Voxel-Based quantitative MRI reveals spatial patterns of grey matter alteration in multiple sclerosis.

Despite robust postmortem evidence and potential clinical importance of gray matter (GM) pathology in multiple sclerosis (MS), assessing GM damage by conventional magnetic resonance imaging (MRI) remains challenging. This prospective cross-sectional study aimed at characterizing the topography of GM microstructural and volumetric alteration in MS using, in addition to brain atrophy measures, three quantitative MRI (qMRI) parameters-magnetization transfer (MT) saturation, longitudinal (R1), and effective transverse (R2*) relaxation rates, derived from data acquired during a single scanning session. Our study involved 35 MS patients (14 relapsing-remitting MS; 21 primary or secondary progressive MS) and 36 age-matched healthy controls (HC). The qMRI maps were computed and segmented in different tissue classes. Voxel-based quantification (VBQ) and voxel-based morphometry (VBM) statistical analyses were carried out using multiple linear regression models. In MS patients compared with HC, three configurations of GM microstructural/volumetric alterations were identified. (a) Co-localization of GM atrophy with significant reduction of MT, R1, and/or R2*, usually observed in primary cortices. (b) Microstructural modifications without significant GM loss: hippocampus and paralimbic cortices, showing reduced MT and/or R1 values without significant atrophy. (c) Atrophy without significant change in microstructure, identified in deep GM nuclei. In conclusion, this quantitative multiparametric voxel-based approach reveals three different spatially-segregated combinations of GM microstructural/volumetric alterations in MS that might be associated with different neuropathology.

Lung and liver sarcoidosis-like reaction induced by tocilizumab.

A drug-induced sarcoidosis-like reaction is a systemic granulomatous reaction indistinguishable from sarcoidosis and occurring in temporal relationship with a drug initiation. In this article, we report a patient who developed lung and liver granulomatous lesions following tocilizumab initiation for a giant cell arteritis. Infectious, toxic, neoplastic and inflammatory differential diagnoses were ruled out and lesions regressed after treatment cessation, leading to the diagnosis of tocilizumab induced sarcoidosis-like reaction. We review the 6 cases reported so far and emphasize the value of a prompt diagnosis. Finally, we discuss the potential pathophysiological mechanisms underlying this rare reaction, which could help to better understand the pathophysiology of sarcoidosis.

Brain microstructure is linked to cognitive fatigue in early multiple sclerosis.

Cognitive fatigue is a major symptom of Multiple Sclerosis (MS), from the early stages of the disease. This study aims to detect if brain microstructure is altered early in the disease course and is associated with cognitive fatigue in people with MS (pwMS) compared to matched healthy controls (HC). Recently diagnosed pwMS (N = 18, age < 45 years old) with either a Relapsing-Remitting or a Clinically Isolated Syndrome course of the disease, and HC (N = 19) matched for sex, age and education were analyzed. Quantitative multiparameter maps (MTsat, PD, R1 and R2*) of pwMS and HC were calculated. Parameters were extracted within the normal appearing white matter, cortical grey matter and deep grey matter (NAWM, NACGM and NADGM, respectively). Bayesian T-test for independent samples assessed between-group differences in brain microstructure while associations between score at a cognitive fatigue scale and each parameter in each tissue class were investigated with Generalized Linear Mixed Models. Patients exhibited lower MTsat and R1 values within NAWM and NACGM, and higher R1 values in NADGM compared to HC. Cognitive fatigue was associated with PD measured in every tissue class and to MTsat in NAWM, regardless of group. Disease-specific negative correlations were found in pwMS in NAWM (R1, R2*) and NACGM (R1). These findings suggest that brain microstructure within normal appearing tissues is already altered in the very early stages of the disease. Moreover, additional microstructure alterations (e.g. diffuse and widespread demyelination or axonal degeneration) in pwMS may lead to disease-specific complaint of cognitive fatigue.

Using quantitative magnetic resonance imaging to track cerebral alterations in multiple sclerosis brain: A longitudinal study.

INTRODUCTION: Quantitative MRI quantifies tissue microstructural properties and supports the characterization of cerebral tissue damages. With an MPM protocol, 4 parameter maps are constructed: MTsat, PD, R1 and R2*, reflecting tissue physical properties associated with iron and myelin contents. Thus, qMRI is a good candidate for in vivo monitoring of cerebral damage and repair mechanisms related to MS. Here, we used qMRI to investigate the longitudinal microstructural changes in MS brain. METHODS: Seventeen MS patients (age 25-65, 11 RRMS) were scanned on a 3T MRI, in two sessions separated with a median of 30 months, and the parameters evolution was evaluated within several tissue classes: NAWM, NACGM and NADGM, as well as focal WM lesions. An individual annual rate of change for each qMRI parameter was computed, and its correlation to clinical status was evaluated. For WM plaques, three areas were defined, and a GLMM tested the effect of area, time points, and their interaction on each median qMRI parameter value. RESULTS: Patients with a better clinical evolution, that is, clinically stable or improving state, showed positive annual rate of change in MTsat and R2* within NAWM and NACGM, suggesting repair mechanisms in terms of increased myelin content and/or axonal density as well as edema/inflammation resorption. When examining WM lesions, qMRI parameters within surrounding NAWM showed microstructural modifications, even before any focal lesion is visible on conventional FLAIR MRI. CONCLUSION: The results illustrate the benefit of multiple qMRI data in monitoring subtle changes within normal appearing brain tissues and plaque dynamics in relation with tissue repair or disease progression.

MRI preclinical detection and asymptomatic course of a progressive multifocal leucoencephalopathy (PML) under natalizumab therapy.

Early detection of progressive multifocal leucoencephalopathy (PML) in the setting of natalizumab therapy currently is performed by rapid evaluation of new symptoms occurring in treated patients. The role of MR scanning has not been investigated but holds promise since MR detection is highly sensitive for PML lesions. The authors report a case of presymptomatic PML of the posterior fossa detected by MR scans. Immediate suspension of natalizumab and plasma exchanges resulted in a rapid decline of natalizumab serum concentration. Intravenous steroids started together with plasma exchanges followed by an oral tapering course were used to minimise the immune reconstitution inflammatory syndrome. No symptoms (beyond mild headache) developed, and the repeat PCR for JC Virus (JCV) DNA detection performed 10 weeks later was negative. This case suggests that: (1) periodic brain MR scans may detect signs of presymptomatic PML in MS patients treated with natalizumab, (2) corticosteroid management of inflammatory reaction may contribute to optimal control of the immune reconstitution inflammatory syndrome routinely seen with natalizumab-associated PML and (3) early radiological detection of PML can have an excellent outcome even in a clinically critical region and despite prior immunosuppressant exposure. The potential benefit of regular MR scanning just using the T2/FLAIR modalities could be further investigated in order to detect early natalizumab-associated PML, leading to benign outcomes.

Comparative study of AQP4-NMOSD, MOGAD and seronegative NMOSD: a single-center Belgian cohort.

PURPOSE: To emphasize physio-pathological, clinical and prognosis differences between conditions causing serious and sometimes very similar clinical manifestations: anti-aquaporin-4 (AQP4) and anti-myelin oligodendrocyte glycoprotein (MOG) antibodies related diseases, and seronegative NMOSD (neuromyelitis optica spectrum disorders). METHODS: Based on Wingerchuk et al. (Neurology 85:177-189, 2015) criteria for NMOSD and on those more recently proposed by Jarius et al. (J Neuroinflammation 15:134, 2018) for MOGAD (MOG associated disorders), we retrospectively surveyed 10 AQP4-NMOSD, 8 MOGAD and 2 seronegative NMOSD, followed at the specialized neuroimmunology unit of the CHU Liège. RESULTS: Female predominance was only observed in AQP4 group. Age at onset was 37.8 and 27.7 years old for AQP4-NMOSD and MOGAD respectively. In both groups, the first clinical event most often consisted of optic neuritis (ON), followed by isolated myelitis. Fifteen of our 20 patients encountered a relapsing course with 90% relapses in AQP4-NMOSD, 62.5% in MOGAD and 50% in seronegative group, and a mean period between first and second clinical event of 7.1 and 4.8 months for AQP4-NMOSD and MOGAD, respectively. In total we counted 54 ON, with more ON per patient in MOGAD. MOG-associated ON mainly affected the anterior part of the optic nerve with a papilledema in 79.2% of cases. Despite a fairly good visual outcome after MOG-associated ON, retinal nerve fibre layer (RNFL) thickness decreased, suggesting a fragility of the optic nerve toward further attacks. CONCLUSION: As observed in larger cohorts, our MOGAD and AQP4-NMOSD cases differ by clinical and prognostic features. A better understanding of these diseases should encourage prompt biological screening and hasten proper diagnosis and treatment.

Pupil response speed as a marker of cognitive fatigue in early Multiple Sclerosis☆.

CONTEXT: Cognitive fatigue (CF) is a disabling symptom frequently reported by patients with Multiple Sclerosis (pwMS). Whether pwMS in the early disease stages present an increased sensitivity to fatigue induction remains debated. Objective measures of CF have been validated neither for clinical nor research purposes. This study aimed at (i) assessing how fatigue induction by manipulation of cognitive load affects subjective fatigue and behavioural performance in newly diagnosed pwMS and matched healthy controls (HC); and (ii) exploring the relevance of eye metrics to describe CF in pwMS. METHODS: Nineteen pwMS with disease duration < 5 years and 19 matched HC participated to this study. CF was induced with a dual-task in two separate sessions with varying cognitive load (High and Low cognitive load conditions, HCL and LCL). Accuracy, reaction times (RTs), subjective fatigue and sleepiness states were assessed. Bayesian Analyses of Variance for repeated measures (rmANOVA) explored the effects of time, group and load condition on the assessed variables. Eye metrics (number of long blinks, pupil size and pupil response speed: PRS) were obtained during the CF task for a sub-sample (16 pwMS and 15 HC) and analysed with Generalized Linear Mixed Models (GLMM). RESULTS: Performance (accuracy and RTs) was lower in the HCL condition and accuracy decreased over time (BFsincl > 100) while RTs did not significantly vary. Performance over task and conditions followed the same pattern of evolution across groups (BFsincl < 0.08) suggesting that pwMS did not show increased alteration of performance during fatigue induction. Regarding subjective state, both fatigue and sleepiness increased following the task (BFsincl > 15), regardless of condition and group (BFsincl < 3). CF in pwMS seems to be associated with PRS, as PRS decreased during the task amongst pwMS only and especially in the HCL condition (all p < .05). A significant Condition*Group interaction was observed regarding long blinks (p < .0001) as well as an expected effect of cognitive load condition on pupil diameter (p < .01). CONCLUSION: These results suggest that newly diagnosed pwMS and HC behave similarly during fatigue induction, in terms of both performance decrement and accrued fatigue sensation. Eye metric data further reveal a susceptibility to CF in pwMS, which can be objectively measured.

Exploratory Radiomic Analysis of Conventional vs. Quantitative Brain MRI: Toward Automatic Diagnosis of Early Multiple Sclerosis.

Conventional magnetic resonance imaging (cMRI) is poorly sensitive to pathological changes related to multiple sclerosis (MS) in normal-appearing white matter (NAWM) and gray matter (GM), with the added difficulty of not being very reproducible. Quantitative MRI (qMRI), on the other hand, attempts to represent the physical properties of tissues, making it an ideal candidate for quantitative medical image analysis or radiomics. We therefore hypothesized that qMRI-based radiomic features have added diagnostic value in MS compared to cMRI. This study investigated the ability of cMRI (T1w) and qMRI features extracted from white matter (WM), NAWM, and GM to distinguish between MS patients (MSP) and healthy control subjects (HCS). We developed exploratory radiomic classification models on a dataset comprising 36 MSP and 36 HCS recruited in CHU Liege, Belgium, acquired with cMRI and qMRI. For each image type and region of interest, qMRI radiomic models for MS diagnosis were developed on a training subset and validated on a testing subset. Radiomic models based on cMRI were developed on the entire training dataset and externally validated on open-source datasets with 167 HCS and 10 MSP. Ranked by region of interest, the best diagnostic performance was achieved in the whole WM. Here the model based on magnetization transfer imaging (a type of qMRI) features yielded a median area under the receiver operating characteristic curve (AUC) of 1.00 in the testing sub-cohort. Ranked by image type, the best performance was achieved by the magnetization transfer models, with median AUCs of 0.79 (0.69-0.90, 90% CI) in NAWM and 0.81 (0.71-0.90) in GM. The external validation of the T1w models yielded an AUC of 0.78 (0.47-1.00) in the whole WM, demonstrating a large 95% CI and a low sensitivity of 0.30 (0.10-0.70). This exploratory study indicates that qMRI radiomics could provide efficient diagnostic information using NAWM and GM analysis in MSP. T1w radiomics could be useful for a fast and automated check of conventional MRI for WM abnormalities once acquisition and reconstruction heterogeneities have been overcome. Further prospective validation is needed, involving more data for better interpretation and generalization of the results.

Multiparameter quantitative histological MRI values in high-grade gliomas: a potential biomarker of tumor progression.

BACKGROUND: Conventional MRI poorly distinguishes brain parenchyma microscopically invaded by high-grade gliomas (HGGs) from the normal brain. By contrast, quantitative histological MRI (hMRI) measures brain microstructure in terms of physical MR parameters influenced by histochemical tissue composition. We aimed to determine the relationship between hMRI parameters in the area surrounding the surgical cavity and the presence of HGG recurrence. METHODS: Patients were scanned after surgery with an hMRI multiparameter protocol that allowed for estimations of longitudinal relaxation rate (R1) = 1/T1, effective transverse relaxation rate (R2)*=1/T2*, magnetization transfer saturation (MTsat), and proton density. The initial perioperative zone (IPZ) was segmented on the postoperative MRI. Once recurrence appeared on conventional MRI, the area of relapsing disease was delineated (extension zone, EZ). Conventional MRI showing recurrence and hMRI were coregistered, allowing for the extraction of parameters R1, R2*, MTsat, and PD in 3 areas: the overlap area between the IPZ and EZ (OZ), the peritumoral brain zone, PBZ (PBZ = IPZ - OZ), and the area of recurrence (RZ = EZ - OZ). RESULTS: Thirty-one patients with HGG who underwent gross-total resection were enrolled. MTsat and R1 were the most strongly associated with tumor progression. MTsat was significantly lower in the OZ and RZ, compared to PBZ. R1 was significantly lower in RZ compared to PBZ. PD was significantly higher in OZ compared to PBZ, and R2* was higher in OZ compared to PBZ or RZ. These changes were detected 4 to 120 weeks before recurrence recognition on conventional MRI. CONCLUSIONS: HGG recurrence was associated with hMRI parameters' variation after initial surgery, weeks to months before overt recurrence.

Multiparameter MRI quantification of microstructural tissue alterations in multiple sclerosis.

OBJECTIVES: Conventional MRI is not sensitive to many pathological processes underpinning multiple sclerosis (MS) ongoing in normal appearing brain tissue (NABT). Quantitative MRI (qMRI) and a multiparameter mapping (MPM) protocol are used to simultaneously quantify magnetization transfer (MT) saturation, transverse relaxation rate R2* (1/T2*) and longitudinal relaxation rate R1 (1/T1), and assess differences in NABT microstructure between MS patients and healthy controls (HC). METHODS: This prospective cross-sectional study involves 36 MS patients (21 females, 15 males; age range 22-63 years; 15 relapsing-remitting MS - RRMS; 21 primary or secondary progressive MS - PMS) and 36 age-matched HC (20 females, 16 males); age range 21-61 years). The qMRI maps are computed and segmented in lesions and 3 normal appearing cerebral tissue classes: normal appearing cortical grey matter (NACGM), normal appearing deep grey matter (NADGM), normal appearing white matter (NAWM). Individual median values are extracted for each tissue class and MR parameter. MANOVAs and stepwise regressions assess differences between patients and HC. RESULTS: MS patients are characterized by a decrease in MT, R2* and R1 within NACGM (p < .0001) and NAWM (p < .0001). In NADGM, MT decreases (p < .0001) but R2* and R1 remain normal. These observations tend to be more pronounced in PMS. Quantitative MRI parameters are independent predictors of clinical status: EDSS is significantly related to R1 in NACGM and R2* in NADGM; the latter also predicts motor score. Cognitive score is best predicted by MT parameter within lesions. CONCLUSIONS: Multiparametric data of brain microstructure concord with the literature, predict clinical performance and suggest a diffuse reduction in myelin and/or iron content within NABT of MS patients.

NMOSD with anti-MOG antibodies following anti-TNFα therapy: A case report.

Tumor necrosis factor α (TNFα) inhibitors are highly effective and a therapeutic choice for several inflammatory diseases. Their broad and long-term use is associated with a growing number of paradoxical autoimmune events including demyelinating lesions of the central nervous system (CNS). We report and discuss a case of neuromyelitis optica spectrum disorder (NMOSD) with positive myelin oligodendrocyte glycoprotein antibodies (MOG-IgG1) following anti-TNFα therapy for a pustular psoriasis.

Motor fatigue measurement by distance-induced slow down of walking speed in multiple sclerosis.

BACKGROUND AND RATIONALE: Motor fatigue and ambulation impairment are prominent clinical features of people with multiple sclerosis (pMS). We hypothesized that a multimodal and comparative assessment of walking speed on short and long distance would allow a better delineation and quantification of gait fatigability in pMS. Our objectives were to compare 4 walking paradigms: the timed 25-foot walk (T25FW), a corrected version of the T25FW with dynamic start (T25FW(+)), the timed 100-meter walk (T100MW) and the timed 500-meter walk (T500MW). METHODS: Thirty controls and 81 pMS performed the 4 walking tests in a single study visit. RESULTS: The 4 walking tests were performed with a slower WS in pMS compared to controls even in subgroups with minimal disability. The finishing speed of the last 100-meter of the T500MW was the slowest measurable WS whereas the T25FW(+) provided the fastest measurable WS. The ratio between such slowest and fastest WS (Deceleration Index, DI) was significantly lower only in pMS with EDSS 4.0-6.0, a pyramidal or cerebellar functional system score reaching 3 or a maximum reported walking distance ≤ 4000 m. CONCLUSION: The motor fatigue which triggers gait deceleration over a sustained effort in pMS can be measured by the WS ratio between performances on a very short distance and the finishing pace on a longer more demanding task. The absolute walking speed is abnormal early in MS whatever the distance of effort when patients are unaware of ambulation impairment. In contrast, the DI-measured ambulation fatigability appears to take place later in the disease course.