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1.  Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility 
The Journal of Clinical Investigation  2014;124(6):2571-2584.
Multiple sclerosis (MS) is an inflammatory disease of the CNS that is characterized by BBB dysfunction and has a much higher incidence in females. Compared with other strains of mice, EAE in the SJL mouse strain models multiple features of MS, including an enhanced sensitivity of female mice to disease; however, the molecular mechanisms that underlie the sex- and strain-dependent differences in disease susceptibility have not been described. We identified sphingosine-1-phosphate receptor 2 (S1PR2) as a sex- and strain-specific, disease-modifying molecule that regulates BBB permeability by destabilizing adherens junctions. S1PR2 expression was increased in disease-susceptible regions of the CNS of both female SJL EAE mice and female patients with MS compared with their male counterparts. Pharmacological blockade or lack of S1PR2 signaling decreased EAE disease severity as the result of enhanced endothelial barrier function. Enhanced S1PR2 signaling in an in vitro BBB model altered adherens junction formation via activation of Rho/ROCK, CDC42, and caveolin endocytosis-dependent pathways, resulting in loss of apicobasal polarity and relocation of abluminal CXCL12 to vessel lumina. Furthermore, S1PR2-dependent BBB disruption and CXCL12 relocation were observed in vivo. These results identify a link between S1PR2 signaling and BBB polarity and implicate S1PR2 in sex-specific patterns of disease during CNS autoimmunity.
doi:10.1172/JCI73408
PMCID: PMC4089451  PMID: 24812668
2.  CXCL13 is a Biomarker of Inflammation in Multiple Sclerosis, Neuromyelitis Optica, and Other Neurological Conditions 
CXCXL13, a B-cell chemokine, has been proposed as a biomarker in a variety of conditions, some of which can mimic multiple sclerosis (MS) and can have very high levels. In this case-control study, CSF CXCL13 was elevated in MS, neuromyelitis optica (NMO), and other inflammatory neurological controls compared to noninflammatory controls. Levels did not differentiate disease groups. For all subjects taken together, CSF CXCL13 correlated with CSF WBC, oligoclonal band numbers, CSF protein, EDSS, and neurofilament levels. In subgroup analyses, CSF CXCL13 correlated with CSF WBC in NMO and IgG index in MS. Additionally, serum CXCL13 was elevated in NMO.
doi:10.1177/1352458512473362
PMCID: PMC3959125  PMID: 23322500
Multiple sclerosis; neuromyelitis optica; CXCL13; neuroinflammation; neurofilament; myelin basic protein; biomarker
3.  Improved in vivo diffusion tensor imaging of human cervical spinal cord 
NeuroImage  2012;67:64-76.
We describe a cardiac gated high in-plane resolution axial human cervical spinal cord diffusion tensor imaging (DTI) protocol. Multiple steps were taken to optimize both image acquisition and image processing. The former includes slice-by-slice cardiac triggering and individually tiltable slices. The latter includes (i) iterative 2D retrospective motion correction, (ii) image intensity outlier detection to minimize the influence of physiological noise, (iii) a non-linear DTI estimation procedure incorporating non-negative eigenvalue priors, and (iv) tract-specific region-of-interest (ROI) identification based on an objective geometry reference. Using these strategies in combination, radial diffusivity (λ⊥) was reproducibly measured in white matter (WM) tracts (adjusted mean [95% confidence interval]=0.25 [0.22, 0.29]µm2/ms), lower than previously reported λ⊥ values in the in vivo human spinal cord DTI literature. Radial diffusivity and fractional anisotropy (FA) measured in WM varied from rostral to caudal as did mean translational motion, likely reflecting respiratory motion effect. Given the considerable sensitivity of DTI measurements to motion artifact, we believe outlier detection is indispensable in spinal cord diffusion imaging. We also recommend using a mixed-effects model to account for systematic measurement bias depending on cord segment.
doi:10.1016/j.neuroimage.2012.11.014
PMCID: PMC3604900  PMID: 23178538
Directional diffusivity; Outlier rejection; Non-negative eigenvalue priors; Reduced FOV; Cardiac gating; Cervical spinal cord; Lateral corticospinal tract; Posterior column; Diffusion tensor imaging; Reproducibility
4.  Increased Radial Diffusivity in Spinal Cord Lesions in Neuromyelitis Optica Compared to Multiple Sclerosis 
Background
Multiple sclerosis (MS) and neuromyelitis optica (NMO) both affect spinal cord with notable differences in pathology.
Objective
Determine the utility of diffusion tensor imaging (DTI) to differentiate the spinal cord lesions of NMO from MS within and outside T2 lesions.
Methods
Subjects ≥12 months from a clinical episode of transverse myelitis underwent a novel transaxial cervical spinal cord DTI sequence. Ten subjects with NMO, 10 with MS, and 10 healthy controls were included.
Results
Within T2 affected white matter regions, radial diffusivity was increased in both NMO and MS compared to healthy controls (p<0.001, respectively), and to a greater extent in NMO than MS (p<0.001). Axial diffusivity was decreased in T2 lesions in both NMO and MS compared to controls (p<0.001, p=0.001), but did not differ between the two diseases. Radial diffusivity and FA within white matter regions upstream and downstream of T2 lesions were different from controls in each disease.
Conclusions
Higher radial diffusivity, within spinal cord white matter tracts derived from diffusion tensor imaging were appreciated in NMO compared to MS, consistent with the known greater tissue destruction seen in NMO. DTI also detected tissue alterations outside T2 lesions, and may be a surrogate of anterograde and retrograde degeneration.
doi:10.1177/1352458512436593
PMCID: PMC3360125  PMID: 22354742
diffusion tensor imaging; neuromyelitis optica (NMO); multiple sclerosis (MS); spinal cord; MRI
5.  Gradient Echo Plural Contrast Imaging – signal model and derived contrasts: T2*, T1, Phase, SWI, T1f, FST2*and T2*-SWI 
Neuroimage  2012;60(2):1073-1082.
Gradient Echo Plural Contrast Imaging (GEPCI) is a post processing technique that, based on a widely available multiple gradient echo sequence, allows simultaneous generation of naturally co-registered images with various contrasts: T1 weighted, R2* = 1/T2* maps and frequency (f) maps. Herein, we present results demonstrating the capability of GEPCI technique to generate image sets with additional contrast characteristics obtained by combing the information from these three basic contrast maps. Specifically, we report its ability to generate GEPCI-susceptibility weighted images (GEPCI-SWI) with improved SWI contrast that is free of T1 weighting and RF inhomogeneities; GEPCI-SWI-like images with the contrast similar to original SWI; T1f images that offer superior GM/WM matter contrast obtained by combining the GEPCI T1 and frequency map data; Fluid Suppressed T2* (FST2*) images that utilize GEPCI T1 data to suppress CSF signal in T2* maps and provide contrast similar to FLAIR T2 weighted images; and T2*-SWI images that combine SWI contrast with quantitative T2* map and offer advantages of visualizing venous structure with hyperintense T2* lesions (e.g. MS lesions). To analyze GEPCI images we use an improved algorithm for combining data from multi-channel RF coils and a method for unwrapping phase/frequency maps that takes advantage of the information on phase evolution as a function of gradient echo time in GEPCI echo train.
doi:10.1016/j.neuroimage.2012.01.108
PMCID: PMC3303959  PMID: 22305993
MRI; GEPCI; SWI; multi-contrast MRI; FLAIR; T2*; phase; phase unwrapping; multi-channel coil
6.  Association of Neuromyelitis Optica With Severe and Intractable Pain 
Archives of neurology  2012;69(11):1482-1487.
Objective
To contrast differences in pain and treatment outcomes between neuromyelitis optica (NMO) and multiple sclerosis (MS).
Design
Retrospective, cross-sectional cohort study.
Setting
Academic MS center.
Patients
Complete ascertainment of an academic MS center cohort of NMO and an MS comparison sample cohort.
Main Outcome Measures
Current pain was quantified by a 10-point scale and the McGill Pain Questionnaire. Expanded Disability Status Scale score and number of involved spinal cord levels were collected in addition to testing for cognition, fatigue, depression, and quality of life. Number and types of pain medications were tabulated.
Results
Current pain was more common in subjects with NMO (n=29) vs MS (n=66) (86.2% vs 40.9%; P<.001) and more severe on a 10-point scale (5.38 vs 1.85; P <.001). Pain remained more common after controlling for disability and number of spinal cord segments (P=.03). Prescription pain medication was used more frequently in subjects with NMO compared with subjects with MS (75.9% vs 37.8%; P<.001), often requiring more than 1 medication (65.5% vs 15.2%; P<.001). No subject with NMO taking pain medication (22 of 29) rated their current pain as 0 of 10, whereas almost half of those taking pain medication with MS were currently free of pain (0% vs 48%; P=.006).
Conclusions
Neuromyelitis optica is frequently associated with severe pain that appears insufficiently controlled by pharmacologic interventions. Future studies should evaluate the efficacy of a multidisciplinary and multimodal approach to pain management.
doi:10.1001/archneurol.2012.768
PMCID: PMC3561507  PMID: 22926050
7.  Spinal cord tract diffusion tensor imaging reveals disability substrate in demyelinating disease 
Neurology  2013;80(24):2201-2209.
Objective:
This study assessed the tissue integrity of major cervical cord tracts by using diffusion tensor imaging (DTI) to determine the relationship with specific clinical functions carried by those tracts.
Methods:
This was a cross-sectional study of 37 patients with multiple sclerosis or neuromyelitis optica with remote cervical cord disease. Finger vibratory thresholds, 25-foot timed walk (25FTW), 9-hole peg test (9HPT), and Expanded Disability Status Scale were determined. DTI covered cervical regions C1 through C6 with 17 5-mm slices (0.9 × 0.9 mm in-plane resolution). Regions of interest included posterior columns (PCs) and lateral corticospinal tracts (CSTs). Hierarchical linear mixed-effect modeling included covariates of disease subtype (multiple sclerosis vs neuromyelitis optica), disease duration, and sex.
Results:
Vibration thresholds were associated with radial diffusivity (RD) and fractional anisotropy (FA) in the PCs (both p < 0.01), but not CSTs (RD, p = 0.29; FA, p = 0.14). RD and FA in PCs, and RD in CSTs were related to 9HPT (each p < 0.0001). 25FTW was associated with RD and FA in PCs (p < 0.0001) and RD in CSTs (p = 0.008). Expanded Disability Status Scale was related to RD and FA in PCs and CSTs (p < 0.0001). Moderate/severe impairments in 9HPT (p = 0.006) and 25FTW (p = 0.017) were more likely to show combined moderate/severe tissue injury within both PCs and CSTs by DTI.
Conclusions:
DTI can serve as an imaging biomarker of spinal cord tissue injury at the tract level. RD and FA demonstrate strong and consistent relationships with clinical outcomes, specific to the clinical modality.
doi:10.1212/WNL.0b013e318296e8f1
PMCID: PMC3721096  PMID: 23667060
8.  Quantification of increased cellularity during inflammatory demyelination 
Brain  2011;134(12):3587-3598.
Multiple sclerosis is characterized by inflammatory demyelination and irreversible axonal injury leading to permanent neurological disabilities. Diffusion tensor imaging demonstrates an improved capability over standard magnetic resonance imaging to differentiate axon from myelin pathologies. However, the increased cellularity and vasogenic oedema associated with inflammation cannot be detected or separated from axon/myelin injury by diffusion tensor imaging, limiting its clinical applications. A novel diffusion basis spectrum imaging, capable of characterizing water diffusion properties associated with axon/myelin injury and inflammation, was developed to quantitatively reveal white matter pathologies in central nervous system disorders. Tissue phantoms made of normal fixed mouse trigeminal nerves juxtaposed with and without gel were employed to demonstrate the feasibility of diffusion basis spectrum imaging to quantify baseline cellularity in the absence and presence of vasogenic oedema. Following the phantom studies, in vivo diffusion basis spectrum imaging and diffusion tensor imaging with immunohistochemistry validation were performed on the corpus callosum of cuprizone treated mice. Results demonstrate that in vivo diffusion basis spectrum imaging can effectively separate the confounding effects of increased cellularity and/or grey matter contamination, allowing successful detection of immunohistochemistry confirmed axonal injury and/or demyelination in middle and rostral corpus callosum that were missed by diffusion tensor imaging. In addition, diffusion basis spectrum imaging-derived cellularity strongly correlated with numbers of cell nuclei determined using immunohistochemistry. Our findings suggest that diffusion basis spectrum imaging has great potential to provide non-invasive biomarkers for neuroinflammation, axonal injury and demyelination coexisting in multiple sclerosis.
doi:10.1093/brain/awr307
PMCID: PMC3235568  PMID: 22171354
magnetic resonance imaging; diffusion tensor imaging; multiple tensor model; white matter injury; inflammation
9.  Diffusion Tensor Imaging in Acute Optic Neuropathies 
Archives of neurology  2011;69(1):65-71.
Objective
To evaluate directional diffusivities within the optic nerve in a first event of acute optic neuritis to determine whether decreased axial diffusivity (AD) would predict 6-month visual outcome and optic nerve integrity measures.
Design
Cohort study.
Setting
Academic multiple sclerosis center.
Patients
Referred sample of 25 individuals who presented within 31 days after acute visual symptoms consistent with optic neuritis. Visits were scheduled at baseline, 2 weeks, and 1, 3, 6, and 12 months.
Main Outcome Measures
Visual acuity, contrast sensitivity, visual evoked potentials (VEPs), and thickness of the retinal nerve fiber layer (RNFL).
Results
An incomplete 6-month visual recovery was associated with a lower baseline AD (1.50 μm2/ms [95% confidence interval {CI}, 1.36–1.64 μm2/ms for incomplete recovery vs 1.75 μm2/ms [95% CI, 1.67–1.83 μm2/ms] for complete recovery). Odds of complete recovery decreased by 53% (95% CI, 27%–70%) for every 0.1-unit decrease in baseline AD. A lower baseline AD correlated with worse 6-month visual outcomes in visual acuity (r=0.40, P=.03), contrast sensitivity (r=0.41, P=.02), VEP amplitude (r=0.55, P<.01), VEP latency (r=−0.38, P=.04), and RNFL thickness (r=0.53, P=.02). Radial diffusivity increased between months 1 and 3 to become higher in those with incomplete recovery at 12 months than in those with complete recovery (1.45 μm2/ms [95% CI, 1.31–1.59 μm2/ms] vs 1.19 μm2/ms [95% CI, 1.10–1.28 μm2/ms]).
Conclusions
Decreased AD in acute optic neuritis was associated with a worse 6-month visual outcome and correlated with VEP and RNFL measures of axon and myelin injury. Axial diffusivity may serve as a marker of axon injury in acute white matter injury.
doi:10.1001/archneurol.2011.243
PMCID: PMC3489058  PMID: 21911658
10.  Rituximab combination therapy in relapsing multiple sclerosis 
In multiple sclerosis (MS), the presence of B cells, plasma cells and excess immunoglobulins in central nervous system lesions and in the cerebrospinal fluid implicate the humoral immune system in disease pathogenesis. However, until the advent of specific B-cell-depleting therapies, the critical role of B cells and their products in MS was unproven. Rituximab, a monoclonal antibody that depletes B cells by targeting the CD20 molecule, has been shown to effectively reduce disease activity in patients with relapsing MS as a single agent. Our investigator-initiated phase II study is the only published clinical trial in which rituximab was used as an add-on therapy in patients with relapsing MS who had an inadequate response to standard injectable disease-modifying therapies (DMTs). The primary endpoint, magnetic resonance imaging (MRI) gadolinium-enhanced (GdE) lesion number before versus after rituximab, showed significant benefit of rituximab (74% of post-treatment MRI scans being free of GdE lesions compared with 26% free of GdE lesions at baseline; p < 0.0001). No differences were noted comparing patients on different DMTs. Several secondary clinical endpoints, safety and laboratory measurements (including B- and T-cell numbers in the blood and cerebrospinal fluid (CSF), serum and CSF chemokine levels, antibodies to myelin proteins) were assessed. Surprisingly, the decline in B-cell number was accompanied by a significant reduction in the number of T cells in both the peripheral blood and CSF. Rituximab therapy was associated with a significant decline of two lymphoid chemokines, CXCL13 and CCL19. No significant changes were observed in serum antibody levels against myelin proteins [myelin basic protein (MBP) and myelin/oligodendrocyte glycoprotein (MOG)] after treatment. These results suggest that B cells play a role in MS independent from antibody production and possibly related to their role in antigen presentation to T cells or to their chemokine/cytokine production.
doi:10.1177/1756285612461165
PMCID: PMC3487534  PMID: 23139702
B cells; chemokines; CXCL13; gadolinium-enhanced magnetic resonance imaging; multiple sclerosis; rituximab; T cells
11.  A little stress is good: IFN-γ, demyelination, and multiple sclerosis 
Journal of Clinical Investigation  2007;117(2):297-299.
The exact role(s) of the cytokine IFN-γ in the demyelinating disease multiple sclerosis remain controversial, with evidence suggesting both detrimental and protective effects of the cytokine in MS and MS models such as EAE. The study by Lin and coworkers in this issue of the JCI produces evidence that protective effects of IFN-γ on mature oligodendrocytes during EAE induction are mediated via activation of the pancreatic ER kinase (PERK), resulting in induction of the endoplasmic reticular stress response pathway (see the related article beginning on page 448). Modulation of this stress pathway has what we believe to be novel therapeutic potential for MS.
doi:10.1172/JCI31254
PMCID: PMC1783822  PMID: 17273549
12.  Radial Diffusivity Predicts Demyelination in ex-vivo Multiple Sclerosis Spinal Cords 
NeuroImage  2011;55(4):1454-1460.
Objective
Correlation of diffusion tensor imaging (DTI) with histochemical staining for demyelination and axonal damage in multiple sclerosis (MS) ex vivo human cervical spinal cords.
Background
In MS, demyelination, axonal degeneration, and inflammation contribute to disease pathogenesis to variable degrees. Based upon in vivo animal studies with acute injury and histopathologic correlation, we hypothesized that DTI can differentiate between axonal and myelin pathologies within humans.
Methods
DTI was performed at 4.7 Tesla on 9 MS and 5 normal control fixed cervical spinal cord blocks following autopsy. Sections were then stained for Luxol fast blue (LFB), Bielschowsky silver, and hematoxylin and eosin (H&E). Regions of interest (ROIs) were graded semi-quantitatively as normal myelination, mild (<50%) demyelination, or moderate-severe (>50%) demyelination. Corresponding axonal counts were manually determined on Bielschowsky silver. ROIs were mapped to co-registered DTI parameter slices. DTI parameters evaluated included standard quantitative assessments of apparent diffusion coefficient (ADC), relative anisotropy (RA), axial diffusivity and radial diffusivity. Statistical correlations were made between histochemical gradings and DTI parameters using linear mixed models. Results: Within ROIs in MS subjects, increased radial diffusivity distinguished worsening severities of demyelination. Relative anisotropy was decreased in the setting of moderate-severe demyelination compared to normal areas and areas of mild demyelination. Radial diffusivity, ADC, and RA became increasingly altered within quartiles of worsening axonal counts. Axial diffusivity did not correlate with axonal density (p=0.091).
Conclusions
Increased radial diffusivity can serve as a surrogate for demyelination. However, radial diffusivity was also altered with axon injury, suggesting that this measure is not pathologically specific within chronic human MS tissue. We propose that radial diffusivity can serve as a marker of overall tissue integrity within chronic MS lesions. This study provides pathologic foundation for on-going in vivo DTI studies in MS.
doi:10.1016/j.neuroimage.2011.01.007
PMCID: PMC3062747  PMID: 21238597
Multiple Sclerosis; Diffusion Tensor Imaging; Post mortum; Spinal cord
13.  Limited Sufficiency of Antigen Presentation by Dendritic Cells in Models of Central Nervous System Autoimmunity 
Journal of autoimmunity  2010;36(1):56-64.
Experimental autoimmune encephalomyelitis (EAE), a model for the human disease multiple sclerosis (MS), is dependent upon the activation and effector functions of autoreactive CD4 T cells. Multiple interactions between CD4 T cells and major histocompatibility class II (MHCII)+ antigen presenting cells (APCs) must occur in both the periphery and central nervous system (CNS) to elicit autoimmunity. The identity of the MHCII+ APCs involved throughout this process remains in question. We investigated which APC in the periphery and CNS mediates disease using transgenic mice with MHCII expression restricted to dendritic cells (DCs). MHCII expression restricted to DCs results in normal susceptibility to peptide-mediated EAE. Indeed, radiation-sensitive bone marrow-derived DCs were sufficient for all APC functions during peptide-induced disease. However, DCs alone were inefficient at promoting disease after immunization with the myelin protein myelin oligodendrocyte glycoprotein (MOG), even in the presence of MHCII-deficient B cells. Consistent with a defect in disease induction following protein immunization, antigen presentation by DCs alone was incapable of mediating spontaneous optic neuritis. These results indicate that DCs are capable of perpetuating CNS-targeted autoimmunity when antigens are readily available, but other APCs are required to efficiently initiate pathogenic cognate CD4 T cell responses.
doi:10.1016/j.jaut.2010.10.006
PMCID: PMC3053076  PMID: 21095100
Dendritic Cells; Experimental Autoimmune Encephalomyelitis/MS; Autoimmunity; Neuroimmunology; Immunopathology; Antigen Presenting Cells
14.  In vivo Quantitative evaluation of brain tissue damage in Multiple Sclerosis using Gradient Echo Plural Contrast Imaging technique 
NeuroImage  2010;51(3):1089-1097.
Conventional MRI based on weighted spin-echo (SE) images aids in the diagnosis of multiple sclerosis (MS); however, MRI markers derived from SE sequences provide limited information about lesion severity and correlate poorly with patient disability assessed with clinical tests. In this study, we introduced a novel method [based on quantitative R2* (1/T2*) histograms] for estimating the severity of brain tissue damage in MS lesions. We applied at 1.5 T an advanced, multi-gradient-echo MRI technique [gradient echo plural contrast imaging (GEPCI)] to obtain images of the brains of healthy control subjects and subjects with MS. GEPCI is a simple yet robust technique allowing simultaneous acquisition of inherently co-registered quantitative T2* and FLAIR-like maps, along with T1-weighted images within a clinically acceptable time frame. Images obtained with GEPCI appear highly similar to standard scans; hence, they can be used in a reliable and conventional way for a clinical evaluation of the disease. Yet, the main advantage of GEPCI approach is its quantitative nature. Analysis of R2* histograms of white matter revealed a difference in the distribution between healthy subjects and subjects with MS. Based on this difference, we developed a new method for grading the severity of tissue damage [tissue-damage score (TDS)] in MS lesions. This method also provides a tissue damage load (TDL) assessing both lesion load and lesion severity, and a mean tissue damage score (MTDS) estimating the average MS lesion damage. We found promising correlations between the results derived from this method and the standard measure of clinical disability.
doi:10.1016/j.neuroimage.2010.03.045
PMCID: PMC2862897  PMID: 20338247
15.  Rostro-Caudal Analysis of Corpus Callosum Demyelination and Axon Damage Across Disease Stages Refines Diffusion Tensor Imaging Correlations with Pathological Features 
Non-invasive assessment of the progression of axon damage is important for evaluating disease progression and developing neuroprotective interventions in multiple sclerosis (MS) patients. We examined the cellular responses correlated with diffusion tensor imaging (DTI)-derived axial (λ||) and radial (λ⊥) diffusivity values throughout acute (4 weeks) and chronic (12 weeks) stages of demyelination and after 6 weeks of recovery using the cuprizone demyelination of the corpus callosum model in C57BL/6 and Thy1-YFP-16 mice. The rostro-caudal progression of pathologic alterations in the corpus callosum enabled spatially and temporally defined correlations of pathological features with DTI measurements. During acute demyelination, microglial/macrophage activation was most extensive and axons exhibited swellings, neurofilament dephosphorylation, and reduced diameters. Axial diffusivity values decreased in the acute phase but did not correlate with axonal atrophy during chronic demyelination. In contrast, radial diffusivity increased with the progression of demyelination but did not correlate with myelin loss or astrogliosis. Unlike other animals models with progressive neurodegeneration and axon loss, the acute axon damage did not progress to discontinuity or loss of axons even after a period of chronic demyelination. Correlations of reversible axon pathology, demyelination, microglia/macrophage activation, and astrogliosis with regional axial and radial diffusivity measurements will facilitate the clinical application of DTI in MS patients.
doi:10.1097/NEN.0b013e3181e3de90
PMCID: PMC2901930  PMID: 20535036
Astrogliosis; Axon damage; Corpus callosum; Cuprizone; Demyelination; Diffusion tensor imaging; Microglia activation
16.  Spinal Cord Ring Enhancement in Multiple Sclerosis 
Archives of neurology  2010;67(11):1395-1398.
Objective
Describe the clinical and imaging characteristics of spinal cord ring enhancement in multiple sclerosis (MS).
Design
Clinical case series.
Setting
Academic referral center.
Patients
Twenty MS subjects with spinal cord ring enhancement were retrospectively identified from 322 cervical and thoracic spinal cord MRI studies over a 3 year period.
Main Outcome Measures
Demographics, disability, pattern of enhancement on spinal cord imaging, and concomitant brain magnetic resonance imaging (MRI) were determined.
Results
Ring enhancement was seen in 20 subjects with spinal cord enhancement, most commonly in the cervical cord. Incomplete or ‘open’ ring enhancement was the dominant pattern in 19 of 20 (95%) subjects. Concurrent ring enhancing brain lesions were present in 40% of subjects. At the time of the MRI, the Expanded Disability Status Scale (EDSS) ranged from 1.0–7.0 (median 3.0).
Conclusion
Ring enhancement is not an uncommon pattern for MS spinal cord lesions, occurring with a prevalence of 6.2% (20/322). The most common pattern was incomplete ring enhancement in the cervical spinal cord. Recognition of this pattern may improve and expedite the diagnosis of MS and preclude need for invasive diagnostic interventions.
doi:10.1001/archneurol.2010.271
PMCID: PMC3057685  PMID: 21060017
17.  Intrathecal Anti-MOG Antibody Production is Elevated in Multiple Sclerosis 
Archives of neurology  2010;67(9):1102-1108.
Objective
Evaluate antibodies (Ab) to myelin oligodendrocyte glycoprotein (MOG) in the serum and cerebrospinal fluid (CSF) of multiple sclerosis (MS) subjects and controls.
Design
Prospective case control series.
Setting
Academic referral center.
Subjects
Twenty-six controls with non-inflammatory neurologic disease (NIND) and 35 MS subjects donated serum and CSF for rMOG Ab determination.
Main Outcome Measures
Serum and CSF rMOG Ab and albumin levels were used to calculate an “rMOG index”. Clinical disability, CSF markers, and magnetic resonance (MR) metrics were correlated to rMOG index.
Results
rMOG index was elevated in MS subjects compared to controls (p=0.012). Progressive MS subjects exhibited elevated rMOG indices compared to relapsing remitting MS (RRMS) (p=0.041). rMOG index was inferior to IgG index in differentiating MS subjects from controls. However, 7 of 16 MS subjects with normal IgG indices had an elevated rMOG index. rMOG index did not correlate with clinical disability, other CSF markers, or radiographic outcome measures.
Conclusions
rMOG index, a marker of intrathecal MOG Ab production, may provide complementary information to routine CSF testing in the diagnosis of MS. Furthermore, intrathecal anti-MOG Ab production may be more pronounced in progressive than relapsing forms of MS.
doi:10.1001/archneurol.2010.197
PMCID: PMC3051403  PMID: 20837855
18.  Genetic Variation in the IL7RA/IL7 Pathway Increases Multiple Sclerosis Susceptibility 
Human genetics  2010;127(5):525-535.
Multiple sclerosis (MS) is characterized as an autoimmune demyelinating disease. Numerous family studies have confirmed a strong genetic component underlying its etiology. After several decades of frustrating research, the advent and application of affordable genotyping of dense SNP maps in large datasets has ushered in a new era in which rapid progress is being made in our understanding of the genetics underlying many complex traits. For MS, one of the first discoveries to emerge in this new era was the association with rs6897932[T244I] in the interleukin-7 receptor alpha chain (IL7RA) gene (Gregory et al. 2007; International Multiple Sclerosis Genetics Consortium 2007; Lundmark 2007), a discovery that was accompanied by functional data that suggest this variant is likely to be causative rather than a surrogate proxy (Gregory et al. 2007). We hypothesized that variations in other genes functionally related to IL7RA might also influence MS. We investigated this hypothesis by examining genes in the extended biological pathway related to IL7RA to identify novel associations. We identified 73 genes with putative functional relationships to IL7RA and subsequently genotyped 7,865 SNPs in and around these genes using an Illumina Infinium BeadChip assay. Using 2,961 case-control dataset, two of the gene regions examined, IL7 and SOCS1, had significantly associated single-nucleotide polymorphisms (SNPs) that further replicated in an independent case-control dataset (4,831 samples) with joint p-values as high as 8.29×10-6 and 3.48×10-7, respectively, exceeding the threshold for experiment-wise significance. Our results also implicate two additional novel gene regions that are likely to be associated with MS: PRKCE with p-values reaching 3.47×10-4 and BCL2 with p-values reaching 4.32×10-4. The TYK2 gene, which also emerged in our analysis, has recently been associated with MS (Ban et al. 2009). These results help to further delineate the genetic architecture of MS and validate our pathway approach as an effective method to identify novel associations in a complex disease.
doi:10.1007/s00439-010-0789-4
PMCID: PMC2854871  PMID: 20112030
19.  Rituximab Therapy Reduces Organ-Specific T Cell Responses and Ameliorates Experimental Autoimmune Encephalomyelitis 
PLoS ONE  2011;6(2):e17103.
Recent clinical trials have established B cell depletion by the anti-CD20 chimeric antibody Rituximab as a beneficial therapy for patients with relapsing-remitting multiple sclerosis (MS). The impact of Rituximab on T cell responses remains largely unexplored. In the experimental autoimmune encephalomyelitis (EAE) model of MS in mice that express human CD20, Rituximab administration rapidly depleted peripheral B cells and strongly reduced EAE severity. B cell depletion was also associated with diminished Delayed Type Hypersensitivity (DTH) and a reduction in T cell proliferation and IL-17 production during recall immune response experiments. While Rituximab is not considered a broad immunosuppressant, our results indicate a role for B cells as a therapeutic cellular target in regulating encephalitogenic T cell responses in specific tissues.
doi:10.1371/journal.pone.0017103
PMCID: PMC3040191  PMID: 21359213
20.  Multiple sclerosis susceptibility alleles in African Americans 
Genes and immunity  2009;11(4):343-350.
Multiple sclerosis (MS) is an autoimmune demyelinating disease characterized by complex genetics and multifaceted gene-environment interactions. Compared to whites, African Americans have a lower risk for developing MS, but African Americans with MS have a greater risk of disability. These differences between African Americans and whites may represent differences in genetic susceptibility and/or environmental factors. SNPs from 12 candidate genes have recently been identified and validated with MS risk in white populations. We performed a replication study using 918 cases and 656 unrelated controls to test whether these candidate genes are also associated with MS risk in African Americans. CD6, CLEC16a, EVI5, GPC5, and TYK2 contained SNPs that are associated with MS risk in the African American dataset. EVI5 showed the strongest association outside the MHC (rs10735781, OR = 1.233, 95% CI = 1.06–1.43, P value = 0.006). In addition, RGS1 appears to affect age of onset whereas TNFRSF1A appears to be associated with disease progression. None of the tested variants showed results that were statistically in-consistent with the effects established in whites. The results are consistent with shared disease genetic mechanisms among individuals of European and African ancestry.
doi:10.1038/gene.2009.81
PMCID: PMC2880217  PMID: 19865102
21.  The present efficacy of multiple sclerosis therapeutics 
Neurology  2009;73(12):984-990.
A challenge for the clinician treating patients with multiple sclerosis (MS) is to determine the most effective treatment while weighing the benefits and risks. Results of the phase 2 and phase 3 studies on natalizumab were received with great interest, in part due to the “improved” risk reduction for relapse rate, disease progression, and MRI metrics observed in comparison to results in trials of beta-interferon and glatiramer acetate. However, comparison across trials is invalid, in large part due to differences in the study populations. The increased efficacy observed in more recent trials has also been attributed to a fundamental change in subjects with MS enrolled in recent trials compared with the prior decade. In this article, we debate the relative efficacy of natalizumab vs the older injectable therapies.
GLOSSARY
= absolute risk reduction;
= clinically isolated syndrome;
= disease-modulating therapy;
= Expanded Disability Status Scale;
= Food and Drug Administration;
= glatiramer acetate;
= interferon;
= multiple sclerosis;
= number needed to treat;
= progressive multifocal leukoencephalopathy;
= relapsing-remitting MS;
= relative risk reduction.
doi:10.1212/WNL.0b013e3181b9c8f7
PMCID: PMC2754334  PMID: 19770475
22.  Changes in B and T lymphocytes and chemokines with rituximab treatment in multiple sclerosis 
Archives of neurology  2010;67(6):707-714.
Background
B cells are implicated in the pathogenesis of multiple sclerosis (MS). A beneficial effect of B cell depletion using rituximab has been shown, but the complete mechanism of action for this drug is unclear.
Objective
To determine the relationship between T cells, B cells, and changes in CSF chemokines with rituximab, a monoclonal antibody that targets CD20.
Design
Phase II trial of rituximab as an add-on therapy.
Setting
The John L. Multiple Sclerosis Center, Washington University, St. Louis, Missouri.
Patients
Thirty relapsing-remitting MS subjects with clinical and MRI activity despite treatment with an immunomodulatory drug received four weekly doses of 375mg/m2 rituximab.
Main Outcome Measures
Lumbar puncture was performed before and after rituximab infusions in 26 subjects. CSF B and T lymphocytes were enumerated by flow cytometry, and chemoattractants were measured by ELISA.
Results
After rituximab administration, CSF B cells were decreased or undetectable in all subjects and CSF T cells were reduced in 81% of subjects. The mean reduction in CSF cellularity was 95% for B cells and 50% for T cells. After rituximab infusion, CSF CXCL13 and CCL19 decreased (P= 0.002, P=0.03, respectively). The proportional decline in CSF T cells correlated with the proportional decrease in CXCL13 (r=0.45;P=0.03), suggesting a possible relationship. CSF IgG index, IgG concentration, and oligoclonal band number were unchanged following treatment.
Conclusions
B cells are critical for T cell trafficking into the CNS in MS patients, and may alter T cell trafficking by influencing chemokine production within the CNS.
doi:10.1001/archneurol.2010.99
PMCID: PMC2918395  PMID: 20558389
23.  Selective Vulnerability of Cerebral White Matter in a Murine Model of Multiple Sclerosis Detected Using Diffusion Tensor Imaging 
Neurobiology of disease  2007;28(1):30-38.
In this study, axial (λ∥) and radial (λ⊥) diffusivities derived from diffusion tensor imaging (DTI) were used to evaluate white matter injury in brains of mice affected by experimental autoimmune encephalomyelitis (EAE). Sixteen female C57BL/6 mice were immunized with amino acids 35-55 of myelin oligodendrocyte glycoprotein (MOG35-55). Three months after immunization, optic nerve and tract were severely affected with 19% and 18% decrease in λ∥ respectively, suggesting the presence of axonal injury. In addition, a 156% and 86% increase in λ⊥ was observed in optic nerve and tract respectively, suggestive of myelin injury. After in vivo DTI, mice were perfusion fixed and immunohistochemistry for the identification of myelin basic protein (MBP) and phosphorylated neurofilament (pNF) was performed to verify the presence of axonal and myelin injury. The present study demonstrated that the visual pathway is selectively affected in MOG35-55 induced murine EAE and these injuries are non-invasively detectable using λ∥ and λ⊥.
doi:10.1016/j.nbd.2007.06.011
PMCID: PMC2905808  PMID: 17683944
EAE; MOG; DTI; visual pathway; optic nerve; optic tract; mouse brain; axonal damage; myelin damage; directional diffusivity
24.  Acute and Bilateral Blindness Due to Optic Neuropathy Associated With Copper Deficiency 
Archives of neurology  2009;66(8):1025-1027.
Background
Acquired copper deficiency in adults is associated with a subacute to chronic progressive myeloneuropathy and optic neuropathy.
Objective
To describe an individual after gastric bypass surgery who developed a chronic progressive myeloneuropathy, an acute optic neuropathy, along with anemia and leukopenia.
Design
Case report.
Setting
Academic center.
Patient
A 55-year-old woman, following gastric bypass surgery 22 years earlier, developed progressive numbness, weakness, and sphincter disturbance over 6 years. She awoke one morning with bilateral blindness. Examination findings showed evidence of severe myelopathy and peripheral neuropathy.
Main Outcome Measures
Magnetic resonance imaging, optical coherence tomography, electrophysiologic studies, nerve and muscle biopsy specimens, and vision testing.
Results
Over 1 year of follow-up, copper infusion therapy seemed to stabilize the progressive myeloneuropathy and improved leukopenia and anemia. It had no effect on the optic neuropathy. Optic nerve tissue injury was observed on magnetic resonance diffusion tensor imaging and on optical coherence tomography.
Conclusions
Copper deficiency should be considered in cases of atypical optic neuropathy. Serum copper levels should be monitored in patients with a compatible neurologic syndrome who have undergone gastric bypass surgery. Although visual acuity did not improve after copper infusion in our patient, prompt recognition of copper deficiency may prevent further deterioration.
doi:10.1001/archneurol.2009.70
PMCID: PMC2893403  PMID: 19667226
25.  Cerebrospinal fluid progranulin levels in patients with different multiple sclerosis subtypes 
Neuroscience letters  2009;469(2):234-236.
Progranulin has recently attracted attention due to the discovery of mutations in its encoding gene (GRN) in several cases of frontotemporal lobar degeneration, but also for a possible role in inflammatory processes. In adult central nervous system, GRN mRNA is expressed in forebrain, olfactory bulbs and spinal cord. Progranulin cerebrospinal fluid (CSF) levels were evaluated in 55 patients with multiple sclerosis (MS) as well as in 35 subjects with non-inflammatory neurological diseases (NIND), 7 individuals with other inflammatory neurological disease (OIND) and 8 controls (CON), matched for ethnic background, gender and age. No statistically significant differences were found in patients compared with either NIND, OIND or CON (P > 0.05), even stratifying according to disease subtype or gender. A positive correlation between progranulin CSF levels and age was observed in patients (ρ = 0.29, P = 0.03). According to these data, progranulin does not likely play a major role in the pathogenesis of MS.
doi:10.1016/j.neulet.2009.12.002
PMCID: PMC2893414  PMID: 19963041
Multiple sclerosis; Cerebrospinal fluid (CSF); Progranulin

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