Neuropathology Of Multiple Sclerosis Research Articles

Analysis of the mitochondrial proteome in multiple sclerosis cortex

Mitochondrial dysfunction has been proposed to play a role in the neuropathology of multiple sclerosis (MS). Previously, we reported significant alterations in the transcription of nuclear-encoded electron transport chain genes in MS and confirmed translational alterations for components of Complexes I and III that resulted in reductions in their activity. To more thoroughly and efficiently elucidate potential alterations in the expression of mitochondrial and related proteins, we have characterized the mitochondrial proteome in postmortem MS and control cortex using Surface-Enhanced Laser Desorption Ionization Time of Flight Mass Spectrometry (SELDI-TOF-MS). Using principal component analysis (PCA) and hierarchical clustering techniques we were able to analyze the differential patterns of SELDI-TOF spectra to reveal clusters of peaks which distinguished MS from control samples. Four proteins in particular were responsible for distinguishing disease from control. Peptide fingerprint mapping unambiguously identified these differentially expressed proteins. Three proteins identified are involved in respiration including cytochrome c oxidase subunit 5b (COX5b), the brain specific isozyme of creatine kinase, and hemoglobin β-chain. The fourth protein identified was myelin basic protein (MBP). We then investigated whether these alterations were consistent in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. We found that MBP was similarly altered in EAE but the respiratory proteins were not. These data indicate that while the EAE mouse model may mimic aspects of MS neuropathology which result from inflammatory demyelinating events, there is another distinct mechanism involved in mitochondrial dysfunction in gray matter in MS which is not modeled in EAE.

Sildenafil (Viagra) ameliorates clinical symptoms and neuropathology in a mouse model of multiple sclerosis

Cyclic GMP (cGMP)-mediated pathways regulate inflammatory responses in immune and CNS cells. Recently, cGMP phosphodiesterase inhibitors such as sildenafil, commonly used to treat sexual dysfunction in humans including multiple sclerosis (MS) patients, have been reported to be neuroprotective in animal models of stroke, Alzheimer's disease, and focal brain lesion. In this work, we have examined if sildenafil ameliorates myelin oligodendrocyte glycoprotein peptide (MOG₃₅₋₅₅)-induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We show for the first time that treatment with sildenafil after disease onset markedly reduces the clinical signs of EAE by preventing axonal loss and promoting remyelination. Furthermore, sildenafil decreases CD3+ leukocyte infiltration and microglial/macrophage activation in the spinal cord, while increasing forkhead box transcription factor 3-expressing T regulatory cells (Foxp3 Tregs). However, sildenafil treatment did not significantly affect MOG₃₅₋₅₅-stimulated proliferation or release of Th1/Th2 cytokines in splenocytes but decreased ICAM-1 in spinal cord infiltrated cells. The presence of reactive astrocytes forming scar-like structures around infiltrates was enhanced by sildenafil suggesting a possible mechanism for restriction of leukocyte spread into healthy parenchyma. These results highlight novel actions of sildenafil that may contribute to its beneficial effects in EAE and suggest that treatment with this widely used and well-tolerated drug may be a useful therapeutic intervention to ameliorate MS neuropathology.

Butyrylcholinesterase activity in multiple sclerosis neuropathology

Butyrylcholinesterase (BuChE) is an enzyme capable of hydrolysing a wide variety of esters including acetylcholine, a molecule involved in neurotransmission and modulation of immune cell activity. In the brain, BuChE is expressed in white matter and certain populations of neurons and glia. Multiple sclerosis (MS) is an autoimmune disease affecting white matter characterized by neuroinflammation and neurodegeneration in the central nervous system. Here we demonstrate alterations in BuChE activity in MS white matter lesions, including diminished enzyme activity associated with myelin and an increased activity in cells with microglial morphology. Increased BuChE activity within MS lesions could contribute to the pro-inflammatory immune responses through hydrolysis of acetylcholine and to demyelination through hydrolytic deacylation of myelin proteins such as proteolipid protein. This suggests that BuChE could be a potential target for novel disease-modifying strategies for MS.

Advances in the molecular imaging of multiple sclerosis

Molecular imaging has had little application to multiple sclerosis thus far. However, advances in preclinical studies and proofs-of-principle provided for other inflammatory disorders highlight the potential for using positron emission tomography, single-photon emission computerized tomography or MRI-based molecular imaging methods to define the distribution and trafficking of specific immune effector cells, or to follow changes in specific molecular neuropathology in multiple sclerosis. If this promise can be realized, novel insights into the dynamics of in vivo multiple sclerosis neuropathology can be expected. Furthermore, powerful new approaches to testing the pharmacology of novel therapeutics will become possible. Molecular imaging could also contribute to ‘personalizing’ treatments for better outcomes.

Early detection of the chemical changes occurring during the induction and prevention of autoimmune-mediated demyelination detected by FT-IR imaging

Multiple sclerosis (MS) is an inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS). Despite progress in understanding immunogenetic aspects of this disease, the mechanisms involved in lesion formation are unknown. To gain new insights into the neuropathology of MS, we used an innovative integration of Fourier transform infrared (FT-IR) microspectroscopy, bioinformatics, and a synchrotron light source to analyze macromolecular changes in the CNS during the course and prevention of experimental autoimmune encephalomyelitis (EAE), an animal model for MS. We report that subtle chemical and structural changes not observed by conventional histology were detected before the onset of clinical signs of EAE. Moreover, trained artificial neural networks (ANNs) could discriminate, with excellent sensitivity and specificity, pathology from surrounding tissues and the early stage of the disease progression. Notably, we show that this novel measurement platform can detect characteristic differences in biochemical composition of lesion pathology in animals partially protected against EAE by vaccination with Nogo-A, an inhibitor of neural outgrowth, demonstrating the potential for automated screening and evaluation of new therapeutic agents.

Cognitive reserve moderates the negative effect of brain atrophy on cognitive efficiency in multiple sclerosis

According to the cognitive reserve hypothesis, neuropsychological expression of brain disease is attenuated among persons with higher education or premorbid intelligence. The current research examined cognitive reserve in multiple sclerosis (MS) by investigating whether the negative effect of brain atrophy on information processing (IP) efficiency is moderated by premorbid intelligence. Thirty-eight persons with clinically definite MS completed a vocabulary-based estimate of premorbid intelligence (Wechsler Vocabulary) and a composite measure of IP efficiency (Symbol Digit Modalities Test and Paced Auditory Serial Addition Task). Brain atrophy was estimated from measurements of third ventricle width using high-resolution anatomical brain magnetic resonance imaging (magnetization-prepared rapid gradient echo). In a hierarchical regression analysis controlling for age and depressive symptomatology, brain atrophy predicted worse IP efficiency (R2 = .23, p = .003) and cognitive reserve predicted better IP efficiency (R2 = .13, p = .013), but these effects were moderated by an Atrophy x Cognitive Reserve interaction (R2 = .15, p = .004). The negative effect of brain atrophy on IP efficiency was attenuated at higher levels of reserve, such that MS subjects with higher reserve were better able to withstand MS neuropathology without suffering cognitive impairment. Results help explain the incomplete and inconsistent relationship between brain atrophy and IP efficiency in previous research.

Interplay between mechanisms of damage and repair in multiple sclerosis

The neuropathology of multiple sclerosis is characterised by focal damage to white matter. However, tissue damage is also present in the cortical grey matter, with a particularly high prevalence of cortical demyelination being observed in secondary progressive and primary progressive forms of the disease. The presence of meningeal B-cell follicle-like structures, which frequently appear during the secondary progressive phase of disease, may be involved in the formation of these subpial cortical lesions. Diffuse white matter inflammation accompanied by axonal damage can also be observed in normal appearing white matter and, again, this is more prominent in chronic progressive forms of multiple sclerosis than in acute stages of disease. Axonal damage is a particularly important component of the pathology of multiple sclerosis and appears to be a critical determinant of clinical outcome. Axons appear to become vulnerable to injury as a result of loss of their myelin sheaths. Remyelination represents an important mechanism of tissue repair in multiple sclerosis and already occurs at an early stage of lesion development and in both white and grey matter lesions. The extent of remyelination appears to be greater in cortical lesions and in lesions further from the ventricles. There is important heterogeneity between patients in terms of the extent of remyelination, which may reflect underlying differences in pathogenetic mechanisms between patients.

Recent advances in the neuropathology of multiple sclerosis

Important insights from multiple sclerosis (MS) pathology have broadened our view of the disease during the last years. Details of the inflammatory response as well as mechanisms of demyelination were elucidated. Damage to neuronal processes was identified as the major predictor of persistent disability in MS patients. Abortive repair mechanisms are increasingly studied, and our increased understanding will pave the way to new therapeutic strategies. This overview highlights some of the current views on MS pathogenesis derived from human neuropathology.

The Neurobiology of Multiple Sclerosis: Genes, Inflammation, and Neurodegeneration

The autoimmune model of multiple sclerosis (MS) pathogenesis provided for many years a useful but incomplete conceptual framework for understanding the complex array of factors that lead to the loss of immune homeostasis, myelin and axonal injury, and progressive neurological symptoms. The availability of novel tools in molecular neurogenetics and increasingly sophisticated neuroimaging technologies, together with the revitalization of MS neuropathology, has created a new paradigm for the multidisciplinary study of this disease. This is reflected by the growing resolution of the MS genomic map, discovery of delicate inflammatory networks that are perturbed in MS, identification of mediators of demyelination, and recognition that cumulative axonal loss and neuronal injury are the histological correlates of neurological disability. Together, these advances have set the stage for the development of therapeutic approaches designed to target the demyelinating and neurodegenerative components of the disease and promote repair.

The macrophage in MS: just a scavenger after all? Pathology and pathogenesis of the acute MS lesion

Advances in the neuropathology of multiple sclerosis (MS) have contributed greatly to our understanding of the mechanisms of tissue injury in the condition. Particular interest has focussed on the active MS lesion, defined by macrophage activity in the presence of partially demyelinated axons. This has led to the prevailing consensus that a T-cell dependent, macrophage-mediated, autoimmune attack on constituents in the normal myelin sheath underlies the disease. This hypothesis, which has been largely supported by comparisons with the animal model, experimental allergic encephalomyelitis, has recently been questioned by an analysis of the pathological events preceding myelin phagocytosis in nascent MS lesions. The prephagocytic changes in evolving lesions examined shortly after the onset of an MS relapse raise the possibility that oligodendrocyte cell death and associated changes within the myelin sheath initiate local macrophage scavenger activity, with subsequent amplification of the inflammatory response. The presence of such lesions in patients with a spectrum of pathological changes in nearby or distant active phagocytic plaques suggests that pathological heterogeneity in MS is largely due to evolution of lesional pathology, rather than pathogenic heterogeneity.

Neuropathology of multiple sclerosis—new concepts

Multiple sclerosis is a chronic inflammatory disease of the central nervous system with profound heterogeneity in clinical course, neuroradiological presentation and response to therapy. The pathological analysis of 235 actively demyelinating lesions coming from three centers revealed different structural and immunological features suggesting that different pathogenetic mechanisms are involved in lesion formation. On the basis of the presence or absence of immunoglobulin and complement deposition, myelin protein loss and the patterns of oligodendrocyte degeneration beside a T cell- and macrophage-dominated immune response, four distinct patterns of demyelination have been identified. In this short review, possible paraclinical markers for tissue destruction on the basis of the main features of myelin destruction are discussed. Furthermore, the importance of early axonal damage in multiple sclerosis is highlighted.

LIF receptor signaling limits immune-mediated demyelination by enhancing oligodendrocyte survival.

Multiple sclerosis (MS) is a disabling inflammatory demyelinating disease of the central nervous system (CNS) that primarily affects young adults. Available therapies can inhibit the inflammatory component of MS but do not suppress progressive clinical disability. An alternative approach would be to inhibit mechanisms that drive the neuropathology of MS, which often includes the death of oligodendrocytes, the cells responsible for myelinating the CNS. Identification of molecular mechanisms that mediate the stress response of oligodendrocytes to optimize their survival would serve this need. This study shows that the neurotrophic cytokine leukemia inhibitory factor (LIF) directly prevents oligodendrocyte death in animal models of MS. We also demonstrate that this therapeutic effect complements endogenous LIF receptor signaling, which already serves to limit oligodendrocyte loss during immune attack. Our results provide a novel approach for the treatment of MS.

Antibody responses to Acinetobacter spp. and Pseudomonas aeruginosa in multiple sclerosis: prospects for diagnosis using the myelin-acinetobacter-neurofilament antibody index.

Antibody responses to Acinetobacter (five strains), Pseudomonas aeruginosa, Escherichia coli, myelin basic protein (MBP), and neurofilaments were measured in sera from 26 multiple sclerosis (MS) patients, 20 patients with cerebrovascular accidents (CVA), 10 patients with viral encephalitis, and 25 healthy blood donors. In MS patients, elevated levels of antibodies against all strains of Acinetobacter tested were present, as well as antibodies against P. aeruginosa, MBP, and neurofilaments, but not antibodies to E. coli, compared to the CVA group and controls. The myelin-Acinetobacter-neurofilament antibody index appears to distinguish MS patients from patients with CVAs or healthy controls. The relevance of such antibodies to the neuropathology of MS requires further evaluation.

Neuropathology in multiple sclerosis: new concepts.

Multiple sclerosis lesions are characterized by inflammation, demyelination and a variable degree of axonal loss. The patterns of inflammation in MS lesions are compatible with a T-lymphocyte mediated immune reaction. The formation of demyelinated plaques, however, seem to require additional immunological mechanisms. In this review evidence is discussed for a pathogenetic role of demyelinating antibodies, toxic macrophage products, cytotoxic T-cells as well as metabolic disturbances of oligodendrocytes. It is suggested that the pathological heterogeneity regarding the patterns and extent of demyelination, remyelination and axonal loss may be the outcome of variable dominant immunopathogenetic mechanisms in different multiple sclerosis patients.

Neuropathology in multiple sclerosis: new concepts

Neuropathology in multiple sclerosis: new concepts

Multiple sclerosis: lessons from neuropathology.

The focus of multiple sclerosis (MS) research has been on attempts to identify the specific pathogenic mechanism responsible for producing the multifocal central nervous system inflammatory demyelinating lesions. However, extensive in vitro and in vivo evidence suggests that multiple different immunological mechanisms may produce the typical demyelinated plaque. A detailed examination of actively demyelinating MS lesions reveals a profound heterogeneity in the structural and immunopathological patterns of demyelination and oligodendrocyte pathology between different MS patients, suggesting multiple pathogenic mechanisms may contribute to oligodendrocyte and myelin injury in MS. These observations raise the question whether MS may be a neurological syndrome with different immunopathological mechanisms triggering a common pathway rather than a single disease with a uniform mechanism of myelin destruction. With the advent of new tools for neurobiological and immunological research applied to actively demyelinated MS lesions, an opportunity exists to reevaluate MS neuropathology. This review highlights the spectrum of the inflammatory demyelinating diseases, the multitude of effector mechanisms that may produce myelin destruction, and the pathologic heterogeneity observed in MS lesions. A careful evaluation of MS neuropathology should provide important clues regarding the induction, target, evolution, and pathogenesis of this complex disease.

Gliotoxicity, reverse transcriptase activity and retroviral RNA in monocyte/macrophage culture supernatants from patients with multiple sclerosis

In investigating a possible link between a novel retroviral agent (provisionally called MSRV), recently characterised in multiple sclerosis (MS), and the neuropathology of MS, it was found that there was a significant correlation between gliotoxicity and reverse transcriptase activity in monocyte/macrophage culture supernatants (MMCS) unique to MS patients. MMCS from healthy controls and patients with other neurological diseases did not display either gliotoxicity or reverse transcriptase activity. The observed gliotoxic effect was an initial, intermediate filament network disorganization and subsequent cell death which was specific to astrocytes and oligodendrocytes. The reverse transcriptase activity and MSRV-specific RNA were observed during the first 2 weeks of culture in MMCS from patients with active MS. The further elucidation of the molecular form(s) of this gliotoxic factor and its original source may be crucial in elucidating important etiopathogenic mechanisms in MS.

Morphology of demyelination in the human central nervous system

The principles of the neuropathological classification of disorders of central nervous system myelin are recalled. They are illustrated by a few selected examples. Dysmyelination is characterized by the production of an abnormal and unstable myelin sheath; it is often associated with hypomyelination (paucity of myelin formation) and is due to metabolic disorders. It is the main process in leukodystrophies. Storage of different lipids (e.g. sulfatides, long-chain fatty acids) or associated pathology of various cell types (in Alexander's disease, for example) are used for classifying these disorders. Biochemical and genetic characterizations are presently ongoing. Demyelination is the destruction of apparently normal myelin. It is often followed by remyelination. Our present knowledge on the neuropathology of multiple sclerosis, the most common demyelinating disease, is summarized. Cell-mediated demyelination affects the myelin sheaths for an obscure reason. The causes of the multifocal and sharply demarcated plaques, and of the fading of the remyelination process at the edge of some plaques, are not clear. A few examples of demyelinating diseases of known etiology and of various mechanisms are given. The similarities between acute disseminated leukoencephalitis and experimental autoimmune encephalitis are stressed. In progressive multifocal leukoencephalopathy, chronic infection of oligodendrocytes by JC virus induces poorly defined areas of demyelination. In AIDS, the pathogenesis of the myelin change is unclear. Macrophages may be responsible. Toxic and vascular disorders provide also good models for the understanding of mechanisms of demyelination.