Retinal small vessel pathology is associated with disease burden in multiple sclerosis.

BACKGROUND: Alterations of the superficial retinal vasculature are commonly observed in multiple sclerosis (MS) and can be visualized through optical coherence tomography angiography (OCTA). OBJECTIVES: This study aimed to examine changes in the retinal vasculature during MS and to integrate findings into current concepts of the underlying pathology. METHODS: In this cross-sectional study, including 259 relapsing-remitting MS patients and 78 healthy controls, we analyzed OCTAs using deep-learning-based segmentation algorithm tools. RESULTS: We identified a loss of small-sized vessels (diameter < 10 µm) in the superficial vascular complex in all MS eyes, irrespective of their optic neuritis (ON) history. This alteration was associated with MS disease burden and appears independent of retinal ganglion cell loss. In contrast, an observed reduction of medium-sized vessels (diameter 10-20 µm) was specific to eyes with a history of ON and was closely linked to ganglion cell atrophy. CONCLUSION: These findings suggest distinct atrophy patterns in retinal vessels in patients with MS. Further studies are necessary to investigate retinal vessel alterations and their underlying pathology in MS.

Longitudinal assessment of neurocognitive function in people with relapsing multiple sclerosis initiating alemtuzumab in routine clinical practice: LEM-COG study results.

BACKGROUND: Alemtuzumab is effective in reducing relapse rate and disability, but limited data exist on its effect on cognitive function in relapsing multiple sclerosis (RMS). The present study assessed neurocognitive function and safety associated with alemtuzumab treatment in RMS. METHODS: This longitudinal, single-arm, prospective study included people with RMS (aged 25-55 years) who were treated with alemtuzumab in clinical practice in the United States of America and Canada. The first participant was enrolled in December 2016. The primary endpoint was the change from baseline to post-baseline (month [M] 12/24) in MS-COGnitive (MS-COG) composite score. Secondary endpoints included Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMT-R), Selective Reminding Test (SRT), Controlled Oral Word Association Test (COWAT), and Automated Neuropsychological Assessment Metrics (ANAM) scores. Depression and fatigue were assessed using Hamilton Rating Scale-Depression (HAM-D) and Fatigue Severity Scale (FSS)/Modified Fatigue Impact Scale (MFIS), respectively. Magnetic resonance imaging (MRI) parameters were assessed when available. Safety was assessed throughout the study. Descriptive statistics were used for the pre-specified statistical analyses. Since the study was terminated early (November 2019) because of operational and resource difficulties, post hoc analyses for statistical inference were performed among participants who had a baseline value and at least one complete post-baseline assessment for cognitive parameters, fatigue, or depression. RESULTS: Of the 112 participants enrolled, 39 were considered as the primary analysis population at M12. At M12, a mean change of 0.25 (95% confidence interval [CI]: 0.04, 0.45; p = 0.0049; effect size [ES]: 0.39) was observed in the MS-COG composite score. Improvements were observed in processing speed (based on PASAT and SDMT; p < 0.0001; ES: 0.62), as well as in individual PASAT, SDMT and COWAT scores. An improvement was also noted in HAM-D (p = 0.0054; ES: -0.44), but not in fatigue scores. Among MRI parameters, decreases in burden of disease volume (BDV; ES: -0.12), new gadolinium-enhancing lesions (ES: -0.41) and newly active lesions (ES: -0.07) were observed at M12. About 92% of participants showed stable or improved cognitive status at M12. There were no new safety signals reported in the study. The most common adverse events (≥10% of participants) were headache, fatigue, nausea, insomnia, urinary tract infection, pain in extremity, chest discomfort, anxiety, dizziness, arthralgia, flushing, and rash. Hypothyroidism (3.7%) was the most frequent adverse event of special interest. CONCLUSION: The findings from this study suggest that alemtuzumab has a positive impact on cognitive function with significant improvements in processing speed and depression in people with RMS over a period of 12 months. The safety profile of alemtuzumab was consistent with previous studies.

Clinical and fringe benefits of rituximab in multiple sclerosis treatment in a poor resource setting: Case series and cost analysis.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory demyelinating condition of the central nervous system that leads to neurological disability and a poor quality of life (QoL). Rituximab has been used off-label in many countries to treat MS because of its high efficacy and affordability. However, there is no evidence of its effectiveness in Thailand. Therefore, the objective of this study was to evaluate the efficacy and additional benefits of rituximab in Thai patients with MS. METHODS: This was a prospective cohort study of patients diagnosed with MS who started treatment with rituximab between November 1, 2020, and October 31, 2022. Patients with MS eligible for the study received intravenous rituximab with a starting dose of 1000 mg at the first visit and another 1000 mg dose 2 weeks later. Thereafter, 1000 mg rituximab was administered every 6 months until the end of the study. The primary outcome was the annualized relapse rate (ARR). In addition, magnetic resonance imaging (MRI) activity of the gadolinium-enhancing lesion, QoL, number of hospital visits, and treatment costs were considered secondary outcomes. RESULTS: Ten patients diagnosed with relapsing-remitting multiple sclerosis were included in the study. The median ARR markedly decreased from 2.14 (0-4) to 0 (0-0.5) (p=0.005). The median Expanded Disability Status Scale score improved from 3.25 (1.5-6.0) to 1 (1-4) (p=0.005). The median number of enhancing lesions decreased from 1 (0-7) to 0 (0-3) (p=0.017). In addition, the median EuroQoL 5 Dimension 5 Level score, indicating QoL, improved from 0.7 (0.41-0.85) to 0.88 (0.68-1.00) (p=0.005). The median number of outpatient department visits significantly decreased from 6 (4-12) to 3 (2-5) (p=0.009). Hospitalization or inpatient department visits diminished from 1 (0-2) to 0 (0-1) (p=0.007). The total direct medical cost of rituximab treatment was not significantly different from that of the pre-treatment condition: 70,891 THB (65,391-116,358) VS 66,961 THB (33,927-109,248) or 1,904 USD (1,756-3,125 USD) VS 1,798 USD (911-2,934) (p=0.173). CONCLUSION: Rituximab was effective in the treatment of MS in Thailand. The use of rituximab reduced the number of relapses, reduced disability, decreased the number of active MRI lesions, and improved QoL. Moreover, the benefit of rituximab in treating MS in Thailand surpasses the current cost of treatment.

Longitudinal assessment of cervical spinal cord compartments in multiple sclerosis.

BACKGROUND: Although cervical spinal cord (cSC) area is an established biomarker in MS, there is currently a lack of longitudinal assessments of cSC gray and white matter areas. OBJECTIVE: We conducted an explorative analysis of longitudinal changes of cSC gray and white matter areas in MS patients. METHODS: 65 MS patients (33 relapsing-remitting; 20 secondary progressive and 12 primary progressive) and 20 healthy controls (HC) received clinical and upper cSC MRI assessments over 1.10±0.28 years. cSC compartments were quantified on MRI using the novel averaged magnetization inversion recovery acquisitions sequence (in-plane resolution=0.67 × 0.67mm2), and in-house developed post-processing methods. Patients were stratified regarding clinical progression. RESULTS: Patients with clinical progression showed faster reduction of cSC areas over time at the level of cSC enlargement (approximate vertebral level C4-C5) compared to stable patients (p<0.05). In addition, when compared to the rostral-cSC (approximate vertebral level C2-C3), a preferential reduction of cSC and white matter areas over time at the level of cSC enlargement (p<0.05 and p<0.01, respectively) was demonstrated only in patients with clinical progression, but not in stable MS patients and HC. Compared to HC, MS patients showed comparable changes over time in all cSC compartments. CONCLUSIONS: MS patients with clinical disease progression demonstrate subtle signs of a more pronounced tissue loss at the level of cSC enlargement. Future studies should consider larger sample sizes and more extended observation periods.

Quantification and Proximal-to-Distal Distribution Pattern of Tibial Nerve Lesions in Relapsing-Remitting Multiple Sclerosis : Assessment by MR Neurography.

PURPOSE: Recent studies suggest an involvement of the peripheral nervous system (PNS) in multiple sclerosis (MS). Here, we characterize the proximal-to-distal distribution pattern of peripheral nerve lesions in relapsing-remitting MS (RRMS) by quantitative magnetic resonance neurography (MRN). METHODS: A total of 35 patients with RRMS were prospectively included and underwent detailed neurologic and electrophysiologic examinations. Additionally, 30 age- and sex-matched healthy controls were recruited. 3T MRN with anatomical coverage from the proximal thigh down to the tibiotalar joint was conducted using dual-echo 2­dimensional relaxometry sequences with spectral fat saturation. Quantification of PNS involvement was performed by evaluating microstructural (proton spin density (ρ), T2-relaxation time (T2app)), and morphometric (cross-sectional area, CSA) MRN markers in every axial slice. RESULTS: In patients with RRMS, tibial nerve lesions at the thigh and the lower leg were characterized by a decrease in T2app and an increase in ρ compared to controls (T2app thigh: p < 0.0001, T2app lower leg: p = 0.0040; ρ thigh: p < 0.0001; ρ lower leg: p = 0.0098). An additional increase in nerve CSA was only detectable at the thigh, while the semi-quantitative marker T2w-signal was not altered in RRMS in both locations. A slight proximal-to-distal gradient was observed for T2app and T2-signal, but not for ρ. CONCLUSION: PNS involvement in RRMS is characterized by a decrease in T2app and an increase in ρ, occurring with proximal predominance at the thigh and the lower leg. Our results indicate microstructural alterations in the extracellular matrix of peripheral nerves in RRMS and may contribute to a better understanding of the pathophysiologic relevance of PNS involvement.

Assessment of T2 lesion-based disease activity volume outcomes in predicting disease progression in multiple sclerosis over 10 years.

BACKGROUND: New/enlarging T2 lesion count and T2-lesion volume (LV) are used as conventional secondary endpoints in clinical trials of patients with multiple sclerosis (PwMS). However, those outcomes may have several limitations, such as inability to account for heterogeneity of lesion formation/enlargement frequency and their dynamic volumetric behavior. Measurement of volume rather than count of new/enlarging lesions may be more representative outcome of dynamic changes over time. OBJECTIVES: To investigate whether new/enlarging T2-LV is more predictive of confirmed disability progression (CDP), compared to total T2-LV or new/enlarging T2 lesion count over long-term follow-up. METHODS: We studied 176 early relapsing-remitting PwMS who were followed with annual MRI examinations over 10 years. T2-LV, new/enlarging T2-LV, and new/enlarging lesion count were determined. Cumulative count/volumes were obtained. 10-year CDP was confirmed after 48-weeks. ANCOVA analysis detected MRI outcome differences in stable (n = 76) and CDP (n = 100) groups at different time points, after correction for multiple comparisons. RESULTS: PwMS with CDP had greater cumulative new/enlarging T2-LV at 4 years (p = 0.049), and enlarging T2-LV at 4- (p = 0.039) and 6-year follow-up (p = 0.032), compared to stable patients. PwMS with CDP did not differ from stable ones in new/enlarging T2 lesion count or total T2-LV at any of the study timepoints. PwMS with Expanded Disability Status Scale change >2.0 had significantly greater enlarging T2 lesion count (p = 0.01) and enlarging T2-LV (p = 0.038) over the 10-year follow-up. CONCLUSION: Enlargement of T2 lesions is more strongly associated with long-term disability progression compared to other conventional T2 lesion-based outcomes.

Brief International Cognitive Assessment for Multiple Sclerosis scores are associated with the cortical thickness of specific cortical areas in relapsing-remitting patients.

BACKGROUND: Cognitive impairment is frequent and disabling in multiple sclerosis (MS). The Brief International Cognitive Assessment in MS (BICAMS) is a recent short battery usable in clinical practice for cognitive evaluation of MS patients. OBJECTIVE: To find cortical areas or brain volumes on magnetic resonance imaging (MRI) structural sequences associated with BICAMS scores in MS. METHODS: In this cross-sectional single-center study (NCT03656055, September 4, 2018), 96 relapsing remitting-MS patients under natalizumab and without recent clinical or radiological inflammation were included. Patients underwent brain MRI and the three BICAMS tests, evaluating information processing speed (SDMT), visuo-spatial memory (BVMT-R), and verbal memory (FVLT). RESULTS: Cortical thickness in the left frontal superior and the right precentral gyri was associated with BVMT-R scores whereas cortical thickness in the left Broca's area and the right superior temporal gyrus was associated with FVLT scores. We observed associations between white matter inflammatory lesions connected to these cortical regions and BICAMS subscores. CONCLUSIONS: BICAMS scores are associated with specific cortical areas, the cognitive domain matching the known functions of the cortical area. Specific cognitive impairments in MS may be associated with specific cortical regions, themselves influenced by white matter inflammatory lesions and demographical parameters (age, sex, education level).

Multimodal assessment of regional gray matter integrity in early relapsing-remitting multiple sclerosis patients with normal cognition: a voxel-based structural and perfusion approach.

OBJECTIVE: There is increasing evidence that gray matter (GM) impairment is strongly associated with clinical performance decline. We aim to perform a voxelwise analysis between regional GM (rGM) perfusion and structural abnormalities in early relapsing-remitting multiple sclerosis patients with normal cognition (RRMS-IC) and explore clinical correlate of early rGM abnormalities. METHODS AND MATERIALS: We studied 14 early RRMS-IC patients and 14 healthy age- and sex-matched controls. Brain perfusion single photon emission computed tomography (SPECT), structural MRI, and a comprehensive neuropsychological examination were acquired from all participants. Neuropsychological tests include expanded disability status scale, minimal mental status examination, short physical performance battery, Wechsler memory scale, and quick smell test. Voxel-based morphometry was used for analyzing SPECT and T1-MR images to identify rGM hypoperfusion and atrophy, respectively (RRMS-IC vs controls (group analysis), and also, each patient vs controls (individual analysis)) (p < 0.001). Then, anatomical location of impaired regions was acquired by automated anatomical labeling software. RESULTS: There was no significant difference in total GM volume between RRMS-IC and healthy controls, however, rGM atrophy and hypoperfusion were detected. Individual analysis revealed more rGM impairment compared with group analysis. rGM hypoperfusion was more extensive rather than rGM atrophy in RRMS-IC. There was no spatial association between rGM atrophy and rGM hypoperfusion (p > 0.05). rGM abnormalities correlated with several relevant minimal clinical deficits. CONCLUSION: Lack of spatial correlation between rGM atrophy and hypoperfusion might suggest that independent mechanisms might underlie atrophy and hypoperfusion. Perfusion SPECT may provide supplementary information along with MRI. ADVANCES IN KNOWLEDGE: Association between rGM atrophy and rGM hypoperfusion and their clinical significance in early RRMS-IC is not well described yet. Our study showed that there is spatial dissociation between rGM atrophy and rGM hypoperfusion, suggesting that different mechanisms might underlie these pathologies.

Assessment of the genetic contribution to brain magnetic resonance imaging lesion load and atrophy measures in multiple sclerosis patients.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) susceptibility is influenced by genetics; however, little is known about genetic determinants of disease expression. We aimed at assessing genetic factors influencing quantitative neuroimaging measures in two cohorts of progressive MS (PMS) and relapsing-remitting MS (RRMS) patients. METHODS: Ninety-nine PMS and 214 RRMS patients underwent a 3-T brain magnetic resonance imaging (MRI) scan, with the measurement of five MRI metrics including T2 lesion volumes and measures of white matter, grey matter, deep grey matter, and hippocampal volumes. A candidate pathway strategy was adopted; gene set analysis was carried out to estimate cumulative contribution of genes to MRI phenotypes, adjusting for relevant confounders, followed by single nucleotide polymorphism (SNP) regression analysis. RESULTS: Seventeen Kyoto Encyclopedia of Genes and Genomes pathways and 42 Gene Ontology (GO) terms were tested. We additionally included in the analysis genes with enriched expression in brain cells. Gene set analysis revealed a differential pattern of association across the two cohorts, with processes related to sodium homeostasis being associated with grey matter volume in PMS (p = 0.002), whereas inflammatory-related GO terms such as adaptive immune response and regulation of inflammatory response appeared to be associated with T2 lesion volume in RRMS (p = 0.004 and p = 0.008, respectively). As for SNPs, the rs7104613T mapping to SPON1 gene was associated with reduced deep grey matter volume (ß = -0.731, p = 3.2*10-7 ) in PMS, whereas we found evidence of association between white matter volume and rs740948A mapping to SEMA3A gene (ß = 22.04, p = 5.5*10-6 ) in RRMS. CONCLUSIONS: Our data suggest a different pattern of associations between MRI metrics and functional processes across MS disease courses, suggesting different phenomena implicated in MS.

Fatigue scores correlate with other self-assessment data, but not with clinical and biomarker parameters, in CIS and RRMS.

BACKGROUND: Fatigue is common in multiple sclerosis and is associated with reduced quality of life. This study aimed to assess the correlation between fatigue scores and data from other self-assessment questionnaires, neuropsychological tests and neuroimaging, as well as data on neuroimmunological markers in cerebrospinal fluid (CSF) and serum/plasma, in clinically isolated syndrome (CIS) and relapsing remitting MS (RRMS). METHODS: Modified fatigue impact scale (MFIS) scores were determined in 38 patients with newly diagnosed CIS or RRMS at baseline and after one year in a prospective longitudinal cohort study. Non-parametric correlation analyses were used to assess associations between MFIS scores and other self-assessment questionnaire data (Hospital Anxiety and Depression scale (HAD), Multiple Sclerosis Impact Scale 29 (MSIS-29) and Short Form 36 (SF-36)), as well as with neuropsychological test performances (e.g. Auditory Consonant Trigram Test (ACTT)), clinical parameters (e.g. disease duration and expanded disability status scale (EDSS)), magnetic resonance imaging (MRI) data (number of T2 lesions in brain MRI and total brain volume) and several neurodegenerative/neuroinflammatory markers in CSF and serum/plasma (IL-1ß, IL-6, CXCL1, CXCL10, CXCL13, CCL-22 in plasma; neurofilament light chain (NFL) in serum; IL-6, CXCL1, CXCL10, CXCL13, CCL22, NFL and chitinase-3-like-1 (CHI3L1) in CSF. CSF and serum/plasma from 21 age- and sex-matched healthy controls were available for comparison. RESULTS: At both baseline and one-year follow-up, fatigue scores correlated significantly with HAD, MSIS-29 and SF-36 scores and ACTT performance (Spearman´s rho 0.45-0.78, all p ≤ 0.01) but not with the other neuropsychological test results, disease duration, EDSS ratings, number of T2 lesions, total brain volume or neurodegenerative/neuroinflammatory markers, including neurofilament light chain levels in CSF and serum. In group comparisons, MFIS scores were similar in patients fulfilling no evidence of disease activity-3 (NEDA-3) (n = 18) and patients not fulfilling NEDA-3 (n = 20) during one year of follow-up (p > 0.01). CONCLUSIONS: In this cohort of patients with newly diagnosed CIS and RRMS, fatigue scores were associated with mood, disease impact on daily life and quality of life as well as with alterations of attentive functions. Study results indicate that subjective fatigue scores are not well reflected by some commonly used and objectively measurable disease parameters like EDSS, T2 lesions and NFL levels.

Joint assessment of brain and spinal cord motor tract damage in patients with early RRMS: predominant impact of spinal cord lesions on motor function.

BACKGROUND: In patients with MS, the effect of structural damage to the corticospinal tract (CST) has been separately evaluated in the brain and spinal cord (SC), even though a cumulative impact is suspected. OBJECTIVE: To evaluate CST damages on both the cortex and cervical SC, and examine their relative associations with motor function, measured both clinically and by electrophysiology. METHODS: We included 43 patients with early relapsing-remitting MS. Lesions were manually segmented on SC (axial T2*) and brain (3D FLAIR) scans. The CST was automatically segmented using an atlas (SC) or tractography (brain). Lesion volume fractions and diffusion parameters were calculated for SC, brain and CST. Central motor conduction time (CMCT) and triple stimulation technique amplitude ratio were measured for 42 upper limbs, from 22 patients. RESULTS: Mean lesion volume fractions were 5.2% in the SC portion of the CST and 0.9% in the brain portion. We did not find a significant correlation between brain and SC lesion volume fraction (r = 0.06, p = 0.68). The pyramidal EDSS score and CMCT were both significantly correlated with the lesion fraction in the SC CST (r = 0.39, p = 0.01 and r = 0.33, p = 0.03), but not in the brain CST. CONCLUSION: Our results highlight the major contribution of SC lesions to CST damage and motor function abnormalities.

The value of anti-JCV antibody index assessment in multiple sclerosis patients treated with natalizumab with respect to demographic, clinical and radiological findings.

BACKGROUND: Natalizumab-related progressive multifocal leukoencephalopathy (PML) is associated with the presence of anti-John Cunningham virus (JCV) antibodies. The aim of this investigation was to evaluate the long-term stability of anti-JCV antibody serum levels and their relation to various demographic, clinical and radiological characteristics in patients suffering from multiple sclerosis (MS). METHODS: Seventy-eight relapsing-remitting MS patients treated with natalizumab and evaluated for the presence of serum anti-JCV antibodies over a time period of 1-6 years (3-11 samples) were included in the study. Anti-JCV antibody levels and their changes were correlated with various demographic, clinical and radiological findings. RESULTS: Median follow-up time was 43.5 months, with a median of 5.3 samples available per patient. At baseline, 46 (59%) of the patients were seropositive. During follow-up, anti-JCV antibody status changed from negative to positive or vice versa in 23% of patients. Baseline anti-JCV antibody index correlated positively with age (p = 0.03). PATIENTS: with stable positive anti-JCV antibody index had more T2 hyperintensities (20.2 vs. 13.1; p < 0.007) on cerebral magnetic resonance imaging (MRI) and were also older than the stable negative anti-JCV antibody index group of patients (45.2.vs. 40.3 years; p < 0.01). No significant increase in T2 hyperintensities after seroconversion was revealed. Average duration from beginning of natalizumab therapy to seroconversion (n = 13) was 33 months. Annual seroconversion rate of anti-JCV antibody status was 6.5%. A baseline anti-JCV antibody index of >0.90 (n = 33) predicted stable seropositivity (100%), while baseline anti-JCV antibody index <0.20 did not predicted stable seronegativity (59%). PML was not diagnosed in any of the patients studied during the follow-up. CONCLUSIONS: A positive baseline anti-JCV antibody index of >0.90 predicts stable positive JCV serostatus, in contrast with a baseline anti-JCV antibody index of <0.20, which remained negative in 59% of cases. Stable positive anti-JCV index patients have more MRI T2 hyperintensities and are older compared with stable negative anti-JCV index patients.

Multimodal assessment of normal-appearing corpus callosum is a useful marker of disability in relapsing-remitting multiple sclerosis: an MRI cluster analysis study.

BACKGROUND AND PURPOSE: Corpus callosum (CC) is frequently involved in relapsing-remitting multiple sclerosis (RRMS). Magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) allow to study CC macrostructural and microstructural tissue integrity. Here, we applied a data-driven approach to MRI and DTI data of normal-appearing CC in RRMS subjects, and subsequently evaluated if differences in tissue integrity corresponded to different levels of physical disability and cognitive impairment. METHODS: 74 RRMS patients and 20 healthy controls (HC) underwent 3 T MRI and DTI. Thickness and fractional anisotropy (FA) along midsagittal CC were extracted, and values from RRMS patients were fed to a hierarchical clustering algorithm. We then used ANOVA to test for differences in clinical and cognitive variables across the imaging-based clusters and HC. RESULTS: We found three distinct MRI-based subgroups of RRMS patients with increasing severity of CC damage. The first subgroup showed callosal integrity similar to HC (Cluster 1); Cluster 2 had milder callosal damage; a third subgroup showed the most severe callosal damage (Cluster 3). Cluster 3 included patients with longer disease duration and worst scores in Expanded Disability Status Scale. Cognitive domains of verbal memory, executive functions and processing speed were impaired in Cluster 3 and Cluster 2 compared to Cluster 1 and HC. CONCLUSIONS: Within the same homogeneous cohort of patients, we could identify three neuroimaging RRMS clusters characterized by different involvement of normal-appearing CC. Interestingly, these corresponded to three distinct levels of clinical and cognitive disability.

Longitudinal Assessment of Dentate Nuclei Relaxometry during Massive Gadobutrol Exposure.

We report the assessment of Dentate Nuclei (DN) R1 (1/T1) and R2* (1/T2*) values in a patient with relapsing-remitting Multiple Sclerosis, exposed to 22 standard (0.1 mmol/kg) doses of gadobutrol, who underwent eight relaxometric MR measurements within 2 years. DN R1 did not significantly increase nor correlated with cumulative gadobutrol administration, even after a total dose of 130 ml. Likewise, DN R2* relaxometry remained unchanged. In conclusion, massive gadobutrol exposure did not induce significant DN relaxometry changes.

Limbic system damage in MS: MRI assessment and correlations with clinical testing.

Volume loss in some limbic region structures has been observed in multiple sclerosis (MS) patients. However, in vivo evaluation of existing tissue cellular microstructure integrity has received less attention. The goal of studies reported here was to quantitatively assess loss of limbic system volumes and tissue integrity, and to evaluate associations of these measures with cognitive and physical dysfunction in MS patients. Thirty-one healthy controls (HC) and 80 MS patients, including 32 relapsing remitting (RRMS), 32 secondary progressive (SPMS) and 16 primary progressive (PPMS), participated in this study. Tissue cellular integrity was evaluated by means of recently introduced tissue-specific parameter R2t* that was calculated from multi-gradient-echo MRI signals using a recently developed method that separates R2t* from BOLD (blood oxygen level dependent) contributions to GRE signal decay rate constant (R2*), and accounting for physiological fluctuations and artifacts from background gradients. Volumes in limbic system regions, normalized to skull size (NV), were measured from standard MPRAGE images. MS patients had lower R2t* and smaller normalized volumes in the hippocampus, amygdala, and several other limbic system regions, compared to HC. Alterations in R2t* of several limbic system regions correlated with clinical and neurocognitive test scores in MS patients. In contrast, smaller normalized volumes in MS were only correlated with neurocognitive test scores in the hippocampus and amygdala. This study reports the novel finding that R2t*, a measure that estimates tissue integrity, is more sensitive to tissue damage in limbic system structures than is atrophy. R2t* measurements can serve as a biomarker that is distinct from and complementary to volume measurements.

Longitudinal quantitative MRI assessment of cortical damage in multiple sclerosis: A pilot study.

PURPOSE: Quantitative MRI (qMRI) allows assessing cortical pathology in multiple sclerosis (MS) on a microstructural level, where cortical damage has been shown to prolong T1 -relaxation time and increase proton density (PD) compared to controls. However, the evolution of these changes in MS over time has not been investigated so far. In this pilot study we used an advanced method for the longitudinal assessment of cortical tissue change in MS patients with qMRI in comparison to cortical atrophy, as derived from conventional MRI. MATERIALS AND METHODS: Twelve patients with relapsing-remitting MS underwent 3T T1 /PD-mapping at two timepoints with a mean interval of 12 months. The respective cortical T1 /PD-values were extracted from the middle of the cortical layer and the cortical thickness was measured for surface-based identification of clusters with increasing/decreasing values. RESULTS: Statistical analysis showed clusters with increasing PD- and T1 -values over time (annualized rate for T1 /PD increase in these clusters: 3.4 ± 2.56% for T1 , P = 0.0007; 2.3 ± 2.59% for PD, P = 0.01). Changes are heterogeneous across the cortex and different patterns of longitudinal PD and T1 increase emerged. Analysis of the cortical thickness yielded only one small cluster indicating a decrease of cortical thickness. CONCLUSION: Changes of cortical tissue composition in MS seem to be reflected by a spatially inhomogeneous, multifocal increase of the PD values, indicating replacement of neural tissue by water, and of the T1 -relaxation time, a surrogate of demyelination, axonal loss, and gliosis. qMRI changes were more prominent than cortical atrophy, showing the potential of qMRI techniques to quantify microstructural alterations that remain undetected by conventional MRI. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1485-1490.

Dynamic Contrast-Enhanced Magnetic Resonance Imaging Suggests Normal Perfusion in Normal-Appearing White Matter in Multiple Sclerosis.

OBJECTIVES: Multiple sclerosis (MS) is a chronic, inflammatory disease of the central nervous system and has been associated with reduced perfusion in normal-appearing white matter (NAWM). The magnitude of this hypoperfusion is unclear. The present study aims to quantify NAWM perfusion with dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) in patients with relapsing-remitting (RR) MS and in a control group. MATERIALS AND METHODS: The statistical power of a DCE-MRI acquisition to reveal hypoperfusion in MS was estimated using a Monte Carlo simulation: synthetic tissue curves with a contrast-to-noise ratio of 8 were generated for MS patients and control group using perfusion values reported in previous studies. A compartment-uptake model was fitted to these curves, yielding estimates of cerebral blood flow (CBF), cerebral blood volume (CBV), and permeability-surface area product (PS). This was repeated 1000 times. Mean and standard deviation of the resulting distributions were used to calculate the statistical power of a DCE-MRI study to detect perfusion differences between 16 control subjects and 24 MS subjects.In an institutional review board-approved study, patients with RR-MS (n = 24; mean age, 36 years; 17 women, mean Enhanced Disability Status Scale score, 3.25) and patients without history or symptoms of neurological disorder (n = 16; mean age, 49 years; 9 women) underwent a DCE-MRI examination with a previously established MRI protocol (3D SPGR sequence; 2.1 seconds temporal resolution; 44 slices; spatial resolution, 1.7 × 1.7 × 3 mm). Regions were defined manually in the middle cerebral artery; in the frontal, periventricular, and occipital NAWM; in the pons; and in the thalamus, and CBF, CBV, and PS were quantified using a compartment-uptake model.Parameter differences between MS and control groups were evaluated using a mixed linear model with subjects as random effect and controlling for age and sex. A P value of less than 0.05 was considered to indicate statistical significance. RESULTS: For all but one of previously reported effect sizes, the simulation study estimated a statistical power of 80% to 100% to detect reduced CBF in MS. In the patient study, mean (standard deviation) CBF in NAWM was 11.0 (15.1) and 10.4 (8.2) mL/100 mL per minute in the MS and control groups, respectively. Mean CBV in NAWM was 0.50 (0.45) mL/100 mL in the MS group and 0.48 (0.28) mL/100 mL in the control group. Mean values of PS in NAWM were 0.002 mL (0.027)/100 mL per minute in the control group and -0.001 (0.015) mL/100 mL per minute in the MS patients. Differences between patient groups were not statistically significant for CBF, CBV, mean transit time, and PS (P = 0.44, P = 0.20, P = 0.78, P = 0.66, respectively). In both groups, the influence of age on any parameter was nonsignificant. Cerebral blood flow and CBV in the thalamus and pons were significantly higher than in NAWM regions (P < 1e-4); mean transit time was significantly shorter than in NAWM (P < 1e-4). Permeability-surface area product was not significantly different from zero (P > 0.25) in all evaluated regions. CONCLUSIONS: Despite high statistical power, we could not confirm previous reports of NAWM hypoperfusion in MS. This indicates that, at least in our patient cohort, potential hypoperfusion is much less pronounced than reported in previous studies.

Assessment of Interleukin-17A, Interleukin-10 and Transforming Growth Factor-Beta1 Serum Titers in Relapsing Remitting Multiple Sclerosis Patients Treated with Avonex, Possible Biomarkers for Treatment Response.

INTRODUCTION: Individual response to interferon beta (IFN-ß) 1a treatment is heterogeneous in multiple sclerosis (MS). Our objective was to find a connection between serum levels of interleukin (IL)-10, IL-17 and transforming growth factor beta (TGF-ß)1 in MS patients treated with IFN-ß in order to identify the nonresponders (NR). MATERIAL AND METHODS: We included in the study 32 healthy subjects and 32 MS patients: 10 naive, 10 early treated and 12 late treated with INF-ß1a. Serum determination of cytokines and brain MRI were performed at the beginning of the study, after 6 and 12 months. Rio score was calculated at the end of the study. RESULTS: MS patients had initially a significant higher level of IL-17 and a lower level of TGF-ß1 compared to healthy subjects. IL-17 level in early treated patients was significantly lower compared to the naive and late treated groups. INF-ß1a treatment significantly increased IL-10 and decreased IL-17 levels. Initial low levels of IL-10 were associated with an increase in physical disability. IL-17 levels positively correlated with the number of relapses and MRI activity. Nine patients were NR to Avonex. Patients with a Rio score of 3 had higher initial levels of IL-17 and those with a Rio score of 0 had higher initial levels of IL-10 and TGF-ß1. CONCLUSION: IFN-ß1a decreased IL-17 and increased IL-10 seric levels; IL-17 significantly correlated with MS activity; TGF-ß1 activity is titer-dependent, increased levels were associated with IL-17 inhibition; NR patients to IFN-ß1a will have initial high IL-17 and low IL-10 and TGF-ß seric levels.

Multimodal quantitative MRI assessment of cortical damage in relapsing-remitting multiple sclerosis.

PURPOSE: To investigate magnetization transfer ratio (MTR), T1 relaxation time, and proton density (PD) as indicators of gray matter damage in relapsing-remitting multiple sclerosis (RRMS), reflecting different aspects of microstructural damage and as imaging correlates of clinical disability. We aimed to determine which of these parameters may optimally quantify cortical damage, and serve as an imaging surrogate of clinical disability. In this study, cortical values of MTR, a surrogate for demyelination in MS, of PD, reflecting replacement of neural tissue by water, and of T1 , indicating a complex array of microstructural changes, were assessed in a group of RRMS patients in comparison to healthy controls (HC). MATERIALS AND METHODS: 22 RRMS patients with varying disease duration (4.0 ± 6.54 years) and 10 HC received quantitative 3T magnetic resonance imaging (MRI) with MTR, T1 , and PD mapping. We tested for differences in cortical measurements between patients and HC. Additionally, correlation with disability as quantified by the Expanded Disability Status Scale was investigated. RESULTS: Cortical parameter values were significantly altered in the RRMS group, with increased values of T1 (P = 0.008) and PD (P = 0.028) and reduced values of MTR (P = 0.043). Only cortical T1 was correlated with clinical disability measurements (P = 0.001, r = 0.65). Receiver operating characteristic analysis demonstrated the best discriminatory power for T1 (area under the curve 0.79, PD: 0.75, MTR 0.73). CONCLUSION: Out of the parameters studied, cortical T1 is best suited to detect cortical damage as an imaging surrogate of clinical disability in RRMS. J. Magn. Reson. Imaging 2016;44:1600-1607.