Slowly expanding lesions are a marker of progressive MS - No.
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ABSTRACT:
SUBMITTER: Arnold DL
PROVIDER: S-EPMC8474324 | biostudies-literature | 2021 Oct
REPOSITORIES: biostudies-literature
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Slowly expanding lesions are a marker of progressive MS - No.
Arnold Douglas L DL Belachew Shibeshih S Gafson Arie R AR Gaetano Laura L Bernasconi Corrado C Elliott Colm C
Multiple sclerosis (Houndmills, Basingstoke, England) 20210903 11
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Project description:Background and purposeSlowly expanding/evolving lesions measured by conventional T1-weighted/T2-weighted brain MR imaging may contribute to progressive disability accumulation in MS. We evaluated the longitudinal change in myelin and axonal tissue integrity in white matter slowly expanding/evolving lesions by means of the magnetization transfer ratio and DTI radial diffusivity.Materials and methodsSlowly expanding/evolving lesions were detected within the Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of BIIB033 in Participants With Relapsing Forms of Multiple Sclerosis When Used Concurrently With Avonex (SYNERGY) Phase 2 clinical trial dataset (NCT01864148), comprising patients with relapsing-remitting and secondary-progressive MS (n = 299) with T1-weighted/T2-weighted MR imaging at all trial time points (baseline to week 72).ResultsCompared with non-slowly expanding/evolving lesions (areas not classified as slowly expanding/evolving lesion) of baseline nonenhancing T2 lesions, slowly expanding/evolving lesions had a lower normalized magnetization transfer ratio and greater DTI radial diffusivity, both in patients with relapsing-remitting MS (n = 242) and secondary-progressive MS (n = 57, P < .001 for all). Although the changes with time in both the normalized magnetization transfer ratio and DTI radial diffusivity between slowly expanding/evolving lesions and non-slowly expanding/evolving lesions were positively correlated (P < .001), a decrease in the normalized magnetization transfer ratio and a greater increase in DTI radial diffusivity were observed in slowly expanding/evolving lesions versus non-slowly expanding/evolving lesions from baseline to week 72 in relapsing-remitting MS and secondary-progressive MS (P < .001 for all).ConclusionsPatterns of longitudinal change in the normalized magnetization transfer ratio and DTI radial diffusivity in slowly expanding/evolving lesions were consistent with progressive demyelination and tissue loss, as seen in smoldering white matter MS plaques.
| S-EPMC7583098 | biostudies-literature
Project description:BACKGROUND:Chronic lesion activity driven by smoldering inflammation is a pathological hallmark of progressive forms of multiple sclerosis (MS). OBJECTIVE:To develop a method for automatic detection of slowly expanding/evolving lesions (SELs) on conventional brain magnetic resonance imaging (MRI) and characterize such SELs in primary progressive MS (PPMS) and relapsing MS (RMS) populations. METHODS:We defined SELs as contiguous regions of existing T2 lesions showing local expansion assessed by the Jacobian determinant of the deformation between reference and follow-up scans. SEL candidates were assigned a heuristic score based on concentricity and constancy of change in T2- and T1-weighted MRIs. SELs were examined in 1334 RMS patients and 555 PPMS patients. RESULTS:Compared with RMS patients, PPMS patients had higher numbers of SELs (p = 0.002) and higher T2 volumes of SELs (p < 0.001). SELs were devoid of gadolinium enhancement. Compared with areas of T2 lesions not classified as SEL, SELs had significantly lower T1 intensity at baseline and larger decrease in T1 intensity over time. CONCLUSION:We suggest that SELs reflect chronic tissue loss in the absence of ongoing acute inflammation. SELs may represent a conventional brain MRI correlate of chronic active MS lesions and a candidate biomarker for smoldering inflammation in MS.
| S-EPMC6876256 | biostudies-literature
Project description:BackgroundMagnetic resonance imaging (MRI) markers for chronic active lesions in MS include slowly expanding lesions (SELs) and paramagnetic rim lesions (PRLs).ObjectivesTo identify the relationship between SELs and PRLs in MS, and their association with disability.Methods61 people with MS (pwMS) followed retrospectively with MRI including baseline susceptibility-weighted imaging, and longitudinal T1 and T2-weighted scans. SELs were computed using deformation field maps; PRLs were visually identified. Mixed-effects models assessed differences in Expanded Disability Status Scale (EDSS) score changes between the group defined by the presence of SELs and or PRLs.ResultsThe median follow-up time was 3.2 years. At baseline, out of 1492 lesions, 616 were classified as SELs, and 80 as PRLs. 92% of patients had ⩾ 1 SEL, 56% had ⩾ 1 PRL, while both were found in 51%. SELs compared to non-SELs were more likely to also be PRLs (7% vs. 4%, p = 0.027). PRL counts positively correlated with SEL counts (ρ= 0.28, p = 0.03). SEL + PRL + patients had greater increases in EDSS over time (beta = 0.15/year, 95% confidence interval (0.04, 0.27), p = 0.009) than SEL+PRL-patients.ConclusionSELs are more numerous than PRLs in pwMS. Compared with either SELs or PRLs found in isolation, their joint occurrence was associated with greater clinical progression.
| S-EPMC9972234 | biostudies-literature
Project description:BackgroundSlowly expanding lesions (SELs) are MRI markers of chronic active lesions in multiple sclerosis (MS). T1-hypointense black holes, and reductions in magnetization transfer ratio (MTR) are pathologically correlated with myelin and axonal loss. While all associated with progressive MS, the relationship between these lesion's metrics and clinical outcomes in relapse-onset MS has not been widely investigated.ObjectivesTo explore the relationship of SELs with T1-hypointense black holes, and longitudinal T1 intensity contrast ratio and MTR, their correlation to brain volume, and their contribution to MS disability in relapse-onset patients.Methods135 patients with relapsing-remitting MS (RRMS) were studied with clinical assessments and brain MRI (T2/FLAIR and T1-weighted scans at 1.5/3 T) at baseline and two subsequent follow-ups; a subset of 83 patients also had MTR acquisitions. Early-onset patients were defined when the baseline disease duration was ≤ 5 years (n = 85). SELs were identified using deformation field maps from the manually segmented baseline T2 lesions and differentiated from the non-SELs. Persisting black holes (PBHs) were defined as a subset of T2 lesions with a signal below a patient-specific grey matter T1 intensity in a semi-quantitative manner. SELs, PBH counts, and brain volume were computed, and their associations were assessed through Spearman and Pearson correlation. Clusters of patients according to low (up to 2), intermediate (3 to 10), or high (more than 10) SEL counts were determined with a Gaussian generalised mixture model. Mixed-effects and logistic regression models assessed volumes, T1 and MTR within SELs, and their correlation with Expanded Disability Status Scale (EDSS) and confirmed disability progression (CDP).ResultsMean age at study onset was 35.5 years (73% female), disease duration 5.5 years and mean time to last follow-up 6.5 years (range 1 to 12.5); median baseline EDSS 1.5 (range 0 to 5.5) and a mean EDSS change of 0.31 units at final follow-up. Among 4007 T2 lesions, 27% were classified as SELs and 10% as PBHs. Most patients (n = 65) belonged to the cluster with an intermediate SEL count (3 to 10 SELs). The percentage of PBHs was higher in SELs than non-SELs (up to 61% vs 44%, p < 0.001) and within-patient SEL volumes positively correlated with PBH volumes (r = 0.53, p < 0.001). SELs showed a decrease in T1 intensity over time (beta = -0.004, 95%CI -0.005 to -0.003, p < 0.001), accompanied by lower cross-sectional baseline and follow-up MTR. In mixed-effects models, EDSS worsening was predicted by the SEL log-volumes increase over time (beta = 0.11, 95%CI 0.03 to 0.20, p = 0.01), which was confirmed in the sub-cohort of patients with early onset MS (beta = 0.14, 95%CI 0.04 to 0.25, p = 0.008). In logistic regressions, a higher risk for CDP was associated with SEL volumes (OR = 5.15, 95%CI 1.60 to 16.60, p = 0.006).ConclusionsSELs are associated with accumulation of more destructive pathology as indicated by an association with PBH volume, longitudinal reduction in T1 intensity and MTR. Higher SEL volumes are associated with clinical progression, while lower ones are associated with stability in relapse-onset MS.
| S-EPMC9130104 | biostudies-literature
Project description:BackgroundParamagnetic rim lesions (PRLs) and slowly expanding lesions (SELs) have been posited as markers of chronic active lesions (CALs).ObjectiveTo assess the lesion-level concordance of PRLs and SELs in MS and to characterize changes in brain tissue integrity in CALs over time.MethodsMRIs were analyzed from a substudy of AFFINITY [NCT03222973], a phase 2 trial of opicinumab in relapsing MS. Assessments included (1) identification of SELs based on longitudinal MRIs over 72 weeks, and identification of PRLs on susceptibility-weighted imaging (SWI) filtered phase images at week 72; (2) evaluation of subject-level correlation of SEL and PRL counts, volumes, and degree of lesion-level overlap between SELs and PRLs; and (3) characterization of tissue integrity over time in overlapping and non-overlapping SELs and PRLs.ResultsIn 41 subjects, 119 chronic PRLs and 267 SELs were detected. Of 119 (39.5%) chronic PRLs, 47 co-localized with a SEL; 46/267 (17.2%) SELs co-localized with a PRL. PRLs co-localized with SELs showed expansion and worsening microstructural damage over time. SELs with and without co-localization with PRLs showed ongoing tissue damage.ConclusionsChronic MS lesions identified as both PRL and SEL were associated with the most severe accumulation of tissue damage.Trial registrationAFFINITY [NCT03222973].
| S-EPMC10176750 | biostudies-literature
Project description:BackgroundAt autopsy, 20%-40% of chronic multiple sclerosis (MS) lesions are labeled "slowly expanding" and feature myelin phagocytosis at the lesion edge. As pathological lesion classification relies on a single, terminal time point, the rate of lesion expansion cannot be directly measured.ObjectiveTo study long-term volume changes in individual MS lesions.MethodsVolumes of individual lesions on proton density magnetic resonance imaging (MRI) acquired between 1992 and 2015 were measured in 22 individuals (one lesion per person). After correction for acquisition protocol, a mixed model evaluated lesion volume changes.ResultsThe mean (standard deviation) lesion volume at baseline was 142 (82) mL, falling to 74 (51) mL after 16 (3) years. All lesions shrank over time. Change in lesion volume did not correlate with change in supratentorial brain volume ( p = 0.33). In simulations, the results could be explained by a process of slow radial expansion superimposed on substantially more rapid resorption of damaged tissue.ConclusionWe noted sustained radiological contraction of MS lesions, a surprising result given that fresh myelin breakdown products within chronic active lesions are observed relatively frequently at autopsy. Therefore, the primary pathological process in chronic lesions, even those described as "slowly expanding," is likely to be tissue loss.
| S-EPMC5182188 | biostudies-literature
Project description:Background and purposeThe secondary progressive phase of multiple sclerosis is characterised by disability progression due to processes that lead to neurodegeneration. Surrogate markers such as those derived from MRI are beneficial in understanding the pathophysiology that drives disease progression and its relationship to clinical disability. We undertook a 1H-MRS imaging study in a large secondary progressive MS (SPMS) cohort, to examine whether metabolic markers of brain injury are associated with measures of disability, both physical and cognitive.Materials and methodsA cross-sectional analysis of individuals with secondary-progressive MS was performed in 119 participants. They underwent 1H-MR spectroscopy to obtain estimated concentrations and ratios to total Cr for total NAA, mIns, Glx, and total Cho in normal-appearing WM and GM. Clinical outcome measures chosen were the following: Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Nine-Hole Peg Test, Timed 25-foot Walk Test, and the Expanded Disability Status Scale. The relationship between these neurometabolites and clinical disability measures was initially examined using Spearman rank correlations. Significant associations were then further analyzed in multiple regression models adjusting for age, sex, disease duration, T2 lesion load, normalized brain volume, and occurrence of relapses in 2 years preceding study entry.ResultsSignificant associations, which were then confirmed by multiple linear regression, were found in normal-appearing WM for total NAA (tNAA)/total Cr (tCr) and the Nine-Hole Peg Test (ρ = 0.23; 95% CI, 0.06-0.40); tNAA and tNAA/tCr and the Paced Auditory Serial Addition Test (ρ = 0.21; 95% CI, 0.03-0.38) (ρ = 0.19; 95% CI, 0.01-0.36); mIns/tCr and the Paced Auditory Serial Addition Test, (ρ = -0.23; 95% CI, -0.39 to -0.05); and in GM for tCho and the Paced Auditory Serial Addition Test (ρ = -0.24; 95% CI, -0.40 to -0.06). No other GM or normal-appearing WM relationships were found with any metabolite, with associations found during initial correlation testing losing significance after multiple linear regression analysis.ConclusionsThis study suggests that metabolic markers of neuroaxonal integrity and astrogliosis in normal-appearing WM and membrane turnover in GM may act as markers of disability in secondary-progressive MS.
| S-EPMC7963233 | biostudies-literature
Project description:Slowly progressive type 1 insulin-dependent diabetes mellitus (SPIDDM), sometimes referred to as latent autoimmune diabetes in adults (LADA), is a heterogeneous disease that is often confused with type 1 and type 2 diabetes. As a result, there were few diagnostic criteria for this disorder until 2012, when the Japan Diabetes Society established criteria that could be used in clinical practice. A primary question is whether pathologic markers for type 1 or type 2 diabetes are present in the pancreas of patients with SPIDDM, because the phenotype of SPIDDM is similar to both type 1 and type 2 diabetes. Recent studies clarified pathologic findings in the pancreas of patients with SPIDDM, which included T-cell-mediated insulitis, a marker of type 1 diabetes; pseudoatrophic islets (islets specifically devoid of beta cells), another hallmark of type 1 diabetes; and a lack of amylin (ie, islet amyloid polypeptide) deposition to the islet cells, a pathologic marker of type 2 diabetes. In terms of preventing the loss of beta-cell function in patients with SPIDDM, several studies have shown that some drugs, including dipeptidyl peptidase-4 inhibitors, are effective. There is an increased need for early diagnosis of SPIDDM to preserve beta-cell function. This review presents updated findings on the pathogenesis and immunologic findings of the affected pancreas, diagnostic markers, risk factors for progression of beta-cell dysfunction, epidemiology, clinical features, diagnostic strategies, prevention strategies, and clinical options for patients with SPIDDM.
| S-EPMC6886592 | biostudies-literature
Project description: Not available
| S-EPMC4451043 | biostudies-literature
Project description:BackgroundSome patients meeting behavioural variant frontotemporal dementia (bvFTD) diagnostic criteria progress slowly and plateau at mild symptom severity. Such patients have mild neuropsychological and functional impairments, lack characteristic bvFTD brain atrophy and have thus been referred to as bvFTD 'phenocopies' or slowly progressive (bvFTD-SP). The few patients with bvFTD-SP that have been studied at autopsy have demonstrated no evidence of FTD pathology, suggesting that bvFTD-SP is neuropathologically distinct from other forms of FTD. Here, two patients with bvFTD-SP with chromosome 9 open reading frame 72 (C9ORF72) hexanucleotide expansions are described.Methods384 patients with an FTD clinical spectrum and Alzheimer's disease diagnoses were screened for C9ORF72 expansion. Two bvFTD-SP mutation carriers were identified. Neuropsychological and functional data, as well as brain atrophy patterns, assessed using voxel based morphometry (VBM), were compared with 44 patients with sporadic bvFTD and 85 healthy controls.ResultsBoth patients were aged 48 years at baseline and met possible bvFTD criteria. In the first patient, VBM revealed thalamic and posterior insula atrophy. Over 7 years, his neuropsychological performance and brain atrophy remained stable. In the second patient, VBM revealed cortical atrophy with subtle frontal and insular volume loss. Over 2 years, her neuropsychological and functional scores as well as brain atrophy remained stable.ConclusionsC9ORF72 mutations can present with a bvFTD-SP phenotype. Some bvFTD-SP patients may have neurodegenerative pathology, and C9ORF72 mutations should be considered in patients with bvFTD-SP and a family history of dementia or motor neuron disease.
| S-EPMC3388906 | biostudies-literature