Atrophy In Multiple Sclerosis Research Articles

Reduction of brain volume in MS. MRI and pathology findings

Atrophy is one of the hallmarks in multiple sclerosis (MS), especially in the advanced stage. Modern magnetic resonance (MR) techniques can reliably measure brain volume and changes therein. Depending on the technique used, changes of about 1% may be detected. Clinicoradiological studies show good corelation between atrophy measures, both in brain and spinal cord, and clinical measures. The exact relationship between focal MS lesions and global atrophy has yet to be established. Number of lesions early in the disease seems to predict later atrophy. The exact pathomechanism of atrophy in MS probably may be explained by both demyelination and axonal loss - which may occur independently from each other.

Microglial imaging with positron emission tomography and atrophy measurements with magnetic resonance imaging in multiple sclerosis: a correlative study

The objectives of the present study were to assess brain atrophy in multiple sclerosis (MS) patients during different disease stages and to investigate by PET and [11C]PK11195, a marker of microglial activation, the relationship between inflammation, atrophy and clinically relevant measures. Eight healthy subjects and 22 MS patients were included. Semiquantitative [11C]PK11195 uptake values, with normalization on cortical grey matter, were measured for magnetic resonance imaging T2- and T1-lesions and normal appearing white matter (NAWM). As atrophy index we used the ratio of the amount of white and grey matter divided by the ventricular size, using an optimized a priori based segmentation algorithm (SPM99). Atrophy was significantly greater in MS patients compared to age-matched controls. A significant correlation was found between brain atrophy and both disease duration and disability, as measured with the Expanded Disability Status Scale. For NAWM, [11C]PK11195 uptake increased with the amount of atrophy, while T2-lesional [11C]PK11195 uptake values decreased according to increasing brain atrophy. The present study suggests that brain atrophy, correlating with disease duration and disability, is directly related to NAWM and T2-lesional inflammation as measured by microglial activation.

Neuronal cell injury precedes brain atrophy in multiple sclerosis

<h3>Introduction</h3> Bacterial vaginosis (BV) and vaginal microbiota disruption during pregnancy are associated with increased risk of spontaneous preterm birth (SPTB), but clinical trials of BV treatment during pregnancy have shown little or no benefit. An alternative hypothesis is that vaginal bacteria present around conception may lead to SPTB by compromising the protective effects of cervical mucus, colonising the endometrial surface before fetal membrane development, and causing low-level inflammation in the decidua, placenta and fetal membranes. This protocol describes a prospective case-cohort study addressing this hypothesis. <h3>Methods and analysis</h3> HIV-seronegative Kenyan women with fertility intent are followed from preconception through pregnancy, delivery and early postpartum. Participants provide monthly vaginal specimens during the preconception period for vaginal microbiota assessment. Estimated date of delivery is determined by last menstrual period and first trimester obstetrical ultrasound. After delivery, a swab is collected from between the fetal membranes. Placenta and umbilical cord samples are collected for histopathology. Broad-range 16S rRNA gene PCR and deep sequencing of preconception vaginal specimens will assess species richness and diversity in women with SPTB versus term delivery. Concentrations of key bacterial species will be compared using quantitative PCR (qPCR). Taxon-directed qPCR will also be used to quantify bacteria from fetal membrane samples and evaluate the association between bacterial concentrations and histopathological evidence of inflammation in the fetal membranes, placenta and umbilical cord. <h3>Ethics and dissemination</h3> This study was approved by ethics committees at Kenyatta National Hospital and the University of Washington. Results will be disseminated to clinicians at study sites and partner institutions, presented at conferences and published in peer-reviewed journals. The findings of this study could shift the paradigm for thinking about the mechanisms linking vaginal microbiota and prematurity by focusing attention on the preconception vaginal microbiota as a mediator of SPTB.

Association of fatigue and brain atrophy in multiple sclerosis

Functional imaging studies have demonstrated a relationship between fatigue and altered cerebral activation patterns in multiple sclerosis patients, but no relationship between fatigue and brain atrophy has been demonstrated. We hypothesized that the subjective complaint of fatigue would predict the severity of destructive brain pathology. We assessed the relationship between fatigue and brain atrophy longitudinally in a cohort of 134 patients previously enrolled in a 2-year clinical trial of interferon β-1a and re-evaluated 8 years after randomization into the trial. Brain atrophy was measured using the brain parenchymal fraction (BPF), and disability was measured using the Multiple Sclerosis Functional Composite at baseline, year 2 and year 8. Fatigue was measured using the Sickness Impact Profile's Sleep and Rest Scale (SIPSR) at baseline, year 2 and year 8. Linear regression analyses were used to assess the relationship between changes in fatigue and atrophy progression . Worsening fatigue on the SIPSR during the initial 2 years was significantly associated with progressive brain atrophy over the subsequent 6 years. The relationships between fatigue and brain atrophy were independent of changes in disability, mood, or other MRI characteristics. This suggests that the subjective complaint of fatigue is linked to destructive pathologic processes in RRMS patients.

Pathological study of spinal cord atrophy in multiple sclerosis suggests limited role of local lesions

Imaging studies in multiple sclerosis have shown that spinal cord atrophy correlates with clinical disability. The pathological substrate of atrophy has not as yet been investigated adequately. In order to determine the cause of spinal cord atrophy in multiple sclerosis, five different sections of the spinal cord were examined histopathologically in 33 controls and 55 multiple sclerosis cases. In the multiple sclerosis cases in each section the total lesion load and the cross-sectional area of the cord were measured. Multiple regression models were estimated, controlling for sex, age, duration of the disease and location of the cord sections. The multiple sclerosis cords were found to be significantly smaller than the controls. The duration of the disease played the most important role in determining cord atrophy. The degree of atrophy varied in different parts of the cord. Individual lesions played a minor role in local atrophy. Our findings suggest that axonal degeneration, possibly caused by the cumulative number of lesions in the brain and cord, or an alternative atrophic process, is responsible for spinal cord atrophy in multiple sclerosis, rather than tissue loss within individual lesions.

Central nervous system atrophy and clinical status in multiple sclerosis.

In this review, the authors focus on clinical aspects of central nervous system (CNS) atrophy in multiple sclerosis (MS), including the relationship between atrophy and disability, disease course, disease duration, quality of life, and fatigue. Cross-sectional studies have demonstrated a moderate but significant correlation between brain or spinal cord atrophy and physical disability in patients with MS. Longitudinal studies (>/= 5 years) have shown that CNS atrophy is a significant predictor of subsequent long-term neurologic deterioration. The clinical relevance of CNS atrophy is reinforced by studies showing that atrophy accounts for more variance than conventional lesion measures in predicting disability. Impaired quality of life and both urodynamic and sexual dysfunction, but not fatigue, are associated with brain atrophy. It is likely that once the level of CNS atrophy reaches a critical threshold, patients begin to suffer clinical impairment and disease progression. Longitudinal studies suggest that CNS atrophy may occur in patients with clinically isolated demyelinating syndromes who are at high risk for developing clinically definite MS. Longitudinal natural history studies in relapsing-remitting, secondary progressive, and primary progressive MS have suggested that patients develop CNS atrophy at a faster rate in the first few years of disease than later in the disease course. Similarly, long-term follow-up studies have shown a poor relationship between disease duration and the rate of brain atrophy. The authors conclude that measurement of atrophy of the CNS is emerging as a clinically relevant biomarker of the MS disease process.

Central Nervous System Atrophy and Clinical Status in Multiple Sclerosis

ABSTRACTIn this review, the authors focus on clinical aspects of central nervous system (CNS) atrophy in multiple sclerosis (MS), including the relationship between atrophy and disability, disease course, disease duration, quality of life, and fatigue. Crosssectional studies have demonstrated a moderate but significant correlation between brain or spinal cord atrophy and physical disability in patients with MS. Longitudinal studies ([.greaterequal] 5 years) have shown that CNS atrophy is a significant predictor of subsequent long‐term neurologic deterioration. The clinical relevance of CNS atrophy is reinforced by studies showing that atrophy accounts for more variance than conventional lesion measures in predicting disability. Impaired quality of life and both urodynamic and sexual dysfunction, but not fatigue, are associated with brain atrophy. It is likely that once the level of CNS atrophy reaches a critical threshold, patients begin to suffer clinical impairment and disease progression. Longitudinal studies suggest that CNS atrophy may occur in patients with clinically isolated demyelinating syndromes who are at high risk for developing clinically definite MS. Longitudinal natural history studies in relapsing‐remitting, secondary progressive, and primary progressive MS have suggested that patients develop CNS atrophy at a faster rate in the first few years of disease than later in the disease course. Similarly, long‐term follow‐up studies have shown a poor relationship between disease duration and the rate of brain atrophy. The authors conclude that measurement of atrophy of the CNS is emerging as a clinically relevant biomarker of the MS disease process.

Measurement of Whole‐Brain Atrophy in Multiple Sclerosis

ABSTRACTBrain atrophy reflects the net result of irreversible and destructive pathological processes in multiple sclerosis (MS). The gross morphological changes can be accurately quantified using standard magnetic resonance imaging (MRI) acquisitions and various image analysis tools. The current methods used to assess whole‐brain atrophy in patients with MS can be classified into 2 groups based on their reliance on segmentation and registration. Segmentation‐based methods employed to measure whole‐brain atrophy in MS include the brain parenchymal fraction, the index of brain atrophy, the whole‐brain ratio, the brain to intracranial capacity ratio, fuzzy connectedness/Udupa's method, 3DVIEWNIX, the Alfano method, and SIENAX. Current registration‐based methods used to measure whole‐brain atrophy in MS include the brain boundary shift integral, SIENA, statistical parametric mapping, template‐driven seg mentation, and voxel‐based morphometry. Most of the methods presented here are sensitive to subtle changes in brain structures and have been successfully applied to MS as measures of whole‐brain atrophy. Yet comparative studies of these methods are limited and are complicated by the lack of a gold standard for image acquisition, a segmentation algorithm, an image analysis method, or a reproducibility measure. Overall, the measure of whole‐brain atrophy from MRI contributes to an appreciation of the dynamics of MS pathology and its relationship to the clinical course of MS. Determination of the relative reproducibility, precision, sensitivity, and validity of these methods will promote the use of whole‐brain atrophy measures as components of comprehensive MRI‐based outcome assessment in MS clinical trials.

Measurement of whole-brain atrophy in multiple sclerosis.

Brain atrophy reflects the net result of irreversible and destructive pathological processes in multiple sclerosis (MS). The gross morphological changes can be accurately quantified using standard magnetic resonance imaging (MRI) acquisitions and various image analysis tools. The current methods used to assess whole-brain atrophy in patients with MS can be classified into 2 groups based on their reliance on segmentation and registration. Segmentation-based methods employed to measure whole-brain atrophy in MS include the brain parenchymal fraction, the index of brain atrophy, the whole-brain ratio, the brain to intracranial capacity ratio, fuzzy connectedness/Udupa's method, 3DVIEWNIX, the Alfano method, and SIENAX. Current registration-based methods used to measure whole-brain atrophy in MS include the brain boundary shift integral, SIENA, statistical parametric mapping, template-driven seg mentation, and voxel-based morphometry. Most of the methods presented here are sensitive to subtle changes in brain structures and have been successfully applied to MS as measures of whole-brain atrophy. Yet comparative studies of these methods are limited and are complicated by the lack of a gold standard for image acquisition, a segmentation algorithm, an image analysis method, or a reproducibility measure. Overall, the measure of whole-brain atrophy from MRI contributes to an appreciation of the dynamics of MS pathology and its relationship to the clinical course of MS. Determination of the relative reproducibility, precision, sensitivity, and validity of these methods will promote the use of whole-brain atrophy measures as components of comprehensive MRI-based outcome assessment in MS clinical trials.

Measurement of Spinal Cord Atrophy in Multiple Sclerosis

ABSTRACTIn multiple sclerosis (MS), the spinal cord is a common area of involvement, and its dysfunction is likely to be responsible for much of motor disability. It has been reported that atrophy in the cervical spinal cord occurs early and is detectable in patients presenting with a clinically isolated syndrome. This finding has important implications for the early treatment of patients with MS because atrophy is thought to reflect destructive, irreversible pathology and subclinical impairment. Recent clinical trials of disease‐modifying agents have included spinal cord imaging and, in particular, the measurement of atrophy as a secondary or exploratory measure of treatment efficacy. This review summarizes the underlying pathology responsible for spinal cord atrophy and the methods available to measure it. The relationships between spinal cord atrophy, other magnetic resonance imaging parameters, and clinical disability are also discussed.

Atrophy of the Brain and Spinal Cord in Multiple Sclerosis

ABSTRACTThe destructive nature of the multiple sclerosis disease process is of growing clinical and neuroscientific interest. Axonal transection, neuronal loss, Wallerian degeneration, and chronic demyelination likely contribute to macroscopic atrophy of the brain and spinal cord in patients with the disease. This neurodegenerative process belies the traditional view of multiple sclerosis as an inflammatory demyelinating disease. Magnetic resonance imaging is a key tool in the diagnosis and longitudinal monitoring of central nervous system atrophy. This supplement to theJournal of Neuroimaging is devoted to brain and spinal cord atrophy in MS, with a focus on the role of magnetic resonance imaging. The authors and topics of the articles have been chosen by the Guest Editor to provide a state‐of‐the‐art review of this important field. An emphasis is placed on several key issues pertaining to central nervous system atrophy in multiple sclerosis: pathogenesis, magnetic resonance imaging techniques for quantification, clinical relevance, and effects of disease‐modifying therapies.

Pathogenesis of Brain and Spinal Cord Atrophy in Multiple Sclerosis

ABSTRACTFor more than a century, multiple sclerosis was viewed as a disease process characterized by oligodendrocyte and myelin loss, and research into the pathogenesis of multiple sclerosis was mainly focused on the mechanisms of inflammation. However, with development of more sophisticated neuroimaging and molecular biology techniques, attention has shifted to new aspects of pathogenesis of multiple sclerosis: axonal loss and neurodegeneration. Evidence is increasing that tissue destruction, primarily axonal loss and neurodegeneration, is a key element in the pathogenesis of multiple sclerosis. In addition, it is now known that brain and spinal cord atrophy begins early in the disease process of multiple sclerosis and advances relentlessly throughout the course of the disease. Cumulative data suggest that axonal loss is the major determinant of progressive neuro logic disability in patients with multiple sclerosis. Magnetic resonance imaging and magnetic resonance spectroscopy in patients with multiple sclerosis for &lt; 5 years indicate brain atrophy and loss of axonal integrity. Neurodegeneration and axonal loss in patients with multiple sclerosis are initially accompanied by a local response from oligodendrocyte progenitor cells and some remyelination. However, these repair mechanisms eventually fail, and patients typically develop generalized brain atrophy, cognitive decline, and permanent disability. Although the exact mechanisms underlying central nervous system atrophy in patients with multiple sclerosis are largely unknown, evidence exists that atrophy may represent an epiphenomenon related to the effects of dynamic inflammation within the central nervous system, including demyelination, axonal injury, neuronal loss, Wallerian degeneration, and possibly iron deposition. This article summarizes the potential mechanisms involved in central nervous system atrophy in patients with multiple sclerosis.

Impact of Disease‐Modifying Therapies on Brain and Spinal Cord Atrophy in Multiple Sclerosis

ABSTRACTBrain and spinal cord atrophy occur early in the course of multiple sclerosis (MS) and continue throughout this lifelong illness, resulting in substantial parenchymal tissue loss at later disease stages. Treatments that slow or prevent atrophy may reduce disability progression in the long term. Disease‐modifying agents (DMAs) such as interferon [.beta]‐1b (IFN[.beta]‐1b), IFN[.beta]‐1a, and glatiramer acetate inhibit inflammatory events believed to initiate and perpetuate the disease process. DMAs have been shown to inhibit aspects of MS related to brain inflammation such as relapses and gadolinium‐enhanced lesions. Because brain inflammation has been linked to irreversible brain tissue injury, DMAs should be effective in reducing the rate of brain atrophy progression. Weekly IFN[.beta]‐1a (Avonex or Rebif) has been shown to slow the rate of brain atrophy; a large study of a frequent injection regimen with IFN[.beta]‐1a (Rebif) showed continued atrophy progression despite IFN[.beta]‐1a at a rate similar to placebo‐treated patients. It is not clear why weekly treatment regimens with lower total doses of IFN[.beta]‐1a would show beneficial effects on brain atrophy compared with frequent injections with larger weekly doses. This article reviews results of clinical trials that have examined the effects of DMAs on brain and spinal cord atrophy in patients with MS. Some of these agents have demonstrated positive effects in well‐controlled studies, suggesting that anti‐inflammatory therapy can delay or prevent the emergence of irreversible central nervous system pathology.

Measurement of Spinal Cord Atrophy in Multiple Sclerosis

In multiple sclerosis (MS), the spinal cord is a common area of involvement, and its dysfunction is likely to be responsible for much of motor disability. It has been reported that atrophy in the cervical spinal cord occurs early and is detectable in patients presenting with a clinically isolated syndrome. This finding has important implications for the early treatment of patients with MS because atrophy is thought to reflect destructive, irreversible pathology and subclinical impairment. Recent clinical trials of disease-modifying agents have included spinal cord imaging and, in particular, the measurement of atrophy as a secondary or exploratory measure of treatment efficacy. This review summarizes the underlying pathology responsible for spinal cord atrophy and the methods available to measure it. The relationships between spinal cord atrophy, other magnetic resonance imaging parameters, and clinical disability are also discussed.

Pathogenesis of brain and spinal cord atrophy in multiple sclerosis.

For more than a century, multiple sclerosis was viewed as a disease process characterized by oligodendrocyte and myelin loss, and research into the pathogenesis of multiple sclerosis was mainly focused on the mechanisms of inflammation. However, with development of more sophisticated neuroimaging and molecular biology techniques, attention has shifted to new aspects of pathogenesis of multiple sclerosis: axonal loss and neurodegeneration. Evidence is increasing that tissue destruction, primarily axonal loss and neurodegeneration, is a key element in the pathogenesis of multiple sclerosis. In addition, it is now known that brain and spinal cord atrophy begins early in the disease process of multiple sclerosis and advances relentlessly throughout the course of the disease. Cumulative data suggest that axonal loss is the major determinant of progressive neurologic disability in patients with multiple sclerosis. Magnetic resonance imaging and magnetic resonance spectroscopy in patients with multiple sclerosis for < 5 years indicate brain atrophy and loss of axonal integrity. Neurodegeneration and axonal loss in patients with multiple sclerosis are initially accompanied by a local response from oligodendrocyte progenitor cells and some remyelination. However, these repair mechanisms eventually fail, and patients typically develop generalized brain atrophy, cognitive decline, and permanent disability. Although the exact mechanisms underlying central nervous system atrophy in patients with multiple sclerosis are largely unknown, evidence exists that atrophy may represent an epiphenomenon related to the effects of dynamic inflammation within the central nervous system, including demyelination, axonal injury, neuronal loss, Wallerian degeneration, and possibly iron deposition. This article summarizes the potential mechanisms involved in central nervous system atrophy in patients with multiple sclerosis.

Impact of disease-modifying therapies on brain and spinal cord atrophy in multiple sclerosis.

Brain and spinal cord atrophy occur early in the course of multiple sclerosis (MS) and continue throughout this lifelong illness, resulting in substantial parenchymal tissue loss at later disease stages. Treatments that slow or prevent atrophy may reduce disability progression in the long term. Disease-modifying agents (DMAs) such as interferon beta-1b (IFNbeta-1b), IFNbeta-1a, and glatiramer acetate inhibit inflammatory events believed to initiate and perpetuate the disease process. DMAs have been shown to inhibit aspects of MS related to brain inflammation such as relapses and gadolinium-enhanced lesions. Because brain inflammation has been linked to irreversible brain tissue injury, DMAs should be effective in reducing the rate of brain atrophy progression. Weekly IFNbeta-1a (Avonex or Rebif) has been shown to slow the rate of brain atrophy; a large study of a frequent injection regimen with IFNbeta-1a (Rebif) showed continued atrophy progression despite IFNbeta-1a at a rate similar to placebo-treated patients. It is not clear why weekly treatment regimens with lower total doses of IFNbeta-1a would show beneficial effects on brain atrophy compared with frequent injections with larger weekly doses. This article reviews results of clinical trials that have examined the effects of DMAs on brain and spinal cord atrophy in patients with MS. Some of these agents have demonstrated positive effects in well-controlled studies, suggesting that anti-inflammatory therapy can delay or prevent the emergence of irreversible central nervous system pathology.

Correction for intracranial volume in analysis of whole brain atrophy in multiple sclerosis: the proportion vs. residual method

Two techniques that correct (normalize) regional and whole brain volumes according to head size—the proportion method (tissue-to-intracranial volume ratio) and the residual method (regression-based predicted brain tissue volumes)—are used pervasively in neuroimaging research, but have received little critical evaluation or direct comparison. Using a quantitatively derived MRI data set of patients with multiple sclerosis ( n = 18) and age-/sex-matched normal controls ( n = 18), we introduced various types of error into estimates of intracranial volume (ICV) and absolute parenchymal volume (APV) to observe how this error affected the final outcome of normalized brain measures and their ability to detect group differences, as computed by a proportion (brain parenchymal fraction [BPF]) and residual method (predicted parenchymal volume [PPV]). The results indicated that systemic error in ICV and APV values considerably affected BPF means based on the proportion method, except with dependent-related systematic APV error, but essentially did not change statistical power associated with group differences in BPF. Random error altered BPF means to a much smaller extent, but was associated with moderate reductions in statistical power. On the other hand, PPV estimates based on the residual method were unaffected by these same ICV and APV errors, except with dependent-related systematic APV error, and were not associated with reductions in statistical power. Our findings suggest that head size correction of brain regions with the residual method generally may provide advantages over the proportion method.

Neuronal cell injury precedes brain atrophy in multiple sclerosis.

Global brain atrophy estimated using MRI and whole brain N-acetylaspartate (WBNAA) concentration measured with proton MR spectroscopy were obtained in 42 patients with relapsing-remitting multiple sclerosis and 41 matched control subjects. Patients exhibited cross-sectional atrophy (0.5%; p = 0.033) and WBNAA decline (1.8%/y; p = 0.005) vs disease duration. The 3.6-fold rate disparity between the two processes suggests that neuronal/axonal dysfunction (N-acetylaspartate decline) precedes parenchyma loss, not its consequence (i.e., is an earlier, more sensitive specific metric of the ongoing disease activity).

Role of MRI in multiple sclerosis II: brain and spinal cord atrophy.

A growing body of evidence indicates that irreversible tissue destruction including axonal and neuronal degeneration is a key component of the multiple sclerosis (MS) disease process. Magnetic resonance imaging (MRI) is a powerful technique that can be combined with semiautomated or automated computer assisted analysis approaches to detect progressive atrophy of the brain and spinal cord with high sensitivity and reproducibility. The pathophysiology of central nervous system (CNS) atrophy in MS is unknown but likely represents an epiphenomenon related to the effects of inflammation including chronic demyelination, axonal injury, neuronal loss and Wallerian degeneration. Other factors that may contribute to tissue atrophy include injury to the normal appearing gray and white matter by mechanisms such as loss of growth factors, altered electrical conduction and pathologic iron deposition. Prospective studies have suggested that atrophy in MS is predicted by previous inflammatory activity as measured by overt MRI lesions. Gadolinium (Gd)-enhancing lesions have shown a particularly strong predictive value in some but not all longitudinal studies of brain atrophy. Brain atrophy has also been related in cross-sectional and longitudinal studies to T2-hypointense lesions in deep grey matter, suggesting a link between tissue iron deposition and atrophy. The measurement of brain atrophy seems to be of growing clinical relevance as a biomarker of the MS disease process. Atrophy should now be included as a secondary endpoint in trials of therapies aimed at limiting disease progression. Currently available anti-inflammatory immunomodulatory agents and immunosuppressive treatments, while effective at preventing clinical deterioration, have shown at best partial effects in preventing CNS atrophy. Thus, there is a need to further validate atrophy as an outcome measure and ultimately develop treatment strategies that will protect against the destructive aspects of the disease process. This should in turn lead to better long term neurologic functioning and a better quality of life for patients with MS.

The longitudinal relation between brain lesion load and atrophy in multiple sclerosis: a 14 year follow up study

Background:Studies have suggested that T2 lesion activity is prominent in early relapsing-remitting multiple sclerosis, whereas brain atrophy, while seen early, appears more evident in later progressive disease. The temporal relation...