Background
The in vivo relation between microglia activation and demyelination in multiple sclerosis is still unclear.
Objective
We combined
11
C-PBR28 positron emission tomography and rapid ...estimation of myelin for diagnostic imaging (REMyDI) to characterize the relation between these pathological processes in a heterogeneous MS cohort.
Methods
11
C-PBR28 standardized uptake values normalized by a pseudo-reference region (SUVR) were used to measure activated microglia. A voxelwise analysis compared
11
C-PBR28 SUVR in the white matter of 38 MS patients and 16 matched healthy controls. The relative difference in SUVR served as a threshold to classify patients’ lesioned, perilesional and normal-appearing white matter as active or inactive. REMyDI was acquired in 27 MS patients for assessing myelin content in active and inactive white matter and its relationship with SUVR. Finally, we investigated the contribution of radiological metrics to clinical outcomes.
Results
11
C-PBR28 SUVR were abnormally higher in several white matter areas in MS. Myelin content was lower in active compared to inactive corresponding white matter regions. An inverse correlation between SUVR and myelin content was found. Radiological metrics correlated with both neurological and cognitive impairment.
Conclusion
our data suggest an inverse relation of microglia activation and myelination, particularly in perilesional white matter tissue.
We used 7 T MRI to: (i) characterize the grey and white matter pathology in the cervical spinal cord of patients with early relapsing-remitting and secondary progressive multiple sclerosis; (ii) ...assess the spinal cord lesion spatial distribution and the hypothesis of an outside-in pathological process possibly driven by CSF-mediated immune cytotoxic factors; and (iii) evaluate the association of spinal cord pathology with brain burden and its contribution to neurological disability. We prospectively recruited 20 relapsing-remitting, 15 secondary progressive multiple sclerosis participants and 11 age-matched healthy control subjects to undergo 7 T imaging of the cervical spinal cord and brain as well as conventional 3 T brain acquisition. Cervical spinal cord imaging at 7 T was used to segment grey and white matter, including lesions therein. Brain imaging at 7 T was used to segment cortical and white matter lesions and 3 T imaging for cortical thickness estimation. Cervical spinal cord lesions were mapped voxel-wise as a function of distance from the inner central canal CSF pool to the outer subpial surface. Similarly, brain white matter lesions were mapped voxel-wise as a function of distance from the ventricular system. Subjects with relapsing-remitting multiple sclerosis showed a greater predominance of spinal cord lesions nearer the outer subpial surface compared to secondary progressive cases. Inversely, secondary progressive participants presented with more centrally located lesions. Within the brain, there was a strong gradient of lesion formation nearest the ventricular system that was most evident in participants with secondary progressive multiple sclerosis. Lesion fractions within the spinal cord grey and white matter were related to the lesion fraction in cerebral white matter. Cortical thinning was the primary determinant of the Expanded Disability Status Scale, white matter lesion fractions in the spinal cord and brain of the 9-Hole Peg Test and cortical thickness and spinal cord grey matter cross-sectional area of the Timed 25-Foot Walk. Spinal cord lesions were localized nearest the subpial surfaces for those with relapsing-remitting and the central canal CSF surface in progressive disease, possibly implying CSF-mediated pathogenic mechanisms in lesion development that may differ between multiple sclerosis subtypes. These findings show that spinal cord lesions involve both grey and white matter from the early multiple sclerosis stages and occur mostly independent from brain pathology. Despite the prevalence of cervical spinal cord lesions and atrophy, brain pathology seems more strongly related to physical disability as measured by the Expanded Disability Status Scale.
Risk of relapse after natalizumab (NAT) cessation and switch to dimethyl fumarate (DMF) is unknown. The objective of this paper is to identify the risk and associated risk factors for relapse after ...switching from NAT to DMF in relapsing-remitting multiple sclerosis. Patients (
n
= 30) were treated with NAT for ≥12 months and then switched to DMF in a mean of 50 days. Patient age, annualized relapse rates (ARR), Expanded Disability Status Scale scores (EDSS), and lymphocyte counts were assessed. Overall, eight patients (27 %) had relapses after switching to DMF. Five patients (17 %) suffered severe relapses with multifocal clinical and radiological findings. New lesions by MRI (T2 hyperintense or enhancing) were observed in 35 % of patients. Relapses occurred at a mean of 3.5 months after NAT cessation. Patient age and elevated ARR prior to NAT use were significantly associated with risk of relapse after switch to DMF. Once on DMF for 4 months prior to relapse, lymphocyte count decreased more significantly in patients without relapses than those with relapses. Switching from NAT to DMF correlated with increased relapses. Young patient age, high ARR and stability of lymphocyte counts were risk factors for relapse after transition from NAT to DMF.
Objective
This study aimed to investigate at 7.0-T MRI a) the role of multiple sclerosis (MS) cortical lesions in cortical tissue loss b) their relation to neurological disability.
Methods
In 76 ...relapsing remitting and 26 secondary progressive MS patients (
N
= 102) and 56 healthy subjects 7.0-T T
2
*
-weighted images were acquired for lesion segmentation; 3.0-T T
1
-weighted structural scans for cortical surface reconstruction/cortical thickness estimation. Patients were dichotomized based on the median cortical lesion volume in low and high cortical lesion load groups that differed by age, MS phenotype and degree of neurological disability. Group differences in cortical thickness were tested on reconstructed cortical surface. Patients were evaluated clinically by means of the Expanded Disability Status Scale (EDSS).
Results
Cortical lesions were detected in 96% of patients. White matter lesion load was greater in the high than in the low cortical lesion load MS group (
p
= 0.01). Both MS groups disclosed clusters (prevalently parietal) of cortical thinning relative to healthy subjects, though these regions did not show the highest cortical lesion density, which predominantly involved frontal regions. Cortical thickness decreased on average by 0.37 mm, (
p
= 0.002) in MS patients for each unit standard deviation change in white matter lesion volume. The odds of having a higher EDSS were associated with cortical lesion volume (1.78,
p
= 0.01) and disease duration (1.15,
p
< 0.001).
Conclusion
Cortical thinning in MS is not directly related to cortical lesion load but rather with white matter lesion volume. Neurological disability in MS is better explained by cortical lesion volume assessment.
With unclear characteristics of post-infection and post-vaccination immunity, the multiple sclerosis community lacks evidence to guide patients on their continued coronavirus disease 2019 (COVID-19) ...infection risk. As disease modifying treatments all modulate the immune system, we expect their use to alter acquired immunity to COVID-19, but the specific impact of individual treatments is unclear. To address this, we analyzed the patient and COVID-19 specific characteristics associated with post-infection humoral immunity in 58 patients with central nervous system (CNS) demyelinating disorders in the Boston metropolitan area. Univariate analysis of variance was performed using Mann Whitney U test for continuous variables, and Chi Square or Fisher Exact test for nominal variables. Univariate and stepwise multivariate nominal logistic regression identified clinical characteristics associated with COVID-19 specific nucleocapsid IgG antibody formation post-infection. Our cohort demonstrated a 42% post-infection seropositive rate with a significantly higher rate observed with shorter duration between infection and antibody collection and use of natalizumab over no/other treatment. Use of anti-CD20 treatments compared to no/other treatment was associated with a significantly lower rate of seropositivity. However, only shorter duration between infection and antibody collection as well as use of no/other treatment compared to anti-CD20 treatment were found to be independently associated with increased likelihood of post-infection seropositivity. Additionally, we demonstrate durability of antibody response up to 9 months in a small subset of patients. Thus, our data supports that patients with CNS demyelinating disorders regardless of DMT are able to form a measurable antibody response after COVID-19 infection, and that patients on anti-CD20 treatments form less robust immunity after COVID-19 infection.
Using quantitative T2* 7-tesla (7T) MRI as a marker of demyelination and iron loss, we investigated, in patients with relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple ...sclerosis (SPMS), spatial and tissue intrinsic characteristics of cortical lesion(s) (CL) types, and structural integrity of perilesional normal-appearing cortical gray matter (NACGM) as a function of distance from lesions.
Patients with MS (18 RRMS, 11 SPMS), showing at least 2 CL, underwent 7T T2* imaging to obtain (1) magnitude images for segmenting focal intracortical lesion(s) (ICL) and leukocortical lesion(s) (LCL), and (2) cortical T2* maps. Anatomical scans were collected at 3T for cortical surface reconstruction using FreeSurfer. Seventeen age-matched healthy participants served as controls.
ICL were predominantly located in sulci of frontal, parietal, and cingulate cortex; LCL distribution was more random. In MS, T2* was higher in both ICL and LCL, indicating myelin and iron loss, than in NACGM (p < 0.00003) irrespective of CL subtype and MS phenotype. T2* was increased in perilesional cortex, tapering away from CL toward NACGM, the wider changes being for LCL in SPMS. NACGM T2* was higher in SPMS relative to RRMS (p = 0.006) and healthy cortex (p = 0.02).
CL had the same degree of demyelination and iron loss regardless of lesion subtype and disease stage. Cortical damage expanded beyond visible CL, close to lesions in RRMS, and more diffusely in SPMS. Evaluation of NACGM integrity, beyond focal CL, could represent a surrogate marker of MS progression.
Unfortunately, the given name and family name of first author was incorrectly tagged in the xml data, therefore it is abbreviated wrongly as “Morales FS” in Pubmed. The correct given name is Fabian ...and family name is Sierra Morales. Auhtor name should be abbreviated as Sierra Morales F.
Patients with a compromised immune system are at risk for converting from latent tuberculosis infection (LTBI) to active tuberculosis (TB) infection. Multiple sclerosis (MS) therapies may put ...individuals with LTBI at higher risk of TB.
Patients at the Beth Israel Deaconess Medical Center MS Clinic were screened for TB as part of routine testing with the QuantiFERON-TB Gold In-Tube (QFT-GIT) assay (Cellestis Ltd) from 2013 to 2017. Patients were tested either before or during immunomodulatory therapy.
Four of 222 patients (1.8%; 95% CI, 0.1%-3.6%) had positive QFT-GIT results; three patients had risk factors for TB, having emigrated from TB-endemic countries or worked in the health care industry. Twenty-eight of 222 patients (12.6%) had an indeterminate assay result, and 75.0% of these occurred in patients taking dimethyl fumarate. Fingolimod, natalizumab, or anti-CD20 treatments showed 0% to 7.7% indeterminate results.
The prevalence of LTBI was 1.8% in the Beth Israel Deaconess Medical Center MS Clinic. Not all LTBI cases were associated with known risk factors for TB. Screening for LTBI before starting immunosuppressive agents for MS could help prevent activation of TB. Dimethyl fumarate use is associated with indeterminate QFT-GIT results, possibly due to functional effects on lymphocytes and levels of cytokines, such as interferon gamma. In contrast, fingolimod use was rarely associated with indeterminate QFT-GIT results despite a high rate of lymphopenia in virtually all patients.
Neurologic disease promoted by microbial pathogens, sterile injury, or neurodegeneration rapidly induces innate immunity in adjacent healthy tissue, which in turn contributes extensively to ...neurologic injury. With more recent focus on innate immune processes, it appears that necrotic, but not apoptotic, death mechanisms provoke inflammatory responses likely due to the release or production of endogenous ligands that activate resident immune cells of the central nervous system. These ligands comprise a diverse set of proteins, nucleic acids, and glycosaminoglycans, including heat shock proteins, HMGB1, RNA, DNA, hyaluronan, and heparin sulfate, that stimulate innate immune mechanisms largely through Toll-like receptors (TLRs). The blockade of interactions between endogenous ligands and TLRs may enable neuroprotective therapeutic strategies for a variety of neurologic diseases.
ABSTRACT
BACKGROUND AND PURPOSE
Meningeal inflammation is implicated in cortical demyelination and disability progression in multiple sclerosis (MS). Gadolinium (Gd)‐enhanced 3‐dimensional (3D) FLAIR ...(fluid‐attenuated inversion recovery) magnetic resonance imaging (MRI) can identify leptomeningeal enhancement (LME) in MS. Further characterization is needed to determine if LME is an imaging biomarker for meningeal inflammation. We sought to characterize the natural history of LME in the community setting, including persistence/resolution, effect of disease‐modifying therapy, scanner variability, timing of acquisition, and imaging pitfalls that may lead to misinterpretation.
METHODS
A total of 341 MRI exams with Gd‐enhanced 3D‐FLAIR were reviewed in MS and non‐MS patients to determine frequency of enhancement by MS subtype and association with therapy. A phantom was used to assess scanner variability. Two MS patients with seven LME were imaged at four postinjection time points to generate time‐intensity curves. Imaging pitfalls were compiled.
RESULTS
A total of 16.6% (40/241) of MS patients revealed LME compared to 8% (8/100) in non‐MS patients (P = .04). There was no association with MS subtype, therapy, or disease activity. Detection using General Electric's version of 3D‐FLAIR (29%) was greater than with Siemen's 3D‐FLAIR (12%) at 1.5T (Tesla) (P < .001). Lesions were generally stable but resolved in 2 patients following high‐dose steroids. LME kinetics were heterogeneous, even within patients, without uniform optimal time for acquisition. Enhancement curves exhibited three different variations, similar to the two‐compartment model. Imaging pitfalls included enhancements of uncertain biologic significance, cortical veins and anatomic structures, and imaging artifacts.
CONCLUSIONS
Awareness of LME characteristics, variability with imaging parameters, and imaging pitfalls will facilitate determining the potential role as an imaging biomarker for meningeal inflammation.
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