Determinants Of Disability In Multiple Sclerosis At Various Disease Stages: A Multiparametric Magnetic Resonance Study
Pulizzi A, Rovaris M, Judica E, Sormani MP, Martinelli V, Comi G, Filippi M
Arch Neurol 2007 Aug;64(8):1163-8
San Raffaele Scientific Institute, NeuroImaging Research Unit, Department of Neurology, Milan, Italy
To investigate whether Diffusion-Tensor Magnetic Resonance Imaging and Whole Brain N-AcetylAspartate (WBNAA) proton Magnetic Resonance Spectroscopy can provide complementary pieces of information.
To achieve a better understanding of the factors associated with disability in Multiple Sclerosis (MS).
Design & Setting
Cross-sectional survey. Referral hospital-based MS center.
Ten healthy control subjects, 27 patients with a Clinically Isolated Neurological Syndrome, 21 patients with Relapsing/Remitting MS, and 29 patients with Secondary/Progressive MS.
Main Outcome Measures
Conventional and Diffusion-Tensor Magnetic Resonance Imaging, as well as WBNAA proton Magnetic Resonance Spectroscopy, of the Brain was performed.
T2-HyperIntense lesion volumes were measured. The mean values of Mean Diffusivity (MD) and Fractional Anisotropy of T2-visible lesions were computed.
Histograms of MD and Fractional Anisotropy values were produced for Normal-Appearing White Matter and Gray Matter (GM).
Patients with a Clinically Isolated Neurological Syndrome had a significantly (P=.002) lower WBNAA concentration than control subjects.
Patients with Relapsing/Remitting MS had significantly higher T2 lesion volume (P=.007), mean lesion MD (P=.003), Normal-Appearing White Matter Fractional Anisotropy peak height (P=.03), and a lower WBNAA concentration (P < .001) than patients with a Clinically Isolated Neurological Syndrome.
Patients with Secondary/Progressive MS had significantly higher T2 lesion volume (P=.01), lower mean Normal-Appearing White Matter Fractional Anisotropy (P=.003), higher mean GM MD (P=.004), and lower GM MD peak height (P=.01) than patients with Relapsing/Remitting MS.
Disease duration, GM MD peak height, and WBNAA concentration entered a multivariate model, explaining nearly 70% of the disability variance.
The accumulation of macroscopic lesions and Normal-Appearing White Matter damage seems to occur mainly during the earliest clinical phases of MS.
Whereas, pathological features of GM may be a hallmark of the late Progressive stage of the disease. This supports the notion of MS as a "2-stage" disease.
Agosta F, Absinta M, Sormani MP, Ghezzi A, Bertolotto A, Montanari E, Comi G, Filippi M
Brain 2007 Aug;130(Pt 8):2211-9
Scientific Institute and University Ospedale San Raffaele, NeuroImaging Research Unit, Department of Neurology, Milan; University of Genoa, Unit of Biostatistics, DISSAL, Genoa; Multiple Sclerosis Center, Gallarate Hospital, Gallarate; Orbassano and Multiple Sclerosis Center, Department of Neurology, Orbassano Hospital, Fidenza Hospital, Fidenza, Italy
Cervical Cord damage is likely to contribute to the accumulation of disability in Multiple Sclerosis (MS) and can be quantified in vivo using MRI.
We used conventional and Diffusion Tensor (DT) MRI to:
- Define the temporal evolution of intrinsic tissue injury and Atrophy in the Cervical Cord from MS patients
- Investigate how these two aspects of Cord damage are interrelated
- Assess the correlation of Cord MRI metrics with concomitant Brain damage and disability
Conventional and DT MRI of the Brain and Cervical Cord were obtained from 42 MS patients and 9 healthy controls at baseline and after a mean follow-up of 2.4 years.
At each time-point, we measured: Cervical Cord lesion number, Cross-Sectional Area, Mean Diffusivity (MD) and Fractional Anisotropy (FA).
Brain T2 lesion volume, Gray Matter MD, Normal-Appearing White Matter (NAWM) MD and FA, as well as longitudinal Normalized percentage Brain Volume changes were also measured.
In MS patients, Cervical Cord Cross-Sectional Area (P < 0.001) and FA (P = 0.01) decreased, and Cervical Cord MD increased (P < 0.001) during follow-up.
Cord FA decrease, but not Cord Cross-Sectional Area and MD, was significantly higher (P = 0.05) in Primary/Progressive MS patients than in those with either Relapsing/Remitting or Secondary/Progressive MS.
At baseline and follow-up, moderate correlations were found between intrinsic Cord Diffusivity abnormalities and Cord Cross-Sectional Area (r values ranging from 0.34 to 0.58), but not between their changes over time.
No cross-sectional and longitudinal correlations were found between these MRI metrics and the number of Cord T2-visible lesions. Brain NAWM MD (P = 0.03) and Brain Volume (P < 0.001) also changed in patients.
There was no significant correlation between Cord and Brain MRI metrics at both time-points, as well as between their changes occurred over the follow-up.
Baseline Cord Cross-Sectional Area (r = -0.40, P = 0.01) and FA (r = -0.40, P = 0.03) correlated with increase in disability at follow-up.
This study shows that both progressive tissue loss and injury to the remaining tissue occur in the Cervical Cord of MS patients.
And, that these two components of Cord damage are not strictly interrelated, thus suggesting that a multiparametric MRI approach is needed to achieve more accurate estimates of such a damage.
MS Cord pathology also seems to be independent of concomitant Brain changes, to develop at different rates according to disease phenotype, and to be associated to medium-term disability accrual.
Niino M, Fukazawa T, Kikuchi S, Sasaki H
Curr Med Chem 2008;15(5):499-505
Hokkaido University Hospital, Kita-14, Department of Neurology, Nishi-5, Kita-ku, Sapporo 060-8648 Japan
Multiple Sclerosis (MS) is a major inflammatory and DeMyelinating Disease of the Central Nervous System and has an increasing prevalence in populations residing at higher latitudes.
This observation may indicate a protective effect of sunlight exposure, which is reduced at higher latitudes and may contribute to insufficient levels of Vitamin-D in the MS population.
The Vitamin-D hormone is important for bone metabolism and can regulate cell proliferation and differentiation as well as Apoptosis and Immune regulation in Immune Cells such as T Helper Cells and Dendritic Cells.
Evidence from Experimental Autoimmune Encephalomyelitis and prospective studies on MS suggests an important role of Vitamin-D as a modifiable environmental factor in MS.
These provide guidance for future studies with regard to the potential role of Vitamin-D in the prevention and/or treatment of MS. Here, we first review the metabolism and Immune functions of Vitamin-D.
Then, we describe the current thinking on the etiology of Vitamin-D in MS and the accumulating evidence pointing to a link between Vitamin-D and MS.
Further, we describe how genetic susceptibility interacts with environmental risk factors at the population level, MS-associated risk factors, and genetic studies related to the Vitamin-D receptor.
This review also discusses the therapeutic potential of Vitamin-D for treating MS.
Quantitative Diffusion Weighted Imaging Measures In Patients With Multiple Sclerosis
Tavazzi E, Dwyer MG, Weinstock-Guttman B, Lema J, Bastianello S, Bergamaschi R, Cosi V, Benedict RH, Munschauer FE, Zivadinov R
NeuroImage 2007 Jul 1;36(3):746-54
State University of New York, University at Buffalo, Buffalo NeuroImaging Analysis Center, Department of Neurology, Buffalo, NY, USA; University of Pavia, Department of Neurology, IRCCS, C. Mondino, Pavia, Italy
Diffusion-Weighted Imaging (DWI) has been proposed as a sensitive measure of disease severity capable of detecting subtle changes in Gray Matter and White Matter Brain compartments in patients with Multiple Sclerosis (MS).
However, DWI has been applied to the study of MS clinical subtypes in only a few studies.
The objective of this study was to demonstrate the validity of a novel, fully automated method for the calculation of quantitative DWI measures.
We also wanted to assess the correlation between Whole Brain (WB)-DWI variables and clinical and MRI measures of disease severity in a large cohort of MS patients.
For this purpose we studied 432 consecutive MS patients (mean age 44.4+/-10.2 years), 16 patients with Clinically Isolated Syndrome (CIS) and 38 normal controls (NC) using 1.5 T brain MRI.
Clinical disease subtypes were as follows: 294 Relapsing/Remitting (RR), 123 Secondary/Progressive (S/P) and 15 Primary/Progressive (PP). Mean disease duration was 12+/-10 years.
Mean Expanded Disability Status Scale (EDSS) was 3.3+/-2.1. Brain Parenchymal Fraction (BPF), Gray Matter Fraction (GMF) and White Matter Fraction (WMF) were calculated using a fully automated method.
Mean Parenchymal Diffusivity (MPD) maps were created. DWI indices of peak position (PP), peak height (PH), MPD and Entropy (ENT) were obtained.
T2- and T1-lesion volumes (LV), EDSS, Ambulation Index (AI) and Nine-Hole Peg Test (9-HPT) were also assessed.
MS patients had significantly lower BPF (d=1.26; p < 0.001) and GMF (d=0.61; p=0.003), and higher ENT (d=1.2; p < 0.0001), MPD (d=1.04; p < 0.0001) and PH (d=0.47; p=0.045) than NC subjects.
A GLM analysis, adjusted for age and multiple comparisons, revealed significant differences between different clinical subtypes for BPF, GMF, ENT, PH, PP, T2-LV and T1-LV (p < 0.0001), WMF (p=0.001) and MPD (p=0.023).
In RR and SP MS patients, ENT showed a more robust correlation with other MRI (r=0.54 to 0.67, p < 0.0001) and clinical (r=0.31 to 0.36, p < 0.0001) variables than MPD (r=0.23 to 0.41, p < 0.001 for MRI and r=0.13 to 0.18; p=0.006 to p < 0.001 for clinical variables).
The GMF and BPF showed a slightly stronger relationship with all clinical variables (r=0.33 to 0.48; p < 0.0001), when compared to both lesion and DWI measures.
ENT (R(2)=0.28; p < 0.0001) and GMF (R(2)=0.26; p < 0.001) were best related with SP disease course.
This study highlights the validity of DWI in discerning differences between NC and MS patients, as well as between different MS subtypes.
ENT is a sensitive marker of overall Brain Damage that is strongly related to clinical impairment in patients with SP MS.
Semi-Automatic Brain Region Extraction (SABRE) Reveals Superior Cortical And Deep Gray Matter Atrophy In MS
Carone DA, Benedict RH, Dwyer MG, Cookfair DL, Srinivasaraghavan B, Tjoa CW, Zivadinov R
NeuroImage 2006 Jan 15;29(2):505-14
Buffalo NeuroImaging Analysis Center, Buffalo, NY 14203, USA
In Multiple Sclerosis (MS), Atrophy occurs in various Cortical and SubCortical regions. However, it is unclear whether this is mostly due to Gray (GM) or White Matter (WM) loss.
Recently, a new Semi-Automatic Brain Region Extraction (SABRE) technique was developed to quantify Parenchyma Volume in 13 Hemispheric regions.
This study utilized SABRE and tissue segmentation to examine whether Regional Brain Atrophy in MS is mostly due to GM or WM loss, correlated with disease duration, and moderated by disease course.
We studied 68 MS patients and 39 normal controls with 1.5 T Brain MRI. As expected, MS diagnosis was associated with significantly lower (P < 0.001) Regional Brain Parenchymal Fractions (RBPFs).
While significant findings emerged in 11 GM comparisons, only four WM comparisons were significant.
The largest mean RBPF percent differences between groups (MS < NC) were in the Posterior Basal Ganglia/Thalamus region (-19.3%), Superior Frontal (-15.7%), and Superior Parietal (-14.3%) regions.
Logistic regression analyses showed GM regions were more predictive of MS diagnosis than WM regions. Eight GM RBPFs were significantly correlated (P < 0.001) with disease duration compared to only one WM region.
Significant trends emerged for differences in GM, but not WM between Secondary/Progressive (SP) and Relapsing/Remitting MS patients.
Percent differences in GM between the two groups were largest in Superior Frontal (-9.9%), Medial Superior Frontal (-6.5%), and Superior Parietal (-6.1%) regions, with SP patients having lower volumes.
Overall, Atrophy in MS is diffuse and mostly related to GM loss particularly in deep GM and Superior Frontal-Parietal regions.
Pathogenesis Of Axonal And Neuronal Damage In Multiple Sclerosis
Multiple Sclerosis (MS) is a chronic inflammatory DeMyelinating disease of the CNS. Approximately 2 million people worldwide have MS, with females outnumbering males 2:1.
Because of its high prevalence, MS is the leading cause of nontraumatic Neurologic Disability in young adults in the United States and Europe.
Axon loss is the major cause of irreversible disability in patients with MS. Axon damage, including transection of the Axon, begins early in MS and correlates with inflammatory activity.
Several mechanisms lead to Axon loss, including inflammatory secretions, loss of Myelin-derived support, disruption of Axonal Ion concentrations, Energy Failure, and Ca2+ accumulation.
Therapeutic interventions directed toward each of these mechanisms need to be tested for their efficacy in enhancing Axon survival and, ultimately, their ability to delay progression of Neurologic Disability in patients with MS.
J Biol Chem 2003 Jul 25;278(30):27620-9
Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Científicas, Granada 18001, Spain
Interferon-gamma (IFN-γ) is one of the most important Microglia stimulators in vivo participating in inflammation and Th1 activation/differentiation.
IFN-γ-mediated signaling involves the activation of the Jak/STAT1 pathway. The NeuroPeptides Vasoactive Intestinal Peptide (VIP).
And, the Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) are two potent Microglia-deactivating factors that inhibit the production of proinflammatory mediators in vitro and in vivo.
The present study investigated the molecular mechanisms involved in the VIP/PACAP regulation of several IFN-γ-induced Microglia-derived factors.
Including IFN-γ-Inducible Protein-10 (IP-10), Inducible Nitric-Oxide Synthase (INOS), and CD40.
The results indicate that VIP/PACAP inhibit Jak1-2 and STAT1 phosphorylation, and the binding of activated STAT1 to the IFN-γ activated site motif.
In the IFN regulatory factor-1 and CD40 promoter and to the IFN-stimulated response element motif of the IP-10 promoter.
Through its effect in the IFN-γ-induced Jak/STAT1 pathway, VIP and PACAP are able to control the gene expression of IP-10, CD40.
And INOS, three Microglia-derived mediators that play an essential role in several pathologies, i.e. Inflammation and Autoimmune Disorders.
The effects of VIP/PACAP are mediated through the specific Receptor VPAC1 and the cAMP/protein kinase A transduction pathway.
Because IFN-γ is a major stimulator of Innate and Adaptive Immune Responses in vivo, the down-regulation of IFN-γ-induced gene expression by VIP.
And, PACAP could represent a significant element in the regulation of the inflammatory response in the Central Nervous System by endogenous NeuroPeptides.