Magnetic Resonance Spectroscopy: Imaging Axonal Damage In MS
J NeuroImmunology 1999 Jul 1;98(1):2-6
Montreal Neurological Institute, MRS Unit, Quebec, Canada
PMID# 10426355; UI# 99353398
Recent observations made using Magnetic Resonance Spectroscopy to measure the Axonal marker N-AcetylAspartate have emphasized the fact that substantial Axonal damage occurs in Multiple Sclerosis, in addition to DeMyelination.
The Axonal damage is present both in Lesions and Normal-Appearing White Matter, progresses over time, and correlates with clinical disability.
These observations, together with observations demonstrating that adaptations of Sodium channels can restore Conduction in DeMyelinated Axons, have led to the hypothesis that Axonal Damage may be responsible for a significant proportion of the chronic disability that accrues in MS.
Relationship Between Brain Atrophy And Disability: An 8-Year Follow-Up Study Of Multiple Sclerosis
Fisher E, Rudick RA, Cutter G, Baier M, Miller D, Weinstock-Guttman B, Mass MK, Dougherty DS, Simonian NA
Mult Scler 2000 Dec;6(6):373-7
The Cleveland Clinic Foundation, Dept of Biomedical Engineering, OH 44195, USA
PMID# 11212131; UI# 21079635
Brain Atrophy measurement can provide an estimate of the amount of tissue destruction due to the pathologic processes in Multiple Sclerosis.
The potential usefulness of Atrophy as a marker of disease progression depends upon the concurrent and predictive relationships between Atrophy and Disability.
A follow-up study was performed to measure Atrophy and Disability Scores in patients from the Multiple Sclerosis Collaborative Research Group's Phase III trial of IFN-ß-1a (Avonex) in Relapsing/Remitting Multiple Sclerosis.
New data were obtained on 160 out of 172 eligible patients from the original trial were enrolled in the follow-up study approximately 8 years after randomization.
The follow-up visit consisted of several tests and questionnaires including a clinical exam to determine Expanded Disability Status Score (EDSS) and Multiple Sclerosis Functional Composite (MSFC), and a MRI exam to calculate the Brain Parenchymal Fraction.
Brain Parenchymal Fraction was correlated with both EDSS and MSFC at each of the four time points for which data were available (baseline 1, 2 and 8 years).
Furthermore, the change in BPF was correlated with the changes in Disability Scores from the end of the Phase III trial to the follow-up exam.
These data suggest that Brain Atrophy may be a useful and clinically relevant marker of disease progression in Relapsing/Remitting MS.
Regional Brain Atrophy Is Associated With Physical Disability In Multiple Sclerosis: Semiquantitative MRI And Relationship To Clinical Findings
Bakshi R, Benedict RH, Bermel RA, Jacobs L
J NeuroImaging 2001 Apr;11(2):129-36
State Univ of New York at Buffalo, Imaging Services, Kaleida Health, Buffalo, NY, USA
PMID# 11296581; UI# 21191295
Brain Atrophy may occur early in the course of Multiple Sclerosis (MS) and may be associated with disability.
Brain Magnetic Resonance Imaging (MRI) of 114 MS patients (group A) were analyzed for Regional Atrophy (vs age-/gender-matched controls) and T1 and T2 lesions using 4-point rating systems.
Thirty-five separate patients (group B) were analyzed for Cortical Atrophy (ordinal scale), Third Ventricular Width, and total T2 HyperIntense Lesion Volume (computer assisted).
In group A, regression modeling indicated that Inferior Frontal Atrophy (P = .0003) and T2 lesions in the Pons (P = .02) predicted physical disability (Expanded Disability Status Scale [EDSS] score).
Secondary/Progressive (S/P) versus Relapsing patients were predicted by Inferior Parietal (P = .002), Superior Parietal (P = .006), Temporal (P = .008), Inferior Frontal (P = .01), Superior Frontal (P = .01), Cerebellum (P = .01), Occipital (P = .01), and MidBrain (P = .02) Atrophy.
S/P patients were also predicted by total Atrophy (P = .01) and Third Ventricular enlargement (P = .03) but not T1 or T2 lesions.
In group B, the regression model predicting EDSS score included only Superior Frontal Atrophy (r = 0.515, P = .002).
Mean kappa coefficients of ordinal ratings were 0.9 (intraobserver) and 0.8 (interobserver). Ordinal ratings correlated well with quantitative assessments.
The authors conclude that Brain Atrophy is closely associated with physical disability and clinical course in MS patients and can be appreciated using a semiquantitative MRI regional rating system.
Bjartmar C, Kinkel RP, Kidd G, Rudick RA, Trapp BD
Neurology 2001 Oct 9;57(7):1248-52
Lerner Research Institute, Department of NeuroSciences; Mellen Center, Department of Neurology; the Center for Clinical Research; and Cleveland Clinic Foundation, Cleveland, OH
PMID# 11591844; UI# 21475997
Brain imaging studies detect abnormalities in Normal-Appearing White Matter in patients with MS.
To investigate the HistoPathologic basis for these changes in autopsy tissue from a patient with MS with 9 months' disease duration and a terminal BrainStem lesion.
The BrainStem and Spinal Cord were analyzed UltraStructurally and ImmunoCytoChemically for Axons, Myelin, and Activated Microglia/Macrophages.
Pathologic findings were consistent with a terminal inflammatory DeMyelinated Lesion at the CervicoMedullary junction.
The Ventral Spinal Cord Column, containing Descending Tracts, exhibited 22% Axonal loss at segment C7, but grossly normal ImmunoStaining for Myelin.
Confocal and electron microscopy revealed Myelin Sheaths without Axonal content and initial stages of Myelin degradation by activated Microglia/Macrophages among intact Myelinated Axons.
Axonal number and appearance was normal in Ascending Sensory Tracts.
These studies confirm Axonal Degeneration in the absence of Myelin loss as one HistoPathologic correlate to abnormal MR findings in patients with MS.
Imaging Axonal Damage In Multiple Sclerosis By Means Of MR Spectroscopy
De Stefano N, Narayanan S, Mortilla M, Guidi L, Bartolozzi ML, Federico A, Arnold DL
Neurol Sci 2000;21(4 Suppl 2):S883-7
University of Siena, Institute of Neurological Sciences, NeuroMetabolic Unit, Italy
Axonal damage in Multiple Sclerosis has become an important issue. This has been emphasized by recent in vivo proton Magnetic Resonance Spectroscopy (MRS) and in vitro pathology studies that have found Axonal damage in both lesions and the surrounding Normal-Appearing White Matter.
In particular, proton MR Spectroscopy, by monitoring levels of N-AcetylAspartate (a putative marker of Axonal integrity), has been particularly illuminating.
As the extent of Axonal injury associated with White Matter Inflammation and DeMyelination had not been well appreciated from classical pathology studies.
Recent MR data demonstrate that Cerebral Axonal damage begins and contributes to disability from the earliest stages of the disease.
This implies that the apparently primary role of Axonal damage and loss in the pathogenesis of the disease should be given due importance, and argues for the early treatment of Multiple Sclerosis with agents directed not only against inflammation, but also towards Axonal protection.
The Contribution Of DeMyelination To Axonal Loss In Multiple Sclerosis
Deluca GC, Williams K, Evangelou N, Ebers GC, Esiri MM
Brain 2006 Jun;129(Pt 6):1507-16
University of Oxford, Department of Clinical Neurology, Oxford, UK
The traditional notion that Multiple Sclerosis is a primary DeMyelinating Disease has led to a plaque-centred view of both aetiology and the pathogenesis of disease progression. The presence of Axonal Loss has received increasing recognition.
However, the relative roles of DeMyelination and Axonal Loss have not been fully clarified in Multiple Sclerosis nor have their possible interrelationships been elucidated.
Post-mortem material from the Cerebrum, BrainStem and Spinal Cord of 55 Multiple Sclerosis patients (29 males) with an age range of 25-83 years (mean = 57.5 years) and length of disease history ranging from 2 to 43 years (mean = 17.1 years) was stained for Myelin.
Plaque load was calculated by summing the relative proportion of plaque area compared with total White Matter area of the CorticoSpinal and Sensory Tracts at each level.
This was related to estimates of Axonal density and of total Axon number in these tracts in the Spinal Cord. Our results indicate that plaque load did not correlate with Brain weight.
Unexpectedly, after adjusting for sex, age and duration of disease, correlations between total plaque load and Axonal Loss in both the CorticoSpinal Tract and Sensory Tracts were weak or absent at each level investigated.
Since there was little correlation between plaque load and Axonal Loss, the possibility that DeMyelination is not the primary determinant of Spinal Cord Axonal Loss warrants consideration.
Thalamic Atrophy And Cognition In Multiple Sclerosis
Houtchens MK, Benedict RH, Killiany R, Sharma J, Jaisani Z, Singh B, Weinstock-Guttman B, Guttmann CR, Bakshi R
Neurology 2007 Sep 18;69(12):1213-23
Brigham and Women's Hospital, Harvard Medical School, Department of Neurology, Partners MS Center, Boston, MA 02115, USA
Recent studies have indicated that Brain Atrophy is more closely associated with Cognitive Impairment in Multiple Sclerosis (MS) than are conventional MRI lesion measures.
Enlargement of the Third Ventricle shows a particularly strong correlation with Cognitive Impairment, suggesting clinical relevance of damage to surrounding structures, such as the Thalamus.
Previous imaging and pathology studies have demonstrated Thalamic involvement in MS.
In this study, we tested the hypothesis that Thalamic Volume is lower in MS than in normal subjects, and that Thalamic Atrophy in MS correlates with Cognitive function.
We studied 79 patients with MS and 16 normal subjects. A subgroup of 31 MS subjects underwent Cognitive testing.
The Thalamus was segmented in whole from three-dimensional MRI scans.
We also determined Whole Brain Atrophy (Brain Parenchymal Fraction), Third Ventricular Width, and Whole Brain T2-weighted (Fluid-Attenuated Inversion Recovery) HyperIntense, T1 HypoIntense, and Gadolinium-enhanced lesion volumes.
Normalized Thalamic Volume was 16.8% lower in the MS group (p < 0.0001) vs controls.
Cognitive performance in all domains was moderately to strongly related to Thalamic Volume in the MS group (r = 0.506 to 0.724, p < 0.005).
And, Thalamic Volume entered and remained in all regression models predicting Cognitive performance. Thalamic Volume showed a weak relationship to physical disability score (r = -0.316, p = 0.005).
These findings suggest that Thalamic Atrophy is a clinically relevant biomarker of the NeuroDegenerative Disease process in Multiple Sclerosis.
Evolution Of Different MRI Measures In Patients With Active Relapsing/Remitting Multiple Sclerosis Over 2 And 5 Years: A Case-Control Study
Horakova D, Cox JL, Havrdova E, Hussein S, Dolezal O, Cookfair D, Dwyer MG, Seidl Z, Bergsland N, Vaneckova M, Zivadinov R
J Neurol NeuroSurg Psychiatry 2008 Apr;79(4):407-14
Charles University in Prague, First Faculty of Medicine, Department of Neurology, Prague, Czech Republic
There is growing evidence for the concept of Multiple Sclerosis (MS) as an Inflammatory NeuroDegenerative Diseases, with a different pattern of Atrophy evolution in Gray Matter (GM) and White Matter (WM) tissue compartments.
We aimed to investigate the evolution of different MRI measures in early Relapsing/Remitting patients with MS and in Normal Controls (NCs) over 2 years.
We also evaluated the progression of these MRI measures in a subset of patients who were followed for up to 5 years.
Included in this study were 147 patients who participated in the combination ASA (Avonex Steroids Azathioprine) study and completed full treatment, clinical and MRI assessment at 0, 12 and 24 months.
A subgroup of 66 patients was followed for 36 months, 51 patients for 48 months and 43 patients for 60 months.
Mean age at baseline was 30.7 years, mean disease duration was 5.5 years, mean EDSS was 1.8 and mean annualised relapse rate before study entry was 1.7.
MRI scans were performed on a 1.5T scanner every 2 months for the first 2 years and thereafter once yearly for up to 5 years.
In addition to the MS group, 27 NCs were examined at months 0, 12 and 24 using the same MRI protocol.
Percentage Brain Volume Change (PBVC), GM Volume (GMV), WM Volume (WMV) and Peripheral Gray Volume (PGV) were measured annually using SIENA/X software.
T2-HyperIntense Lesion Volume (LV), Lateral Ventricle Volume (LVV) and Third Ventricle Width (3VW) were also assessed annually.
Over the period of 0-24 months, patients with MS lost significantly more GMV (-2.6% vs -0.72%, p < 0.001), PGV (-2.4% vs -1.03%, p < 0.001) and PBVC (-1.2% vs -0.22%, p < 0.001).
And increased in LVV (+16.6% vs +0.55%, p < 0.003) and 3VW (+9.3% vs 0%, p = 0.003), when compared with NCs.
Within-person change in MRI measures for patients with MS over 5 years was -4.2% for PBVC, -6.2% for GMV, -5.8% for PGV, -0.5% for WMV
Our study confirmed a different pattern of GM, WM and Central Atrophy progression over 2 years between patients with MS and NCs.
The study showed a different evolution of tissue compartment Atrophy measures in patients with MS, with faster decline in Cortical and deep GM regions, as well as PeriVentricular WM regions, over a 5-year period.