Exploring in vivo multiple sclerosis brain microstructural damage through T1w/T2w ratio: a multicentre study

Magnetic resonance fingerprinting in multiple sclerosis

The purpose of this work was to evaluate the influence of residual quadrupolar interaction on the determination of human brain apparent tissue sodium concentrations (aTSCs) using quantitative sodium magnetic resonance imaging ( 23 Na MRI) in healthy controls (HCs) and patients with multiple sclerosis (MS). Especially, it was investigated if the more detailed examination of residual quadrupolar interaction effects enables further analysis of the observed 23 Na MRI signal increase in MS patients. 23 Na MRI with a 7 T MR system was performed on 21 HC and 50 MS patients covering all MS subtypes (25 patients with relapsing-remitting MS, 14 patients with secondary progressive MS, and 11 patients with primary progressive MS) using 2 different 23 Na pulse sequences for quantification: a commonly used standard sequence (aTSC Std ) as well as a sequence with shorter excitation pulse length and lower flip angle for minimizing signal loss resulting from residual quadrupolar interactions (aTSC SP ). Apparent tissue sodium concentration was determined using the same postprocessing pipeline including correction of the receive profile of the radiofrequency coil, partial volume correction, and relaxation correction. Spin dynamic simulations of spin-3/2 nuclei were performed to aid in the understanding of the measurement results and to get deeper insight in the underlying mechanisms. In normal-appearing white matter (NAWM) of HC and all MS subtypes, the aTSC SP values were approximately 20% higher than the aTSC Std values ( P < 0.001). In addition, the ratio aTSC SP /aTSC Std was significantly higher in NAWM than in normal-appearing gray matter (NAGM) for all subject cohorts ( P < 0.002). In NAWM, aTSC Std values were significantly higher in primary progressive MS compared with HC ( P = 0.01) as well as relapsing-remitting MS ( P = 0.03). However, in contrast, no significant differences between the subject cohorts were found for aTSC SP . Spin simulations assuming the occurrence of residual quadrupolar interaction in NAWM were in good accordance with the measurement results, in particular, the ratio aTSC SP /aTSC Std in NAWM and NAGM. Our results showed that residual quadrupolar interactions in white matter regions of the human brain have an influence on aTSC quantification and therefore must be considered, especially in pathologies with expected microstructural changes such as loss of myelin in MS. Furthermore, the more detailed examination of residual quadrupolar interactions may lead to a better understanding of the pathologies themselves.

In this multicenter study, a new semiautomatic method for segmenting the cervical cord from C2 to C5 was used to investigate the correlation between cord atrophy and clinical disability in a large sample of patients with multiple sclerosis (MS). T2 and 3-dimensional T1-weighted cervical cord scans and dual-echo brain scans were acquired from 143 healthy controls, 22 patients with clinically isolated syndromes (CIS), 101 patients with relapsing-remitting MS (RRMS), 79 patients with secondary progressive MS (SPMS), 58 patients with benign MS (BMS), and 75 patients with primary progressive MS (PPMS) in 3 European centers. Normalized cervical cord cross-sectional area (CSAn) was measured by an active surface cord model. Between-group comparisons were performed using linear mixed-effect models. A nonparametric kernel estimator was used to obtain smoothed plots of CSA along the cervical cord. Cord CSAn was significantly lower in PPMS vs healthy controls, BMS vs RRMS, SPMS vs BMS, and RRMS. From C2 to C5, a net separation and definition of the plots of patients with BMS, PPMS, and SPMS was seen with respect to those of the other study groups. CSAn was correlated with Expanded Disability Status Scale (r = -0.49, p < 0.0001), with a differential effect among disease clinical phenotypes: no association in either CIS or in BMS; association in RRMS (r = -0.30, p = 0.001), SPMS (r = -0.34, p = 0.001), and PPMS (r = -0.27, p = 0.01). Cervical cord atrophy provides a relevant and useful marker for the characterization of clinical heterogeneity of patients with MS. The stability of this measure among different centers supports its use as potential outcome measure to monitor disease progression in multicenter trials.

Objectives and aimsQuantitative MRI (qMRI) has greatly improved the sensitivity and specificity of microstructural brain pathology in multiple sclerosis (MS) when compared to conventional MRI (cMRI). More than cMRI, qMRI also provides means to assess pathology within the normal-appearing and lesion tissue. In this work, we further developed a method providing personalized quantitative T1 (qT1) abnormality maps in individual MS patients by modeling the age dependence of qT1 alterations. In addition, we assessed the relationship between qT1 abnormality maps and patients’ disability, in order to evaluate the potential value of this measurement in clinical practice. MethodsWe included 119 MS patients (64 relapsing-remitting MS (RRMS), 34 secondary progressive MS (SPMS), 21 primary progressive MS (PPMS)), and 98 Healthy Controls (HC). All individuals underwent 3T MRI examinations, including Magnetization Prepared 2 Rapid Acquisition Gradient Echoes (MP2RAGE) for qT1 maps and High-Resolution 3D Fluid Attenuated Inversion Recovery (FLAIR) imaging. To calculate personalized qT1 abnormality maps, we compared qT1 in each brain voxel in MS patients to the average qT1 obtained in the same tissue (grey/white matter) and region of interest (ROI) in healthy controls, hereby providing individual voxel-based Z-score maps. The age dependence of qT1 in HC was modeled using linear polynomial regression. We computed the average qT1 Z-scores in white matter lesions (WMLs), normal-appearing white matter (NAWM), cortical grey matter lesions (GMcLs) and normal-appearing cortical grey matter (NAcGM). Lastly, a multiple linear regression (MLR) model with the backward selection including age, sex, disease duration, phenotype, lesion number, lesion volume and average Z-score (NAWM/NAcGM/WMLs/GMcLs) was used to assess the relationship between qT1 measures and clinical disability (evaluated with EDSS). ResultsThe average qT1 Z-score was higher in WMLs than in NAWM. (WMLs: 1.366 ± 0.409, NAWM: −0.133 ± 0.288, [mean ± SD], p < 0.001). The average Z-score in NAWM in RRMS patients was significantly lower than in PPMS patients (p = 0.010). The MLR model showed a strong association between average qT1 Z-scores in white matter lesions (WMLs) and EDSS (R2 = 0.549, β = 0.178, 97.5 % CI = 0.030 to 0.326, p = 0.019). Specifically, we measured a 26.9 % increase in EDSS per unit of qT1 Z-score in WMLs in RRMS patients (R2 = 0.099, β = 0.269, 97.5 % CI = 0.078 to 0.461, p = 0.007). ConclusionsWe showed that personalized qT1 abnormality maps in MS patients provide measures related to clinical disability, supporting the use of those maps in clinical practice.

Activated microglia are thought to play a major role in cortical gray matter (GM) demyelination in multiple sclerosis (MS). Our objective was to evaluate microglial activation in cortical GM of patients with MS in vivo and to explore its relationship to measures of disability. Using PET and optimized modeling and segmentation procedures, we investigated cortical (11)C-PK11195 (PK11195) binding in patients with relapsing-remitting MS (RRMS), patients with secondary progressive MS (SPMS), and healthy controls. Disability was assessed with the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Impact Scale (MSIS-29). Patients with MS showed increased cortical GM PK11195 binding relative to controls, which was multifocal and highest in the postcentral, middle frontal, anterior orbital, fusiform, and parahippocampal gyri. Patients with SPMS also showed additional increases in precentral, superior parietal, lingual and anterior superior, medial and inferior temporal gyri. Total cortical GM PK11195 binding correlated with EDSS scores, with a stronger correlation for the subgroup of patients with SPMS. In patients with SPMS, PK11195 binding also correlated with MSIS-29 scores. No correlation with disability measures was seen for PK11195 binding in white matter. Higher EDSS scores correlated with higher levels of GM PK11195 binding in the postcentral gyrus for patients with RRMS and in precentral gyrus for those with SPMS. Microglial activation in cortical GM of patients with MS can be assessed in vivo. The distribution is not uniform and shows a relationship to clinical disability. We speculate that the increased PK11195 binding corresponds to enhanced microglial activation described in postmortem SPMS cortical GM.

Background: Serum uric acid (UA), a natural scavenger of peroxynitrite, has been found to be of lower levels in patients with multiple sclerosis (MS) in some recent preliminary studies.Objective: To evaluate the correlation between serum UA levels and several clinical parameters of MS reliably.Methods: We surveyed studies on the serum UA levels and MS patients with comprehensive search and review of the references. A meta-analysis was performed to demonstrate the potential association between serum UA levels in MS patients and their clinical characteristics by random effects models.Results The serum UA levels were lower in patients with MS than in healthy controls (standardized mean difference (SMD) = −0·68; 95% confidence interval (CI): −0·82 to −0·55), as well as in other inflammatory neurological diseases (OINDs) (SMD = −0·45; 95% CI: −0·60 to −0·30). Similarly, the serum UA levels decreased in MS patients with clinical activity when compared to MS with clinical inactivity (SMD = −0·29; 95% CI: −0·48 to −0·10), as well as in relapsing–remitting MS (RRMS) patients with relapse in comparison to RRMS patients with remission (SMD = 0·64; 95% CI: 0·39 to 0·89). However, the results suggested that serum UA levels did not correlate with higher (or lower) expanded disability status scale (SMD = −0·09; 95% CI: −0·10 to 0·27) and magnetic resonance imaging (MRI) activity (SMD = −0·14; 95% CI: −0·13 to 0·41). In the subtypes of MS group, there were significant differences in serum UA levels between secondary progressive MS (SPMS) and RRMS (SMD = −0·34; 95% CI: 0·16 to 0·52), or primary progressive MS (PPMS) (SMD = −0·58; 95% CI: −0·89 to −0·27), but no significant difference between RRMS and PPMS (SMD = −0·18; 95% CI: −0·44 to 0·08).Conclusions: Our study suggests that UA is relevant to MS. Future research is needed to determine whether the administration of UA levels by inosine might be considered as a novel treatment strategy for MS.

The purpose of this work was to determine the extent of disease and disease severity in the conventional MR normal-appearing gray matter (NAGM) and white matter (NAWM) in patients with relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS) utilizing quantitative magnetization transfer ratio (MTR) histogram analysis. Twenty-seven patients with MS (16 RR, 11 SP) and 16 healthy control subjects were studied. MTR was calculated in the totally segmented GM and WM without T2 lesions in each group. Each of the RR and SP MS patient groups had significantly smaller MTR histogram mean values in NAGM and NAWM than the healthy subjects (p </= 0.0015). SP MS patients had a significantly lower first quartile and MTR histogram peak height for NAGM only (p </= 0.004) when compared with both RR MS patients and healthy subjects. The T2 lesion load had a modest negative correlation with MTR values in both RR and SP MS, but only in NAGM. Separate analysis of GM and WM MTR histograms may allow better detection of subtle damage and better understanding of the natural history of MS disease and ultimately the response to therapeutics.

To investigate the relationship between myelin density measured by q-space diffusional MRI (q-space myelin map; qMM) in normal-appearing white matter (NAWM) and clinical disability in multiple sclerosis (MS).

BackgroundHigh mobility group box protein 1 (HMGB1) is a transcriptional regulator that is receiving increasing attention in autoimmune disorders including multiple sclerosis (MS). Here, we investigated the role of HMGB1 in the peripheral blood compartment from MS patients.MethodsHMGB1 mRNA expression levels were determined by PCR in peripheral blood mononuclear cells (PBMC) of 29 healthy controls and 57 untreated MS patients (26 with relapsing-remitting MS - RRMS, 13 with secondary progressive MS - SPMS, and 18 with primary progressive MS - PPMS). HMGB1 protein levels were measured by ELISA in serum samples from 18 HC and 37 untreated MS patients (13 with RRMS, 14 with SPMS, and 10 with PPMS).ResultsHMGB1 expression levels were increased in PBMC from the whole MS group compared with controls (P = 0.03). Further stratification of the MS group revealed higher expression levels in PBMC from patients with relapse-onset MS, and differences were statistically significant for RRMS patients compared with PPMS patients and controls (P = 4 × 10−5 and P = 0.005, respectively) and also for SPMS patients compared with PPMS patients (P = 0.001). HMGB1 serum levels were increased in the whole MS group compared with controls (P = 2 × 10−4). In MS clinical forms, the highest HMGB1 serum levels were observed in RRMS patients, and differences were statistically significant compared to PPMS patients (P = 5 × 10−5), SPMS patients (P = 0.001), and controls (P = 0.001).ConclusionsThese results point to a role of HMGB1 mRNA and protein levels as disease activity biomarkers to discriminate the more inflammatory relapse-onset MS forms, particularly RRMS, from the less inflammatory PPMS form of the disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0269-9) contains supplementary material, which is available to authorized users.

Background In multiple sclerosis, grey matter (GM) damage appears more clinically relevant than either white matter damage or lesion load. Objective We investigated if normal-appearing white matter (NAWM) and grey matter tissue changes assessed by magnetization transfer ratio were associated with long-term disability. Methods Sixty-nine people were assessed 20 years after presentation with a clinically isolated syndrome (CIS) [28 still CIS, 31 relapsing-remitting multiple sclerosis, 10 secondary progressive multiple sclerosis], along with 19 healthy subjects. Mean magnetization transfer ratio, peak height (PH) and peak location of the normalized magnetization transfer ratio histograms were determined in NAWM and grey matter, as well as, white matter and GM Fraction (GMF) and T2-weighted lesion load. Results Median expanded disability status scale for multiple sclerosis patients was 2.5 (range 1–8). GM-PH, and less so, NAWM mean and peak location, were lower in multiple sclerosis patients (P = 0.009) versus controls, relapsing-remitting multiple sclerosis versus CIS (P = 0.008) and secondary progressive multiple sclerosis versus relapsing-remitting multiple sclerosis (P = 0.002). GM-PH (as well as GMF) correlated with expanded disability status scale (r s = −0.49; P = 0.001) and multiple sclerosis functional score (r s = 0.51; P = 0.001). GM-PH independently predicted disability with similar strength to the associations of GMF with clinical measures. Conclusion Grey matter damage was related to long-term disability in multiple sclerosis cohort with a relatively low median expanded disability status scale. Markers of intrinsic grey matter damage (magnetization transfer ratio) and tissue loss offer clinically relevant information in multiple sclerosis.

Vitamin B6 status is related to disease severity and modulated by endurance exercise in individuals with multiple sclerosis: a secondary analysis of a randomized controlled trial.

Autoimmune demyelinating disorders, such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), are caused by persistent inflammation and damage to the central nervous system. Cognitive impairment (CI) is a growing challenge in these diseases, underscoring the need for a thorough exploration of its prevalence and risk across various subtypes. This study aimed to assess the prevalence and odds of CI using the Symbol Digit Modalities Test (SDMT) in various MS subtypes and NMOSD. A case-control study involving 616 participants, including healthy controls (HC) and individuals with different MS subtypes (Relapsing Remitting MS (RRMS), Secondary Progressive MS (SPMS), Primary Progressive MS (PPMS)), clinically isolated syndrome (CIS), and NMOSD, was conducted. CI was defined as SDMT z-scores 1.5 standard deviations below the HC average. The chi-square test was used to assess the risk of CI. The prevalence of CI varied across different groups: HC (10.7%), RRMS (33.8%), SPMS (71.3%), PPMS (62.8%), CIS (19.2%), and NMOSD (32.8%). Odds ratios (OR) for CI were significantly increased in RRMS (OR: 4.23, confidence interval (CI): 2.18-8.22, P < 0.001), SPMS (OR: 20.58, CI: 10.36-40.88, P < 0.001), PPMS (OR: 14.02, CI: 5.80-33.86, P < 0.001), and NMOSD (OR: 4.04, CI: 2.07-7.87, P < 0.001) compared to HC. This study emphasizes a significantly increased risk of CI in MS subtypes and NMOSD compared to HC. Although no significant difference in CI risk was found between individuals with RRMS and NMOSD, those with progressive forms of MS exhibited notably higher risks of CI.

Dysphagia is one of the most common symptoms in multiple sclerosis (MS) patients. It can reduce the quality of life and increase the risk of mortality by developing complications such as aspiration pneumonia. The present study was conducted to estimate the prevalence of dysphagia in MS patients and investigate the associations between dysphagia and disease characteristics. The Persian version of the DYMUS questionnaire was used to assess dysphagia in 865 patients with MS, including 738 (85.3%) relapsing-remitting MS (RRMS), 106 (12.3%) secondary progressive MS (SPMS), and 21 (2.4%) primary progressive MS (PPMS). Also, demographic and clinical data, including age, sex, smoking status, Expanded Disability Status Scale (EDSS) score, disease duration, disease-modifying therapies exposure, initial symptoms of MS, were recorded. The mean (SD) age was 37.95(9.25) years, and 83.1% of the participants were female. The prevalence of dysphagia was estimated to be 25.4% among all patients. According to the DYMUS questionnaire results, the prevalence of dysphagia in RRMS, SPMS, and PPMS patients was 22.2%, 44.3%, and 42.9%, respectively. After multivariate analysis the current EDSS score (OR = 1.197, CI: 1.062, 1.350, p = 0.003), cerebellar impairment (OR = 1.335, CI: 1.450, 4.716, p = 0.004) and motor dysfunction (OR = 1.651, CI: 1.004, 2.715, p = 0.048) emerged as the risk factors for dysphagia. Since dysphagia, as previously mentioned, is a common symptom in multiple sclerosis, particularly in SPMS and PPMS courses, active screening for this condition is recommended in all patients, particularly those with identified risk factors.

Many MR spectroscopy (MRS) studies of multiple sclerosis (MS) have focussed on metabolism in normal-appearing white matter (NAWM) and in white matter lesions (WML). In this study, eight patients suffering from primary or secondary progressive MS (PPMS/SPMS) and seven patients with relapsing/remitting MS (RRMS) were examined by (1)H-MRS to assess metabolite levels in gray matter (GM) as well. (1)H-MRS chemical-shift imaging of a cerebral volume of interest of 8x8x2 cm(3) above the lateral ventricles revealed differences between the metabolite concentrations in the three groups varying from almost significant [NAWM, choline (cho); P=0.0547] to highly significant [GM, N-acetylaspartate (NAA); P=0.0003]. In PPMS/SPMS patients, the decreases in choline, creatine (Cr) and N-acetylaspartate compared with six healthy controls were significant in GM and to a lesser extent, in NAWM. No significant differences in metabolite concentrations were found between RRMS and controls. In WML, all metabolites were reduced compared with white matter in controls (Cho: P=0.0020; Cr and NAA: P<0.0001, both). In conclusion, the concentrations of Cho, Cr and NAA are reduced in PPMS/SPMS patients, especially in GM and in WML. Despite contrary observations in previous studies, increases in the concentrations of Cr and/or Cho were not observed.

IntroductionDisease development in multiple sclerosis (MS) causes dramatic structural changes, but the exact changing patterns are unclear. Our objective is to investigate the differences in brain structure locally and spatially between relapsing-remitting MS (RRMS) and its advanced form, secondary progressive MS (SPMS), through advanced analysis of diffusion magnetic resonance imaging (MRI) and image texture.MethodsA total of 20 patients with RRMS and nine patients with SPMS from two datasets underwent 3T anatomical and diffusion tensor imaging (DTI). The DTI was harmonized, augmented, and then modeled, which generated six voxel- and sub-voxel-scale measures. Texture analysis focused on T2 and FLAIR MRI, which produced two phase-based measures, namely, phase congruency and weighted mean phase. Data analysis was 3-fold, i.e., histogram analysis of whole-brain normal appearing white matter (NAWM); region of interest (ROI) analysis of NAWM and lesions within three critical white matter tracts, namely, corpus callosum, corticospinal tract, and optic radiation; and along-tract statistics. Furthermore, by calculating the z-score of core-rim pathology within lesions based on diffusion measures, we developed a novel method to define chronic active lesions and compared them between cohorts.ResultsHistogram features from diffusion and all but one texture measure differentiated between RRMS and SPMS. Within-tract ROI analysis detected cohort differences in both NAWM and lesions of the corpus callosum body in three measures of neurite orientation and anisotropy. Along-tract statistics detected cohort differences from multiple measures, particularly lesion extent, which increased significantly in SPMS in posterior corpus callosum and optic radiations. The number of chronic active lesions were also significantly higher (by 5–20% over z-scores 0.5 and 1.0) in SPMS than RRMS based on diffusion anisotropy, neurite content, and diameter.ConclusionAdvanced diffusion MRI and texture analysis may be promising approaches for thorough understanding of brain structural changes from RRMS to SPMS, thereby providing new insight into disease development mechanisms in MS.