MS Abstracts 03b-2g4

  1. Biomarkers and surrogate outcomes in NeuroDegenerative Disease: Lessons from Multiple Sclerosis
    Neurorx 2004 Apr;1(2):284-294

  2. Neuronal cell injury precedes Brain Atrophy in Multiple Sclerosis
    Neurology 2004 Feb 24;62(4):624-7

  3. Axonal damage in Multiple Sclerosis: a complex issue in a complex disease
    Clin Neurol NeuroSurg 2004 Jun;106(3):211-7

  4. Molecular changes in Neurons in Multiple Sclerosis: altered Axonal expression of Nav1.2 and Nav1.6 Sodium Channels and Na+/Ca2+ Exchanger
    Proc Natl Acad Sci USA 2004 May 25;101(21):8168-73

  5. Direct impact of T-Cells on Neurons revealed by two-photon microscopy in living Brain tissue
    J NeuroSci 2004 Mar 10;24(10):2458-64

  6. Indirect evidence for early widespread Gray Matter involvement in Relapsing/Remitting Multiple Sclerosis
    NeuroImage 2004 Apr;21(4):1825-9

  7. Estimation of the macromolecular proton fraction and bound pool T2 in Multiple Sclerosis
    Mult Scler 2004 Dec;10(6):607-13

  8. Gray and White Matter Atrophy in early clinical stages of Primary/Progressive Multiple Sclerosis
    NeuroImage 2004 May;22(1):353-9

  9. UltraStructural Hippocampal and White Matter alterations in Mild Cognitive Impairment: a Diffusion Tensor imaging study
    Dement Geriatr Cogn Disord 2004;18(1):101-8

  10. Diffusion Tensor Imaging of early Relapsing/Remitting Multiple Sclerosis with Histogram analysis using automated segmentation and Brain Volume correction
    Mult Scler 2004 Feb;10(1):9-15

  11. Altered expression of Ion Channel isoforms at the Node of Ranvier in P0-deficient Myelin mutants
    Mol Cell NeuroSci 2004 Jan;25(1):83-94

  12. Diffusion Tensor Imaging as potential biomarker of White Matter injury in diffuse Axonal injury
    AJNR Am J NeuroRadiol 2004 Mar;25(3):370-6


Biomarkers And Surrogate Outcomes In NeuroDegenerative Disease: Lessons From Multiple Sclerosis

Miller DH
Neurorx 2004 Apr;1(2):284-294
Institute of Neurology, Multiple Sclerosis NMR Research Unit, Department of NeuroInflammation, London WC1N 3BG, United Kingdom
PMID# 15717029

Multiple Sclerosis (MS) is a chronic disease of the CNS that most commonly affects young adults.

It is usually characterized in the early years by acute relapses followed by partial or complete remission; in later years progressive and irreversible disability develops.

Because of the protracted and unpredictable clinical course, biological surrogate markers are much needed to make clinical trials of potential disease-modifying treatments more efficient.

Magnetic Resonance (MR) outcome measures are now widely used to monitor treatment outcome in MS trials.

Areas of multifocal inflammation are detected with a high sensitivity as new areas of Gadolinium enhancement and T2 abnormality, and these may be considered as surrogate markers for clinical relapses.

However, progressive disability is not clearly related to inflammatory lesions but rather to a progressive and diffuse process with increasing NeuroAxonal Loss.

MR surrogate measures for NeuroAxonal Loss include Atrophy (tissue loss in Brain and Spinal Cord), N-AcetylAspartate, and T1 HypoIntense lesions.

Diffuse abnormality in Normal-Appearing Brain Tissue may also be monitored using Magnetization Transfer Ratio and other quantitative MR measures.

For treatment trials of new agents aimed at preventing disability, measures of NeuroAxonal damage should be acquired, especially Atrophy, which occurs at all stages of MS and which can be quantified in a sensitive and reproducible manner.

Because the MR surrogates for NeuroAxonal Loss are not yet validated as predicting future disability, definitive trials should continue to monitor an appropriate disability endpoint.


Neuronal Cell Injury Precedes Brain Atrophy In Multiple Sclerosis

Ge Y, Gonen O, Inglese M, Babb JS, Markowitz CE, Grossman RI
Neurology 2004 Feb 24;62(4):624-7
New York University School of Medicine, Department of Radiology, New York, NY 10016, USA
PMID# 14981182

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).


Axonal Damage In Multiple Sclerosis: A Complex Issue In A Complex Disease

Grigoriadis N, Ben-Hur T, Karussis D, Milonas I
Clin Neurol NeuroSurg 2004 Jun;106(3):211-7
AHEPA University Hospital, Aristotle University of Thessaloniki, Department of Neurology, 1 Stilp. Kyriakidi Str., 54636 Thessaloniki, Greece
PMID# 15177770

Multiple Sclerosis is no longer considered to simply be an AutoImmune DeMyelinating Disease. Axonal destruction is another Central pathological feature and a contributor to the accumulating disability of disease progression.

The mechanism underlying Axonal pathology has not been fully clarified but does not appear to be a simple one.

The relationship between Axonal damage and other components of the pathological features such as DeMyelination, Inflammation and ReMyelination are under intense investigation.

Experimental data suggest that therapeutic interventions such as the induction of rapid ReMyelination may lead to the protection of Axons.

In addition to ImmunoModulation, future strategies for NeuroProtection may be of great importance.


Molecular Changes In Neurons In Multiple Sclerosis: Altered Axonal Expression Of Nav1.2 And Nav1.6 Sodium Channels And Na+/Ca2+ Exchanger

Craner MJ, Newcombe J, Black JA, Hartle C, Cuzner ML, Waxman SG
Proc Natl Acad Sci USA 2004 May 25;101(21):8168-73
Yale School of Medicine, Department of Neurology and Paralyzed Veterans of America/Eastern Paralyzed Veterans Association NeuroScience Research Center, New Haven, CT 06510, USA
PMID# 15148385

Although Voltage-gated Sodium Channels are known to be deployed along experimentally DeMyelinated Axons, the molecular identities of the Sodium Channels expressed along Axons in human DeMyelinating Diseases such as Multiple Sclerosis (MS) have not been determined.

Here we demonstrate changes in the expression of Sodium Channels in DeMyelinated Axons in MS, with Nav1.6 confined to Nodes of Ranvier in controls.

But, with diffuse distribution of Nav1.2 and Nav1.6 along extensive regions of DeMyelinated Axons within acute MS plaques.

Using triple-labeled fluorescent ImmunoCytoChemistry, we also show that Nav1.6, which is known to produce a persistent Sodium Current, and the Na+/Ca2+ Exchanger.

Which, can be driven by persistent Sodium Current to import damaging levels of Calcium into Axons, are colocalized with beta-Amyloid Precursor Protein, a marker of Axonal injury, in acute MS lesions.

Our results demonstrate the molecular identities of the Sodium Channels expressed along DeMyelinated and degenerating Axons in MS and suggest that coexpression of Nav1.6 and Na+/Ca2+ Exchanger is associated with Axonal degeneration in MS.


Direct Impact Of T-Cells On Neurons Revealed By Two-Photon Microscopy In Living Brain Tissue

Nitsch R, Pohl EE, Smorodchenko A, Infante-Duarte C, Aktas O, Zipp F
J NeuroSci 2004 Mar 10;24(10):2458-64
Humboldt University Medical School Charite, Institute of Anatomy, Department of Cell and NeuroBiology, D-10098 Berlin, Germany
PMID# 15014121

Encephalitogenic T-Cells invade the Brain during NeuroInflammation such as Multiple Sclerosis (MS), inducing damage to Myelin Sheaths and Oligodendrocytes.

Only recently, Neuronal structures were reported to be a crucial target in the disease. Here, two-photon microscopy using Ion-sensitive dyes revealed that within the complex cellular network of living Brain tissue.

ProteoLipid Protein (PLP)-specific T-Cells and T-Cells recognizing the nonmurine Antigen Ovalbumin (OVA) directly and independently of the Major Histocompatibility Complex (MHC) contact Neurons in which they induce Calcium oscillations.

T-Cell contact finally resulted in a lethal increase in Neuronal Calcium levels. This could be prevented by blocking both Perforin and Glutamate Receptors.

For the first time, our data provide direct insight into the activity of T-Cells in the living Brain and their detrimental impact on Neurons.


Indirect Evidence For Early Widespread Gray Matter Involvement In Relapsing/Remitting Multiple Sclerosis

Inglese M, Ge Y, Filippi M, Falini A, Grossman RI, Gonen O
NeuroImage 2004 Apr;21(4):1825-9
New York University School of Medicine, Department of Radiology, New York, NY 10016, USA
PMID# 15050603

Multiple Sclerosis (MS) has traditionally been viewed as an Inflammatory DeMyelinating White Matter (WM) Disease of the Central Nervous System. However, recent pathology and MRI studies have shown lesions in the Gray Matter (GM) as well.

To ascertain the extent of GM involvement, we obtained with nonlocalizing proton MR Spectroscopy the concentration of N-AcetylAspartate (NAA), a metabolite found almost exclusively in Neuronal Cells, T2-lesion loads.

And, GM and WM fractions in the entire Brain of 71 Relapsing/Remitting (RR) MS patients (51 women, 20 men, 25-55 years old) and 41 healthy controls (27 women, 14 men, 23-55 years old).

The average Whole Brain NAA (WBNAA) difference between the patients and the controls was -2.9 mM (-22%, P < 0.0001); range: +1.2 to -7.8 mM (+8% to -63%). The patients' median T2 Lesion Volume was 5.5 (range: 0.140-28) cm(3).

GM and WM comprised 50.4 +/- 3.8% and 30.4 +/- 5.0% (mean +/- standard deviation), respectively, of the total Brain Volume in the patients; 53.8 +/- 3.7% and 35.4 +/- 4.7% in the controls.

Because WM and GM constitute approximately 40% and 60% of the Brain Parenchyma, respectively, and the NAA concentration in the former is 2/3 of the latter, WBNAA loss greater than 40% x 2/3 = 27% cannot be explained in terms of WM (Axonal) Pathology alone.

And, must include widespread GM (Neuronal) Deficits. Therefore, the concept of MS, even at its earlier stages, as a WM disease might need to be re-examined.


Estimation Of The Macromolecular Proton Fraction And Bound Pool T2 In Multiple Sclerosis

Davies GR, Tozer DJ, Cercignani M, Ramani A, Dalton CM, Thompson AJ, Barker GJ, Tofts PS, Miller DH
Mult Scler 2004 Dec;10(6):607-13
NMR Research Unit, Institute of Neurology, UCL, Queen Square, London WC1N 3BG, UK
PMID# 15584482

This study used a model for Magnetization Transfer (MT) to estimate two underlying parameters: the Macromolecular Proton Fraction (f) and the bound pool T2 (T2b) in patients with Multiple Sclerosis (MS).

Sixty patients with Clinically Definite MS and 27 healthy controls were imaged using:

  1. A dual echo fast spin echo sequence
  2. A MT sequence (with ten MT power and offset frequency combinations)
  3. Proton density and T1 weighted sequences (for T1 relaxation time estimation)

Fourteen Normal-Appearing White Matter (NAWM) regions of interest (ROI) and six Normal-Appearing Gray Matter (NAGM) ROIs were outlined in all subjects.

Lesions were also contoured in subjects affected by MS. The model was fitted to the data leading to estimates of T2b and f.

Results showed that T2b was increased in lesions whereas f was reduced. In NAWM, f was decreased while T2b was only increased in Secondary/Progressive MS.

NAWM f correlated modestly with disability. Further studies are needed to investigate the pathological basis of the abnormalities observed.


Gray And White Matter Atrophy In Early Clinical Stages Of Primary/Progressive Multiple Sclerosis

Sastre-Garriga J, Ingle GT, Chard DT, Ramio-Torrenta L, Miller DH, Thompson AJ
NeuroImage 2004 May;22(1):353-9
Institute of Neurology, UCL, 23 Queen Square, London WC1N 3BG, UK
PMID# 15110026

There is little information available on Gray and White Matter (GM and WM) Atrophy in Primary/Progressive Multiple Sclerosis (PPMS) and on their relationships with clinical and other Magnetic Resonance Imaging (MRI) measures.

To evaluate disease progression in the early phase of PPMS, focusing on Axonal Loss as assessed by Volumetric MRI measures of WM and GM.

And, to determine their relationships with clinical outcomes and lesion load measures.

Forty-three patients with PPMS within 5 years of symptom onset and 45 control subjects were studied.

Three-dimensional Brain scans were acquired and segmented into WM, GM, and CerebroSpinal Fluid (CSF) using SPM99.

Brain Parenchymal (BPF), WM (WMF), and GM Fractions (GMF) normalized against Total IntraCranial Volumes were estimated.

T2-weighted (T2) and enhancing lesion loads were also determined. Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) scores were recorded in all patients.

There were significant differences between patients and controls in BPF, WMF, and GMF values (P < 0.001). BPF (r = -0.469; P = 0.002) and WMF (r = -0.532; P < 0.001) but not GMF (r = -0.195; P = 0.2) correlated with EDSS scores.

PF (r = 0.518; P = 0.001), WMF (r = 0.483; P = 0.001), and GMF (r = 0.337; P = 0.031) correlated with MSFC scores. Correlations with enhancing lesion and T2 loads were only significant for BPF and WMF.

Brain Atrophy is seen in the early stages of PPMS and affects both GM and WM. WM Atrophy appears more closely related to clinical outcome and WM focal damage than GM Atrophy in this patient group.


UltraStructural Hippocampal And White Matter Alterations In Mild Cognitive Impairment: A Diffusion Tensor Imaging Study

Fellgiebel A, Wille P, Muller MJ, Winterer G, Scheurich A, Vucurevic G, Schmidt LG, Stoeter P
Dement Geriatr Cogn Disord 2004;18(1):101-8
University of Mainz, Department of Psychiatry, Mainz, Germany
PMID# 15087585

Mild Cognitive Impairment (MCI) is considered to be a transitional stage between normal aging and Dementia. In Alzheimer's Disease (AD), White Matter structural pathology is due to Wallerian Degeneration and Central Angiopathy.

However, in MCI patients, the presence and extent of White Matter alterations as a possible correlate of Impaired Memory Function and as predictor of subsequent progression to AD is not clarified yet.

Diffusion Tensor Imaging (DTI) reveals the UltraStructural integrity of Cerebral White Matter Tracts. Therefore, it could detect pathological processes that modify tissue integrity in patients with MCI.

In our prospective study, conventional and Diffusion Tensor MR scans were obtained from 14 patients with MCI, 19 patients with AD, and 10 healthy controls.

Mean Diffusivity (MD) and Fractional Anisotropy (FA) were measured in Temporal, Frontal, Parietal and Occipital White Matter regions as well as in the Corpus Callosum (Genu and Splenium) and the Hippocampus.

MCI patients showed higher MD values in the Left Centrum Semiovale (p = 0.013; Right: p = 0.026), in the Left Temporal (p = 0.006), the Right temporal (p = 0.014) and the Left Hippocampal (p = 0.002) region.

As compared to the control group, FA values of MCI patients and controls did not differ significantly in any region.

Compared to controls, AD patients had increased MD values in the Left Centrum Semiovale (p = 0.012), the Left Parietal (p = 0.001), the Right Parietal (p = 0.028), the Left Temporal (p = 0.018), the Right Temporal (p = 0.011) and the Left Hippocampal region (p = 0.002).

Decreased FA values were measured in the Left Temporal Area (p = 0.017) and in the Left Hippocampus (p = 0.031) in AD patients compared to controls. FA and MD values did not differ significantly between AD and MCI patients.

Elevated MD values indicating Brain tissue alterations in MCI patients were found in regions that are typically involved in early changes due to AD, particularly the Left Hippocampus.

The sensitivity of distinguishing MCI patients from controls was 71.4% (with a specificity set at 80%).

Therefore, the DTI technique validates the MCI concept, and Diffusion Tensor MR measurement can be a helpful tool to quantify MCI pathology in vivo.

Copyright 2004 S. Karger AG, Basel


Diffusion Tensor Imaging Of Early Relapsing/Remitting Multiple Sclerosis With Histogram Analysis Using Automated Segmentation And Brain Volume Correction

Rashid W, Hadjiprocopis A, Griffin CM, Chard DT, Davies GR, Barker GJ, Tofts PS, Thompson AJ, Miller DH
Mult Scler 2004 Feb;10(1):9-15
Institute of Neurology, University College London, MS NMR Research Unit, Department of NeuroInflammation, Queen Square, London WC1N 3BG, UK
PMID# 14760947

Diffusion Tensor Magnetic Resonance Imaging (DTI) reveals measurable abnormalities in Normal-Appearing Brain Tissue (NABT) in established Multiple Sclerosis (MS). However, it is unclear how early this occurs.

Recent studies have employed Whole Brain Histogram analysis to improve sensitivity, but concern exists regarding reliability of Tissue/CerebroSpinal Fluid Segmentation and possible intersubject Brain Volume differences, which can introduce partial volume error:

To address this, 28 early Relapsing/Remitting MS subjects [median disease duration 1.6 years; median Expanded Disability Status Scale (EDSS) score 1.5].

And 20 controls were compared with Whole Brain Histogram analysis using an automated segmentation algorithm to improve reproducibility.

Brain Parenchymal Volumes (BPV) were estimated for each subject in the analysis. The mean, peak height and peak location were calculated for DTI Parameters [Fractional Anisotropy (FA), Mean Diffusivity and Volume Ratio].

An increased FA peak height in MS subject NABT was observed (P = 0.02) accounting for age, gender and BPV. Removing BPV revealed additional abnormalities in NABT.

    The main conclusions are:
  1. A peak height is increased in NABT in early MS
  2. Partial volume edge effects may contribute to apparent NABT Histogram abnormalities
  3. Correction for Brain Volume differences should reduce potential partial volume edge effects


Altered Expression Of Ion Channel Isoforms At The Node Of Ranvier In P0-Deficient Myelin Mutants

Ulzheimer JC, Peles E, Levinson SR, Martini R
Mol Cell NeuroSci 2004 Jan;25(1):83-94
University of Wuerzburg, Department of Neurology, Section of Developmental NeuroBiology, D-97080 Wuerzburg, Germany
PMID# 14962742

To elucidate the impact of Myelinating Schwann Cells on the molecular architecture of the Nodes of Ranvier, we investigated the Nodal expression of Voltage-gated Sodium Channel (VGSC) Isoforms.

And, the localization of ParaNodal and JuxtaParaNodal membrane proteins in a severely affected Schwann Cell mutant, the mouse deficient in Myelin protein zero (P0).

The abnormal Myelin formation and compaction was associated with immature Nodal cluster types of VGSC.

Most strikingly, P0-deficient Motor Nerves displayed an ectopic Nodal expression of the Na(v)1.8 isoform, where it is coexpressed with the ubiquitous Na(v)1.6 channel.

Furthermore, Caspr was distributed asymmetrically or was even absent in the mutant Nerve Fibers.

The Potassium Channel K(v)1.2 and Caspr2 were not confined to JuxtaParaNodes, but often protruding into the ParaNodes.

Thus, deficiency of P0 leads to dysregulation of Nodal VGSC isoforms and to altered localization of ParaNodal and JuxtaParaNodal components of the Nodal complex.


Diffusion Tensor Imaging As Potential Biomarker Of White Matter Injury In Diffuse Axonal Injury

Huisman TA, Schwamm LH, Schaefer PW, Koroshetz WJ, Shetty-Alva N, Ozsunar Y, Wu O, Sorensen AG
AJNR Am J NeuroRadiol 2004 Mar;25(3):370-6
Massachusetts General Hospital and Harvard Medical School, MGH-NMR Center, Division of NeuroRadiology, Boston, MA, USA
PMID# 15037457

Background And Purpose
Multiple biomarkers are used to quantify the severity of Traumatic Brain Injury (TBI) and to predict outcome. Few are satisfactory.

CT and conventional MR imaging underestimate injury and correlate poorly with outcome.

New MR imaging techniques, including Diffusion Tensor Imaging (DTI), can provide information about Brain UltraStructure by quantifying Isotropic and Anisotropic Water Diffusion.

Our objective was to determine if changes in Anisotropic Diffusion in TBI correlate with acute Glasgow Coma Scale (GCS) and/or Rankin scores at discharge.

Twenty patients (15 male, five Female; mean age, 31 years) were evaluated.

Apparent Diffusion Coefficients (ADCs) and Fractional Anisotropy (FA) values were measured at multiple locations and correlated with clinical scores. Results were compared with those of 15 healthy control subjects.

ADC values were significantly reduced within the Splenium (Delta18%, P =.001). FA values were significantly reduced in the Internal Capsule (Delta14%; P < .001) and Splenium (Delta16%; P =.002).

FA values were significantly correlated with GCS (r = 0.65-0.74; P < .001) and Rankin (r = 0.68-0.71; P < .001) scores for the Internal Capsule and Splenium.

The correlation between FA and clinical markers was better than for the corresponding ADC values. No correlation was found between ADC of the Internal Capsule and GCS/Rankin scores.

DTI reveals changes in the White Matter that are correlated with both acute GCS and Rankin scores at discharge. DTI may be a valuable biomarker for the severity of tissue injury and a predictor for outcome.

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