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ABSTRACT: Brain magnetic resonance imaging is widely used as a diagnostic and monitoring tool in multiple sclerosis and provides a non-invasive, sensitive and reproducible way to track the disease. Topological characteristics relating to the distribution and shape of lesions are recognized as important neuroradiological markers in the diagnosis of multiple sclerosis, although these have been much less well characterized quantitatively than have traditional measures such as T(2) hyperintense or T(1) hypointense lesion volumes. Here, we used voxel-level 3 T magnetic resonance imaging T(1)-weighted scans to reconstruct the 3D topology of lesions in 284 subjects with multiple sclerosis and tested whether this is a heritable phenotype. To this end, we extracted the genotypes from a published genome-wide association study on these same individuals and searched for genetic associations with lesion load, shape and topological distribution. Lesion probability maps were created to identify frequently affected areas and to assess the overall distribution of T(1) lesions in the subject population as a whole. We then developed an original algorithm to cluster adjacent lesional voxels (cluxels) in each subject and tested whether cluxel topology was significantly associated with any single-nucleotide polymorphism in our data set. To focus on patterns of lesion distribution, we computed the first 10 principal components. Although principal component 1 correlated with lesion load, none of the remaining orthogonal components correlated with any other known variable. We then conducted genome-wide association studies on each of these and found 31 significant associations (false discovery rate <0.01) with principal component 8, which represents a mode of variation of lesion topology in the population. The majority of the loci can be linked to genes related to immune cell function and to myelin and neural growth; some (SYK, MYT1L, TRAPPC9, SLITKR6 and RIC3) have been previously associated with the distribution of white matter lesions in multiple sclerosis. Finally, we used a bioinformatics approach to identify a network of 48 interacting proteins showing genetic associations (P < 0.01) with cluxel topology in multiple sclerosis. This network also contains proteins expressed in immune cells and is enriched in molecules expressed in the central nervous system that contribute to neural development and regeneration. Our results show how quantitative traits derived from brain magnetic resonance images of patients with multiple sclerosis can be used as dependent variables in a genome-wide association study. With the widespread availability of powerful computing and the availability of genotyped populations, integration of imaging and genetic data sets is likely to become a mainstream tool for understanding the complex biological processes of multiple sclerosis and other brain disorders.
Brain 02/2013; · 9.46 Impact Factor
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ABSTRACT: Natalizumab is an effective treatment for patients with multiple sclerosis (MS) that is associated with a risk of progressive multifocal leukoencephalopathy (PML). Recommendations were published in 2006 to improve early diagnosis of PML using magnetic resonance imaging (MRI). However, due to the small number of MS patients initially diagnosed with PML, the imaging criteria could only be derived from PML lesions in patients with human immunodeficiency virus. Therefore, there is an urgent need to assess the MRI characteristics of PML in MS patients to update the existing recommendations.
In this retrospective review, the first 40 natalizumab-treated MS patients diagnosed with PML in the postmarketing setting were identified, of whom 22 (10 with clinically diagnosed immune reconstitution inflammatory syndrome) fulfilled the inclusion criteria for this study. Magnetic resonance images were analyzed according to predefined criteria by 5 independent readers.
The most frequent lesion pattern in early scans from PML patients was that of large (>3 cm, 15 of 18), subcortical (18 of 18), T2 or fluid-attenuated inversion recovery hyperintense (18 of 18), T1-hypointense (17 of 18), and diffusion-hyperintense (15 of 15) lesions, with a sharp border toward the gray matter and an ill-defined border toward the white matter (18 of 18) on T2-weighted images. We could detect contrast enhancement in 41% (7 of 17) of the cases on the first scan at clinical presentation.
Attention to characteristic MRI patterns, especially the presence of contrast enhancement, and the subcortical location may have utility in screening and early diagnosis of PML in natalizumab-treated MS patients. ANN NEUROL 2012;72:779-787.
Annals of Neurology 11/2012; 72(5):779-87. · 11.09 Impact Factor
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Ellen M Mowry,
Emmanuelle Waubant,
Charles E McCulloch,
Darin T Okuda,
Alan A Evangelista,
Robin R Lincoln,
Pierre-Antoine Gourraud,
Don Brenneman,
Mary C Owen,
Pamela Qualley,
Monica Bucci,
Stephen L Hauser, Daniel Pelletier
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ABSTRACT: We sought to determine whether vitamin D status is associated with developing new T2 lesions or contrast-enhancing lesions on brain magnetic resonance imaging (MRI) in relapsing multiple sclerosis (MS).
EPIC is a 5-year longitudinal MS cohort study at the University of California at San Francisco. Participants had clinical evaluations, brain MRI, and blood draws annually. From the overall cohort, we evaluated patients with clinically isolated syndrome or relapsing-remitting MS at baseline. In univariate and multivariate (adjusted for age, sex, ethnicity, smoking, and MS treatments) repeated measures analyses, annual 25-hydroxyvitamin D levels were evaluated for their association with subsequent new T2-weighted and gadolinium-enhancing T1-weighted lesions on brain MRI, clinical relapses, and disability (Expanded Disability Status Scale [EDSS]).
A total of 2,362 3T brain MRI scans were acquired from 469 subjects. In multivariate analyses, each 10ng/ml higher 25-hydroxyvitamin D level was associated with a 15% lower risk of a new T2 lesion (incidence rate ratio [IRR], 0.85; 95% confidence interval [CI], 0.76-0.95; p = 0.004) and a 32% lower risk of a gadolinium-enhancing lesion (IRR, 0.68; 95% CI, 0.53-0.87; p = 0.002). Each 10ng/ml higher vitamin D level was associated with lower subsequent disability (-0.047; 95% CI, -0.091 to -0.003; p = 0.037). Higher vitamin D levels were associated with lower, but not statistically significant, relapse risk. Except for the EDSS model, all associations were stronger when the within-person change in vitamin D level was the predictor.
Vitamin D levels are inversely associated with MS activity on brain MRI. These results provide further support for a randomized trial of vitamin D supplementation.
Annals of Neurology 08/2012; 72(2):234-40. · 11.09 Impact Factor
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ABSTRACT: Background: Magnetic resonance (MR) phase imaging using high field MR scanners has demonstrated excellent contrast in multiple sclerosis (MS) lesions that is thought to be closely correlated to the local iron content. This pilot study acquired serial in vivo MR scans at 7T to track the evolution of phase contrast as MS lesions progress.Methods: Five MS patients with relapsing-remitting MS were serially scanned for about 2.5 years at 7T using a high resolution T2*-weighted gradient-echo sequence. Magnitude and phase images were reconstructed for each scan and co-registered to their baseline study.Results: Five non-enhancing ring and 70 nodular phase lesions were found in the five patients at baseline. None of the baseline phase lesions (including all five ring phase lesions) showed obvious qualitative variation on phase images during the study. Of note, we observed that three magnitude lesions, not initially read as abnormal signal, were either better appreciated using phase contrast imaging (two lesions) or preceded (one lesion) by phase changes.Conclusion: The observation that ring phase lesions remained unchanged over 2.5 years of follow-up challenges the notion that such lesions reveal the presence of acute activated iron-rich macrophages. It suggests that either different phenotypes of macrophages persist longer than previously expected or other mechanisms related to tissue injury contribute to the phase contrast.
Multiple Sclerosis 05/2012; · 4.26 Impact Factor
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New England Journal of Medicine 01/2012; 366(4):339-47. · 53.30 Impact Factor
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Stefan D Roosendaal,
Kerstin Bendfeldt,
Hugo Vrenken,
Chris H Polman,
Stefan Borgwardt,
Ernst W Radue,
Ludwig Kappos, Daniel Pelletier,
Stephen L Hauser,
Paul M Matthews,
Frederik Barkhof,
Jeroen J G Geurts
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ABSTRACT: Although grey matter damage in multiple sclerosis is currently recognized, determinants of grey matter volume and its relationship with disability are not yet clear.
The objectives of the study were to measure grey and white matter volumes across different disease phenotypes; identify MRI parameters associated with grey matter volume; and study grey and white matter volume as explanatory variables for clinical impairment.
This is a cross-sectional study in which MRI data of 95 clinically isolated syndrome, 657 relapsing-remitting, 125 secondary-progressive and 50 primary-progressive multiple sclerosis patients from three centres were acquired. Grey and white matter volumes were determined, together with T2 and T1 lesion volumes. Physical disability was assessed with the Expanded Disability Status Scale, cognitive impairment with the Paced Auditory Serial Addition Task. Data were analysed using multiple regression.
Grey matter volume was lower in relapsing-remitting patients (mean [SD]: 0.80 [0.05] L) than in clinically isolated syndrome patients (0.82 [0.05] L), and even greater relative atrophy was found in secondary-progressive patients (0.77 [0.05] L). In contrast, white matter volume in secondary-progressive patients was comparable to that in relapsing-remitting patients. Grey matter volume was the strongest independent predictor of physical disability and cognitive impairment, and was associated with both T2 and T1 lesion volume.
Our findings show that grey matter volume is lower in secondary-progressive than in relapsing-remitting disease. Grey matter volume explained physical and cognitive impairment better than white matter volume, and is itself associated with T2 and T1 lesion volume.
Multiple Sclerosis 05/2011; 17(9):1098-106. · 4.26 Impact Factor
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Tamara Castillo-Trivino,
Ellen M Mowry,
Alberto Gajofatto,
Dorothee Chabas,
Elizabeth Crabtree-Hartman,
Bruce A Cree,
Douglas S Goodin,
Ari J Green,
Darin T Okuda, Daniel Pelletier,
Scott S Zamvil,
Eric Vittinghoff,
Emmanuelle Waubant
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ABSTRACT: Multiple sclerosis (MS) patients with breakthrough disease on immunomodulatory drugs are frequently offered to switch to natalizumab or immunosuppressants. The effect of natalizumab monotherapy in patients with breakthrough disease is unknown.
This is an open-label retrospective cohort study of 993 patients seen at least four times at the University of California San Francisco MS Center, 95 had breakthrough disease on first-line therapy (60 patients switched to natalizumab, 22 to immunosuppressants and 13 declined the switch [non-switchers]). We used Poisson regression adjusted for potential confounders to compare the relapse rate within and across groups before and after the switch.
In the within-group analyses, the relapse rate decreased by 70% (95% CI 50,82%; p<0.001) in switchers to natalizumab and by 77% (95% CI 59,87%; p<0.001) in switchers to immunosuppressants; relapse rate in non-switchers did not decrease (6%, p = 0.87). Relative to the reduction among non-switchers, the relapse rate was reduced by 68% among natalizumab switchers (95% CI 19,87%; p = 0.017) and by 76% among the immunosuppressant switchers (95% CI 36,91%; p = 0.004).
Switching to natalizumab or immunosuppressants in patients with breakthrough disease is effective in reducing clinical activity of relapsing MS. The magnitude of the effect and the risk-benefit ratio should be evaluated in randomized clinical trials and prospective cohort studies.
PLoS ONE 01/2011; 6(2):e16664. · 4.09 Impact Factor
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Joanne H Wang,
Derek Pappas,
Philip L De Jager, Daniel Pelletier,
Paul Iw de Bakker,
Ludwig Kappos,
Chris H Polman,
Lori B Chibnik,
David A Hafler,
Paul M Matthews,
Stephen L Hauser,
Sergio E Baranzini,
Jorge R Oksenberg
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ABSTRACT: Multiple sclerosis (MS) is the most common cause of chronic neurologic disability beginning in early to middle adult life. Results from recent genome-wide association studies (GWAS) have substantially lengthened the list of disease loci and provide convincing evidence supporting a multifactorial and polygenic model of inheritance. Nevertheless, the knowledge of MS genetics remains incomplete, with many risk alleles still to be revealed.
We used a discovery GWAS dataset (8,844 samples, 2,124 cases and 6,720 controls) and a multi-step logistic regression protocol to identify novel genetic associations. The emerging genetic profile included 350 independent markers and was used to calculate and estimate the cumulative genetic risk in an independent validation dataset (3,606 samples). Analysis of covariance (ANCOVA) was implemented to compare clinical characteristics of individuals with various degrees of genetic risk. Gene ontology and pathway enrichment analysis was done using the DAVID functional annotation tool, the GO Tree Machine, and the Pathway-Express profiling tool.
In the discovery dataset, the median cumulative genetic risk (P-Hat) was 0.903 and 0.007 in the case and control groups, respectively, together with 79.9% classification sensitivity and 95.8% specificity. The identified profile shows a significant enrichment of genes involved in the immune response, cell adhesion, cell communication/signaling, nervous system development, and neuronal signaling, including ionotropic glutamate receptors, which have been implicated in the pathological mechanism driving neurodegeneration. In the validation dataset, the median cumulative genetic risk was 0.59 and 0.32 in the case and control groups, respectively, with classification sensitivity 62.3% and specificity 75.9%. No differences in disease progression or T2-lesion volumes were observed among four levels of predicted genetic risk groups (high, medium, low, misclassified). On the other hand, a significant difference (F = 2.75, P = 0.04) was detected for age of disease onset between the affected misclassified as controls (mean = 36 years) and the other three groups (high, 33.5 years; medium, 33.4 years; low, 33.1 years).
The results are consistent with the polygenic model of inheritance. The cumulative genetic risk established using currently available genome-wide association data provides important insights into disease heterogeneity and completeness of current knowledge in MS genetics.
Genome Medicine 01/2011; 3(1):3.
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ABSTRACT: Glutamate is the main excitatory neurotransmitter in the mammalian brain. Appropriate transmission of nerve impulses through glutamatergic synapses is required throughout the brain and forms the basis of many processes including learning and memory. However, abnormally high levels of extracellular brain glutamate can lead to neuroaxonal cell death. We have previously reported elevated glutamate levels in the brains of patients suffering from multiple sclerosis. Here two complementary analyses to assess the extent of genomic control over glutamate levels were used. First, a genome-wide association analysis in 382 patients with multiple sclerosis using brain glutamate concentration as a quantitative trait was conducted. In a second approach, a protein interaction network was used to find associated genes within the same pathway. The top associated marker was rs794185 (P < 6.44 x 10(-7)), a non-coding single nucleotide polymorphism within the gene sulphatase modifying factor 1. Our pathway approach identified a module composed of 70 genes with high relevance to glutamate biology. Individuals carrying a higher number of associated alleles from genes in this module showed the highest levels of glutamate. These individuals also showed greater decreases in N-acetylaspartate and in brain volume over 1 year of follow-up. Patients were then stratified by the amount of annual brain volume loss and the same approach was performed in the 'high' (n = 250) and 'low' (n = 132) neurodegeneration groups. The association with rs794185 was highly significant in the group with high neurodegeneration. Further, results from the network-based pathway analysis remained largely unchanged even after stratification. Results from these analyses indicated that variance in the activity of neurochemical pathways implicated in neurodegeneration is explained, at least in part, by the inheritance of common genetic polymorphisms. Spectroscopy-based imaging provides a novel quantitative endophenotype for genetic association studies directed towards identifying new factors that contribute to the heterogeneity of clinical expression of multiple sclerosis.
Brain 09/2010; 133(9):2603-11. · 9.46 Impact Factor
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Annals of Neurology 11/2009; 66(6):867. · 11.09 Impact Factor
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ABSTRACT: To compare initial brain magnetic resonance imaging (MRI) characteristics of children and adults at multiple sclerosis (MS) onset.
Retrospective analysis of features of first brain MRI available at MS onset in patients with pediatric-onset and adult-onset MS.
A pediatric and an adult MS center.
Patients with pediatric-onset <18 years) and adult-onset (> or =18 years) MS.
We evaluated initial and second (when available) brain MRI scans obtained at the time of first MS symptoms for lesions that were T2-bright, ovoid and well defined, large (> or =1cm), or enhancing.
We identified 41 patients with pediatric-onset MS and 35 patients with adult-onset MS. Children had a higher number of total T2- (median, 21 vs 6; P < .001) and large T2-bright areas (median, 4 vs 0; P < .001) than adults. Children more frequently had T2-bright foci in the posterior fossa (68.3% vs 31.4%; P = .001) and enhancing lesions (68.4% vs 21.2%; P < .001) than adults. On the second brain MRI, children had more new T2-bright (median, 2.5 vs 0; P < .001) and gadolinium-enhancing foci (P < .001) than adults. Except for corpus callosum involvement, race/ethnicity was not strongly associated with disease burden or lesion location on the first scan, although other associations cannot be excluded because of the width of the confidence intervals.
While it is unknown whether the higher disease burden, posterior fossa involvement, and rate of new lesions in pediatric-onset MS are explained by age alone, these characteristics have been associated with worse disability progression in adults.
Archives of neurology 09/2009; 66(8):967-71. · 6.31 Impact Factor
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ABSTRACT: Detection of glutathione (GSH) is technically challenging at clinical field strengths of 1.5 or 3 T due to its low concentration in the human brain coupled with the fact that conventional single-echo acquisitions, typically used for magnetic resonance (MR) spectroscopy acquisitions, cannot be used to resolve GSH given its overlap with other resonances. In this study, an MR spectral editing scheme was used to generate an unobstructed detection of GSH at 7 T. This technique was used to obtain normative white (WM) and gray matter (GM) GSH concentrations over a two-dimensional region. Results indicated that GSH was significantly higher (P<.001) in GM relative to WM in normal subjects. This finding is consistent with previous radionuclide experiments and histochemical staining and validates this 7 T MR spectroscopy technique. To our knowledge, this is the first study to report normative differences in WM and GM glutathione concentrations in the human brain. Glutathione is a biomarker for oxidative status and this non-invasive in vivo measurement of GSH was used to explore its sensitivity to oxidative state in multiple sclerosis (MS) patients. There was a significant reduction (P<.001) of GSH between the GM in MS patients and normal controls. No statistically significant GSH differences were found between the WM in controls and MS patients. Reduced GSH was also observed in a MS WM lesion. This preliminary investigation demonstrates the potential of this marker to probe oxidative state in MS.
Magnetic Resonance Imaging 08/2009; 28(2):163-70. · 1.99 Impact Factor
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ABSTRACT: Distinguishing between a first episode of multiple sclerosis and acute disseminated encephalomyelitis in children who present with an initial demyelinating event can be a clinical challenge. New brain MRI criteria that aim to differentiate these clinical presentations, and revised McDonald MRI criteria specific for the pediatric population, are both worthy of note.
Nature Reviews Neurology 05/2009; 5(4):186-8. · 12.46 Impact Factor
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ABSTRACT: Previous studies suggest that thalamic degeneration is prominent in multiple sclerosis (MS) and even in pre-MS patients presenting with a clinically isolated syndrome (CIS). However, the relationships between white matter lesions and deep grey matter loss are not well understood. We analyzed the association between white matter lesions and the thalami in CIS patients to determine if connectivity is an important determinant. We studied 24 CIS patients and 18 normal controls with anatomical and diffusion tensor (DTI) MRI images. DTI fiber tracking was used to create probabilistic templates of the thalamocortical white matter and to define white matter connecting lesions and thalami. DTI metrics in the lesions and normal-appearing white matter (NAWM) regions were compared between CIS and controls, and correlated with thalamic volume changes estimated by voxel-based morphometry. There was 10 times higher density of lesions in thalamocortical compared to other brain white matter. Increased diffusivities and decreased fractional anisotropies were measured in the thalamocortical NAWM of CIS patients compared to controls. A step-wise regression analysis demonstrated that thalamocortical lesion volume and the mean diffusivity in track regions connecting lesion and thalami were significantly correlated with thalamic volumes in patients (Rsq=0.66, p<0.001), a finding not observed in regions outside the thalamocortical white matter. These results provide compelling evidence for a direct relationship between white matter lesions and thalamic atrophy in CIS patients.
Journal of the neurological sciences 05/2009; 282(1-2):61-6. · 2.32 Impact Factor
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Sergio E Baranzini,
Nicholas W Galwey,
Joanne Wang,
Pouya Khankhanian,
Raija Lindberg, Daniel Pelletier,
Wen Wu,
Bernard M J Uitdehaag,
Ludwig Kappos,
Chris H Polman,
Paul M Matthews,
Stephen L Hauser,
Rachel A Gibson,
Jorge R Oksenberg,
Michael R Barnes
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ABSTRACT: Genome-wide association studies (GWAS) testing several hundred thousand SNPs have been performed in multiple sclerosis (MS) and other complex diseases. Typically, the number of markers in which the evidence for association exceeds the genome-wide significance threshold is very small, and markers that do not exceed this threshold are generally neglected. Classical statistical analysis of these datasets in MS revealed genes with known immunological functions. However, many of the markers showing modest association may represent false negatives. We hypothesize that certain combinations of genes flagged by these markers can be identified if they belong to a common biological pathway. Here we conduct a pathway-oriented analysis of two GWAS in MS that takes into account all SNPs with nominal evidence of association (P < 0.05). Gene-wise P-values were superimposed on a human protein interaction network and searches were conducted to identify sub-networks containing a higher proportion of genes associated with MS than expected by chance. These sub-networks, and others generated at random as a control, were categorized for membership of biological pathways. GWAS from eight other diseases were analyzed to assess the specificity of the pathways identified. In the MS datasets, we identified sub-networks of genes from several immunological pathways including cell adhesion, communication and signaling. Remarkably, neural pathways, namely axon-guidance and synaptic potentiation, were also over-represented in MS. In addition to the immunological pathways previously identified, we report here for the first time the potential involvement of neural pathways in MS susceptibility.
Human Molecular Genetics 04/2009; 18(11):2078-90. · 7.64 Impact Factor
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ABSTRACT: Recent advancement for magnetic resonance imaging (MRI) involves the incorporation of higher-field strengths. Although imagers with higher magnetic field strengths were developed and tested in research labs, the direct application to patient MR studies have been extremely limited. Imaging at 7 Tesla (7T) affords advantages in signal-to-noise ratio and image contrast and resolution; however, these benefits can only be realized if the correct coils exist to capture the images. The objective of this study was to develop optimized high-resolution 7T MRI techniques using high sensitivity, specialized phased-array coils, for improved gray matter (GM) and white matter differentiation, in an effort to improve visualization of multiple sclerosis (MS) lesions in vivo. Twenty-three subjects were enrolled in this preliminary study, 17 with clinically definite MS (11 females, 6 males; mean age 43.4 years; range 22-64 years) and 6 healthy controls (2 females, 4 males; mean age 39.0 years; range 27-67 years). MR imaging of MS patients at 7T was demonstrated to be safe, well tolerated, and provided high-resolution anatomical images allowing visualization of structural abnormalities localized near or within the cortical layers. Clear involvement of the GM was observed with improved morphological detail in comparison to imaging at lower-field strength.
Journal of neuroimaging: official journal of the American Society of Neuroimaging 02/2009; 20(2):141-7. · 1.72 Impact Factor
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Sergio E Baranzini,
Joanne Wang,
Rachel A Gibson,
Nicholas Galwey,
Yvonne Naegelin,
Frederik Barkhof,
Ernst-Wilhelm Radue,
Raija L P Lindberg,
Bernard M G Uitdehaag,
Michael R Johnson, [......],
Bruce A C Cree,
Ari J Green,
Emmanuelle Waubant,
Douglas S Goodin, Daniel Pelletier,
Paul M Matthews,
Stephen L Hauser,
Ludwig Kappos,
Chris H Polman,
Jorge R Oksenberg
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ABSTRACT: Multiple sclerosis (MS), a chronic disorder of the central nervous system and common cause of neurological disability in young adults, is characterized by moderate but complex risk heritability. Here we report the results of a genome-wide association study performed in a 1000 prospective case series of well-characterized individuals with MS and group-matched controls using the Sentrix HumanHap550 BeadChip platform from Illumina. After stringent quality control data filtering, we compared allele frequencies for 551 642 SNPs in 978 cases and 883 controls and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from magnetic resonance imaging exams. A multi-analytical strategy identified 242 susceptibility SNPs exceeding established thresholds of significance, including 65 within the MHC locus in chromosome 6p21.3. Independent replication confirms a role for GPC5, a heparan sulfate proteoglycan, in disease risk. Gene ontology-based analysis shows a functional dichotomy between genes involved in the susceptibility pathway and those affecting the clinical phenotype.
Human Molecular Genetics 12/2008; 18(4):767-78. · 7.64 Impact Factor
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ABSTRACT: Magnetic resonance imaging at 7 Tesla produces high-resolution gradient-echo phase images of patients with multiple sclerosis (MS) that quantify the local field shifts from iron in the basal ganglia and lesions. Phase imaging is easily integrated into clinical examinations because it is a postprocessing technique and does not require additional scanning. The purpose of this study was to quantify local field shifts in MS and to investigate their relation to disease duration and disability status.
Thirty-two subjects including 19 patients with MS and 13 age- and sex-matched control subjects were scanned at a spatial resolution of up to 195 x 260 microm. Data were postprocessed to produce anatomical quantitative phase images of local field shifts, as well as conventional magnitude images.
The phase images showed an increased local field in the caudate, putamen, and globus pallidus of patients relative to control subjects (p < 0.01). The local field in the caudate was strongly correlated with disease duration (r(2) = 0.77; p < 0.001). Phase images showed contrast in 74% of the 403 lesions, increasing the total lesion count by more than 30% and showing distinct peripheral rings and a close association with vasculature.
The increased field in the basal ganglia and correlation with disease duration suggest pathological iron content increases in MS. The peripheral phase rings are consistent with histological data demonstrating iron-rich macrophages at the periphery of a subset of lesions. The clearly defined vessels penetrating MS lesions should increase our ability to detect focal vascular abnormalities specifically related to demyelinating processes.
Annals of Neurology 12/2008; 64(6):707-13. · 11.09 Impact Factor
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Jean-Christophe Corvol, Daniel Pelletier,
Roland G Henry,
Stacy J Caillier,
Joanne Wang,
Derek Pappas,
Simona Casazza,
Darin T Okuda,
Stephen L Hauser,
Jorge R Oksenberg,
Sergio E Baranzini
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ABSTRACT: Clinically isolated syndrome (CIS) refers to the earliest clinical manifestation of multiple sclerosis (MS). Currently there are no prognostic biological markers that accurately predict conversion of CIS to clinically definite MS (CDMS). Furthermore, the earliest molecular events in MS are still unknown. We used microarrays to study gene expression in naïve CD4(+) T cells from 37 CIS patients at time of diagnosis and after 1 year. Supervised machine-learning methods were used to build predictive models of disease conversion. We identified 975 genes whose expression segregated CIS patients into four distinct subgroups. A subset of 108 genes further discriminated patients in one of these (group 1) from other CIS patients. Remarkably, 92% of patients in group 1 converted to CDMS within 9 months. Consistent down-regulation of TOB1, a critical regulator of cell proliferation, was characteristic of group 1 patients. Decreased TOB1 expression at the RNA and protein levels also was confirmed in experimental autoimmune encephalomyelitis. Finally, a genetic association was observed between TOB1 variation and MS progression in an independent cohort. These results indicate that CIS patients at high risk of conversion have impaired regulation of T cell quiescence, possibly resulting in earlier activation of pathogenic CD4(+) cells.
Proceedings of the National Academy of Sciences 09/2008; 105(33):11839-44. · 9.68 Impact Factor
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ABSTRACT: The presence and degree of neuronal degeneration already existing in patients at their initial presentation with a clinically isolated syndrome suggestive of multiple sclerosis (CIS) is unclear, and whole brain or whole normalised grey matter analyses have not demonstrated significant atrophy in CIS cohorts at clinical presentation. Voxel-based analyses allow detection of regional atrophy throughout the brain and, therefore, may be sensitive to regional atrophy in CIS patients, and these changes may correspond with clinical disability.
This study used a modified voxel-based morphometry (VBM) method to correct for lesion effects to analyse regional atrophy and perform voxel-wise correlations between volume and clinical metrics in 41 untreated CIS patients at presentation compared with 49 healthy controls.
The results confirmed that there was no significant difference in whole normalised grey matter volume between CIS and controls, whereas VBM showed significant areas of bilateral thalamic, hypothalamic, putamen and caudate atrophy. Voxel-wise correlations with clinical measures showed that cerebellar volumes correlated with clinical cerebellar function, nine-hole peg test scores and the Multiple Sclerosis Functional Composite (MSFC) score, and that the MSFC score was also correlated with putamen volume. Lastly, T1 lesion volumes were found to correlate with thalamic and hippocampal atrophy, suggesting a link between white matter lesions and grey matter degeneration at the earliest stages of multiple sclerosis.
Atrophy is present in CIS patients at presentations, particularly in the thalamus, and other deep grey matter structures. Furthermore, the correlations with clinical metrics suggest the importance of this atrophy to clinical status and the correlation with T1 lesion load suggests a possible role of Wallerian degeneration.
Journal of neurology, neurosurgery, and psychiatry 06/2008; 79(11):1236-44. · 4.87 Impact Factor
