive MS, 9 with benign MS, and 10 healthy controls. Compared to controls, PCr/β-ATP and PCr/total 31P ratios were significantly increased in subjects with progressive MS, but not with benign MS. There was no correlation between PCr ratios and the N-acetylaspartate/creatine ratio, suggesting that elevated PCr levels in NAWM were not secondary to axonal loss. In the central nervous system, PCr is degraded by creatine kinase B (CK-B), which in the white matter is confined to astrocytes. In homogenates of NAWM from 10 subjects with progressive MS and 10 controls without central nervous system disease, we measured CK-B levels with an ELISA, and measured its activity with an enzymatic assay kit. Compared to controls, both CK-B levels and activity were decreased in subjects with MS (22.41 versus 46.28 µg/ml; p = 0.0007, and 2.89 versus 7.76 U/l; p<0.0001).

    Our results suggest that PCr metabolism in the NAWM in MS is impaired due to decreased CK-B levels. Our findings raise the possibility that a defective PCr metabolism in astrocytes might contribute to the degeneration of oligodendrocytes and axons in MS.

    Christel Steen1, Nadine Wilczak1, Johannes M. Hoogduin2,3, Marcus Koch1, Jacques De Keyser1,4

    1 Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands, 2 Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands, 3 BCN-Neuroimaging Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands, 4 Department of Neurology, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium

    Source: PLOS One  (31/05/10)

    Mayo Clinic research provides new insight into tissue damage in Multiple Sclerosis

    Multiple Sclerosis MRIA new Mayo Clinic study has found that the type of tissue damage changes throughout the course of multiple sclerosis (MS).

    In early relapsing disease stages, the plaques, or areas where the nervous system is inflamed or demyelinated, are predominantly active with distinct heterogeneous patterns of myelin damage. Later in the chronic progressive phase of the disease, smoldering and inactive plaques predominate, and are characterized by a uniform pattern of tissue damage.

    The study's findings provide important information at the microscopic level regarding the dynamic changes occurring in MS white matter plaques over the course of the disease that can help inform subsequent studies that characterize the disease based on advanced imaging techniques or clinical outcomes.

    According to Mayo Clinic researchers, a better understanding of the pathology of MS may eventually lead to new therapeutic targets. This study will be presented at the American Academy of Neurology Annual Meeting in Toronto on April 14.

    Mayo Clinic provides care for nearly 2,500 patients with MS each year. MS is a disease of the central nervous system that includes the brain, spinal cord and optic nerves. MS is called a demyelinating disease because it results from damage to myelin, the insulating covering of nerve fibers. It occurs most commonly in those between the ages of 20 and 40, and is the most common cause of non-traumatic neurological disability in young adults in North America and Europe. Approximately 330,000 people in the United States have MS. Symptoms include loss of muscle coordination, strength, vision, balance and cognition.

    "We have pretty good therapies to treat and reduce the frequency of relapses in MS, but as the disease progresses and the relapses become less frequent, we need to better understand the biologic basis for that progression," says Claudia Lucchinetti, M.D., a Mayo Clinic neurologist and author of this study. "This study showed us that smoldering MS plaques are more commonly found during progressive disease phases. These plaques, unlike active MS plaques, show a limited degree of ongoing demyelination that occurs at the expanding plaque border of an established MS lesion, and are characterized by a uniform pattern of myelin damage. By studying these plaques and attempting to understand the key mechanisms involved in their formation, we can begin thinking of alternative therapies that might better target the processes that contribute to disease progression."

    Dr. Lucchinetti and a team of Mayo Clinic researchers and collaborators studied tissue from the autopsies of 143 individuals with multiple sclerosis. The tissue was analyzed and 2,479 plaques were classified as active (new lesion in which myelin is being stripped), smoldering (limited degree of ongoing myelin damage in an established plaque), inactive (no evidence for ongoing myelin breakdown) or shadow (evidence of remyelination). The team found that the tissue damage changes over the duration of disease. Early in the disease when relapses are common, numerous active plaques with distinct heterogeneous patterns were readily identified. This study confirms data in previous Mayo Clinic studies that found distinct, heterogeneous patterns in which white matter plaques are formed, and that the pattern is similar among all active plaques in a given patient.

    According to Dr. Lucchinetti, these active plaques likely represent the pathologic basis of clinical relapses in MS, and are thought to reflect distinct immune mechanisms of demyelination operating in different subgroups of MS patients. The findings suggest therapies that target MS relapses need to be individualized in order to address the heterogeneity in plaque formation observed early in the disease, however, as the disease progresses, these diverse patterns are less commonly found, given the rarity of active plaques in later disease stages, she explains.

    According to Dr. Lucchinetti, there is a very low likelihood of having any active plaques when the disease is beyond 20 years. Rather, there is a predominance of inactive or smoldering plaques that demonstrate a uniform pattern of tissue injury. The study suggests that when the disease is more chronic and progressive in nature, the progression may in part be driven by the accumulation of smoldering plaques in which a low degree of ongoing demyelination is occurring at the plaque edge. Since active new MS plaques show up more readily on gadolinium-enhanced MRI, Dr. Lucchinetti says this might explain why a patient goes to the doctor and feels that his or her disease is progressing, but an MRI shows no new lesions.

    "We recognize that there's not just one therapy that works for everyone with MS; patients already know this. We need to better understand why that might be, study it, model it in the laboratory, and then hopefully translate it into something that makes a difference in patients' lives," says Dr. Lucchinetti.

    According to Dr. Lucchinetti, the next step with this research is examining what other factors contribute to progression and irreversible disability in multiple sclerosis, with a particular focus on understanding how the cortex is involved in the disease. To date, most MS research has focused on the white matter plaque. Although the presence of new active white matter plaques likely account for MS relapses, researchers are increasingly recognizing that in addition to smoldering MS plaques, cortical demyelination is also an important pathologic substrate of progression and disability in the disease.

    A better understanding of the relationship between white matter and cortical demyelination in MS is necessary in order to target the many processes that contribute to disease progression, explains Dr. Lucchinetti.

    "At first glance, it might seem that we're making everything more complicated, but that's really the only way that you can start to break down a disease. If we accept it to be a simple, linear straightforward disease, I don't think we're going to get very far in knowing how to treat the different aspects that are causing the relapses and progression of MS," says Dr. Lucchinetti.

    This study was part of the MS Lesion Project funded by the National Multiple Sclerosis Society and National Institutes of Health. The Mayo Clinic research team also included Joseph Parisi, M.D.; Stephen Weigand, Kristine Thomsen and Jay Mandrekar, Ph.D. Other collaborators included Josa Frischer, M.D., and Hans Lassmann, M.D., of Medical University of Vienna in Austria; and Wolfgang Brueck, M.D., of University of Goettingen, Germany.

    Source: Mayo Clinic ©2001-2010 Mayo Foundation for Medical Education and Research (08/04/10)

    Grey matter under attack in Multiple Sclerosis

    MS Brain MRI

    Autoimmune disease is a condition in which the immune system attacks the body’s own material just as aggressively as it would attack a foreign pathogen. Multiple sclerosis, MS for short, is just one such autoimmune disease, and is one of the most common neurological diseases in the 20 to 30 years age group. The disease can have very severe consequences for those afflicted, since the body’s defenses attack the central nervous system.

    It has long been assumed that myelin is the most important target for the misdirected immune response. This white, fat-rich protective layer of specialized cells enshrouds the long extensions of neurons. However, the central nervous systems of MS patients also exhibit damage in the grey matter, where the nerve cell bodies are located. How the patient’s disability develops depends greatly on the damage of the gray matter.

    An international group headed by medical scientist Professor Edgar Meinl of LMU Munich has now discovered a possible connection: The protein Contactin-2 is produced both in the myelin sheathing and by neurons in the grey matter – and is attacked by misdirected immune factors. “Our results suggest that these processes also play a role in MS patients,” says Meinl. “It could even be that proteins existing both in myelin and in the grey matter are in fact the critical points of attack.”

    Multiple sclerosis often advances in phases, where nerve fibers are successively and irreversibly destroyed by attacks from certain immune cells – so-called T-lymphocytes. The axons that make up nerve fibers are sheathed in myelin. This protective layer consists of individual cells that wrap around the long extensions of the neurons to insulate them and to allow signals to propagate all the way along the nerve cells. MS first causes in an irrecoverable loss of myelin, and then ultimately to the demise of the neurons thus exposed.

    “It is the irreversible destruction of axons in particular that causes the lasting disability of patients," explains Professor Edgar Meinl of the Institute of Clinical Neuroimmunology at LMU Munich Klinikum and of the Max Planck Institute of Neurobiology. Little by little, damage spreads out in the brain and spinal cord. Different symptoms can follow, depending on where these lesions first appear and how severe they are. These could be loss of sight and speech, or tremors, numbness, impaired bladder function or impaired mobility.

    It is only a recent discovery that the immune system actually attacks the grey matter in the early stages, along with the myelin sheathing. “This extensive damage is a factor in the advancement of the symptoms,” says Meinl. “Until now, it has been unclear which molecules direct the immune system against the grey matter.” The researchers therefore performed large-scale tests to investigate which proteins in human brain tissue the antibodies of MS patients dock onto, instead of docking onto foreign intruders as they are supposed to.

    In the course of their investigations, they identified Contactin-2 as a new autoantigen – a molecular structure that belongs to the body but which provokes an immune response. This protein is found in the brain and spinal cord, and is present in both the myelin sheathing and in the neurons themselves – which means it exists in the grey matter. "Contactin-2 triggers an immune response in which T-cells and antibodies turn against this molecule,” reports Meinl. “In some ways, this immune response is similar to those that occur in pathogen-induced inflammations.”

    In an animal model, autoresponsive T-cells responded to TAG-1, the animal protein analogous to human Contactin-2. The T-cells triggered an inflammation in the brain, predominantly in the grey matter. Furthermore, these immune cells also opened the blood-brain barrier, which is a barrier that most molecules and cells can normally not get past. “Without this barrier, the antibodies were able to invade the brain in great numbers, where they caused severe damage to the grey matter,” says Meinl. “What we now need to clarify is whether these mechanisms also take place in human MS patients, and what role is played by antigens that occur inside the neurons.”

    Source: Science Daily © 1995-2009 ScienceDaily LLC (01/05/09)

    Contribution of white matter lesions to gray matter atrophy in Multiple Sclerosis

    White Matter of the Brain

    Evidence From Voxel-Based Analysis of T1 Lesions in the Visual Pathway

    Background:  The biological basis of gray matter (GM) atrophy in multiple sclerosis is not well understood, but GM damage seems to be the most critical factor leading to permanent disability.

    Objective:  To assess to what extent white matter (WM) lesions contribute to regional GM atrophy in multiple sclerosis.

    Design:  Because optic pathway GM atrophy and optic radiation lesions, rather than being related to each other, could be independent results of the disease, we applied a nonaprioristic WM method to analyze the interrelationships of both phenomena. On a voxel-by-voxel basis, we correlated T1 magnetic resonance imaging–derived lesion probability maps of the entire brain with atrophy of the lateral geniculate nuclei and calcarine/pericalcarine cortices.

    Setting:  Multiple sclerosis center, University of Navarra, Pamplona, Spain.

    Patients:  Sixty-one patients with multiple sclerosis.

    Main Outcome Measure:  Mapping of WM regions contributing to GM atrophy in the optic pathway.

    Results:  Patients with multiple sclerosis had lateral geniculate nucleus atrophy, which correlated with the presence of lesions specifically in the optic radiations but not in the rest of the brain. Optic pathway lesions explained up to 28% of the change of variance in lateral geniculate nucleus atrophy. Patients also had occipital cortex atrophy, which did not correlate with lesions in the optic radiations or any other WM region.

    Conclusions:  Focal WM damage is associated with upstream GM atrophy, suggesting that retrograde damage of the perikarya from axonal injury in multiple sclerosis plaques is one of the significant factors in the genesis of GM atrophy, although other neurodegenerative processes are probably at work as well.

    Jorge Sepulcre, MD; Joaquín Goñi, BS; Joseph C. Masdeu, MD; Bartolome Bejarano, MD; Nieves Vélez de Mendizábal, BS; Juan B. Toledo, MD; Pablo Villoslada, MD

    Author Affiliations: Department of Neurology and Neurosurgery, Clínica Universitaria de Navarra (Drs Sepulcre, Masdeu, Bajarano, Toledo, and Villoslada, Mr Goñi, and Ms Vélez de Menizábal), Department of Physics and Applied Mathematics (Mr Goñi), and Neuroimaging Laboratory, Center for Applied Medical Research (Dr Masdeu), University of Navarra, Pamplona, Spain.

    Source: Archives of Neurology 2009;66(2):173-179. (10/02/09)

    Normal-appearing white matter in multiple sclerosis is in a subtle balance between inflammation and neuroprotection

    Multiple sclerosis is a chronic inflammatory disease of the CNS. Although progressive axonal injury and diffuse inflammatory damage has been shown in the chronic phase of the disease, little is known about the molecular mechanisms underlying these pathological processes.

    In order to identify these mechanisms, we have studied the gene expression profile in non-lesion containing tissue, the so-called normal-appearing white matter (NAWM). We performed differential gene expression analysis and quantitative RT-PCR on subcortical white matter from 11 multiple sclerosis and 8 control cases. Differentially expressed genes were further analysed in detail by in situ hybridization and immunofluorescence studies.

    We show that genes known to be involved in anti-inflammatory and protective mechanisms such as STAT6, JAK1, IL-4R, IL-10, Chromogranin C and Hif-1 are consistently upregulated in the multiple sclerosis NAWM. On the other hand, genes involved in pro-inflammatory mechanisms, such as STAT4, IL-1β and MCSF, were also upregulated but less regularly.

    Immunofluorescence colocalization analysis revealed expression of STAT6, JAK1, IL-4R and IL-13R mainly in oligodendrocytes, whereas STAT4 expression was detected predominantly in microglia. In line with these data, in situ hybridization analysis showed an increased expression in multiple sclerosis NAWM of HIF-1 in oligodendrocytes and HLA-DR in microglia cells. The consistency of the expression levels of STAT6, JAK1, JAK3 and IL-4R between the multiple sclerosis cases suggests an overall activation of the STAT6-signalling pathway in oligodendrocytes, whereas the expression of STAT4 and HLA-DR indicates the activation of pro-inflammatory pathways in microglia.

    The upregulation of genes involved in anti-inflammatory mechanisms driven by oligodendrocytes may protect the CNS environment and thus limit lesion formation, whereas the activation of pro-inflammatory mechanisms in microglia may favour disease progression. Altogether, our data suggests an endogenous inflammatory reaction throughout the whole white matter of multiple sclerosis brain, in which oligodendrocytes actively participate. This reaction might further influence and to some extent facilitate lesion formation.

    Thomas Zeis1, Ursula Graumann1, Richard Reynolds2 and Nicole Schaeren-Wiemers1

    1Neurobiology, Department of Research, University Hospital Basel, Pharmacenter, Basel, Switzerland and 2Department of Cellular & Molecular Neuroscience, Division of Neuroscience, Imperial College, Charing Cross Hospital Campus, London W6 8RP, UK

    Source: Brain Copyright © 2007 Guarantors of Brain (17/12/07)

    Low Choline Concentrations in Normal-Appearing White Matter of Patients with Multiple Sclerosis and Normal MR Imaging Brain Scans
    Spectroscopic studies (1H-MR spectroscopy) of normal-appearing white matter (NAWM) in patients with multiple sclerosis (MS) with MR imaging brain lesions have already been performed, but our intention was to investigate NAWM in MS patients who lack brain lesions to elucidate whether the same pathologic changes could be identified.

    We checked 350 medical files of patients with MS who are registered in our institution. Fourteen patients (11 women and 3 men; mean age, 48.6 years; handicap score, Expanded Disability Status Scale [EDSS] 2.9; range, 1–6.5) with clinically definite MS and a normal MR imaging of the brain were included. 1H-MR spectroscopy was performed in 4 voxels (size approximately 17 x 17 x 17 mm3) using absolute quantification of metabolite concentrations. Fourteen healthy control subjects (11 women and 3 men; mean age, 43.3 years) were analyzed in the same way.

    Significant differences in absolute metabolite concentrations were observed, with the patients with MS showing a lower total concentration of N-acetyl compounds (tNA), including N-acetylaspartate and N-acetyl aspartylglutamate (13.5 mmol/L versus 14.6 mmol/L; P = .002) compared with the healthy control subjects. Unexpectedly, patients with MS presented significantly lower choline-containing compounds (Cho) compared with healthy control subjects (2.2 mmol/L versus 2.4 mmol/L; P < .001). The EDSS showed a positive correlation to myo-inositol concentrations (0.14 mmol/L per EDSS; r2 = 0.06) and a negative correlation to tNA concentrations (–0.41 mmol/L per EDSS; r2 = 0.22).

    The unexpected finding of lower Cho concentrations has not been reported previously. We suggest that patients with MS who lack lesions in the brain constitute a separate entity and may have increased protective or healing abilities.

    M.C. Gustafssona, O. Dahlqvistb,d, J. Jaworskia, P. Lundbergb,c,d and A.-M.E. Landtbloma  

    a Division of Neurology, University Hospital, Linköping, Sweden
    b Department of Radiation Physics, University Hospital, Linköping, Sweden
    c Department of Radiology, University Hospital, Linköping, Sweden
    d Center for Medical Imaging and Visualization, University Hospital, Linköping, Sweden

    Source: American Journal of Neuroradiology 28:1306-1312, August 2007 © 2007 American Society of Neuroradiology (13/08/07)

    Gray matter involvement in multiple sclerosis

    Gray matter (GM) involvement is detected even in the earliest stages of multiple sclerosis (MS), and GM atrophy occurs at a faster rate than white matter (WM) atrophy early in the disease course.

    Studies published to date establish that 1) GM involvement and in particular cortical demyelination can be extensive in MS; 2) GM pathology may occur in part independently of WM lesion formation; 3) a primarily GM-related process may be the earliest manifestation of MS; 4) GM involvement is associated with physical disability, fatigue, and cognitive impairment in MS; and 5) GM disease might help explain the observed dissociation between markers of inflammatory demyelination (relapses, WM gadolinium enhancement, WM lesion burden) and disease progression.

    It remains likely that GM damage is related to WM damage. However, continued studies of GM pathology as well as neuronal and axonal involvement in MS and related experimental models are necessary to better understand the etiology and pathogenesis of the degenerative components.

    Istvan Pirko, MD, Claudia F. Lucchinetti, MD, Subramaniam Sriram, MD and Rohit Bakshi, MD

    From the Department of Neurology (I.P.), University of Cincinnati, OH; Department of Neurology (C.F.L.), Mayo Clinic College of Medicine, Rochester, MN; Department of Neurology (S.S.), Vanderbilt Medical Center, Nashville, TN; and Departments of Neurology and Radiology (R.B.), Partners MS Center, Center for Neurological Imaging, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA.

    Source: Neurology 2007 68: 628-629. © 2007 American Academy of Neurology (27/02/07)

    Extent of brain involvement at diagnosis may predict rate of later brain atrophy in patients with MS

    In patients with recently diagnosed multiple sclerosis, the extent of accumulated brain tissue loss and overall lesion load as determined by magnetic resonance imaging (MRI) may predict the rate of cerebral atrophy over the following two years, according to a report in the February issue of Archives of Neurology.

    MRI provides valuable information about the progression of multiple sclerosis (MS), according to background information in the article. MRI is used to monitor the number and volume of MS-related lesions (damaged tissue), which can help monitor the evolution of the disease but does not appear to be associated with the patient's disability status. Brain volume, also measured by MRI, "is currently considered to be a marker of the neurodegenerative component of MS pathological features, thereby better reflecting the pathological background of irreversible clinical disability in MS," the authors write.

    Bas Jasperse, M.D., and colleagues at the VU University Medical Center, Amsterdam, the Netherlands, performed brain MRI shortly after diagnosis and again after two years in 89 patients with MS (average age, 37.5). The numbers and volume of two types of lesions apparent on MRI, black hole (dark appearing lesions that indicate the loss of myelin, neurons' protective coating) and T2 (newer, brighter appearing lesions), were recorded along with brain volume. Change in brain volume between scans was calculated, and participants were also assessed for neurologic disability.

    "The mean [average] annualised rate of cerebral atrophy was -0.9 percentage of brain volume change per year," the authors write. "Baseline normalised brain volume and baseline T2 lesion load were identified as explanatory variables for the subsequent percentage of brain volume change per year and yielded a regression model that explained 31.2 percent of the variance in percentage of brain volume change per year."

    In other words, "patients who have acquired more brain tissue loss and more T2 lesions are prone to have a higher rate of subsequent brain atrophy," the authors conclude. "In this relationship, the extent of brain tissue loss seemed more important than lesional activity. Because a higher rate of cerebral atrophy is predictive of worse clinical functioning at a later stage in the MS disease course, our findings suggest that these two baseline variables could have prognostic value for clinical functioning in early MS."

    Understanding How MS Worsens

    In patients with MS, "the unpredictable and often dramatic appearance of clinical relapses and focal MRI abnormalities tend to catch our attention," writes J. Theodore Phillips, M.D., Ph.D., of The Multiple Sclerosis Center at Texas Neurology, Dallas, in an accompanying editorial. "However, these events can often obscure more insidious, but no less important, destructive changes, such as irreversible disability progression and MRI-evident brain atrophy."

    "In this issue of Archives, Jasperse and colleagues demonstrate that the rate of new brain atrophy in newly diagnosed MS patients studied over two years is significantly predicted by MRI-determined brain atrophy and T2 lesion load at the time of diagnosis. Lower brain volume and higher T2 lesion load at the time of diagnosis predict greater brain volume loss over a two-year observation period.

    "This finding provides not only important clinical prognostic information, but also indicates the necessity of accounting for these baseline MRI variables in future clinical study designs that use brain atrophy as an outcome variable," Dr. Phillips continues.

    Note: The Netherlands Organisation for Scientific Research supported this study. The MS center Amsterdam is financially supported by the Dutch MS research foundation. 

    Source: Archives of Neurology - (Arch Neurol. 2007;64:190-194.)(13/02/07)

    © Multiple Sclerosis Resource Centre

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