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MS Abstracts 04b-2g7

  1. Responsiveness and predictive value of EDSS and MSFC in Primary/Progressive MS
    Neurology 2008 Mar 25;70(13 Pt 2):1084-91

  2. Functional NeuroImaging in Multiple Sclerosis with radiolabelled Glia markers: Preliminary comparative PET studies with [(11)C]Vinpocetine and [(11)C]PK11195 in patients
    J Neurol Sci 2008 Jan 15;264(1-2):9-17

  3. Longitudinal Magnetic Resonance Spectroscopic imaging of Primary/Progressive Multiple Sclerosis patients treated with Glatiramer Acetate: multicenter study
    Mult Scler 2008 Jan;14(1):73-80

  4. Cervical Spinal Cord Lesions in Multiple Sclerosis: T1-weighted Inversion-Recovery MR Imaging with Phase-Sensitive Reconstruction
    Radiology 2008 Jan;246(1):258-264

  5. Mitoxantrone as induction treatment in aggressive Relapsing/Remitting Multiple Sclerosis: treatment response factors in a 5 year follow-up observational study of 100 consecutive patients
    J Neurol NeuroSurg Psychiatry 2008 Jan;79(1):52-6

  6. Contribution of relapses to disability in Multiple Sclerosis
    J Neurol 2008 Feb;255(2):280-7.

  7. Relating functional changes during hand movement to clinical parameters in patients with Multiple Sclerosis in a multi-center fMRI study
    Eur J Neurol 2008 Feb;15(2):113-22

  8. Unexpected Multiple Sclerosis: follow-up of 30 patients with Magnetic Resonance Imaging and clinical conversion profile
    J Neurol NeuroSurg Psychiatry 2008 Feb;79(2):195-8

  9. Mapping the Brain pathways of Declarative Verbal Memory: Evidence from White Matter lesions in the living human Brain
    NeuroImage 2008 Sep 1;42(3):1237-43

  10. ImmunoGlobulins and Complement in postmortem Multiple Sclerosis tissue
    Ann Neurol 2009 Feb 4;65(1):32-46

  11. Therapeutic vaccination with a trivalent T-Cell Receptor (TCR) Peptide Vaccine restores deficient FoxP3 expression and TCR recognition in subjects with Multiple Sclerosis
    Immunology 2008 Jan;123(1):66-78

  12. Mouse model mimics Multiple Sclerosis in the Clinico-Radiological Paradox
    Eur J NeuroSci 2007 Jul;26(1):190-8





#1

Responsiveness And Predictive Value Of EDSS And MSFC In Primary/Progressive MS

Kragt JJ, Thompson AJ, Montalban X, Tintoré M, Río J, Polman CH, Uitdehaag BM
Neurology 2008 Mar 25;70(13 Pt 2):1084-91
VU University Medical Center, Departments of Neurology, and Clinical Epidemiology and Biostatistics, Amsterdam, the Netherlands; Institute of Neurology, University College, Neurological Outcome Measures Unit, London, UK; and Hospital Universitari Vall d'Hebron, Unitat de NeuroImmunologia Clínica, Barcelona, Spain
PMID# 18184917
Abstract

Introduction
We studied the responsiveness and predictive value of two widely used clinical outcome measures that document Multiple Sclerosis (MS) disease progression.

The Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC)-in patients with Primary/Progressive (PP) MS. Disease course in PPMS shows less fluctuation than in Relapsing/Remitting (RR) MS.

Methods
In a group of 161 patients with PPMS, EDSS and MSFC were performed at three timepoints.

To assess responsiveness, mean change scores and variances were plotted against baseline scores and effect sizes were calculated.

Predictive value was determined by calculating sensitivity, specificity, and likelihood ratios (LRs) of 1-year changes to predict changes over 2 years.

Furthermore, multivariate logistic regression models were used to assess the predictive value of short-term worsening on EDSS and MSFC.

Results
Responsiveness of both EDSS and MSFC was shown to be limited and mean changes were highly dependent on the baseline scores. Effect sizes for EDSS and MSFC were small and inconclusive (0.239 and 0.161).

The predictive value of a short-term worsening (baseline to year 1) to predict worsening in the long term (baseline to year 2) was expressed for EDSS by a sensitivity of 0.55 and a LR+ of 8.64. For MSFC, sensitivity was 0.68 and LR+ was 3.14.

However, short-term worsening was a poor predictor of subsequent worsening (year 1 to year 2) for EDSS (LR+ 1.06) and this relationship was actually inverse for MSFC (LR+ 0.61).

Conclusion
In this study over a period of 2 years in Primary/Progressive Multiple Sclerosis, the Multiple Sclerosis Functional Composite (MSFC) was less responsive than the Expanded Disability Status Scale (EDSS).

The predictive value of neither EDSS nor MSFC was very powerful.



#2

Functional NeuroImaging In Multiple Sclerosis With Radiolabelled Glia Markers: Preliminary Comparative PET studies with [(11)C]Vinpocetine And [(11)C]PK11195 In Patients

Vas A, Shchukin Y, Karrenbauer VD, Cselényi Z, Kostulas K, Hillert J, Savic I, Takano A, Halldin C, Gulyás B
J Neurol Sci 2008 Jan 15;264(1-2):9-17
Chemical Works of Gedeon Richter Ltd., Gyomroi ut 19/21, H-1103 Budapest, Hungary
PMID# 17727889
Abstract

With the purpose of demonstrating the use of Positron Emission Tomography (PET) and radiolabelled Glia Markers to indicate Regional Cerebral damage.

We measured with PET in four young Multiplex Sclerosis (MS) patients in two consecutive measurements the global and regional Brain uptake as well as regional distribution and Binding Potential (BP) of [(11)C]Vinpocetine and [(11)C]PK11195.

Both Ligands showed increased uptake and BP in the regions of local Brain Damage. However, regional BP values for [(11)C]Vinpocetine were markedly higher than those for [(11)C]PK11195.

This feature of the former RadioLigand may be related to its high Brain uptake and marked affinity to the Peripheral Benzodiazepine Receptor Binding Sites (PBRS), characteristic for Glia Cells.

As local Brain traumas entail reactive Glia accumulation in and around the site of the damage:

The present findings may indicate that [(11)C]Vinpocetine marks the place or boundaries of local Brain damage by binding to the PBBS present in Glia Cells, which, in turn, accumulate in the region of the damage.

    The present findings:
  1. confirm earlier observations with [(11)C]PK11195 as a potential Glia Marker in PET studies and

  2. support the working hypothesis that [(11)C]Vinpocetine is a potentially useful PET marker of regional and global Brain damage resulting in Glia accumulation locally or globally in the human Brain

    The comparative analysis of the two Ligands indicate that [(11)C]Vinpocetine shows a number of characteristics favorable in comparison with [(11)C]PK11195.



    #3

    Longitudinal Magnetic Resonance Spectroscopic Imaging Of Primary/Progressive Multiple Sclerosis Patients Treated With Glatiramer Acetate: Multicenter Study

    TSajja BR, Narayana PA, Wolinsky JS, Ahn CW
    The PROMiSe Trial MRSI Group
    Mult Scler 2008 Jan;14(1):73-80
    University of Texas Medical School at Houston, Department of Diagnostic and Interventional Imaging, TX 77030, USA
    PMID# 17881390
    Abstract

    Multicenter proton Magnetic Resonance Spectroscopic Imaging (MRSI) studies were performed on 58 Primary/Progressive Multiple Sclerosis (PPMS) patients from four centers for investigating the efficacy of Glatiramer Acetate (GA) treatment.

    These patients were drawn from 943 subjects who participated in the PROMiSe trial. In these MRSI studies, patients were followed over a period of 3 years.

    MRSI data were acquired by all the centers using the same pulse sequence, and spectral analysis was performed at a single site using a customized analysis software package.

    Quantitative metabolite ratios, N-Acetyl Aspartate (NAA)/Creatine (Cr) and Choline (Cho)/Cr, were compared between GA-treated and placebo-treated PPMS patients.

    There was no significant difference in metabolite ratios between GA-treated and placebo-treated patients.

    The difference in metabolite ratios between the Normal-Appearing Tissues (NAT) and lesion-containing regions (LCR) in GA treated patients was not significantly different from placebo treated patients.

    Strong Lipid resonances, even in the absence of lesions, were observed on MRSI data in both Gray Matter and White Matter in placebo- and GA-treated PPMS patients.

    No significant difference in number of patients with Lipids between the two groups over a period of 3 years was found.

    Multiple Sclerosis 2008; 14: 73-80. http://msj.sagepub.com/.



    #4

    Cervical Spinal Cord Lesions In Multiple Sclerosis: T1-Weighted Inversion-Recovery MR Imaging With Phase-Sensitive Reconstruction

    The 2006 RSNA Annual Meeting
    Poonawalla AH, Hou P, Nelson FA, Wolinsky JS, Narayana PA
    Radiology 2008 Jan;246(1):258-264
    The University of Texas Medical School at Houston, Department of Diagnostic and Interventional Radiology and Department of Neurology, 6431 Fannin Street, Houston, TX 77030
    PMID# 17991786
    Abstract

    This Magnetic Resonance (MR) imaging study was approved by the institutional review board and was HIPAA compliant. Written informed consent was obtained from all participants.

    The purpose of the study was to prospectively compare T1-weighted Inversion Recovery with Short Inversion Time Inversion Recovery (STIR) and dual Fast Spin Echo (FSE) for imaging Cervical Spinal Cord lesions in patients with Multiple Sclerosis (MS).

    Twelve patients (eight men, four women; median age, 44 years) were imaged by using T1-weighted inversion recovery, STIR, and FSE.

    Contrast between lesions and normal Cervical Cord was measured for each sequence, and generalized estimating equation analysis was used to test statistical significance of the results.

    Normalized contrast between lesion and Normal-Appearing Spinal Cord was significantly higher for T1-weighted inversion recovery than for the other sequences (P < .0001).

    Use of phase-sensitive reconstruction improved lesion localization and boundary definition.

    These advantages of T1-weighted inversion recovery over STIR and dual-echo FSE suggest that it has potential in Cervical Spinal Cord imaging of MS.

    (c) RSNA, 2007.



    #5

    Mitoxantrone As Induction Treatment In Aggressive Relapsing/Remitting Multiple Sclerosis: Treatment Response Factors In A 5 Year Follow-Up Observational Study Of 100 Consecutive Patients

    Le Page E, Leray E, Taurin G, Coustans M, Chaperon J, Morrissey SP, Edan G
    J Neurol NeuroSurg Psychiatry 2008 Jan;79(1):52-6
    Service de Neurologie, Hôpital Pontchaillou, rue Henri Le Guilloux, 35 033 Rennes Cedex, France
    PMID# 17846110
    Abstract

    Background
    Mitoxantrone was approved by the French health authority (AFSAPPS) in October 2003 to treat patients with aggressive Multiple Sclerosis (MS).

    Objective
    To report the long term effectiveness and safety of Mitoxantrone as induction therapy in patients with aggressive Relapsing/Remitting MS, and to assess treatment response factors.

    Material And Methods
    100 consecutive patients with aggressive Relapsing/Remitting MS received mitoxantrone 20 mg monthly combined with MethylPrednisolone 1 g for 6 months.

    Relapses, Expanded Disability Status Scale (EDSS) and drug safety were assessed every 6 months for up to at least 5 years.

    Within 6 months after induction, 73 patients received maintenance therapy (Mitoxantrone every 3 months (n = 21); IFN-ß (n = 25); Azathioprine (n = 15); Methotrexate (n = 7); Glatiramer Acetate (n = 5)).

    Results
    During the 12 months following initiation of Mitoxantrone, the Annual Relapse Rate (ARR) was reduced by 91%.

    78% of patients remained relapse free, MRI activity was reduced by 89%, the mean EDSS decreased by 1.2 points (p < 10(-6)) and 64% of patients improved by 1 point or more on the EDSS.

    In the longer term, the ARR reduction was sustained (0.29-0.42 for up to 5 years), the median time to the first relapse was 2.8 years and disability remained improved after 5 years.

    Younger age and lower EDSS score at the start of Mitoxantrone treatment were predictive of better treatment response.

    Three patients presented with an asymptomatic decrease in left Ventricular ejection fraction to less than 50% (one reversible).

    One patient was diagnosed with acute Myeloid Leukaemia (remission 5 years after diagnosis).

    Conclusion
    Mitoxantrone monthly for 6 months as induction therapy followed by maintenance treatment showed sustained clinical benefit for up to 5 years with an acceptable adverse events profile in patients with aggressive Relapsing/Remitting MS.



#6

Contribution Of Relapses To Disability In Multiple Sclerosis

Hirst C, Ingram G, Pearson O, Pickersgill T, Scolding N, Robertson N
J Neurol 2008 Feb;255(2):280-7
University Hospital of Wales, Helen Durham Neuro-inflammatory Centre, Clinical Research Fellow in Neurology, Dept. of Neurology, Heath Park, Cardiff, UK, CF14 4XN
PMID# 18204919
Abstract

The impact of relapses on long-term disability in Multiple Sclerosis remains unclear; however some evidence suggests that relapses play an important role in determining subsequent prognosis.

We report on outcome, prognostic factors for recovery and the contribution of relapses to the accumulation of fixed disability in a large series of patients with documented relapses.

Two hundred and seventynine relapses in 182 patients were assessed before, during and after relapse by Expanded Disability Status scale and data analysed to assess degree of recovery.

Factors affecting outcome were considered including sex, age and site of relapse. Mean EDSS prior to relapse was 3.73, during relapse 5.18 and post relapse 4.23.

Mean interval to post relapse assessment was 127 days post relapse. Mean residual change in EDSS score (pre to post relapse) was 0.50 points.

Overall 49.4 % of patients had a residual increase in disability post relapse of at least 0.5 EDSS points and 32.7 % had an increase of at least 1 point.

No significant difference was observed in mean residual EDSS for sex, site of relapse or age at relapse or in the proportion of patients with a residual increase in disability of >/= 1 EDSS point post relapse.

14.4 % of patients had no increase in EDSS score during relapse compared to pre relapse.

These results suggest that acute relapses are commonly associated with an objective worsening of disability in the majority of patients with MS and that recovery is incomplete in approximately half and not influenced by gender, age or site of lesion.

Therapies which reduce relapse frequency and/or severity might therefore be expected to slow or prevent worsening of disability if initiated prior to the onset of more permanent damage.



#7

Relating Functional Changes During Hand Movement To Clinical Parameters In Patients With Multiple Sclerosis In A Multi-Center fMRI Study

Wegner C, Filippi M, Korteweg T, Beckmann C, Ciccarelli O, De Stefano N, Enzinger C, Fazekas F, Agosta F, Gass A, Hirsch J, Johansen-Berg H, Kappos L, Barkhof F, Polman C, Mancini L, Manfredonia F, Marino S, Miller DH, Montalban X, Palace J, Rocca M, Ropele S, Rovira A, Smith S, Thompson A, Thornton J, Yousry T, Matthews PM
Eur J Neurol 2008 Feb;15(2):113-22
Centre for Functional Magnetic Resonance Imaging of the Brain, University of Oxford, UK
PMID# 18217881
Abstract

We performed a prospective multi-center study using functional Magnetic Resonance Imaging (fMRI) to better characterize the relationships between clinical expression and Brain function.

In patients with Multiple Sclerosis (MS) at eight European sites (56 MS patients and 60 age-matched, healthy controls).

Patients showed greater task-related activation bilaterally in Brain regions including the Pre- and Post-Central, Inferior and Superior Frontal, Cingulate and Superior Temporal Gyri and Insula (P < 0.05, all statistics corrected for multiple comparisons).

Both patients and healthy controls showed greater Brain activation with increasing age in the Ipsilateral Pre-Central and Inferior Frontal Gyri (P < 0.05).

Patients, but not controls, showed greater Brain activation in the Anterior Cingulate Gyrus and the Bilateral Ventral Striatum (P < 0.05) with less hand dexterity. An interaction between functional activation changes in MS and age was found.

This large fMRI study over a broadly selected MS patient population confirms that movement for patients demands significantly greater Cognitive 'resource allocation' and suggests age-related differences in Brain responses to the disease.

These observations add to evidence that brain functional responses (including potentially Adaptive Brain Plasticity) contribute to modulation of clinical expression of MS pathology and demonstrate the feasibility of a multi-site functional MRI study of MS.



#8

Unexpected Multiple Sclerosis: Follow-Up Of 30 Patients With Magnetic Resonance Imaging And Clinical Conversion Profile

CFSEP
Lebrun C, Bensa C, Debouverie M, De Seze J, Wiertlievski S, Brochet B, Clavelou P, Brassat D, Labauge P, Roullet E
J Neurol NeuroSurg Psychiatry 2008 Feb;79(2):195-8
Neurology, CHU de Nice, France
PMID# 18202208
Abstract

The concept of preclinical Multiple Sclerosis is now well recognised, and a diagnosis of silent Brain T2 lesions is frequent because of the ease of performing MRI. Nevertheless, patients with incidental Brain MRI fulfilling Barkhof- Tintoré criteria are more rare.

We report a descriptive retrospective study of clinical and 5 year MRI follow-up in patients with subclinical DeMyelinating lesions fulfilling MRI Barkhof-Tintoré criteria with a normal Neurological Examination.

30 patients were identified and the first Brain MRI was performed for various medical events: Headaches (n = 14), Migraine with (n = 2) or without (n = 4) aura, CranioCerebral Trauma (n = 3), Depression (n = 3), Dysmenorrhoea (n = 2), Epilepsy (n = 1) and Cognitive Changes (n = 1).

Mean time for the second Brain MRI was 6 months (range 3-30). 23 patients had TemporoSpatial dissemination (eight with gadolinium enhancement). 11 patients had clinical conversion: Optic Neuritis (n = 5), BrainStem (n = 3), Sensitive Symptoms (n = 2) and Cognitive Deterioration (n = 1).

Eight (72%) already had criteria of Dissemination to Space and Time before the clinical event. Mean time between the first Brain MRI and Clinically Isolated Syndrome (CIS) was 2.3 years.

To our knowledge, this is the first cohort of CIS with preclinical follow-up. Early treatment should be discussed in view of the predictive value on conversion of the MRI burden of the disease.



#9

Mapping The Brain Pathways Of Declarative Verbal Memory: Evidence From White Matter Lesions In The Living Human Brain

Sepulcre J, Masdeu JC, Sastre-Garriga J, Gońi J, Vélez-de-Mendizábal N, Duque B, Pastor MA, Bejarano B, Villoslada P
NeuroImage 2008 Sep 1;42(3):1237-43
University of Navarra, Clinica Universitaria de Navarra, Department of Neurology and NeuroSurgery, Pamplona, Spain
PMID# 18585467
Abstract

Understanding the contribution of the Brain White Matter pathways to Declarative Verbal Memory Processes has been hindered by the lack of an adequate model in humans.

An attractive and underexplored approach to study White Matter region functionality in the living human Brain is through the use of non-aprioristic models which specifically search disrupted White Matter pathways.

For this purpose, we employed Voxel-based Lesion-Function Mapping to correlate White Matter lesions on the Magnetic Resonance Images of 46 Multiple Sclerosis patients with their performance on Declarative Verbal Memory Storage and Retrieval.

White Matter correlating with storage was in the Temporal Lobe-particularly lateral to the Hippocampus and in the Anterior Temporal Stem-, in the Thalamic region and in the Anterior Limb of the Internal Capsule, all on the Left Hemisphere, and also in the Right Anterior Temporal Stem.

The same volumes were relevant for Retrieval, but to them were added Temporo-Parieto-Frontal Paramedian bundles, particularly the Cingulum and the Fronto-Occipital Fasciculus.

These 3D maps indicate the White Matter regions most critically involved in Declarative Verbal Memory in humans.



#10

ImmunoGlobulins And Complement In Postmortem Multiple Sclerosis Tissue

Barnett MH, Parratt JD, Cho ES, Prineas JW
Ann Neurol 2009 Feb 4;65(1):32-46
University of Sydney, Department of Medicine, Institute of Clinical NeuroSciences, New South Wales, Australia
PMID# 19194879
Abstract

Objective
To identify evidence of a discrete, specific Immune Response in Multiple Sclerosis (MS) by analyzing the distribution of ImmunoGlobulins and Complement.

In tissue derived from cases of MS, and from control Inflammatory White Matter Diseases known to express Viral and AutoAntigens in the Brain and Spinal Cord.

Methods
Autopsy tissue from 25 MS patients and 24 patients with Other Neurological Diseases was examined ImmunoHistoChemically for ImmunoGlobulins and activated Complement (C3d and C9neo).

Results
In tissue remote from focal lesions in MS and Other Neurological Diseases, IgG was detected in many normal structures but not in Myelin or Ramified Microglia.

Disrupted Myelin in areas of active Myelin breakdown and in Phagocytes stained positively for C3d and C9neo, and equivocally for IgG in MS and all other Neurological Diseases examined, including Ischemic infarcts.

Disease-specific deposits of IgG or Complement were detected in Virus-infected cells in Progressive Multifocal Leukoencephalopathy, Subacute Sclerosing PanEncephalitis, and CytomegaloVirus Encephalitis; in Glial-limiting membranes in NeuroMyelitis Optica; and in senile plaques in Alzheimer's Dementia.

Specific to MS were unusual Microglial nodules containing short, linear deposits of activated Complement (C3d) on partly DeMyelinated Axons located in Normal-Appearing PeriPlaque White Matter.

Interpretation
IgG and Complement immunostaining of disrupted Myelin in MS lesions, frequently cited as an indication of pathogenic Anti-Myelin AntiBodies:

Is a nonspecific feature that cannot be interpreted as evidence of a distinct pathogenesis or serve to define particular variants of the disease.

The unusual Microglial nodules described in this study may constitute a specific biomarker with pathogenetic significance in MS.

Ann Neurol 2009;65:32-46.



#11

Therapeutic Vaccination With A Trivalent T-Cell Receptor (TCR) Peptide Vaccine Restores Deficient FoxP3 expression And TCR Recognition In Subjects With Multiple Sclerosis

Vandenbark AA, Culbertson NE, Bartholomew RM, Huan J, Agotsch M, LaTocha D, Yadav V, Mass M, Whitham R, Lovera J, Milano J, Theofan G, Chou YK, Offner H, Bourdette DN
Immunology 2008 Jan;123(1):66-78
Department of Veterans Affairs Medical Center, NeuroImmunology Laboratory, Portland, OR 97239, USA
PMID# 17944900
Abstract

Therapeutic Vaccination using T-Cell Receptor (TCR) Peptides from V genes commonly expressed by potentially pathogenic T-Cells remains an approach of interest for treatment of Multiple Sclerosis (MS) and other Autoimmune Diseases.

We developed a trivalent TCR Vaccine containing Complementarity Determining Region (CDR) 2 Peptides from BV5S2, BV6S5 and BV13S1:

Emulsified in incomplete Freund's adjuvant that reliably induced high frequencies of TCR-specific T-Cells.

To evaluate induction of regulatory T-Cell subtypes, Immunological and Clinical parameters were followed in 23 treatment-naďve subjects with Relapsing/Remitting or Progressive MS.

Who received 12 monthly injections of the Trivalent Peptide Vaccine over 1 year in an open-label study design.

Prior to Vaccination, subjects had reduced expression of Forkhead Box (Fox) P3 message and protein, and reduced recognition of the expressed TCR repertoire by TCR-reactive Cells compared with healthy control donors.

After three or four injections, most Vaccinated MS subjects developed high frequencies of circulating InterLeukin-10 (IL-10)-secreting T-Cells specific for the injected TCR Peptides.

And significantly enhanced expression of FoxP3 by regulatory T-Cells present in both 'native' CD4+ CD25+ and 'inducible' CD4+ CD25- Peripheral Blood Mononuclear Cells (PBMC).

At the end of the trial, PBMC from vaccinated MS subjects retained or further increased FoxP3 expression levels.

Exhibited significantly enhanced recognition of the TCR V gene repertoire apparently generated by perturbation of the TCR network, and significantly suppressed NeuroAntigen but not Recall Antigen responses.

These findings demonstrate that therapeutic Vaccination using only three commonly expressed BV gene determinants can induce an expanded ImmunoRegulatory Network in vivo that may optimally control complex AutoReactive responses that characterize the inflammatory phase of MS.



#12

Mouse Model Mimics Multiple Sclerosis In The Clinico-Radiological Paradox

Wuerfel J, Tysiak E, Prozorovski T, Smyth M, Mueller S, Schnorr J, Taupitz M, Zipp F
Eur J NeuroSci 2007 Jul;26(1):190-8
Cecilie-Vogt-Clinic for Molecular Neurology, Charité - University Medicine Berlin, and Max-Delbrueck-Center for Molecular Medicine, Germany
PMID# 17596194
Abstract

The value of Experimental Autoimmune Encephalomyelitis (EAE), an animal model of Multiple Sclerosis, in deriving novel diagnostic and therapeutic input has been subject to recent debate.

This study is the first to report a disseminated distribution of plaques including Cranial Nerves, prior to or at early stages of disease in murine adoptive transfer EAE, irrespective of the development of clinical symptoms.

We induced EAE by adoptive ProteoLipid Protein-specific T-Cell transfer in 26 female SJL/J mice, and applied high-field-strength Magnetic Resonance Imaging (MRI) scans longitudinally, assessing Blood-Brain Barrier (BBB) disruption by Gadopentate dimeglumine enhancement.

We visualized inflammatory Nerve Injury by Gadofluorine M accumulation, and Phagocytic Cells in inflamed tissue by Very Small Anionic Iron Oxide Particles (VSOP-C184).

MRI was correlated with ImmunoHistological sections. In this study, we discovered very early BBB breakdown of White and Gray Brain Matter in 25 mice; one mouse developed exclusively Spinal Cord inflammation.

Widely disseminated Contrast-Enhancing Lesions preceded the onset of disease in 10 animals.

Such lesions were present despite the absence of any clinical disease formation in four mice, and coincided with the first detectable symptoms in others.

Cranial Nerves, predominantly the Optic and Trigeminal Nerves, showed signal intensity changes in Nuclei and Fascicles of 14 mice. At all sites of MRI lesions we detected cellular infiltrates on corresponding Histological sections.

The discrepancy between the disease burden visualized by MRI and the extent of disability indeed mimics the human Clinico-Radiological Paradox.

MRI should therefore be implemented into evaluational in vivo routines of future therapeutic EAE studies.




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