Whole-Brain T1 Mapping In Multiple Sclerosis: Global Changes Of Normal-Appearing Gray And White Matter
Vrenken H, Geurts JJ, Knol DL, van Dijk LN, Dattola V, Jasperse B, van Schijndel RA, Polman CH, Castelijns JA, Barkhof F, Pouwels PJ
Radiology 2006 Sep;240(3):811-20
VU University Medical Center, Departments of Radiology, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
To prospectively investigate whether T1 changes in Normal-Appearing White Matter (WM) and Normal-Appearing Gray Matter (GM) in Multiple Sclerosis (MS) are global or regional and their relationship to disease type.
Materials And Methods
The institutional ethics review board approved study; written informed consent was obtained.
Whole-Brain T1 maps were obtained in 67 patients with MS and 24 healthy control subjects with three-dimensional fast low-angle shot flip angle-array method, with correction for B(1) imperfections.
Analysis of variance was performed on T1 Histogram parameters of global Normal-Appearing WM and GM. Regional mean T1 values were analyzed with a multilevel approach.
Multiple linear regression analysis was performed to investigate associations with clinical disability and overall Atrophy. For patients, T2 lesion load was determined.
T1 Histograms of Normal-Appearing WM had significantly higher peak positions for patients with MS (792 msec +/- 36 in Secondary/Progressive [SP] MS) than for control subjects (746 msec +/- 23) and were significantly broader and lower (all P < .001).
Histograms for Cortical Normal-Appearing GM were significantly shifted (peak positions, 1263 msec +/- 44 in control subjects and 1355 msec +/- 62 in patients with SP MS) (P < .001).
Histogram peak positions were significantly higher in SP MS than in Relapsing/Remitting (RR) and Primary/Progressive MS (P < .05). In SP disease, at least 31% of Normal-Appearing WM and 20% of Cortical Normal-Appearing GM were affected.
In MS, T1 was significantly elevated in all Normal-Appearing WM and Cortical Normal-Appearing GM regions (all P < .01) but was elevated only in the Thalamus in deep GM (P < .05).
Cortical T1 Histogram peak position was associated with clinical disability; T2 lesion load was not.
Results suggest that a global disease process affects large parts of both Normal-Appearing WM and GM in MS and effects are worse for SP MS than for RR MS.
(c) RSNA, 2006.
Voxel-Based Analysis Of Quantitative T1 Maps Demonstrates That Multiple Sclerosis Acts Throughout The Normal-Appearing White Matter
Vrenken H, Rombouts SA, Pouwels PJ, Barkhof F
AJNR Am J NeuroRadiol 2006 Apr;27(4):868-74
VU University Medical Center, MR Center for MS Research, Department of Radiology, Amsterdam, the Netherlands
Background And Purpose
Disease activity in Normal-Appearing White Matter (NAWM) in Multiple Sclerosis (MS) has been demonstrated in vivo with T1 relaxation time measurements.
We aimed to investigate the spatial distribution of T1 increases in MS NAWM without a priori selection of specific regions.
Whole-Brain quantitative T1 maps were measured in 67 patients with one of the 3 main clinical types of MS (13 Primary/Progressive [PP], 36 Relapsing/Remitting [RR], and 18 Secondary/Progressive [SP]) and in 23 healthy control subjects.
After registration to standard space and segmentation of NAWM, the maps were analyzed by using Voxel-based analyses with a cluster-based corrected P threshold of .05.
Group mean T1 relaxation times throughout NAWM increased when going from control subjects to PPMS to RR to SP MS.
In the RR and SP MS groups, the T1 increases compared with control subjects were significant throughout the NAWM, without apparent preference for specific Brain regions.
In RR MS, 16% of NAWM voxels displayed a significant increase in T1 compared with control subjects, and in SP, this fraction was 49%.
The comparison between RR MS and the subsequent phase SP MS revealed that, in these patients, disease progression occurs throughout the NAWM.
In patients with PP MS, the spatial extent of significant T1 increases is limited. There were no correlations with clinical disability scales or Brain Volume in a substantial fraction of voxels.
This study demonstrates that in patients with RR MS and SP MS, NAWM disease processes have no regional preferences but can occur throughout the Brain.
Sharma J, Zivadinov R, Jaisani Z, Fabiano AJ, Singh B, Horsfield MA, Bakshi R
J NeuroImaging 2006 Oct;16(4):302-10
Harvard Medical School, Brigham/Women's Hospital, Center for Neurological Imaging, Department of Neurology, Partners MS Center, Boston, Massachusetts 02115, USA
Gray Matter involvement in Multiple Sclerosis (MS) is of growing interest with respect to disease pathogenesis.
Magnetization Transfer Imaging (MTI), an advanced MRI technique, is sensitive to disease in Normal-Appearing White Matter (NAWM) in patients with MS.
We tested if MTI detected SubCortical (deep) Gray Matter abnormalities in patients with MS (n= 60) vs age-matched normal controls (NL, n= 20).
Magnetization Transfer Ratio (MTR) maps were produced from axial proton density, conventional spin-echo, 5 mm gapless slices covering the Whole Brain.
Region-of-interest-derived MTR Histograms for the Caudate, Putamen, Globus Pallidus, Thalamus, and NAWM were obtained. Whole Brain MTR was also measured.
Mean whole brain MTR and the peak position of the NAWM MTR Histogram were lower in patients with MS than NL (P < .001) and mean Whole Brain MTR was lower in Secondary/Progressive (SP, n= 10) than Relapsing/Remitting (RR, n= 50, P < .001) patients.
However, none of the SubCortical Gray Matter Nuclei showed MTR differences in MS vs. NL, RR vs. SP, or SP vs. NL.
The MTI technique used in this cohort was relatively insensitive to disease in the deep Gray Matter Nuclei despite showing sensitivity for Whole Brain disease in MS.
It remains to be determined if other MRI techniques are more sensitive than MTI for detecting pathology in these areas.
Manfredonia F, Ciccarelli O, Khaleeli Z, Tozer DJ, Sastre-Garriga J, Miller DH, Thompson AJ
Arch Neurol 2007 Mar;64(3):411-5
Institute of Neurology, University College London, Departments of Brain Repair and Rehabilitation and NeuroInflammation, London, England
To investigate whether patients with early Primary/Progressive Multiple Sclerosis show changes in T1 relaxation time (T1-RT) in Normal-Appearing White Matter (NAWM) and Normal-Appearing Gray Matter (NAGM) during 2 years and whether T1-RT at baseline predicts disability.
Twenty-one patients and 12 control subjects were studied at baseline and after 2 years. Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) scores were assessed.
T1 relaxation time Histograms of NAWM and NAGM were obtained in all subjects, and mean, peak height, and peak location of the Histograms were measured.
Paired t tests were used to compare baseline and 2-year histogram values in patients and control subjects.
To investigate whether T1-RT predicted clinical changes, multiple linear regression analysis was used.
Patients showed increases in NAWM and NAGM T1-RT mean and peak location during follow-up, and significant decreases in NAWM and NAGM peak height.
Baseline NAWM T1-RT mean values and peak height predicted disability at 2 years, as measured with the Multiple Sclerosis Functional Composite score.
T1 relaxometry is a good marker of disease progression and has prognostic potential in Primary/Progressive Multiple Sclerosis.
Interferon-beta In Secondary/Progressive Multiple Sclerosis: Daily Clinical Practice
Rio J, Tintore M, Nos C, Tellez N, Galan I, Pelayo R, Montalban X
J Neurol 2007 Jul;254(7):849-53
Hospital Universitario Vall d'Hebron, feminine planta EUI, Unitat de NeuroImmunologia Clinica, Psg Vall d'Hebron 119-120, 08035, Barcelona, Spain
Background And Objective
Observational studies may provide additional information about the behavior of different drugs in the post-marketing period.
We present the data from a cohort of Secondary/Progressive Multiple Sclerosis (SPMS) patients treated with Interferon-beta-1b (IFN-ß-1b) at our MS clinic.
This was an independent, open-label, non-randomized, observational study.
Within the period 1998 to 2005, all patients with SPMS who started therapy with IFN-ß-1b at our center were studied.
Each patient was included in a follow-up protocol collecting demographic and baseline clinical data.
We studied 146 SPMS patients with a median follow-up of 60 months. Over the total study period, 62.2% of patients had confirmed progression.
The analysis of the time to confirmed progression showed that patients with two or more relapses in the 2 years before IFN-ß-1b initiation, had a higher risk of disability increase than those patients with less than two relapses (p = 0.002).
Multiple regression analysis showed disease activity in terms of relapses as the only factor to predict increase of disability during the follow-up period.
A significant proportion of patients (36%) stopped treatment during the follow-up period. IFN-ß-1b was safe, although some unexpected adverse events were observed.
A higher disease activity before the beginning of treatment with IFN-ß-1b in SPMS patients with a given EDSS rank could identify those with faster disability progression after treatment initiation.
Calabrese M, Atzori M, Bernardi V, Morra A, Romualdi C, Rinaldi L, McAuliffe MJ, Barachino L, Perini P, Fischl B, Battistin L, Gallo P
J Neurol 2007 Sep;254(9):1212-20
The Multiple Sclerosis Centre of Veneto Region, First Neurology Clinic, Dept. of NeuroSciences, University Hospital of Padova, Via Giustiniani 5, 35128, Padova, Italy
Increasing evidence suggests relevant Cortical Gray Matter pathology in patients with Multiple Sclerosis (MS).
But how early this pathology begins; its impact on clinical disability and which Cortical areas are primarily affected needs to be further elucidated.
115 consecutive patients (10 Clinically Isolated Syndrome (CIS), 32 possible MS (p-MS), 42 Relapsing/Remitting MS (RR-MS), 31 Secondary/Progressive MS (SP-MS)), and 40 age/gender-matched Healthy Volunteers (HV) underwent a Neurological Examination and a 1.5 T MRI.
Global and regional Cortical Thickness (CTh) measurements, Brain Parenchymal Fraction and T2 lesion load were analyzed.
We found a significant global Cortical thinning in p-MS (2.22 +/- 0.09 mm), RR-MS (2.16 +/- 0.10 mm) and SP-MS (1.98 +/- 0.11 mm) compared to CIS (2.51 +/- 0.11 mm) and HV (2.48 +/- 0.08 mm).
The correlations between mean CTh and White Matter (WM) lesion load was only moderate in MS (r = -0.393, p = 0.03) and absent in p-MS (r = -0.147, p = 0.422).
Analysis of regional CTh revealed that the majority of Cortical areas were involved not only in MS, but also in p-MS.
The type of clinical picture at onset (in particular, Pyramidal Signs/Symptoms and Optic Neuritis) correlated with Atrophy in the corresponding Cortical areas.
Cortical thinning is a diffuse and early phenomenon in MS already detectable at clinical onset. It correlates with clinical disability and is partially independent from WM inflammatory pathology.
Activation Of The SubVentricular Zone In Multiple Sclerosis: Evidence For Early Glial Progenitors
Nait-Oumesmar B, Picard-Riera N, Kerninon C, Decker L, Seilhean D, Hoglinger GU, Hirsch EC, Reynolds R, Baron-Van Evercooren A
Proc Natl Acad Sci USA 2007 Mar 13;104(11):4694-9
Institut National de la Sante et de la Recherche Medicale, Unite 546, 75013 Paris, France
In Multiple Sclerosis (MS), Oligodendrocyte and Myelin destruction lead to DeMyelination with subsequent Axonal Loss.
Experimental DeMyelination in rodents has highlighted the activation of the SubVentricular zone (SVZ) and the involvement of Progenitor Cells expressing the polysialylated form of Neural Cell Adhesion Molecule (PSA-NCAM) in the repair process.
In this article, we studied the distribution of early PSA-NCAM+ Progenitors in the SVZ and MS lesions in human postmortem Brains.
Compared with controls, MS SVZ showed a 2- to 3-fold increase in cell density and proliferation, which correlated with enhanced numbers of PSA-NCAM+ and Glial Fibrillary Acidic Protein-Positive (GFAP+) cells.
PSA-NCAM+ Progenitors mainly were Sox9+, and a few expressed Sox10 and Olig2, markers of Oligodendroglial specification.
PSA-NCAM+ Progenitors expressing Sox10 and Olig2 also were detected in DeMyelinated MS lesions.
In active and chronic active lesions, the number of PSA-NCAM+ progenitors was 8-fold higher compared with chronic silent lesions, shadow plaques, and Normal-Appearing White Matter.
In active and chronic active lesions, PSA-NCAM+ progenitors were more frequent in PeriVentricular lesions (30-50%) than in lesions remote from the Ventricular wall.
These data indicate that, as in rodents, activation of Gliogenesis in the SVZ occurs in MS and suggest the mobilization of SVZ-derived early Glial Progenitors to PeriVentricular lesions, where they could give rise to Oligodendrocyte Precursors.
These early Glial Progenitors could be a potential target for therapeutic strategies designed to promote Myelin repair in MS.