Matter Of Multiple Sclerosis Patients Research Articles

Multimodal magnetic resonance longitudinal study on the deep gray matter in multiple sclerosis patients with teriflunomide

Disease-modifying therapies (DMTs) are used in an increasing number of patients with multiple sclerosis (MS). However, whether DMTs have intrinsic effects on deep gray matter (DGM) microstructure and atrophy is still poorly understood. In this study, we described the quantitative susceptibility values (QSV) and diffusion kurtosis imaging (DKI) metrics of DGM in relapsing–remitting MS (RRMS) patients and their association with cognitive deficits. We recruited 62 patients with RRMS receiving DMTs and 30 patients with RRMS not receiving DMTs underwent MRI on a 3T scanner. Fractional anisotropy (FA), kurtosis fractional anisotropy (KFA), mean diffusivity (MD), mean kurtosis (MK), QSV and volumes of bilateral caudate nucleus (CAU), amygdala (AMYG), putamen (PUT), hippocampus (Hipp), globus pallidus (GP) and thalamus (THA) were measured. Correlation analysis was performed between those image indexes with longitudinal significant changes and clinical neurological scores, including Expanded Disability Status Scale (EDSS), Digit Span Testand (DST), Symbol Digit Modalities Test (SDMT), Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Significant longitudinal increases in FA, KFA and MK values were found in both groups in bilateral CAU, AMYG, PUT, Hipp, GP and THA (all p < 0.005). MD values of the right of CAU in the two groups were significant longitudinal increase (p = 0.009, p = 0.047); MD values of the right of GP (p = 0.042), the left of THA (p = 0.003), the right of THA (p = 0.001) in treated MS were significant longitudinal decrease; There were no significant longitudinal changes between treated and untreated groups in normalized deep gray matter volume. For QSV, longitudinal increase in the right of PUT (p = 0.022) in the treated MS group and in the left of Hipp (p = 0.045) in the untreated MS group. The QSV and DKI measures were highly correlated with cognitive and disability tests. The treated RRMS patients showed different longitudinal changes of MD value and QSV with untreated in several DGM regions, and these differences were correlated with cognitive and microstructural integrity.

A study of the correlation between gray matter atrophy in multiple sclerosis and impairment of cognitive function domains

Objective: To quantify cerebral cortical and deep gray matter atrophy in patients with multiple sclerosis (MS) and explore its correlation with impairment in domains of cognitive function. Methods: Twenty patients with MS and 16 healthy controls (HC) matched for age, sex, and education level were included. Using FreeSurfer software, based on 3D-MRI technology, the differences in cortical thickness and deep gray matter volume between the two groups were comparatively analyzed. A neuropsychological scale that included six domains of cognitive function was scored on both study groups to analyze the correlation between cortical thickness and volume of deep gray matter in MS patients with impairment in cognitive function domains. Results: Impairment in domains of cognitive function: cognitive impairment was present in 60% MS patients in this study, mainly manifesting as impairment of verbal memory, verbal fluency, visuospatial memory, and information processing speed function (all P<0.05). Of these, the majority had impaired visuospatial memory function (55.0%), and the least number of patients had impaired information processing speed (15.0%). Changes in cortical thickness: compared with the HC group, the MS group showed that cortical atrophy was mainly concentrated in the frontoparietal region, including significant thinning of cortical thickness in the left inferior parietal gyrus, right superior frontal gyrus, and the right superior parietal gyrus (all P<0.05). Among them, atrophy of the left inferior parietal gyrus was significantly positively correlated with the impairment of verbal memory, verbal fluency, and information processing speed (all P<0.05). There was a significant positive correlation between the right superior frontal gyrus atrophy and verbal memory, verbal fluency, and visuospatial memory impairment (all P<0.05). Changes in deep gray matter volume: compared with the HC group, deep gray matter volume in the MS group decreased significantly in the bilateral thalamus, bilateral putamen, bilateral pallidum (all P<0.01), and right nucleus accumbens (P<0.05). Among them, left thalamus atrophy was significantly positively correlated with visuospatial memory impairment (r=0.45, P=0.046), and left putamen atrophy was both significantly positively correlated with visuospatial memory (r=0.45, P=0.047) and information processing speed impairment (r=0.50, P=0.026). Conclusions: Early structural brain changes in MS are dominated by gray matter atrophy. Deep gray matter is more prominent than cortical atrophy.

The clinical value of deep gray matter 3T MRI perfusion in patients with multiple sclerosis

Background. Multiple sclerosis (MS) is a common neurological disorder between adults. Magnetic resonance imaging (MRI) is the imaging modality of choice, new MRI techniques helped in more accurate assessment of the disease extent, activity and severity. In dynamic susceptibility contrast (DSC), the perfusion of the lesions as well as normally appearing white and gray matter of the brain have been assessed. Objective. To highlight the role of MRI perfusion of the deep gray matter in multiple sclerosis patients and its relation to their clinical disability and cognitive impairment Methods. 40 patients with MS were enrolled in this study, they were divided into two groups (group A with mild clinical disease and preserved cognitive functions, and group B with marked clinical disease and cognitive functions impairment) they were divided according to their clinical disability and cognitive impairment assessed by experienced neurologist, Additional 20 healthy controls were included. Perfusion parameters including cerebral blood volume(CBV), cerebral blood flow (CBF) and mean transit time (MTT) of the deep gray matter were compared for healthy controls and for the study groups. Results. The perfusion values of the thalamus, putamen and caudate were significantly changed in group B that shows marked decrease in CBV and CBF and increased MTT compared with group A and the controls, With respect to group (A), there was no significant difference between the patients and controls Conclusion. The decrease of perfusion of the deep gray matter in patients with MS is associated with the severity of the disease and cognitive impairment.

Relaxation-Compensated Chemical Exchange Saturation Transfer MRI in the Brain at 7T: Application in Relapsing-Remitting Multiple Sclerosis.

Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) can probe tissue biochemistry in vivo with high resolution and sensitivity without requiring exogenous contrast agents. Applying CEST MRI at ultrahigh field provides advantages of increasing spectral resolution and improving sensitivity to metabolites with faster proton exchange rates such as glutamate, a critical neurotransmitter in the brain. Prior magnetic resonance spectroscopy and CEST MRI studies have revealed altered regulation of glutamate in patients with multiple sclerosis (MS). While CEST imaging facilitates new strategies for investigating the pathology underlying this complex and heterogeneous neurological disease, CEST signals are contaminated or diluted by concurrent effects (e.g., semi-solid magnetization transfer (MT) and direct water saturation) and are scaled by the T1 relaxation time of the free water pool which may also be altered in the context of disease. In this study of 20 relapsing-remitting MS patients and age- and sex-matched healthy volunteers, glutamate-weighted CEST data were acquired at 7.0 T. A Lorentzian fitting procedure was used to remove the asymmetric MT contribution from CEST z-spectra, and the apparent exchange-dependent relaxation (AREX) correction was applied using an R1 map derived from an inversion recovery sequence to further isolate glutamate-weighted CEST signals from concurrent effects. Associations between AREX and cognitive function were examined using the Minimal Assessment of Cognitive Function in MS battery. After isolating CEST effects from MT, direct water saturation, and T1 effects, glutamate-weighted AREX contrast remained higher in gray matter than in white matter, though the difference between these tissues decreased. Glutamate-weighted AREX in normal-appearing gray and white matter in MS patients did not differ from healthy gray and white matter but was significantly elevated in white matter lesions. AREX in some cortical regions and in white matter lesions correlated with disability and measures of cognitive function in MS patients. However, further studies with larger sample sizes are needed to confirm these relationships due to potential confounding effects. The application of MT and AREX corrections in this study demonstrates the importance of isolating CEST signals for more specific characterization of the contribution of metabolic changes to tissue pathology and symptoms in MS.

DNA methylation changes in glial cells of the normal-appearing white matter in Multiple Sclerosis patients

ABSTRACT Multiple Sclerosis (MS), the leading cause of non-traumatic neurological disability in young adults, is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS). Due to the poor accessibility to the target organ, CNS-confined processes underpinning the later progressive form of MS remain elusive thereby limiting treatment options. We aimed to examine DNA methylation, a stable epigenetic mark of genome activity, in glial cells to capture relevant molecular changes underlying MS neuropathology. We profiled DNA methylation in nuclei of non-neuronal cells, isolated from 38 post-mortem normal-appearing white matter (NAWM) specimens of MS patients (n = 8) in comparison to white matter of control individuals (n = 14), using Infinium MethylationEPIC BeadChip. We identified 1,226 significant (genome-wide adjusted P-value < 0.05) differentially methylated positions (DMPs) between MS patients and controls. Functional annotation of the altered DMP-genes uncovered alterations of processes related to cellular motility, cytoskeleton dynamics, metabolic processes, synaptic support, neuroinflammation and signaling, such as Wnt and TGF-β pathways. A fraction of the affected genes displayed transcriptional differences in the brain of MS patients, as reported by publically available transcriptomic data. Cell type-restricted annotation of DMP-genes attributed alterations of cytoskeleton rearrangement and extracellular matrix remodelling to all glial cell types, while some processes, including ion transport, Wnt/TGF-β signaling and immune processes were more specifically linked to oligodendrocytes, astrocytes and microglial cells, respectively. Our findings strongly suggest that NAWM glial cells are highly altered, even in the absence of lesional insult, collectively exhibiting a multicellular reaction in response to diffuse inflammation.

Neurocognitive performance in relapsing-remitting multiple sclerosis patients is associated with metabolic abnormalities of the thalamus but not the hippocampus– GABA-edited 1H MRS study

ABSTRACT Objectives Multiple sclerosis (MS) is an inflammatory demyelinating disease that may cause physical disabling as well as cognitive dysfunction. The presented study investigated how the neuropsychological status depends on the thalamus and hippocampus’s metabolic processes, using γ-aminobutyric acid-edited magnetic resonance spectroscopy (GABA-edited 1H MRS) in patients with early MS, and how the results differ from healthy volunteers. Methods We recruited 36 relapsing-remitting (RRMS) MS patients and 22 controls (CON). In addition to common 1H MRS metabolites, such as N-acetyl-aspartate (tNAA), myoinositol (mIns), total choline and creatine (tCr, tCho), we also evaluated GABA and glutamate/glutamine (Glx). Metabolite ratios were correlated with the results of Single-Digit Modality Test (SDMT) and Expanded Disability Status Score (EDSS). Results In the thalamus, GABA ratios (GABA/tCr, GABA/tNAA) were significantly lower in RRMS patients than in CON. Both tCho- and mIns-ratios correlated with lower scores of SDMT but not with EDSS. Metabolic ratios in the hippocampus did not differ between RRMS and CON and did not correlate with any of performed tests. Discussion This study is the first to provide GABA-edited 1H MRS evidence for MS-related metabolic changes of the thalamus and hippocampus. The findings underline the importance of evaluating subcortical grey matter in MS patients to improve understanding of the clinical manifestations of MS and as a potential future target for treatment.

Positivity of oligoclonal bands in the cerebrospinal fluid predisposed to metabolic changes and rearrangement of inhibitory/excitatory neurotransmitters in subcortical brain structures in multiple sclerosis

BackgroundThe latest diagnostic criteria for multiple sclerosis (MS) have revitalized the role of oligoclonal bands synthesis in the cerebrospinal fluid (CSF-OCB). This study identifies predictors of CSF-OCB-positivity among in vivo metabolic markers in the subcortical gray/white matter in MS patients after their first episode (CIS) and in patients with relapsing-remitting course (RRMS). MethodsThe study enrolled 13 CIS and 23 RRMS patients. Metabolism was evaluated using Mescher-Garwood-edited proton-magnetic resonance spectroscopy on a 3T MR scanner. In addition to N-acetyl-aspartate (tNAA), myoinositol (mIns), and choline- and creatine compounds (tCho, tCr) were also evaluated γ-aminobutyric acid (GABA) and glutamate-glutamine (Glx) ratios. ResultsCSF-OCB-positivity was found in 76.9% of CIS and 78.2% of RRMS patients. GABA and Glx ratios in putamen and corpus callosum strongly determined CSF-OCB-positive CIS patients. Other essential predictors of CSF-OCB-positive CIS were mIns and Glx ratios in the putamen, and tCho/tNAA in the corpus callosum. In RRMS, GABA ratios in the right thalamus and Glx ratios in the left hippocampus strongly predicted CSF-OCB-positive patients. tCho/tNAA and tNAA/tCr in the left hippocampus were also identified as essential predictors of CSF-OCB-positive RRMS patients. ConclusionThis is the first in vivo evidence of GABA-Glx rearrangement in CSF-OCB-positive patients since its early stages of MS.

Volumetric imaging of myelin in vivo using 3D inversion recovery-prepared ultrashort echo time cones magnetic resonance imaging.

Direct myelin imaging is promising for characterization of multiple sclerosis (MS) brains at diagnosis and in response to therapy. In this study, a 3D inversion recovery-prepared ultrashort echo time cones (IR-UTE-Cones) sequence was used for both morphological and quantitative imaging of myelin on a clinical 3 T scanner. Myelin powder phantoms with different myelin concentrations were imaged with the 3D UTE-Cones sequence and it showed a strong correlation between concentrations and UTE-Cones signals, demonstrating the ability of the UTE-Cones sequence to directly image myelin in the brain. Quantitative myelin imaging with multi-echo IR-UTE-Cones sequences show similar T2 * values for a D2 O-exchanged myelin phantom (T2 * = 0.33 ± 0.04 ms), ex vivo brain specimens (T2 * = 0.20 ± 0.04 ms) and in vivo healthy volunteers (T2 * = 0.254 ± 0.023 ms), further confirming the feasibility of 3D IR-UTE-Cones sequences for direct myelin imaging in vivo. In ex vivo MS brain study, signal loss is observed in MS lesions, which was confirmed with histology. For the in vivo study, the lesions in MS patients also show myelin signal loss using the proposed direct myelin imaging method, demonstrating the clinical potential for MS diagnosis. Furthermore, the measured IR-UTE-Cones signal intensities show a significant difference between normal-appearing white matter in MS patients and normal white matter in volunteers, which cannot be found in clinical used T2 -FLAIR sequences. Thus, the proposed 3D IR-UTE-Cones sequence showed clinical potential for MS diagnosis with the capability of direct myelin detection of the whole brain.

Increased mean R2* in the deep gray matter of multiple sclerosis patients: Have we been measuring atrophy?

Magnetic resonance relaxometry studies in multiple sclerosis (MS) have suggested that iron accumulates within deep gray matter (DGM) structures early in the disease course. However, the commonly utilized mean R2* and magnetic susceptibility measures reflect regional iron concentration but not a structure's total iron content. Thus, tissue atrophy could impact mean R2* and magnetic susceptibility estimates. To demonstrate that both average iron concentration and total iron content need to be reported in order to distinguish between atrophy-related and definite magnetic susceptibility changes. Observational. The study was performed on 30 healthy controls (HCs) and 39 people with definite MS. 3T Philips Achieva using an 8-channel SENSE head coil. R2* data were acquired using a multiecho gradient echo sequence and diffusion tensor imaging data were acquired using an echo-planar sequence. Total iron content in DGM structures was assessed by calculating the sum of all R2* values within a region (denoted as ) and compared to the mean R2* as a measure of iron concentration. Significant group differences were investigated in a linear regression model. All DGM structures were assessed individually and the significance threshold was adjusted using the Bonferroni-Holm correction for multiple comparisons. There was an increased mean DGM R2* in MS patients compared to HCs (significant in the pallidus, P = 0.0051). In contrast, in patients was found to be lower in the thalamus and the caudate (P = 0.0011) compared to HCs, and similar between the two cohorts in the other DGM regions. An increase in mean R2* may not necessarily reflect increased iron accumulation. We propose as an additional metric to account for the effects of tissue atrophy when assessing tissue content changes, such as iron deposition or loss. 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;50:201-208.

Relationship of acute axonal damage, Wallerian degeneration, and clinical disability in multiple sclerosis

BackgroundAxonal damage and loss substantially contribute to the incremental accumulation of clinical disability in progressive multiple sclerosis. Here, we assessed the amount of Wallerian degeneration in brain tissue of multiple sclerosis patients in relation to demyelinating lesion activity and asked whether a transient blockade of Wallerian degeneration decreases axonal loss and clinical disability in a mouse model of inflammatory demyelination.MethodsWallerian degeneration and acute axonal damage were determined immunohistochemically in the periplaque white matter of multiple sclerosis patients with early actively demyelinating lesions, chronic active lesions, and inactive lesions. Furthermore, we studied the effects of Wallerian degeneration blockage on clinical severity, inflammatory pathology, acute axonal damage, and long-term axonal loss in experimental autoimmune encephalomyelitis using Wallerian degeneration slow (WldS) mutant mice.ResultsThe highest numbers of axons undergoing Wallerian degeneration were found in the perilesional white matter of multiple sclerosis patients early in the disease course and with actively demyelinating lesions. Furthermore, Wallerian degeneration was more abundant in patients harboring chronic active as compared to chronic inactive lesions. No co-localization of neuropeptide Y-Y1 receptor, a bona fide immunohistochemical marker of Wallerian degeneration, with amyloid precursor protein, frequently used as an indicator of acute axonal transport disturbance, was observed in human and mouse tissue, indicating distinct axon-degenerative processes. Experimentally, a delay of Wallerian degeneration, as observed in WldS mice, did not result in a reduction of clinical disability or acute axonal damage in experimental autoimmune encephalomyelitis, further supporting that acute axonal damage as reflected by axonal transport disturbances does not share common molecular mechanisms with Wallerian degeneration. Furthermore, delaying Wallerian degeneration did not result in a net rescue of axons in late lesion stages of experimental autoimmune encephalomyelitis.ConclusionsOur data indicate that in multiple sclerosis, ongoing demyelination in focal lesions is associated with axonal degeneration in the perilesional white matter, supporting a role for focal pathology in diffuse white matter damage. Also, our results suggest that interfering with Wallerian degeneration in inflammatory demyelination does not suffice to prevent acute axonal damage and finally axonal loss.

Correlation between white matter damage and gray matter lesions in multiple sclerosis patients.

We observed the characteristics of white matter fibers and gray matter in multiple sclerosis patients, to identify changes in diffusion tensor imaging fractional anisotropy values following white matter fiber injury. We analyzed the correlation between fractional anisotropy values and changes in whole-brain gray matter volume. The participants included 20 patients with relapsing-remitting multiple sclerosis and 20 healthy volunteers as controls. All subjects underwent head magnetic resonance imaging and diffusion tensor imaging. Our results revealed that fractional anisotropy values decreased and gray matter volumes were reduced in the genu and splenium of corpus callosum, left anterior thalamic radiation, hippocampus, uncinate fasciculus, right corticospinal tract, bilateral cingulate gyri, and inferior longitudinal fasciculus in multiple sclerosis patients. Gray matter volumes were significantly different between the two groups in the right frontal lobe (superior frontal, middle frontal, precentral, and orbital gyri), right parietal lobe (postcentral and inferior parietal gyri), right temporal lobe (caudate nucleus), right occipital lobe (middle occipital gyrus), right insula, right parahippocampal gyrus, and left cingulate gyrus. The voxel sizes of atrophic gray matter positively correlated with fractional anisotropy values in white matter association fibers in the patient group. These findings suggest that white matter fiber bundles are extensively injured in multiple sclerosis patients. The main areas of gray matter atrophy in multiple sclerosis are the frontal lobe, parietal lobe, caudate nucleus, parahippocampal gyrus, and cingulate gyrus. Gray matter atrophy is strongly associated with white matter injury in multiple sclerosis patients, particularly with injury to association fibers.

Multiple sclerosis-associated CLEC16A controls HLA class II expression via late endosome biogenesis.

C-type lectins are key players in immune regulation by driving distinct functions of antigen-presenting cells. The C-type lectin CLEC16A gene is located at 16p13, a susceptibility locus for several autoimmune diseases, including multiple sclerosis. However, the function of this gene and its potential contribution to these diseases in humans are poorly understood. In this study, we found a strong upregulation of CLEC16A expression in the white matter of multiple sclerosis patients (n = 14) compared to non-demented controls (n = 11), mainly in perivascular leukocyte infiltrates. Moreover, CLEC16A levels were significantly enhanced in peripheral blood mononuclear cells of multiple sclerosis patients (n = 69) versus healthy controls (n = 46). In peripheral blood mononuclear cells, CLEC16A was most abundant in monocyte-derived dendritic cells, in which it strongly co-localized with human leukocyte antigen class II. Treatment of these professional antigen-presenting cells with vitamin D, a key protective environmental factor in multiple sclerosis, downmodulated CLEC16A in parallel with human leukocyte antigen class II. Knockdown of CLEC16A in distinct types of model and primary antigen-presenting cells resulted in severely impaired cytoplasmic distribution and formation of human leucocyte antigen class II-positive late endosomes, as determined by immunofluorescence and electron microscopy. Mechanistically, CLEC16A participated in the molecular machinery of human leukocyte antigen class II-positive late endosome formation and trafficking to perinuclear regions, involving the dynein motor complex. By performing co-immunoprecipitations, we found that CLEC16A directly binds to two critical members of this complex, RILP and the HOPS complex. CLEC16A silencing in antigen-presenting cells disturbed RILP-mediated recruitment of human leukocyte antigen class II-positive late endosomes to perinuclear regions. Together, we identify CLEC16A as a pivotal gene in multiple sclerosis that serves as a direct regulator of the human leukocyte antigen class II pathway in antigen-presenting cells. These findings are a first step in coupling multiple sclerosis-associated genes to the regulation of the strongest genetic factor in multiple sclerosis, human leukocyte antigen class II.

11C-acetate PET imaging in patients with multiple sclerosis.

BackgroundActivation of glial cells is a cardinal feature in multiple sclerosis (MS) pathology, and acetate has been reported to be selectively uptaken by astrocytes in the CNS. The aim of this study was to investigate the efficacy of PET with 11C-acetate for MS diagnosis.Materials and MethodsSix patients with relapsing-remitting MS and 6 healthy volunteers (HV) were enrolled. The 11C-acetate brain uptake on PET was measured in patients with MS and HV. Volume-of-interest analysis of cerebral gray and white matter based on the segmentation technique for co-registered MRI and voxel-based statistical parametric analysis were performed. Correlation between 11C-acetate uptake and the lesion number in T1- and T2- weighted MR images were also assessed.ResultsThe standardized uptake value (SUV) of 11C-acetate was increased in both white and gray matter in MS patients compared to HV. Voxel-based statistical analysis revealed a significantly increased SUV relative to that in the bilateral thalami (SUVt) in a broad area of white matter, particularly in the subcortical white matter of MS patients. The numbers of T2 lesions and T1 black holes were significantly correlated with SUV of 11C-acetate in white and gray matter.ConclusionsThe 11C-acetate uptake significantly increased in MS patients and correlated to the number of MRI lesions. These preliminary data suggest that 11C-acetate PET can be a useful clinical examination for MS patients.

VLA-4 blockade promotes differential routes into human CNS involving PSGL-1 rolling of T cells and MCAM-adhesion of TH17 cells.

The focus of this study is the characterization of human T cell blood-brain barrier migration and corresponding molecular trafficking signatures. We examined peripheral blood and cerebrospinal fluid immune cells from patients under long-term anti-very late antigen-4 (VLA-4)/natalizumab therapy (LTNT) and from CNS specimens. LTNT patients' cerebrospinal fluid T cells exhibited healthy central-/effector-memory ratios, but lacked CD49d and showed enhanced myeloma cell adhesion molecule (MCAM) expression. LTNT led to an increase of PSGL-1 expression on peripheral T cells. Although vascular cell adhesion molecule-1 (VLA-4 receptor) was expressed at all CNS barriers, P-selectin (PSGL-1-receptor) was mainly detected at the choroid plexus. Accordingly, in vitro experiments under physiological flow conditions using primary human endothelial cells and LTNT patients' T cells showed increased PSGL-1-mediated rolling and residual adhesion, even under VLA-4 blockade. Adhesion of MCAM(+)/TH17 cells was not affected by VLA-4 blocking alone, but was abrogated when both VLA-4 and MCAM were inhibited. Consistent with these data, MCAM(+) cells were detected in white matter lesions, and in gray matter of multiple sclerosis patients. Our data indicate that lymphocyte trafficking into the CNS under VLA-4 blockade can occur by using the alternative adhesion molecules, PSGL-1 and MCAM, the latter representing an exclusive pathway for TH17 cells to migrate over the blood-brain barrier.

In Vivo Assessment of Brain White Matter Inflammation in Multiple Sclerosis with (18)F-PBR111 PET.

PET radioligand binding to the 18-kD translocator protein (TSPO) in the brains of patients with multiple sclerosis (MS) primarily reflects activated microglia and macrophages. We previously developed genetic stratification for accurate quantitative estimation of TSPO using second-generation PET radioligands. In this study, we used (18)F-PBR111 PET and MR imaging to measure relative binding in the lesional, perilesional, and surrounding normal-appearing white matter of MS patients, as an index of the innate immune response. (18)F-PBR111 binding was quantified in 11 MS patients and 11 age-matched healthy volunteers, stratified according to the rs6971 TSPO gene polymorphism. Fluid-attenuated inversion recovery and magnetization transfer ratio (MTR) MR imaging were used to segment the white matter in MS patients as lesions, perilesional volumes, nonlesional white matter with reduced MTR, and nonlesional white matter with normal MTR. (18)F-PBR111 binding was higher in the white matter lesions and perilesional volumes of MS patients than in white matter of healthy controls (P < 0.05). Although there was substantial heterogeneity in binding between different lesions, a within-subject analysis showed higher (18)F-PBR111 binding in MS lesions (P < 0.05) and in perilesional (P < 0.05) and nonlesional white matter with reduced MTR (P < 0.005) than in nonlesional white matter with a normal MTR. A positive correlation was observed between the mean (18)F-PBR111 volume of distribution increase in lesions relative to nonlesional white matter with a normal MTR and the MS severity score (Spearman ρ = 0.62, P < 0.05). This study demonstrates that quantitative TSPO PET with a second-generation radioligand can be used to characterize innate immune responses in MS in vivo and provides further evidence supporting an association between the white matter TSPO PET signal in lesions and disease severity. Our approach is practical for extension to studies of the role of the innate immune response in MS for differentiation of antiinflammatory effects of new medicines and their longer term impact on clinical outcome.

Determinants of iron accumulation in deep grey matter of multiple sclerosis patients

Background: Iron accumulation in deep grey matter (GM) structures is a consistent finding in multiple sclerosis (MS) patients. This study focused on the identification of independent determinants of iron accumulation using R2* mapping. Subjects and methods: Ninety-seven MS patients and 81 healthy controls were included in this multicentre study. R2* mapping was performed on 3T MRI systems. R2*in deep GM was corrected for age and was related to disease duration, disability, T2 lesion load and brain volume. Results: Compared to controls, R2* was increased in all deep GM regions of MS patients except the globus pallidus and the substantia nigra. R2* increase was most pronounced in the progressive stage of the disease and independently predicted by disease duration and disability. Reduced cortical volume was not associated with iron accumulation in the deep GM with the exception of the substantia nigra and the red nucleus. In lesions, R2* was inversely correlated with disease duration and higher total lesion load. Conclusion: Iron accumulation in deep GM of MS patients is most strongly and independently associated with duration and severity of the disease. Additional associations between cortical GM atrophy and deep GM iron accumulation appear to exist in a region specific manner.

Iron deposition in the precentral grey matter in patients with multiple sclerosis: A quantitative study using susceptibility-weighted imaging

PurposeSeveral studies suggest that iron deposition may play a role in multiple sclerosis (MS) pathology. Three-dimensional (3D) enhanced T2*-weighted angiography (ESWAN) at 3T was used to quantify iron deposition in the precentral grey matter in MS and its relationship with disease duration, atrophy and Expanded Disability Status Scale (EDSS) scores. MethodsWe recruited 33 patients with diagnosis of clinically definite MS and 31 age- and sex-matched healthy controls who underwent conventional brain MRI, 3D-ESWAN and 3D T1sequences. We obtained the mean phase values (MPVs) of the precentral grey matter on ESWAN-filtered phase images and volume of the precentral gyrus on 3D T1 images. We investigated the correlation between precentral grey matter MPVs, precentral gyrus volume, disease duration and EDSS scores of MS patients and healthy controls. ResultsThe precentral grey matter MPVs in MS patients and controls were 1870.83±56.61 and 1899.22±51.73 respectively and had significant difference in the MS group vs. the control group (t=−2.09, P=0.04). There was significant negative correlation between precentral grey matter MPVs and disease duration (r=−0.365, P=0.03). No correlation was found between MPVs and EDSS scores. Mean precentral gyrus volume in MS patients was 4368.55±867.78 whereas in controls was 5701.00±1184.03 with significant difference between volume of the precentral gyrus in MS patients compared to healthy controls (t=−5.167, P<0.001). There was a positive correlation between MPVs and precentral gyrus volume (r=0.291, P=0.020). ConclusionsOur study demonstrated that quantitative assessment of abnormal iron deposition in the precentral grey matter in MS patients can be measured using 3D-ESWAN.

141 Can MRI be used as a diagnostic tool in neuromyelitis optica spectrum disorder?

Differentiating neuromyelitis optica spectrum disorder (NMOSD) from relapsing multiple sclerosis (MS) can be difficult in aquaporin-4 antibody (AQP4ab) negative cases. Additionally MS like lesions on brain MRI are not uncommon...

Angioplasty Used to Treat Multiple Sclerosis Patients: A Potential Revolution in Health Care Technology

Multiple sclerosis (MS) has long been labeled as a neurological disease with a high incidence among Canadians, women in particular. The disease first manifests itself in young adulthood (between the ages of 15 and 40 years). Areas of demyelination with a proliferation of astrocytes are found scattered in the white matter of MS patients, this leads to muscle weakness, numbness, disequilibrium, sphincter disturbance and other neurological dysfunctions. Recently Dr. Paolo Zamboni, a vascular surgeon at the University of Ferrara in Italy, found that many multiple sclerosis patients have a narrowing of some of the neck veins responsible for draining blood from the brain. According to Dr. Zamboni, this narrowing of the blood vessels leads to the deposit of iron in the defected veins, which restricts blood flow and is responsible for some of the MS complications. Dr. Zamboni achieved unblocking of the veins through angioplasty, a procedure normally used to open arteries affected by atherosclerosis. In one of his trials, 65 patients were given the procedure, which decreased the rate of occurrence of lesions, from 50% to 12% in patients. There was an improvement in mental and physical quality of life in most of the patients in this trial. Ethical questions are also discussed in this review. Dr. Zamboni`s studies suggest a genetic inheritance of factors that may lead to MS. Should health care providers institute a screening procedure in newborns? Would these screenings be mandatory? Would the screenings be free?

Targeting Inflammatory Demyelinating Lesions to Sites of Wallerian Degeneration

In Theiler’s murine encephalomyelitis virus (TMEV) infection, an animal model for multiple sclerosis (MS), axonal injury precedes inflammatory demyelinating lesions, and the distribution of axonal damage present during the early phase of infection corresponds to regions where subsequent demyelination occurs during the chronic phase. We hypothesized that axonal damage recruits inflammatory cells to sites of Wallerian degeneration, leading to demyelination. Three weeks after TMEV infection, axonal degeneration was induced in the posterior funiculus of mice by injecting the toxic lectin Ricinus communis agglutinin (RCA) I into the sciatic nerve. Neuropathology was examined 1 week after lectin injection. Control mice, infected with TMEV but receiving no RCA I, had inflammatory demyelinating lesions in the anterior/lateral funiculi. Other control mice that received RCA I alone did not develop inflammatory lesions. In contrast, RCA I injection into TMEV-infected mice induced lesions in the posterior funiculus in addition to the anterior/lateral funiculi. We found no differences in lymphoproliferative responses or antibody titers against TMEV among the groups. This suggests that axonal degeneration contributes to the recruitment of inflammatory cells into the central nervous system by altering the local microenvironment. In this scenario, lesions develop from the axon (inside) to the myelin (outside) (Inside-Out model).