Molecular changes in white matter adjacent to an active demyelinating lesion in early multiple sclerosis.
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ABSTRACT:
SUBMITTER: Zeis T
PROVIDER: S-EPMC8094783 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Introduction: Changes in cortical and white matter lesion (CL, WML) load are pivotal metrics to diagnose and monitor multiple sclerosis patients. Yet, the relationship between (i) changes in CL/WML load and disease progression and between (ii) changes in CL/WML load and neurodegeneration at early MS stages is not yet established. In this work, we have assessed the hypothesis that the combined CL and WML load as well as their 2-years evolution are surrogate markers of neurodegeneration and clinical progression at early MS stages. To achieve this goal, we have studied a group of RRMS patients and have investigated the impact of both CL and WML load on neuroaxonal damage as measured by serum neurofilament light chain (sNfL). Next, we have explored whether changes in CL/WML load over 2 years in the same cohort of early-MS are related to motor and cognitive changes. Methods: Thirty-two RRMS patients (<5 years disease duration) underwent: (i) 3T MRI for CL/WML detection and clinical assessment at baseline and 2-years follow-up; and (ii) baseline blood test for sNfL. The correlation between the number and volume of CL/WML and sNfL was assessed by using the Spearman's rank correlation coefficient and a generalized linear model (GLM). A GLM was also used to assess the relationship between (i) the number/volume of new, enlarged, resolved, shrunken, stable lesions and (ii) the difference in clinical scores between two time-points. Results: At baseline, sNfL levels correlated with both total CL count/volume (ρ = 0.6/0.7, Corr-P <0.017/Corr-P < 0.001) and with total WML count/volume (ρ = 0.6/0.6, Corr-P < 0.01 for both). Baseline sNfL levels also correlated with new WML count/volume (ρ = 0.6/0.5, Corr-P < 0.01/Corr-P < 0.05) but not with new CL. Longitudinal changes in CL and WML count and volume were significantly associated with (i) sustained attention, auditory information, processing speed and flexibility (p < 0.01), (ii) verbal memory (p < 0.01); (iii) verbal fluency (p < 0.05); and (iv) hand-motor function (p < 0.05). Discussion: Changes in cortical and white matter focal damage in early MS patients correlate with global neuroaxonal damage and is associated to cognitive performances.
| S-EPMC7498574 | biostudies-literature
Project description:BackgroundLesion location is a prognostic factor of disease progression and disability accrual.ObjectiveTo investigate lesion formation in 11 brain regions, assess correlation between lesion location and physical and cognitive disability measures and investigate treatment effects by region.MethodsIn 2355 relapsing-remitting multiple sclerosis patients from the FREEDOMS and FREEDOMS II studies, we extracted T2-weighted lesion number, volume and density for each brain region; we investigated the (Spearman) correlation in lesion formation between brain regions, studied association between location and disability (at baseline and change over 2 years) using linear/logistic regression and assessed the regional effects of fingolimod versus placebo in negative binomial models.ResultsAt baseline, the majority of lesions were found in the supratentorial brain. New and enlarging lesions over 24 months developed mainly in the frontal and sublobar regions and were substantially correlated to pre-existing lesions at baseline in the supratentorial brain (p = 0.37-0.52), less so infratentorially (p = -0.04-0.23). High sublobar lesion density was consistently and significantly associated with most disability measures at baseline and worsening of physical disability over 24 months. The treatment effect of fingolimod 0.5 mg was consistent across the investigated areas and tracts.ConclusionThese results highlight the role of sublobar lesions for the accrual of disability in relapsing-remitting multiple sclerosis.
| S-EPMC7031799 | biostudies-literature
Project description:Background and purposeLoss of integrity in nonlesional white matter occurs as a fundamental feature of multiple sclerosis in adults. The purpose of our study was to evaluate DTI-derived measures of white matter microstructure in children with MS compared with age- and sex-matched controls by using tract-based spatial statistics.Materials and methodsFourteen consecutive pediatric patients with MS (11 female/3 male; mean age, 15.1 ± 1.6 years; age range, 12-17 years) and age- and sex-matched healthy subjects (11 female/3 male; mean age, 14.8 ± 1.7 years) were included in the study. After we obtained DTI sequences, data processing was performed by using tract-based spatial statistics.ResultsCompared with healthy age- and sex-matched controls, children with multiple sclerosis showed a global decrease in mean fractional anisotropy (P ≤ .001), with a concomitant increase in mean (P < .001), radial (P < .05), and axial diffusivity (P < .001). The most pronounced fractional anisotropy value decrease in patients with MS was found in the splenium of the corpus callosum (P < .001). An additional decrease in fractional anisotropy was identified in the right temporal and right and left parietal regions (P < .001). Fractional anisotropy of the white matter skeleton was related to disease duration and may, therefore, serve as a diagnostic marker.ConclusionsThe microstructure of white matter is altered early in the disease course in childhood multiple sclerosis.
| S-EPMC7965410 | biostudies-literature
Project description:Chronic active and slowly expanding lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis pathology. T1 hypointense volume and signal intensity on T1-weighted MRI reflect brain tissue damage that may develop within newly formed acute focal inflammatory lesions or in chronic pre-existing lesions without signs of acute inflammation. Using a recently developed method to identify slowly expanding/evolving lesions in vivo from longitudinal conventional T2- and T1-weighted brain MRI scans, we measured the relative amount of chronic lesion activity as measured by change in T1 volume and intensity within slowly expanding/evolving lesions and non-slowly expanding/evolving lesion areas of baseline pre-existing T2 lesions, and assessed the effect of ocrelizumab on this outcome in patients with primary progressive multiple sclerosis participating in the phase III, randomized, placebo-controlled, double-blind ORATORIO study (n = 732, NCT01194570). We also assessed the predictive value of T1-weighted measures of chronic lesion activity for clinical multiple sclerosis progression as reflected by a composite disability measure including the Expanded Disability Status Scale, Timed 25-Foot Walk and 9-Hole Peg Test. We observed in this clinical trial population that most of total brain non-enhancing T1 hypointense lesion volume accumulation was derived from chronic lesion activity within pre-existing T2 lesions rather than new T2 lesion formation. There was a larger decrease in mean normalized T1 signal intensity and greater relative accumulation of T1 hypointense volume in slowly expanding/evolving lesions compared with non-slowly expanding/evolving lesions. Chronic white matter lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in slowly expanding/evolving lesions and in non-slowly expanding/evolving lesion areas of pre-existing lesions predicted subsequent composite disability progression with consistent trends on all components of the composite. In contrast, whole brain volume loss and acute lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in new focal T2 lesions did not predict subsequent composite disability progression in this trial at the population level. Ocrelizumab reduced longitudinal measures of chronic lesion activity such as T1 hypointense lesion volume accumulation and mean normalized T1 signal intensity decrease both within regions of pre-existing T2 lesions identified as slowly expanding/evolving and in non-slowly expanding/evolving lesions. Using conventional brain MRI, T1-weighted intensity-based measures of chronic white matter lesion activity predict clinical progression in primary progressive multiple sclerosis and may qualify as a longitudinal in vivo neuroimaging correlate of smouldering demyelination and axonal loss in chronic active lesions due to CNS-resident inflammation and/or secondary neurodegeneration across the multiple sclerosis disease continuum.
| S-EPMC6736181 | biostudies-literature
Project description:Subpial cortical demyelination is an important component of multiple sclerosis (MS) pathology contributing to disease progression, yet mechanism(s) underlying its development remain unclear. Compartmentalized inflammation involving the meninges may drive this type of injury. Given recent findings identifying substantial white matter (WM) lesion activity in patients with progressive MS, elucidating whether and how WM lesional activity relates to meningeal inflammation and subpial cortical injury is of interest. Using postmortem FFPE tissue blocks (range, 5-72 blocks; median, 30 blocks) for each of 27 patients with progressive MS, we assessed the relationship between meningeal inflammation, the extent of subpial cortical demyelination, and the state of subcortical WM lesional activity. Meningeal accumulations of T cells and B cells, but not myeloid cells, were spatially adjacent to subpial cortical lesions, and greater immune cell accumulation was associated with larger subpial lesion areas. Patients with a higher extent of meningeal inflammation harbored a greater proportion of active and mixed active/inactive WM lesions and an overall lower proportion of inactive and remyelinated WM lesions. Our findings support the involvement of meningeal lymphocytes in subpial cortical injury and point to a potential link between inflammatory subpial cortical demyelination and pathological mechanisms occurring in the subcortical WM.
| S-EPMC8983127 | biostudies-literature
Project description:Long term irreversible disability in multiple sclerosis (MS) is thought to be primarily driven by axonal degeneration. Axonal degeneration leads to degenerative atrophy, therefore early markers of axonal degeneration are required to predict clinical disability and treatment efficacy. Given that additional pathologies such as inflammation, demyelination and oedema are also present in MS, it is essential to develop axonal markers that are not confounded by these processes. The present study investigated a novel method for measuring axonal degeneration in MS based on high angular resolution diffusion magnetic resonance imaging. Unlike standard methods, this novel method involved advanced acquisition and modelling for improved axonal sensitivity and specificity. Recent work has developed analytical methods, two novel axonal markers, fibre density and cross-section, that can be estimated for each fibre direction in each voxel (termed a "fixel"). This technique, termed fixel-based analysis, thus simultaneously estimates axonal density and white matter atrophy from specific white matter tracts. Diffusion-weighted imaging datasets were acquired for 17 patients with a history of acute unilateral optic neuritis (35.3 ± 10.2 years, 11 females) and 14 healthy controls (32.7 ± 4.8 years, 8 females) on a 3 T scanner. Fibre density values were compared to standard diffusion tensor imaging parameters (fractional anisotropy and mean diffusivity) in lesions and normal appearing white matter. Group comparisons were performed for each fixel to assess putative differences in fibre density and fibre cross-section. Fibre density was observed to have a comparable sensitivity to fractional anisotropy for detecting white matter pathology in MS, but was not affected by crossing axonal fibres. Whole brain fixel-based analysis revealed significant reductions in fibre density and fibre cross-section in the inferior fronto-occipital fasciculus (including the optic radiations) of patients compared to controls. We interpret this result to indicate that this fixel-based approach is able to detect early loss of fibre density and cross-section in the optic radiations in MS patients with a history of optic neuritis. Fibre-specific markers of axonal degeneration should be investigated further for use in early stage therapeutic trials, or to monitor axonal injury in early stage MS.
| S-EPMC5842545 | biostudies-literature
Project description:T2-hyperintense lesions are the key imaging marker of multiple sclerosis (MS). Previous studies have shown that the white matter surrounding such lesions is often also affected by MS. Our aim was to develop a new method to visualize and quantify the extent of white matter tissue changes in MS based on relaxometry properties. We applied a fast, multi-parametric quantitative MRI approach and used a multi-component MR Fingerprinting (MC-MRF) analysis. We assessed the differences in the MRF component representing prolongedrelaxation time between patients with MS and controls and studied the relation between this component's volume and structural white matter damage identified on FLAIR MRI scans in patients with MS. A total of 48 MS patients at two different sites and 12 healthy controls were scanned with FLAIR and MRF-EPI MRI scans. MRF scans were analyzed with a joint-sparsity multi-component analysis to obtain magnetization fraction maps of different components, representing tissues such as myelin water, white matter, gray matter and cerebrospinal fluid. In the MS patients, an additional component was identified with increased transverse relaxation times compared to the white matter, likely representing changes in free water content. Patients with MS had a higher volume of the long- component in the white matter of the brain compared to healthy controls (B (95%-CI) = 0.004 (0.0006-0.008), p = 0.02). Furthermore, this MRF component had a moderate correlation (correlation coefficient R 0.47) with visible structural white matter changes on the FLAIR scans. Also, the component was found to be more extensive compared to structural white matter changes in 73% of MS patients. In conclusion, our MRF acquisition and analysis captured white matter tissue changes in MS patients compared to controls. In patients these tissue changes were more extensive compared to visually detectable white matter changes on FLAIR scans. Our method provides a novel way to quantify the extent of white matter changes in MS patients, which is underestimated using only conventional clinical MRI scans.
| S-EPMC10589890 | biostudies-literature
Project description:The heterogeneity of multiple sclerosis is reflected by dynamic changes of different lesion types in the brain white matter (WM). To identify potential drivers of this process, we RNA-sequenced 73 WM areas from patients with progressive MS (PMS) and 25 control WM. Lesion endophenotypes were described by a computational systems medicine analysis combined with RNAscope, immunohistochemistry, and immunofluorescence. The signature of the normal-appearing WM (NAWM) was more similar to control WM than to lesions: one of the six upregulated genes in NAWM was CD26/DPP4 expressed by microglia. Chronic active lesions that become prominent in PMS had a signature that were different from all other lesion types, and were differentiated from them by two clusters of 62 differentially expressed genes (DEGs). An upcoming MS biomarker, CHI3L1 was among the top ten upregulated genes in chronic active lesions expressed by astrocytes in the rim. TGFβ-R2 was the central hub in a remyelination-related protein interaction network, and was expressed there by astrocytes. We used de novo networks enriched by unique DEGs to determine lesion-specific pathway regulation, i.e. cellular trafficking and activation in active lesions; healing and immune responses in remyelinating lesions characterized by the most heterogeneous immunoglobulin gene expression; coagulation and ion balance in inactive lesions; and metabolic changes in chronic active lesions. Because we found inverse differential regulation of particular genes among different lesion types, our data emphasize that omics related to MS lesions should be interpreted in the context of lesion pathology. Our data indicate that the impact of molecular pathways is substantially changing as different lesions develop. This was also reflected by the high number of unique DEGs that were more common than shared signatures. A special microglia subset characterized by CD26 may play a role in early lesion development, while astrocyte-derived TGFβ-R2 and TGFβ pathways may be drivers of repair in contrast to chronic tissue damage. The highly specific mechanistic signature of chronic active lesions indicates that as these lesions develop in PMS, the molecular changes are substantially skewed: the unique mitochondrial/metabolic changes and specific downregulation of molecules involved in tissue repair may reflect a stage of exhaustion.
| S-EPMC6482546 | biostudies-literature
Project description:To identify pathogenetic markers and potential drivers of different lesion types in the white matter (WM) of patients with progressive multiple sclerosis (PMS), we sequenced RNA from 73 different WM areas. Compared to 25 WM controls, 6713 out of 18,609 genes were significantly differentially expressed in MS tissues (FDR?<?0.05). A computational systems medicine analysis was performed to describe the MS lesion endophenotypes. The cellular source of specific molecules was examined by RNAscope, immunohistochemistry, and immunofluorescence. To examine common lesion specific mechanisms, we performed de novo network enrichment based on shared differentially expressed genes (DEGs), and found TGF?-R2 as a central hub. RNAscope revealed astrocytes as the cellular source of TGF?-R2 in remyelinating lesions. Since lesion-specific unique DEGs were more common than shared signatures, we examined lesion-specific pathways and de novo networks enriched with unique DEGs. Such network analysis indicated classic inflammatory responses in active lesions; catabolic and heat shock protein responses in inactive lesions; neuronal/axonal specific processes in chronic active lesions. In remyelinating lesions, de novo analyses identified axonal transport responses and adaptive immune markers, which was also supported by the most heterogeneous immunoglobulin gene expression. The signature of the normal-appearing white matter (NAWM) was more similar to control WM than to lesions: only 465 DEGs differentiated NAWM from controls, and 16 were unique. The upregulated marker CD26/DPP4 was expressed by microglia in the NAWM but by mononuclear cells in active lesions, which may indicate a special subset of microglia before the lesion develops, but also emphasizes that omics related to MS lesions should be interpreted in the context of different lesions types. While chronic active lesions were the most distinct from control WM based on the highest number of unique DEGs (n?=?2213), remyelinating lesions had the highest gene expression levels, and the most different molecular map from chronic active lesions. This may suggest that these two lesion types represent two ends of the spectrum of lesion evolution in PMS. The profound changes in chronic active lesions, the predominance of synaptic/neural/axonal signatures coupled with minor inflammation may indicate end-stage irreversible molecular events responsible for this less treatable phase.
| S-EPMC6907342 | biostudies-literature
Project description:Microglial nodules in the normal-appearing white matter have been suggested as the earliest stage(s) of multiple sclerosis (MS) lesion formation. Such nodules are characterized by an absence of leukocyte infiltration, astrogliosis or demyelination, and may develop into active demyelinating MS lesions. Although the etiology of MS is still not known, inflammation and autoimmunity are considered to be the central components of this disease. Previous studies provide evidence that Wallerian degeneration, occurring as a consequence of structural damage in MS lesions, might be responsible for observed pathological abnormalities in connected normal-appearing white matter. As innate immune cells, microglia/macrophages are the first to react to even minor pathological changes in the CNS. Biopsy tissue from 27 MS patients and autopsy and biopsy tissue from 22 normal and pathological controls were analyzed to determine the incidence of microglial nodules. We assessed MS periplaque white matter tissue from early disease stages to determine whether microglial nodules are associated with altered axons. With immunohistochemical methods, the spatial relation of the two phenomena was visualized using HLA-DR antibody for MHC II expression by activated microglia/macrophages and by applying antibodies against damaged axons, i.e., SMI32 (non-phosphorylated neurofilaments) and amyloid precursor protein as well as neuropeptide Y receptor Y1, which marks axons undergoing Wallerian degeneration. Our data demonstrate that the occurrence of microglial nodules is not specific to MS and is associated with degenerating as well as damaged axons in early MS. In addition, we show that early MS microglial nodules exhibit both pro- and antiinflammatory phenotypes.
| S-EPMC3611040 | biostudies-literature