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MS Abstracts 11a-2g

  1. Numerical tissue characterization in MS via standardization of the MR image intensity scale
    J Magn Reson Imaging 2000 Nov;12(5):715-721

  2. The peripheral Benzodiazepine binding site in the Brain in Multiple Sclerosis: Quantitative in vivo imaging of Microglia as a measure of disease activity
    Brain 2000 Nov;123(Pt 11):2321-2337

  3. Evidence for adaptive functional changes in the Cerebral Cortex with Axonal injury from Multiple Sclerosis
    Brain 2000 Nov;123(Pt 11):2314-2320

  4. The effect of Interferon-ß-1b treatment on MRI measures of Cerebral atrophy in Secondary/Progressive Multiple Sclerosis
    Brain 2000 Nov;123(Pt 11):2256-2263

  5. Human HerpesVirus 6 and Multiple Sclerosis: Systemic active infections in patients with early disease
    Clin Infect Dis 2000 Oct;31(4):894-903

  6. Surges of increased T-Cell reactivity to an Encephalitogenic region of Myelin ProteoLipid Protein occur more often in Multiple Sclerosis than in healthy subjects
    J Immunol 2000 Nov 1;165(9):5322-5331

  7. Temporal development of autoreactive Th1 responses and endogenous presentation of self Myelin Epitopes by Central Nervous System-resident APCs in Theiler's Virus-Infected Mice
    J Immunol 2000 Nov 1;165(9):5304-5314

  8. InterLeukin-6 expression in human Multiple Sclerosis lesions
    NeuroSci Lett 2000 Nov 10;294(1):45-48

  9. Morphometric analysis of Axons in the minute Multiple Sclerosis lesions and shadow plaques in Multiple Sclerosis
    Folia Neuropathol 2000;38(3):104-10

  10. Enhanced Magnetic Resonance Imaging in Multiple Sclerosis
    Mult Scler 2000 Oct;6(5):320-6


Numerical Tissue Characterization In MS Via Standardization Of The Mr Image Intensity Scale

Ge Y, Udupa JK, Nyul LG, Wei L, Grossman RI
J Magn Reson Imaging 2000 Nov;12(5):715-721
Hospital of the Univ of Pennsylvania, Dept of Radiology, Philadelphia, Pennsylvania 19104-6021
PMID# 11050641; UI# 20504139

Image intensity standardization is a recently developed postprocessing method that is capable of correcting the signal intensity variations in MR images.

We evaluated signal intensity of healthy and diseased tissues in 10 Multiple Sclerosis (MS) patients based on standardized dual fast Spin-Echo MR images using a numerical postprocessing technique.

The main idea of this technique is to deform the volume image Histogram of each study to match a standard Histogram and to utilize the resulting transformation to map the image intensities into standard scale.

Upon standardization, the coefficients of variation of signal intensities for each segmented tissue (Gray Matter, White Matter, Lesion Plaques, and diffuse abnormal White Matter) in all patients were significantly smaller (2.3-9.2 times) than in the original images.

And the same tissues from different patients looked alike, with similar intensity characteristics.

Numerical tissue characterizability of different tissues in MS achieved by standardization offers a fixed tissue-specific meaning for the numerical values and can significantly facilitate image segmentation and analysis.

J. Magn. Reson. Imaging 2000;12:715-721. Copyright 2000 Wiley-Liss, Inc.


The Peripheral Benzodiazepine Binding Site In The Brain In Multiple Sclerosis: Quantitative In Vivo Imaging Of Microglia As A Measure Of Disease Activity

Banati RB, Newcombe J, Gunn RN, Cagnin A, Turkheimer F, Heppner F, Price G, Wegner F, Giovannoni G, Miller DH, Perkin GD, Smith T, Hewson AK, Bydder G, Kreutzberg GW, Jones T, Cuzner ML, Myers R
Brain 2000 Nov;123(Pt 11):2321-2337
MRC Cyclotron Unit and Robert Steiner Magnetic Resonance Imaging Unit, Imperial College School of Medicine, Hammersmith Hospital, Dept of NeuroScience, Imperial College School of Medicine, Charing Cross Hospital, NeuroInflammation Group and NMR Research Unit, Institute of Neurology, Univ, College London, Eisai London Research Laboratories, Univ, College London, London, Dept of NeuroScience Research, SmithKline-Beecham Pharmaceuticals, Harlow, Dept of Physiology, Univ of Cambridge, Cambridge, UK, Paul Flechsig Institute, Leipzig, Dept of Neuromorphology,Max-Planck-Institute of NeuroBiology, Munich, Germany and Dept of Neuropathology, Univ of Zurich, Switzerland
PMID# 11050032; UI# 20504122

This study identifies by MicroAutoRadiography activated Microglia/Macrophages as the main cell type expressing the Peripheral Benzodiazepine Binding Site (PBBS) at sites of active CNS pathology.

Quantitative measurements of PBBS expression in vivo obtained by PET and [(11)C](R:)-PK11195 are shown to correspond to animal experimental and human post-mortem data on the distribution pattern of activated Microglia in Inflammatory Brain Disease.

Film AutoRadiography with [(3)H](R:)-PK11195, a specific Ligand for the PBBS, showed minimal binding in normal control CNS, whereas maximal binding to MonoNuclear Cells was found in Multiple Sclerosis plaques.

However, there was also significantly increased [(3)H](R:)-PK11195 binding on activated Microglia outside the HistoPathologically defined borders of Multiple Sclerosis plaques.

And in areas, such as the Cerebral Central Gray Matter, that are not normally reported as sites of pathology in Multiple Sclerosis.

A similar pattern of [(3)H](R:)-PK11195 binding in areas containing activated Microglia was seen in the CNS of animals with Experimental Allergic EncephaloMyelitis (EAE).

In areas without identifiable focal pathology, ImmunoCytoChemical staining combined with high-resolution emulsion AutoRadiography demonstrated that the Cellular source of [(3)H](R:)-PK11195 binding is activated Microglia, which frequently retains a ramified morphology.

Furthermore, in vitro RadioLigand Binding studies confirmed that Microglial activation leads to a rise in the number of PBBS and not a change in binding affinity.

Quantitative [(11)C](R:)-PK11195 PET in Multiple Sclerosis patients demonstrated increased PBBS expression in areas of focal pathology identified by T1- and T2-weighted MRI and, importantly, also in Normal-Appearing Anatomical Structures, including Cerebral Central Gray Matter.

The additional binding frequently delineated Neuronal projection areas, such as the Lateral Geniculate Bodies in patients with a history of Optic Neuritis. In summary, [(11)C](R:)-PK11195 PET provides a cellular marker of disease activity in vivo in the human Brain.


Evidence For Adaptive Functional Changes In The Cerebral Cortex With Axonal Injury From Multiple Sclerosis

Reddy H, Narayanan S, Arnoutelis R, Jenkinson M, Antel J, Matthews PM, Arnold DL
Brain 2000 Nov;123(Pt 11):2314-2320
Centre for Functional Magnetic Resonance Imaging of the Brain, Dept of Clinical Neurology, and Univ of Oxford, John Radcliffe Hospital, Oxford, UK and Montreal Neurological Institute, McGill University, Dept of Neurology and NeuroSurgery, Montreal, Canada
PMID# 11050031; UI# 20504121

Axonal injury occurs even in the earliest stages of Multiple Sclerosis.

Magnetic Resonance Spectroscopic Imaging (MRSI) measurements of Brain N:-AcetylAspartate (NAA), a marker of Axonal integrity, show that this Axonal injury can occur even in the absence of clinically evident functional impairments.

To test whether Cortical adaptive responses contribute to the maintenance of normal Motor Function in patients with Multiple Sclerosis, we performed MRSI and functional MRI (fMRI) examinations of nine Multiple Sclerosis patients who had unimpaired hand function.

We found that activation of the IpsiLateral SensoriMotor Cortex with simple hand movements was increased by a mean of fivefold relative to normal controls (n = 8) and that the extent of this increase was strongly correlated (sigma = -0.93, P: = 0.001) with decreases in Brain NAA.

These results suggest that compensatory Cortical adaptive responses may help to account for the limited relationship between conventional MRI measures of lesion burden and clinical measures of disability.

And that therapies directed towards promoting Cortical reorganization in response to Brain injury could enhance recovery from relapses of Multiple Sclerosis.


The Effect Of Interferon-ß-1b treatment on MRI Measures Of Cerebral Atrophy In Secondary/Progressive Multiple Sclerosis

Molyneux PD, Kappos L, Polman C, Pozzilli C, Barkhof F, Filippi M, Yousry T, Hahn D, Wagner K, Ghazi M, Beckmann K, Dahlke F, Losseff N, Barker GJ, Thompson AJ, Miller DH
Brain 2000 Nov;123(Pt 11):2256-2263
Institue of Neurology, NMR Research Unit, National Hospital, Queen Square, London WC1N 3BG, UK
PMID# 11050025; UI# 20504115

The recently completed European trial of Interferon-ß-1b (IFN-ß-1b) in patients with Secondary/Progressive Multiple Sclerosis (SP Multiple Sclerosis) has given an opportunity to assess the impact of treatment on Cerebral Atrophy using serial MRI.

Unenhanced T1-weighted Brain imaging was acquired in a subgroup of 95 patients from five of the European centers; imaging was performed at 6-month intervals from month 0 to month 36.

A blinded observer measured Cerebral volume on four contiguous 5 mm Cerebral Hemisphere slices at each time point, using an algorithm with a high level of reproducibility and automation.

There was a significant and progressive reduction in Cerebral volume in both placebo and treated groups, with a mean reduction of 3.9 and 2.9%, respectively, by month 36 (P: = 0.34 between groups).

Exploratory subgroup analyzes indicated that patients without Gadolinium (Gd) enhancement at the baseline had a greater reduction of Cerebral volume in the placebo group (mean reduction at month 36: placebo 5.1%, IFN-ß-1b 1.8%, P: < 0.05).

Whereas those with Gd-enhancing lesions showed a trend to greater reduction of Cerebral volume if the patient was on IFN-ß-1b (placebo 2.6%, IFN-ß-1b 3.7%; P: > 0.05).

These results are consistent with ongoing tissue loss in both arms of this study of Secondary/Progressive Multiple Sclerosis. This finding is concordant with previous observations that disease progression, although delayed, is not halted by IFN-ß.

The different pattern seen in patients with and without baseline Gadolinium enhancement suggests that part of the Cerebral volume reduction observed in IFN-ß-treated patients may be due to the AntiInflammatory/AntiEdematous effect of the drug.

Longer periods of observation and larger groups of patients may be needed to detect the effects of treatment on Cerebral Atrophy in this population of patients with advanced disease


Human HerpesVirus 6 And Multiple Sclerosis: Systemic Active Infections In Patients With Early Disease

Knox KK, Brewer JH, Henry JM, Harrington DJ, Carrigan DR
Clin Infect Dis 2000 Oct;31(4):894-903
Institute for Viral Pathogenesis, Milwaukee, WI 53226, USA
PMID# 11049767; UI# 20503988

By means of ImmunoHistoChemical staining, cells actively infected with Human HerpesVirus 6 (HHV-6) were found in Central Nervous System tissues from 8 (73%) of 11 patients with Definite Multiple Sclerosis (MS).

Interestingly, 17 (90%) of 19 tissue sections showing active DeMyelination were positive for HHV-6-infected cells compared with only 3 (13%) of 23 tissue sections free of active disease (P<.0001).

Central Nervous System tissues from 2 of 28 normal persons and patients with other Inflammatory DeMyelinative Diseases were positive for HHV-6-infected cells (P<.0001), and the 2 positive cases were diagnosed as having HHV-6 LeukoEncephalitis.

By use of a rapid culture assay, blood samples from 22 (54%) of 41 patients with definite MS were found to contain active HHV-6 infections, compared with 0 of 61 normal controls (P<.0001).

No significant difference was found between HHV-6 Viremia-positive and HHV-6 Viremia-negative MS patients with respect to type of disease (Relapsing/Remitting or Progressive).

In contrast, patients with active HHV-6 Viremia were significantly younger and had shorter durations of disease than did HHV-6 Viremia-negative patients.


Surges Of Increased T-Cell Reactivity To An Encephalitogenic Region Of Myelin ProteoLipid Protein Occur More Often In Multiple Sclerosis Than In Healthy Subjects

Pender MP, Csurhes PA, Greer JM, Mowat PD, Henderson RD, Cameron KD, Purdie DM, McCombe PA, Good MF
J Immunol 2000 Nov 1;165(9):5322-5331
Royal Brisbane Hospital, Dept of Medicine, and Dept of Neurology and Division of Radiology, and Queensland Institute of Medical Research, Brisbane, Australia
PMID# 11046067; UI# 20501142

We have previously shown that patients with Multiple Sclerosis (MS) have increased T-Cell responses to the ImmunoDominant region (residues 184-209) of Myelin ProteoLipid protein (PLP).

The present study investigated whether this reactivity fluctuates over time and correlates with disease activity.

We performed monthly limiting dilution assays for 12-16 mo in four healthy subjects and five patients with Relapsing/Remitting MS to quantify the frequencies of circulating T-Cells proliferating in response to PLP(41-58), PLP(184-199), PLP(190-209), Myelin Basic Protein (MBP), MBP(82-100), and Tetanus Toxoid.

Disease activity was monitored by clinical assessment and Gadolinium-enhanced Magnetic Resonance Imaging of the Brain.

There were fluctuations in the frequencies of AutoReactive T-Cells in all subjects. Compared with healthy controls, MS patients had significantly more frequent surges of T-Cells reactive to the 184-209 region of PLP, but infrequent surges of T-Cell reactivity to MBP(82-100).

There was temporal clustering of the surges of T-Cell reactivity to MBP(82-100) and MBP, suggesting T-Cell activation by environmental stimuli.

Some clinical relapses were preceded by surges of T-Cell reactivity to PLP(184-209), and in one patient there was significant correlation between the frequency of T-Cells reactive to PLP(184-199) and the total number of Gadolinium-enhancing Magnetic Resonance Imaging lesions.

However, other relapses were not associated with surges of T-Cell reactivity to the Ags tested. T-Cells reactive to PLP(184-209) may contribute to the development of some of the CNS Lesions in MS.


Temporal Development of Autoreactive Th1 Responses and Endogenous Presentation of Self Myelin Epitopes by Central Nervous System-Resident APCs in Theiler's Virus-Infected Mice

Katz-Levy Y, Neville KL, Padilla J, Rahbe S, Begolka WS, Girvin AM, Olson JK, Vanderlugt CL, Miller SD
J Immunol 2000 Nov 1;165(9):5304-5314
Northwestern Univ, Medical School, Dept of Microbiology-Immunology and
Interdepartmental Immunobiology Center, Chicago, IL 60611
PMID# 11046065; UI# 20501140

Theiler's Murine EncephaloMyelitis Virus (TMEV)-induced DeMyelinating Disease is a Chronic/Progressive, Immune-mediated CNS DeMyelinating Disease and a relevant model of Multiple Sclerosis.

Myelin destruction is initiated by TMEV-specific CD4+ T-Cells targeting persistently infected CNS-resident APCs leading to activation of Myelin Epitope-specific CD4+ T-Cells via Epitope spreading.

We examined the temporal development of Virus- and Myelin-specific T-Cell responses and acquisition of Virus and Myelin Epitopes by CNS-resident APCs during the Chronic disease course.

CD4+ T-Cell responses to Virus Epitopes arise within 1 wk after infection and persist over a >300-day period.

In contrast, Myelin-specific T-Cell responses are first apparent approximately 50-60 days PostInfection, appear in an ordered progression associated with their relative Encephalitogenic dominance, and also persist.

Consistent with disease initiation by Virus-specific CD4+ T-Cells, CNS MonoNuclear Cells from TMEV-infected SJL mice endogenously process and present Virus epitopes throughout the disease course, while Myelin Epitopes are presented only after initiation of Myelin damage (>50-60 days PostInfection).

Activated F4/80+ APCs expressing high levels of MHC Class II and B7 CoStimulatory molecules and ingested Myelin debris chronically accumulate in the CNS.

These results suggest a process of AutoImmune induction in which Virus-specific T-Cell-mediated bystander Myelin destruction leads to the recruitment and activation of infiltrating and CNS-resident APCs that process and present endogenous Myelin Epitopes to AutoReactive T-Cells in a hierarchical order.


InterLeukin-6 Expression In Human Multiple Sclerosis Lesions

Schonrock LM, Gawlowski G, Bruck W
NeuroSci Lett 2000 Nov 10;294(1):45-48
Univ of Gottingen, Dept of Neuropathology, Gottingen, Germany
PMID# 11044583; UI# 20501237

The present study investigated InterLeukin-6 (IL-6) expression in 36 Multiple Sclerosis (MS) cases by ImmunoCytoChemistry.

The numbers of IL-6 expressing cells were correlated to the stage of DeMyelinating activity and the pattern of Oligodendrocyte pathology. IL-6 positive cells were identified as Macrophages and Astrocytes by morphological criteria.

Approximately 10-17% of the Astrocytes and up to 2% of the Macrophages within the lesion expressed IL-6. Highest numbers of IL-6 expressing cells were found in inactive DeMyelinating lesions.

There was a significant increase of IL-6 positive cells in lesions with Oligodendrocyte preservation, whereas absence of IL-6 expression correlated with Oligodendrocyte loss.

These observations indicate a possible important role for IL-6 in Oligodendrocyte protection and survival in MS lesions.


Morphometric Analysis Of Axons In The Minute Multiple Sclerosis Lesions And Shadow Plaques In Multiple Sclerosis

Nowacki P, Potemkowski A, Korwin-Piotrowska T, Nocon D
Folia Neuropathol 2000;38(3):104-10
Pomeranian Medical Academy, Dept of Neurology, Szczecin, Poland
PMID# 11043971; UI# 20496687

The objective of the present study was to quantitatively detect Axons in the minute Multiple Sclerosis (MS) lesions and in shadow plaques, taking into consideration the Relapsing/Remitting (RR) and Secondary/Progressive (SP) stages of MS.

The Brain tissue of 12 patients deceased due to MS was investigated. An image-computerized analysis was made for measurements of Axons.

Based on the findings we concluded that damage to Axons appears in both the minute MS lesions and in shadow plaques. DeMyelination and ineffective (too late or too slow) ReMyelination seemed to be very important factors in Axonal damage.

Irreversible damage to Axons may appear in both the Secondary/Progressive and Relapsing/Remitting stages of MS, causing permanent Neurological deficits, irrespective of the duration of the disease.


Enhanced Magnetic Resonance Imaging In Multiple Sclerosis

Filippi M
Mult Scler 2000 Oct;6(5):320-6
Univ of Milan, NeuroImaging Research Unit, and Scientific Institute, Ospedale San Raffaele, Dept of NeuroScience, Via Olgettina 60 - 20132, Milan, Italy
PMID# 11064441; UI# 20519925

Gadolinium-enhanced Magnetic Resonance Imaging (MRI) is very sensitive in the detection of active lesions of Multiple Sclerosis (MS) and has become a valuable tool to monitor the evolution of the disease either natural or modified by treatment.

In the past few years, several studies, on the one hand, have assessed several ways to increase the sensitivity of enhanced MRI to disease activity and, on the other, have investigated in vivo the nature and evolution of enhancing lesions using different non-conventional MR techniques to better define the relationship between enhancement and tissue loss in MS.

The present review is a summary of these studies whose results are discussed in the context of MS clinical trial planning and monitoring.

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