White Matter Diffusion Changes during the First Year of Natalizumab Treatment in Relapsing-Remitting Multiple Sclerosis.

BACKGROUND AND PURPOSE: Natalizumab treatment strongly affects relapsing-remitting multiple sclerosis, possibly by restraining white matter damage. This study investigated changes in white matter diffusivity in patients with relapsing-remitting multiple sclerosis during their first year of natalizumab treatment by using diffusion tensor imaging. MATERIALS AND METHODS: The study included patients with relapsing-remitting multiple sclerosis initiating natalizumab at baseline (n = 22), patients with relapsing-remitting multiple sclerosis continuing interferon-ß or glatiramer acetate (n = 17), and healthy controls (n = 12). Diffusion tensor imaging parameters were analyzed at baseline and month 12. We measured the extent and severity of white matter damage with diffusion tensor imaging parameters such as fractional anisotropy, comparing the patient groups with healthy controls at both time points. RESULTS: The extent and severity of white matter damage were reduced significantly in the natalizumab group with time (fractional anisotropy-based extent, 56.8% to 47.2%; severity, z = -0.67 to -0.59; P = .02); this reduction was not observed in the interferon-ß/glatiramer acetate group (extent, 41.4% to 39.1%, and severity, z = -0.64 to -0.67; P = .94). Cognitive performance did not change with time in the patient groups but did correlate with the severity of damage (r = 0.53, P = < .001). CONCLUSIONS: In patients with relapsing-remitting multiple sclerosis starting natalizumab treatment, the extent and severity of white matter damage were reduced significantly in the first year of treatment. These findings may aid in explaining the large observed clinical effect of natalizumab in relapsing-remitting multiple sclerosis.

A 10-year follow-up of the European multicenter trial of interferon ß-1b in secondary-progressive multiple sclerosis.

OBJECTIVES: To explore long-term effects of treatment and prognostic relevance of variables assessed at baseline and during the European secondary progressive multiple sclerosis (SPMS) trial of interferon beta 1b (IFNB-1b). METHODS: We assessed 362 patients (60% female; median age 41 years; Expanded Disability Status Scale (EDSS): 5.5; 51% randomized to IFNB-1b) for their EDSS and treatment history after 10 years. Non-parametric analysis of covariance (ANCOVA) and multivariate linear regression models were applied. RESULTS: Median EDSS was 6.0 at the end of the randomized controlled trial (RCT), in the IFNB-1b and placebo groups, and 7.0 in long-term follow-up patients (those receiving IFNB-1b in the RCT were 6.5 and those receiving placebo in the RCT were 7.0; p = 0.086). 24 patients (6.6%) were deceased. The EDSS at baseline and the EDSS change during the RCT were the most important predictors of the EDSS 10 years later (partial R(2): 0.47). The ability to predict changes in EDSS 10 years after the RCT was limited (R(2): 0.12). Magnetic resonance imaging (MRI) measures remained in the predictive models, but explained < 5% of the variability. CONCLUSIONS: The results from this analysis did not provide convincing evidence to support a favorable long-term outcome in those patients allocated IFNB-1b during the RCT, in our SPMS cohort. The progressive stage of the disease remains largely unpredictable by clinical and conventional MRI measures, so better prognostic markers are needed.

Enhanced axonal metabolism during early natalizumab treatment in relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: The considerable clinical effect of natalizumab in patients with relapsing-remitting multiple sclerosis might be explained by its possible beneficial effect on axonal functioning. In this longitudinal study, the effect of natalizumab on absolute concentrations of total N-acetylaspartate, a marker for neuronal integrity, and other brain metabolites is investigated in patients with relapsing-remitting multiple sclerosis by using MR spectroscopic imaging. MATERIALS AND METHODS: In this explorative observational study, 25 patients with relapsing-remitting multiple sclerosis initiating natalizumab treatment were included and scanned every 6 months for 18 months. Additionally 18 matched patients with relapsing-remitting multiple sclerosis continuing treatment with interferon-ß or glatiramer acetate were included along with 12 healthy controls. Imaging included short TE 2D-MR spectroscopic imaging with absolute metabolite quantification of total N-acetylaspartate, creatine and phosphocreatine, choline-containing compounds, myo-inositol, and glutamate. Concentrations were determined for lesional white matter, normal-appearing white matter, and gray matter. RESULTS: At baseline in both patient groups, lower concentrations of total N-acetylaspartate and creatine and phosphocreatine were found in lesional white matter compared with normal-appearing white matter and additionally lower glutamate in lesional white matter of patients receiving natalizumab. In those patients, a significant yearly metabolite increase was found for lesional white matter total N-acetylaspartate (7%, P < .001), creatine and phosphocreatine (6%, P = .042), and glutamate (10%, P = .028), while lesion volumes did not change. In patients receiving interferon-ß/glatiramer acetate, no significant change was measured in lesional white matter for any metabolite, while whole-brain normalized lesion volumes increased. CONCLUSIONS: Patients treated with natalizumab showed an increase in total N-acetylaspartate, creatine and phosphocreatine, and glutamate in lesional white matter. These increasing metabolite concentrations might be a sign of enhanced axonal metabolism.

Application of serum natalizumab levels during plasma exchange in MS patients with progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab treatment. Restoring immune function by plasmapheresis/immunoadsorption (PLEX/IA) is important for the outcome of PML. We report on four multiple sclerosis (MS) patients whom developed PML during natalizumab treatment, in whom we measured serum natalizumab concentrations before and during PLEX. Depending on the serum natalizumab concentration at the time of PML diagnosis, the number of PLEX treatments necessary to reach subtherapeutic serum natalizumab concentrations is variable. Measuring serum natalizumab concentrations before and during PLEX is helpful to determine the optimum number of PLEX treatments in individual MS patients with PML.

Bidirectional trans-synaptic axonal degeneration in the visual pathway in multiple sclerosis.

OBJECTIVE: To investigate the coexistence of anterograde and retrograde trans-synaptic axonal degeneration, and to explore the relationship between selective visual pathway damage and global brain involvement in longstanding multiple sclerosis (MS). METHODS: In this single-centre, cross-sectional study, patients with longstanding MS (N=222) and healthy controls (HC, N=62) were included. We analysed thickness of retinal layers (optical coherence tomography), damage within optic radiations (OR) (lesion volume and fractional anisotropy and mean diffusivity by diffusion tensor imaging) and atrophy of the visual cortex and that of grey and white matter of the whole-brain (structural MRI). Linear regression analyses were used to assess associations between the different components and for comparing patients with and without optic neuritis and HC. RESULTS: In patients with MS, an episode of optic neuritis (MSON) was significantly associated with decreased integrity of the ORs and thinning of the peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell complex (GCC). Lesion volume in the OR was negatively associated with pRNFL and GCC thickness in patients without optic neuritis (MSNON). The pRNFL and GCC showed associations with integrity of the OR, thickness of the primary visual cortex (only in patients with MSON), and also with global white and grey matter atrophy. In HCs, no such relationships were demonstrated. INTERPRETATION: This study provides evidence for presence of bidirectional (both anterograde and retrograde) trans-synaptic axonal degeneration in the visual pathway of patients with MS. Additionally, thinning of the retinal pRNFL and GCC are related to global white and grey matter atrophy in addition to pathology of the visual pathway.

Detecting clinically-relevant changes in progressive multiple sclerosis.

OBJECTIVE: To investigate which changes in different clinical outcome measures contribute most to increased disease impact, as reported by the patient, in progressive multiple sclerosis (MS). METHODS: From a cohort of prospectively-followed MS patients, we selected progressive patients with two visits, 4-6 years apart. We assessed long-term changes on the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT) and Guy's Neurological Disability Scale (GNDS). We defined the presence or absence of clinically meaningful change by using the Multiple Sclerosis Impact Scale (MSIS-29) as an anchor measure. We also studied change on recently identified sub-scales of GNDS. RESULTS: Change on GNDS (especially the spinal-plus subscale) contributed most to increased disease impact. Also change on the T25FW contributed largely. Specific profiles of change in T25FW and MSIS seemed to exist (generally, a lower increase in disease impact in patients with longer disease duration and higher baseline impact/disability). In some patients a dissociation existed between increased impact, according to the MSIS-29, and objective physical worsening of the T25FW. CONCLUSION: These results support using GNDS (particularly the spinal-plus domain) and T25FW in outcome measurement in progressive MS. We suggest there is a relation between baseline clinical characteristics and an increased impact at follow-up. This may have implications for patient selection in trials for progressive MS.

Structural degree predicts functional network connectivity: a multimodal resting-state fMRI and MEG study.

Communication between neuronal populations in the human brain is characterized by complex functional interactions across time and space. Recent studies have demonstrated that these functional interactions depend on the underlying structural connections at an aggregate level. Multiple imaging modalities can be used to investigate the relation between the structural connections between brain regions and their functional interactions at multiple timescales. We investigated if consistent modality-independent functional interactions take place between brain regions, and whether these can be accounted for by underlying structural properties. We used functional MRI (fMRI) and magnetoencephalography (MEG) recordings from a population of healthy adults together with a previously described structural network. A high overlap in resting-state functional networks was found in fMRI and especially alpha band MEG recordings. This overlap was characterized by a strongly interconnected functional core network in temporo-posterior brain regions. Anatomically realistically coupled neural mass models revealed that this strongly interconnected functional network emerges near the threshold for global synchronization. Most importantly, this functional core network could be explained by a trade-off between the product of the degrees of structurally-connected regions and the Euclidean distance between them. For both fMRI and MEG, the product of the degrees of connected regions was the most important predictor for functional network connectivity. Therefore, irrespective of the modality, these results indicate that a functional core network in the human brain is especially shaped by communication between high degree nodes of the structural network.

A dam for retrograde axonal degeneration in multiple sclerosis?

OBJECTIVE: Trans-synaptic axonal degeneration is a mechanism by which neurodegeneration can spread from a sick to a healthy neuron in the central nervous system. This study investigated to what extent trans-synaptic axonal degeneration takes place within the visual pathway in multiple sclerosis (MS). METHODS: A single-centre study, including patients with long-standing MS and healthy controls. Structural imaging of the brain (MRI) and retina (spectral-domain optical coherence tomography) were used to quantify the extent of atrophy of individual retinal layers and the primary and secondary visual cortex. Generalised estimation equations and multivariable regression analyses were used for comparisons. RESULTS: Following rigorous quality control (OSCAR-IB), data from 549 eyes of 293 subjects (230 MS, 63 healthy controls) were included. Compared with control data, there was a significant amount of atrophy of the inner retinal layers in MS following optic neuritis (ON) and also in absence of ON. For both scenarios, atrophy stopped at the level of the inner nuclear layer. In contrast, there was significant localised atrophy of the primary visual cortex and secondary visual cortex in MS following ON, but not in MS in absence of ON. INTERPRETATION: These data suggest that retrograde (trans-synaptic) axonal degeneration stops at the inner nuclear layer, a neuronal network capable of plasticity. In contrast, there seems to be no neuroplasticity of the primary visual cortex, rendering the structure vulnerable to anterograde (trans-synaptic) degeneration.

Disease course heterogeneity and OCT in multiple sclerosis.

BACKGROUND: The heterogeneity of the disease course in multiple sclerosis (MS) remains a challenge for patient management and clinical trials. OBJECTIVE: The objective of this paper is to investigate the relationship between disease course heterogeneity and retinal layer thicknesses in MS. METHODS: A total of 230 MS patients and 63 healthy control subjects were included. Spectral-domain OCT scanning of the peripapillary and macular regions was performed, followed by automated eight-layer segmentation. Generalised estimation equations were used for comparisons. Receiver operating characteristic (ROC) curves were calculated for distinguishing a benign from a typical disease course. RESULTS: Primary progressive patients showed relative preservation of inner retinal layers, compared to the relapsing onset MS types. Only in MS eyes without optic neuritis did patients with typical MS show more severe thinning of the inner retinal layers (RNFL to INL) compared to patients with a benign disease course, even after an average disease course of 20 years. CONCLUSION: The thicknesses, particularly of the innermost retinal layers (RNFL, GCC), were significantly related to the heterogeneous disease course in MS. The relative preservation of these layers in primary progressive and benign MS suggests rather limited susceptibility of the retina to neurodegeneration, which may be relevant for future neurodegenerative treatment trials employing OCT as a secondary outcome measure in primary progressive MS.

Long-term impact of interferon beta-1b in patients with CIS: 8-year follow-up of BENEFIT.

OBJECTIVE: To examine the long-term impact of early treatment initiation of interferon beta-1b (IFNB1b, Betaferon/Betaseron) in patients with a first event suggestive of multiple sclerosis (MS). METHODS: In the original placebo-controlled phase of BENEFIT, patients were randomised to IFNB1b 250 µg or placebo subcutaneously every other day. After 2 years or diagnosis of clinically definite MS (CDMS), all patients were offered open-label IFNB1b treatment for a maximum duration of 5 years. Thereafter, patients were enrolled in an observational extension study for up to 8.7 years. RESULTS: Of the initial 468 patients, 284 (60.7%; IFNB1b: 178 (61.0% of the original arm), placebo: 106 (60.2% of original arm)) were enrolled in the extension study. 94.2% of patients were receiving IFNB1b. Patients originally randomised to IFNB1b had a reduced risk of developing CDMS by 32.2% over the 8-year observation period (HR 0.678; 95% CI 0.525 to 0.875; p=0.0030), a longer median time to CDMS by 1345 days (95% CI 389 to 2301), and a lower annualised relapse rate (0.196 (95% CI 0.176 to 0.218) versus 0.255 (95% CI 0.226 to 0.287), p=0.0012), with differences mainly emerging in the first year of the study. Cognitive outcomes remained higher in the early treated patients. EDSS remained low over time with a median of 1.5 in both arms. CONCLUSIONS: These 8-year results provide further evidence supporting early initiation of treatment with IFNB1b in patients with a first event suggestive of MS.

Changes in functional network centrality underlie cognitive dysfunction and physical disability in multiple sclerosis.

BACKGROUND: Cognitive dysfunction in multiple sclerosis (MS) has a large impact on the quality of life and is poorly understood. OBJECTIVE: The aim of this study was to investigate functional network integrity in MS, and relate this to cognitive dysfunction and physical disability. METHODS: Resting state fMRI scans were included of 128 MS patients and 50 controls. Eigenvector centrality mapping (ECM) was applied, a graph analysis technique that ranks the importance of brain regions based on their connectivity patterns. Significant ECM changes were related to physical disability and cognitive dysfunction. RESULTS: In MS patients, ECM values were increased in bilateral thalamus and posterior cingulate (PCC) areas, and decreased in sensorimotor and ventral stream areas. Sensorimotor ECM decreases were related to higher EDSS (rho = -0.24, p = 0.007), while ventral stream decreases were related to poorer average cognition (rho = 0.23, p = 0.009). The thalamus displayed increased connectivity to sensorimotor and ventral stream areas. CONCLUSION: In MS, areas in the ventral stream and sensorimotor cortex appear to become less central in the entire functional network of the brain, which is associated with clinico-cognitive dysfunction. The thalamus, however, displays increased connectivity with these areas. These findings may aid in further elucidating the function of functional reorganization processes in MS.

Functional brain network analysis using minimum spanning trees in Multiple Sclerosis: an MEG source-space study.

Cognitive dysfunction in Multiple Sclerosis (MS) is closely related to altered functional brain network topology. Conventional network analyses to compare groups are hampered by differences in network size, density and suffer from normalization problems. We therefore computed the Minimum Spanning Tree (MST), a sub-graph of the original network, to counter these problems. We hypothesize that functional network changes analysed with MSTs are important for understanding cognitive changes in MS and that changes in MST topology also represent changes in the critical backbone of the original brain networks. Here, resting-state magnetoencephalography (MEG) recordings from 21 early MS patients and 17 age-, gender-, and education-matched controls were projected onto atlas-based regions-of-interest (ROIs) using beamforming. The phase lag index was applied to compute functional connectivity between regions, from which a graph and subsequently the MST was constructed. Results showed lower global integration in the alpha2 (10-13Hz) and beta (13-30Hz) bands in MS patients, whereas higher global integration was found in the theta band. Changes were most pronounced in the alpha2 band where a loss of hierarchical structure was observed, which was associated with poorer cognitive performance. Finally, the MST in MS patients as well as in healthy controls may represent the critical backbone of the original network. Together, these findings indicate that MST network analyses are able to detect network changes in MS patients, which may correspond to changes in the core of functional brain networks. Moreover, these changes, such as a loss of hierarchical structure, are related to cognitive performance in MS.

Oxysterols and cholesterol precursors correlate to magnetic resonance imaging measures of neurodegeneration in multiple sclerosis.

BACKGROUND: Cholesterol homeostasis is important for formation and maintenance of myelin and axonal membranes in the central nervous system (CNS). The concentrations of the brain specific cholesterol metabolite 24S-hydroxycholesterol (24OHC) and cholesterol precursors have been shown to be altered in multiple sclerosis (MS). However, how changes in sterol levels relate to the pathological processes in MS is not clear. METHODS: In this study, we compared serum and cerebrospinal fluid (CSF) sterol levels between 105 MS (51 relapsing-remitting (RR); 39 secondary progressive (SP) and 15 primary progressive (PP)) and 49 control patients. Sterol levels were correlated to magnetic resonance imaging (MRI) markers of disease activity. RESULTS: We found decreased serum 24OHC and 27-hydroxycholesterol (27OHC) and increased CSF lathosterol in MS patients compared to control patients (p=0.018, p=0.002 and p=0.002, respectively). Subgroup analysis showed that serum 24OHC levels were negatively correlated to normalized brain volume measurements in relapse-onset MS patients (r= -0.326, p=0.004). CONCLUSIONS: These results confirm that cholesterol homeostasis is disturbed in MS and suggest that changes in cholesterol synthesis are related to neurodegenerative pathological processes as seen on the MRI. The data seem to be in line with the recently reported observation that high dose statins may have a positive effect on clinical disability in secondary progressive MS.

Early detection of neutralizing antibodies to interferon-beta in multiple sclerosis patients: binding antibodies predict neutralizing antibody development.

BACKGROUND: Neutralizing antibodies (NAb) affect efficacy of interferon-beta (IFN-b) treatment in multiple sclerosis (MS) patients. NAbs evolve in up to 44% of treated patients, usually between 6-18 months on therapy. OBJECTIVES: To investigate whether early binding antibody (BAb) titers or different IFN-b biomarkers predict NAb evolution. METHODS: We included patients with MS or clinically isolated syndrome (CIS) receiving de novo IFN-b treatment in this prospective European multicenter study. Blood samples were collected at baseline, before and after the first IFN-b administration, and again after 3, 12 and 24 months on that therapy; for determination of NAbs, BAbs, gene expression of MxA and protein concentrations of MMP-9, TIMP-1, sTRAIL, CXCL-10 and CCL-2. RESULTS: We found that 22 of 164 (13.4%) patients developed NAbs during a median time of 23.8 months on IFN-b treatment. Of these patients, 78.9% were BAb-positive after 3 months. BAb titers ≥ 1:2400 predicted NAb evolution with a sensitivity of 74.7% and a specificity of 98.5%. Cross-sectionally, MxA levels were significantly diminished in the BAb/NAb-positive samples; similarly, CXCL-10 and sTRAIL concentrations in BAb/NAb-positive and BAb-positive/NAb-negative samples, respectively, were also diminished compared to BAb/NAb-negative samples. CONCLUSIONS: BAb titers reliably predict NAbs. CXCL-10 is a promising sensitive biomarker for IFN-b response and its abrogation by anti-IFN-b antibodies.

Magnetic resonance imaging correlates of physical disability in relapse onset multiple sclerosis of long disease duration.

BACKGROUND: Understanding long-term disability in multiple sclerosis (MS) is a key goal of research; it is relevant to how we monitor and treat the disease. OBJECTIVES: The Magnetic Imaging in MS (MAGNIMS) collaborative group sought to determine the relationship of brain lesion load, and brain and spinal cord atrophy, with physical disability in patients with long-established MS. METHODS: Patients had a magnetic resonance imaging (MRI) scan of their brain and spinal cord, from which we determined brain grey (GMF) and white matter (WMF) fractional volumes, upper cervical spinal cord cross-sectional area (UCCA) and brain T2-lesion volume (T2LV). We assessed patient disability using the Expanded Disability Status Scale (EDSS). We analysed associations between EDSS and MRI measures, using two regression models (dividing cohort by EDSS into two and four sub-groups). RESULTS: In the binary model, UCCA (p < 0.01) and T2LV (p = 0.02) were independently associated with the requirement of a walking aid. In the four-category model UCCA (p < 0.01), T2LV (p = 0.02) and GMF (p = 0.04) were independently associated with disability. CONCLUSIONS: Long-term physical disability was independently linked with atrophy of the spinal cord and brain T2 lesion load, and less consistently, with brain grey matter atrophy. Combinations of spinal cord and brain MRI measures may be required to capture clinically-relevant information in people with MS of long disease duration.

Cognition in MS correlates with resting-state oscillatory brain activity: An explorative MEG source-space study.

Clinical and cognitive dysfunction in Multiple Sclerosis (MS) is insufficiently explained by structural damage as identified by traditional magnetic resonance imaging (MRI) of the brain, indicating the need for reliable functional measures in MS. We investigated whether altered resting-state oscillatory power could be related to clinical and cognitive dysfunction in MS. MEG recordings were acquired using a 151-channel whole-head MEG system from 21 relapsing remitting MS patients and 17 healthy age-, gender-, and education-matched controls, using an eyes-closed no-task condition. Relative spectral power was estimated for 78 regions of interest, using an atlas-based beamforming approach, for classical frequency bands; delta, theta, alpha1, alpha2, beta and gamma. These cortical power estimates were compared between groups by means of permutation analysis and correlated with clinical disability (Expanded Disability Status Scale: EDSS), cognitive performance and MRI measures of atrophy and lesion load. Patients showed increased power in the alpha1 band and decreased power in the alpha2 band, compared to controls, mainly in occipital, parietal and temporal areas, confirmed by a lower alpha peak-frequency. Increased power in the alpha1 band was associated with worse overall cognition and especially with information processing speed. Our quantitative relative power analysis of MEG recordings showed abnormalities in oscillatory brain dynamics in MS patients in the alpha band. By applying source-space analyses, this study provides a detailed topographical view of abnormal brain activity in MS patients, especially localized to occipital areas. Interestingly, poor cognitive performance was related to high resting-state alpha1 power indicating that changes in oscillatory activity might be of value as an objective measure of disease burden in MS patients.

Walking speed, rather than Expanded Disability Status Scale, relates to long-term patient-reported impact in progressive MS.

OBJECTIVE: To study the relationships between 1-2 year changes in well-known physician-rated measurements (Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT)) and the long-term (≥ 5 years) outcome in patient-reported outcome (PRO) measures (Multiple Sclerosis Impact Scale (MSIS-29), Multiple Sclerosis Walking Scale (MSWS-12)) that reflect the patient-perceived impact of disease, in progressive MS. METHODS: We selected all progressive patients having at least two complete visits within 1-2 years, from a larger cohort of prospectively-followed MS patients. These were invited for another visit, at least 5 years later, consisting of another series of similar examinations, plus 2 PRO scales: the MSIS-29 and MSWS-12. We explored associations between early changes in physician-rated measurements and the long-term outcome as per the PRO measures. RESULTS: In this study,134 patients fulfilled the selection criteria. We found that early change in T25FW was the only physician-rated change that was significantly related to long-term physical impact experienced by the patient, as was assessed by MSIS-29 (Kruskal-Wallis test: χ(2)=7.8, p=0.020). Early T25FW change, and to a lesser degree early 9HPT change, were significantly related to the reported long-term walking limitations, as assessed by MSWS-12 (Kruskal-Wallis test: χ(2)=13.8 and p=0.001 for T25FW, χ(2)=6.5 and p=0.038 for 9HPT). None of the early physician-rated changes were related to the long-term psychological impact experienced by the patient. CONCLUSION: Early changes on physician-rated scales do have long-term impact in terms of potentially predictive value of outcomes for groups of patients in progressive MS, regarding walking limitations and more global physical impact. Surprisingly, early change in T25FW, rather than early change in EDSS, was significantly associated with longer-term patient-reported disease impact. Our study data support the value of using early physician-rated examinations in clinical trials in progressive MS.

Multicontrast MR imaging at 7T in multiple sclerosis: highest lesion detection in cortical gray matter with 3D-FLAIR.

BACKGROUND AND PURPOSE: 7T MR imaging has led to improved detection and classification of cortical MS lesions, mainly based on T2*-weighted gradient-echo sequences. Depiction of cortical GM by using the recommended MS imaging protocol has not yet been investigated at 7T. We aimed to investigate prospectively which recommended sequence for clinical use has the highest value at 7T, in terms of GM and WM lesion detection. MATERIALS AND METHODS: Thirty-seven patients with MS (mean age, 43.8 years; 25 women) and 7 healthy controls (mean age, 40.4 years; 5 women) underwent multicontrast 7T MR imaging including the recommended clinical 2D-T2WI, 3D-T1WI, 3D-FLAIR, and GM-specific 3D-DIR. Lesions were scored and categorized anatomically by 3 raters, in consensus. The value of sequences was evaluated lesion-wise and patient-wise (Wilcoxon signed-rank test). RESULTS: At 7T, 3D-FLAIR detected the highest number of total cortical GM lesions (217), 89% more than 3D-DIR and 87% and 224% more than 2D-T2WI and 3D-T1WI. Patient-wise analysis showed that this difference between 3D-FLAIR and 3D-DIR was statistically significant (P<.04), and most pronounced for the number of mixed lesions (P<.03). 3D-FLAIR also detected the highest number of total WM lesions (2605), but the difference with 3D-DIR and 3D-T1WI was not significant. CONCLUSIONS: When using recommended clinical sequences at 7T, the best way to detect cortical GM lesions is with 3D-FLAIR and not by GM-specific 3D-DIR or by conventional 2D-T2WI and 3D-T1WI sequences.

Cerebrospinal fluid anti-whole myelin antibodies are not correlated to magnetic resonance imaging activity in multiple sclerosis.

BACKGROUND: The role of antimyelin antibodies as biomarker in multiple sclerosis is subject of debate. Here antimyelin antibody reactivity against native myelin is studied in CSF and serum. OBJECTIVE: To compare antimyelin antibody reactivity between patients with multiple sclerosis (MS) and patients with other neurological diseases in CSF and serum. In addition, MRI measures were studied in relation to antimyelin antibody reactivity. METHODS: 77 MS patients (13 primary progressive, 27 secondary progressive and 37 relapsing remitting), 26 patients with other non-inflammatory neurological diseases and 9 patients with inflammatory neurological diseases other than MS were included. A myelin flow cytometry assay was used to detect anti-myelin antibody levels which were expressed as mean fluorescence intensity (myelin-MFI). MRI outcome measures were new or persistent T2 lesions, gadolinium enhancing T1 lesions and brain atrophy which were assessed by normalized brain volumes. RESULTS: There was no significant difference between myelin-MFI values in serum and CSF between MS patients and controls (Mann-Whitney test p=0.19 and p=0.51). Myelin-MFI values in CSF were not correlated with number of T2 lesions (Spearman r=-0.023, p=0.85), number of gadolinium enhancing T1 lesions (Spearman r=-0.066, p=0.588) or normalized brain volume (Spearman r=-0.065, p=0.594). CONCLUSIONS: These results do not confirm an association between anti-myelin antibody reactivity and the presence of MS or MRI measures of disease activity.

Increased plasma 8,12-iso-iPF2alpha- VI levels in relapsing multiple sclerosis patients are not predictive of disease progression.

BACKGROUND: Oxidative stress plays an important role in multiple sclerosis (MS). Isoprostanes are biomarkers for oxidative stress and have been related to neurological disease progression. OBJECTIVE: To study whether plasma isoprostane levels were related to disease progression in MS. METHODS: Plasma levels of 8,12-iso-iPF2alpha-VI were determined in 17 patients with clinically isolated syndrome (CIS), 41 relapsing-remitting MS (RRMS) patients and 5 primary progressive MS (PPMS) patients and related to MRI and clinical disease parameters. RESULTS: Isoprostane levels were similar in CIS (60.9, interquartile range (IQR): 47.7-77.7 pg/ml) and RRMS patients (65.3, IQR: 51.9-82.8 pg/ml). The plasma levels were lower in PPMS patients (42.5, IQR: 37.1-49.9) pg/ml, p<0.05) compared to CIS and RRMS patients in this cohort, which was not confirmed in a second cohort. Baseline isoprostane levels were not related to clinical progression defined by conversion form CIS to RRMS or change in Expanded Disability Status Scale (EDSS) or MS Functional Composite (MSFC) scores during six years of follow-up (CIS + RRMS), nor to change in volume of gadolinium enhancing lesions, T2 lesion load or T1 hypointense lesion load during 2.8 years of follow-up (CIS + RRMS). CONCLUSION: These results do not support a strong role of 8,12-iso-iPF2alpha-VI in the prediction of disease progression in MS.