Histopathology of Multiple Sclerosis Lesions Detected by Magnetic Resonance Imaging in Unfixed Postmortem Central Nervous System Tissue

Newcombe, Jia; Hawkins, C. P.; Henderson, C. L.; Patel, Harish M.; Woodroofe, Nicola; Hayes, G. M.; Cuzner, M. L.; MacManus, David; Boulay, Emmanuel; McDonald, W. I.

doi:10.1093/brain/114.2.1013

Cited by 157 publications

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“…The pathology of MS is usually thought of as being confined to the white matter, but the observation that autoantibodies to neurofilaments were seen in MS patients and not controls indicates that gray matter of the brain may also be involved in the disease. This confirms previous observations indicating the presence of gray matter pathology in MS patients using magnetic resonance imaging (12) and studies demonstrating the presence of antibodies to the 69-kDa neurofilament protein (11).…”

Section: Discussionsupporting

confidence: 92%

Antibody Responses toAcinetobacterspp. andPseudomonas aeruginosain Multiple Sclerosis: Prospects for Diagnosis Using the Myelin-Acinetobacter-Neurofilament Antibody Index

Hughes

Bonell

Natt

et al. 2001

Clin Diagn Lab Immunol

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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.Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system, affecting approximately 80,000 individuals in the United Kingdom and 400,000 in the United States. It is generally thought to be an autoimmune disease that is triggered by an infectious agent, possibly through a molecular mimicry mechanism of induction (1), similar to the situation occurring in the pathology of rheumatic fever (8).A number of different microbial sequences, including Pseudomonas peptides, are capable of activating myelin basic protein (MBP)-specific T-cell clones from MS patients (19), thereby indicating that several microorganisms may carry mimicry epitopes of myelin. This could explain the difficulty of linking the immunopathogenesis of MS to a single microbial agent, suggesting that several such bacteria could be involved in initiating the autoimmune process (6).It was decided to investigate MS patients for possible immune responses to pathogens that carry molecular mimicry sequences resembling brain components, such as Acinetobacter species and Pseudomonas aeruginosa. We have identified an amino acid sequence similarity between the encephalitogenic peptide of bovine MBP (5) and a sequence present in 4-carboxymuconolactone decarboxylase of Acinetobacter calcoaceticus (3). A similar sequence was also found in ␥-carboxymuconolactone decarboxylase of P. aeruginosa (Swissprot).The aims of this study were to determine whether MS patients have elevated levels of antibodies to five different strains of Acinetobacter as well as to P. aeruginosa, Escherichia coli, MBP, and neurofilaments, compared to cerebrovascular-accident (CVA) patients and control healthy blood donors. A further study was carried out, incorporating an inflammatory non-MS disease control, viral encephalitis, and a new set of control subjects, to assess whether MS patients have elevated levels of immunoglobulin G (IgG) antibodies to A. calcoaceticus 16904. MATERIALS AND METHODSSerum samples. Sera from 26 MS patients (nine males and 17 females; mean age, 42 years; range, 29 to 55 years) were obtained from the Institute of Neurology at the Hospital for Nervous Diseases, London, United Kingdom. Diagnosis was made according to the Poser criteria (13). Benign MS patients...

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Section: Discussionsupporting

confidence: 92%

Antibody Responses toAcinetobacterspp. andPseudomonas aeruginosain Multiple Sclerosis: Prospects for Diagnosis Using the Myelin-Acinetobacter-Neurofilament Antibody Index

Hughes

Bonell

Natt

et al. 2001

Clin Diagn Lab Immunol

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“…Several dedicated pulse sequences have been designed to disentangle the complex contrast mechanisms, in order to highlight one speci¢c physical property. In doing so, one can obtain information about the physical properties 1676 F. Barkhof and M. vanWalderveen (Newcombe et al 1991;Stewart et al 1984;Van Waesberghe et al 1999;Barkhof et al 1993). The typical sclerotic lesions that are found macroscopically at post-mortem are displayed as clearly demarcated lesions with a very high signal.…”

Section: Conventional Nmr Imaging: a Mixture Of Physical Parametersmentioning

confidence: 99%

Characterization of tissue damage in multiple sclerosis by nuclear magnetic resonance

Barkhof

Walderveen²

1999

Phil. Trans. R. Soc. Lond. B

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Nuclear magnetic resonance (NMR) imaging is an established diagnostic medium to diagnose multiple sclerosis (MS). In clinically stable MS patients, NMR detects silent disease activity, which is the reason why it is being used to monitor treatment trials, in which it serves as a secondary outcome parameter. The absence of a clear correlation with clinical disability, the so-called`clinico-radiological' paradox, and the poor predictive value of NMR prohibit the use of NMR as a primary outcome parameter in clinical trials. This isöamong othersöa result of the limited histopathological speci¢city of conventional, or T2-weighted' imaging, the most commonly used NMR technique. In this paper we review additional NMR techniques with higher tissue speci¢city, most of which show marked heterogeneity within NMRvisible lesions, re£ecting histopathological heterogeneity.Gadolinium enhancement identi¢es the early in£ammatory phase of lesion development, with active phagocytosis by macrophages. Persistently hypointense lesions on T1-weighted images (`black holes') relate to axonal loss and matrix destruction, and show a better correlation with clinical disability. Marked prolongation of T1 relaxation time correlates with enlargement of the extracellular space, which occurs as a result of axonal loss or oedema. Axonal viability can also be measured using the concentration of N-acetyl aspartate (NAA) using NMR spectroscopy; this technique is also capable of showing lactate and mobile lipids in lesions with active macrophages. The multi-exponential behaviour of T2 relaxation time in brain white matter provides a tool to monitor the myelin water component in MS lesions (short T2 component) as well as the expansion of the extracellular space (long T2 component). Chemical exchange with macromolecules (e.g. myelin) can be measured using magnetization transfer imaging, and correlates with demyelination, axonal loss and matrix destruction. Increased water di¡usion has been found in MS lesions (relating to oedema and an expanded extracellular space) and a loss of anisotropy may indicate a loss of ¢bre orientation (compatible with demyelination).Apart from the histopathological heterogeneity within focal MS lesions, the normal-appearing white matter shows de¢nite abnormalities with all quanti¢able NMR techniques. A decrease in the concentration of NAA, decreased magnetization transfer values and prolonged T1 relaxation time values are probably all related to microscopic abnormalities, including axonal damage. This`invisible' lesion load may constitute a signi¢cant proportion of the total lesion load but is not visible on conventional NMR. Similarly, mechanisms for clinical recovery exist, which are not distinguished using MR imaging. Therefore, it is highly unlikely that the clinico-radiological paradox will ever be solved completely. However, NMR provides an opportunity to sequentially measure tissue changes in vivo. Using MR parameters with (presumed) histopathological speci¢city, the development of (irreversible) tissue damage can be ...

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“…However, both the pathologic (17,18) and imaging studies (19,20) have shown that lesions could involve gray matter, although sparsely. Recent study indicates that neuronal axons may be damaged in acute and chronic lesions, suggesting that gray matter (neuronal cell bodies) may ultimately suffer damage (21).…”

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confidence: 99%

Magnetization Transfer Ratio Histogram Analysis of Normal-Appearing Gray Matter and Normal-Appearing White Matter in Multiple Sclerosis

Grossman

Udupa

et al. 2002

Journal of Computer Assisted Tomography

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BACKGROUND AND PURPOSE:Gray matter may be affected by multiple sclerosis (MS), a white matter disease. Magnetization transfer ratio (MTR) is a sensitive and quantitative marker for structural abnormalities, and has been used frequently in the imaging of MS. In this study, we evaluated the amount of MTR of gray matter among patients with relapsingremitting MS and healthy control subjects as well as the correlation between gray matter MTR abnormality and neurologic disability associated with relapsing-remitting MS. METHODS:We obtained fast spin-echo dual-echo and magnetization transfer (with and without MT saturation pulses) images from eighteen patients with relapsing-remitting MS and 18 age-matched healthy control subjects. Gray matter was segmented using a semiautomated system. Gray matter MTR histogram parameters, Kurtzke Expanded Disability Status Scale (EDSS), total T2 lesion volume, and gray matter volumes were obtained for statistical analysis. RESULTS: A significant difference was found in gray matter MTR between patients with relapsing-remitting MS and healthy subjects (mean and median). Gray matter MTR histogram normalized peak heights in patients inversely correlated with EDSS (r ‫؍‬ Ϫ0.65, P ‫؍‬ .01).There was also an inverse correlation between mean MTR of gray matter and total T2 lesion volume.CONCLUSION: The MTR of gray matter significantly differed between patients with relapsing-remitting MS and healthy control subjects, suggesting that MS is a more diffuse disease affecting the whole brain, and neuronal damage accumulates in step with T2 lesion volume. Our finding of the relationship between gray matter MTR and EDSS indicates that measurement of gray matter abnormality may be a potentially useful tool for assessing clinical disability in MS.

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Histopathology of Multiple Sclerosis Lesions Detected by Magnetic Resonance Imaging in Unfixed Postmortem Central Nervous System Tissue

Cited by 157 publications

References 0 publications

Antibody Responses toAcinetobacterspp. andPseudomonas aeruginosain Multiple Sclerosis: Prospects for Diagnosis Using the Myelin-Acinetobacter-Neurofilament Antibody Index

Antibody Responses toAcinetobacterspp. andPseudomonas aeruginosain Multiple Sclerosis: Prospects for Diagnosis Using the Myelin-Acinetobacter-Neurofilament Antibody Index

Characterization of tissue damage in multiple sclerosis by nuclear magnetic resonance

Magnetization Transfer Ratio Histogram Analysis of Normal-Appearing Gray Matter and Normal-Appearing White Matter in Multiple Sclerosis

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