Optimizing The Association Between Disability And Biological Markers In MS
Kalkers NF, Bergers E, Castelijns JA, van Walderveen MA, Bot JC, Ader HJ, Polman CH, Barkhof F
Neurology 2001 Oct 9;57(7):1253-8
MS-MRI Center, VU Medical Center, Amsterdam, the Netherlands
Axonal Damage is an important feature of MS pathology and the likely substrate of development of progressive disability. Brain Volume measurement on MRI can be used as an overall marker of tissue damage and Axonal loss.
The authors studied the relation of Brain Volume measurements with the MS Functional
Composite (MSFC) in an attempt to improve the ClinicoRadiologic association.
In 137 patients with MS (80 Relapsing/Remitting [RR], 36 Secondary/Progressive [SP], and 21 Primary/Progressive [PP]) and 12 healthy controls, a Brain MRI scan was obtained.
Patients also underwent MSFC and Expanded Disability Status Scale (EDSS) assessments.
MRI analysis included determination of:
- HypoIntense T1 & T2-weighted lesion load
- Two Brain Volume measurements:
- Parenchymal fraction (PF):
- Whole Brain Parenchyma/IntraCranial volume
- Ventricular Fraction (VF):
- Ventricular volume/Whole Brain Parenchyma
The median PF was smaller and the median VF larger in the patient group (0.81 for PF and 0.029 for VF) than in the control group (0.87 for PF, p < 0.001; and 0.013 for VF, p < 0.01).
For the patient population, moderate correlations were found between Brain Volume measurements and MSFC (0.36 for PF and -0.40 for VF).
Patients with short disease duration showed a correlation of MSFC with both Brain and lesion volume measurements on MRI, whereas patients with long disease duration only showed a correlation with Brain Volume measurements.
Brain Volume measurements are correlated with disability as assessed by the MSFC.
Although in the early phase of the disease the amount of focal DeMyelination is important, the residual Brain Volume seems to be more relevant in determining disability in later phases of the disease.
HypoIntense Lesions On T1-Weighted Spin-Echo Magnetic Resonance Imaging: Relation To Clinical Characteristics In Subgroups Of Patients With Multiple Sclerosis
van Walderveen MA, Lycklama A Nijeholt GJ, Ader HJ, Jongen PJ, Polman CH, Castelijns JA, Barkhof F
Arch Neurol 2001 Jan;58(1):76-81
University Hospital "Vrije Universiteit," Magnetic Resonance Center for Multiple Sclerosis Research, PO Box 7057, 1007 MB Amsterdam, the Netherlands
HypoIntense lesions on T1-weighted Spin-Echo Magnetic Resonance images (T1 lesions) represent destructive Multiple Sclerosis (MS) lesions, consisting of Axonal loss and Matrix destruction.
These lesions are being used as a secondary outcome measure in Phase III clinical trials. Clinical determinants of T1 lesions may differ between subgroups of patients with MS and subsequently may have implications for the selection of patients for clinical trials.
To determine if clinical characteristics of patients with MS are related to T1 lesion volume.
A survey of 138 patients with MS (52 with Relapsing/Remitting MS, 44 with Secondary/Progressive MS, and 42 with Primary/Progressive MS).
The Magnetic Resonance Center for Multiple Sclerosis Research, University Hospital "Vrije Universiteit," Amsterdam, the Netherlands.
Main Outcome Measures
Type of MS, Expanded Disability Status Scale (EDSS) score, sex, age at first symptoms, and T1 lesion volume.
Patients with Secondary/Progressive MS have the highest T1 lesion volume.
Patients with Relapsing/Remitting MS have a lower T1/T2 ratio than patients with Secondary/Progressive MS and patients with Primary/Progressive MS.
In patients with Relapsing/Remitting MS and Secondary/Progressive MS, T1 lesion volume relates to disease duration and EDSS score, while in patients with Primary/Progressive MS sex is important.
A trend toward higher T1 lesion volume was shown for male patients with Primary/Progressive MS when compared with female patients with Primary/Progressive MS (1.0 cm(3) vs 0.3 cm(3), P=.03);
A trend toward higher T1 lesion volume was found with age at onset in patients with Relapsing/Remitting MS and in patients with Primary/Progressive MS.
In patients with MS different clinical characteristics associate with T1 lesion volume, suggesting a more destructive type of lesions in certain subgroups.
A possible sex difference in (destructive) lesion development on Magnetic Resonance Imaging should be evaluated in more detail, preferably in a cohort.
Localized (1)H Magnetic Resonance Spectroscopy In Mainly Cortical Gray Matter Of Patients With Multiple Sclerosis
Sarchielli P, Presciutti O, Tarducci R, Gobbi G, Alberti A, Pelliccioli GP, Chiarini P, Gallai V
J Neurol 2002 Jul;249(7):902-10
Neurologic Clinic, NeuroScience Department, Policlinico Monteluce, Via E. Dal Pozzo, 06126 Perugia, Italy
The Brain Water Fraction (R), the Brain water transverse relaxation time (T2), the Atrophy index (alpha) and the absolute concentration of the principal Brain metabolites (NAA, Cho and Cr) were measured.
By localized Proton Magnetic Resonance Spectroscopy in the Occipito-Parietal Cortex (mainly Gray Matter), of 15 Relapsing/Remitting (RR) Multiple Sclerosis (MS) patients, 15 Secondary/Progressive (SP) MS patients and 8 healthy subjects.
Significantly lower values of N-AcetylAspartate (NAA), Creatine (Cr) and the NAA/Cr ratio in the Occipito-Parietal Cortex were detected in SP MS patients than in R-R MS and control subjects (p < 0.01).
Moreover, MS patients showed shorter T2 water relaxation times and reduced Brain water fraction compared with controls.
Higher Atrophy indices were also detected in the mainly Occipito-Parietal Gray Matter of MS patients, particularly in those with the Progressive form.
These findings suggest that the pathological process in MS is not limited to either White Matter lesions or Normal-Appearing White Matter.
But extends into the Cortical Gray Matter (Occipito-Parietal), particularly in the Progressive form of the disease. This can involve changes in Neural metabolism or Neural shrinkage and Neuron loss.
The significant increase in Atrophy indices could be the expression of the relatively higher CerebroSpinal Fluid signal from the Occipito-Parietal Cortex, even in the absence of obvious Cortical Atrophy.
Relapsing/Remitting Multiple Sclerosis And Whole-Brain N-AcetylAspartate Measurement: Evidence For Different Clinical Cohorts Initial Observations
Gonen O, Moriarty DM, Li BS, Babb JS, He J, Listerud J, Jacobs D, Markowitz CE, Grossman RI
Radiology 2002 Oct;225(1):261-8
New York University School of Medicine, Department of Radiology, 560 First Ave, New York, NY 10016, USA
To quantify the rate of concentration decline of Neuronal marker N-AcetylAspartate (NAA) in the entire Brain of patients with Relapsing/Remitting Multiple Sclerosis (MS) in relation to healthy age-matched control subjects.
Materials And Methods
Whole-Brain NAA (WBNAA) concentration was quantified in 49 patients with Relapsing/Remitting MS by using Magnetic Resonance (MR) imaging and Proton MR Spectroscopy.
It was statistically analyzed by using Spearman rank correlation coefficients to test the intragroup relationship between WBNAA and Expanded Disability Status Scale (EDSS) score and Mann-Whitney analyzes.
To test for differences between subgroups' EDSS scores versus previously published WBNAA values for healthy subjects, disease duration, and age.
Analyzes indicated three subgroups of WBNAA dynamics:
- Ten patients' conditions were "stable,"
exhibiting an insignificant change of about 0% (0.02/14.37) per year, of clinically definite disease duration (P =.54)
- 27 patients showed "moderate" decline,
-2.8% (-0.34/12.18) per year (P <.01)
- 12 patients experienced "rapid" decline,
-27.9% (-3.39/12.14) per year (P <.01).
No correlation was found between WBNAA deficit, EDSS score, and age.
Ascertaining an individual's NAA concentration dynamics might enable early forecast of disease course, reflect disease severity and thus influence treatment decisions.
And improve clinical trial efficiency by allowing selection of candidates on the basis of WBNAA dynamics in addition to clinical status.
Correlations Of Brain MRI Parameters To Disability In Multiple Sclerosis
Schreiber K, Sorensen PS, Koch-Henriksen N, Wagner A, Blinkenberg M, Svarer C, Petersen HC
Acta Neurol Scand 2001 Jul;104(1):24-30
Copenhagen University Hospital, Rigshospital, Department of Neurology, Denmark
The objective was to correlate Magnetic Resonance Imaging (MRI) T2-weighted lesion load and measures of White Matter Atrophy in the Brain to disability in a population-based sample of patients with Multiple Sclerosis (MS).
Material And Methods
A well defined cohort of patients was drawn at random from the general MS population by using the Danish Multiple Sclerosis Registry.
A semi-automated local thresholding technique was used to quantify T2-weighted lesions on MRI.
Whereas manual tracing was applied to measure the Corpus Callosum Brain Ratio (CCR) and the Ventricle Brain Ratio (VBR).
A sample of 86 patients with a mean age of 43.3 years (SD 4.3), mean disease duration of 13.6 years (SD 4.4) and a median Expanded Disability Status Score (EDSS) of 6.0 was identified.
The correlation between total lesion area of the Brain (TLA) and Disability (EDSS) for the whole sample was moderate (Spearman rank correlation coefficient r=0.48, P<0.001).
Also correlations of CCR and VBR to disability (r=0.32-0.46) were significant.
Correlations of TLA and disability in this study were rather strong.
Hence, T2-weighted MRI lesion load in the Brain still plays an important role as a surrogate marker of disease and as a secondary outcome measure in Phase III Treatment Trials.
Correlating Multiple MRI Parameters With Clinical Features: An Attempt To Define A New Strategy In MS
Tourbah A, Stievenart JL, Abanou A, Fontaine B, Cabanis EA, Lyon-Caen O
NeuroRadiology 2001 Sep;43(9):712-20
Federation de Neurologie, Hjpital de la Salpetriere, Paris, France
MRI is the most powerful imaging technique in managing patients with suspected or confirmed Multiple Sclerosis (MS). However, conventional MRI variables show nonspecific abnormalities weakly correlated with clinical progression of the disease.
New techniques, now routinely available, offer better characterization of the PathoPhysiology.
We combined conventional MRI, including lesion load, contrast enhancement and "black holes" with Magnetization Transfer and Diffusion-weighted imaging and localized Proton MR Spectroscopy (MRS) to study their relationship with disability, course and duration of MS.
The variables that were the most significantly linked to the course of the disease (Relapsing/Remitting versus Secondary/Progressive) were lesion load, mean overall Magnetization Transfer Ratio and Apparent Diffusion Coefficient (MGADC).
The percentage of ADC in (PADCIMD), and out of (PAD-COMD) modal distribution, and the ratio N-AcetylAspartate and Creatine-containing compounds on MRS of the Centrum Semiovale.
MGADC and PADCIMD were the independent factors most related to disability and duration of disease.
Combining MRI techniques is clinically relevant and feasible for studies of MS and may be applied to other diseases of the Central Nervous System.