T2 Lesion Load Research Articles

Investigating colour vision and its structural correlates 15 years following a first demyelinating event

BackgroundWe investigated the long-term colour and contrast vision outcomes, 15 years after a first demyelinating event, with their structural correlates using optical coherence tomography (OCT) and brain MRI.MethodsPatients recruited with...

Enlarged perivascular spaces are associated with brain microangiopathy and aging in multiple sclerosis

Background: Growing evidence links brain-MRI enlarged perivascular spaces (EPVS) and multiple sclerosis (MS), but their role remains unclear. Objective: This study aimed to investigate the cross-sectional associations of EPVS with several neuroinflammatory and neurodegenerative features in a large multicentric-MS cohort. Methods: In total, 207 patients underwent 3T axial-T2-weighted brain-MRI for EPVS assessment (EPVS dichotomized into high/low according to ⩾ 2/< 2 rating categories). MRI biomarkers included brain-predicted age and brain-predicted age difference (brain-PAD), central vein sign (CVS)-positive lesion percentage (CVS%), paramagnetic rim and cortical lesions, T2-lesion load, and brain volumetry. The variable relative importance for EPVS-category prediction was explored using a classification random forest approach. Results: High EPVS patients were older (49 vs 44 years, p = 0.003), had ⩾ 1 vascular risk factors (VRFs; p = 0.005), lower CVS% (67% vs 78%, p < 0.001), reduced brain volumes (whole brain: 0.63 vs 0.73, p = 0.01; gray matter: 0.36 vs 0.40; p = 0.002), and older brain-predicted age (58 vs 50 years, p < 0.001). No differences were found for neuroinflammatory markers. After adjusting for age and VFRs (multivariate analyses), the high EPVS category correlated with lower CVS% (odds ratio (OR) = 0.98, 95% confidence interval (CI) = 0.96–0.99; p = 0.02), lower whole brain (OR = 0.01, 95% CI = 0.0003–0.5; p = 0.02), gray matter (OR = 0.0004, 95% CI = 0.0000004–0.4; p = 0.03) volumes, and higher brain-PAD (OR = 1.05, 95% CI = 1.01–1.09; p = 0.02). Random forest identified brain-PAD as the most important predictor of high EPVS. Conclusion: EPVS in MS likely reflect microangiopathic disease rather than neuroinflammation, potentially contributing to accelerated neurodegeneration.

Magnetic resonance imaging prognostic factors for survival and relapse in dogs with meningoencephalitis of unknown origin.

Canine meningoencephalitis of unknown origin (MUO) is a debilitating disease associated with high mortality. The prognostic value of magnetic resonance imaging (MRI) findings for predicting survival at 12 months and long-term relapse remains uncertain. This was a retrospective cohort study evaluating the prognostic value of different MRI variables using multivariable logistic regression and Cox proportional hazards analysis. In total, 138 dogs were presumptively diagnosed with MUO. The most common location for lesions identified on MRI were the white matter tracts of the corona radiata and corpus callosum, followed by the frontal, sensorimotor and temporal cortices. Lower T2 lesion load (p = 0.006, OR = 0.942, CI = 0.902-0.983) was associated with longer survival and higher T1 post-contrast lesion load (p = 0.023, OR = 1.162, CI = 1.021-1.322) was associated with relapse. This study has identified prognostic factors that may help identify dogs at higher risk of death and relapse and therefore guide treatment recommendations.

Diffusion tensor imaging and voxel-based morphometry in differentiating multiple sclerosis and its mimics

BackgroundThe discrimination between multiple sclerosis (MS) and other white matter lesions in adults is still problematic as multiple diseases have similar clinical and radiological findings, especially at the disease onset. This case–control study aimed to evaluate the efficacy of diffusion tensor imaging (DTI) and brain morphometry in the differentiation between adult MS and its magnetic resonance imaging (MRI) mimics.MethodsFifty-eight patients (49 women and 9 men; mean age 35.74 ± 11.86 years, range 18–50 years) with clinically suspected MS and age- and sex-matched fifteen healthy subjects were included. All study subjects underwent MRI using 3D FLAIR, 3D T1 MPRAGE, axial T2WI fast spin echo, and DTI sequences. The included patients were classified into MS and mimics groups according to MC Donald’s criteria 2017. Image post-processing using the region of interest (ROI) analysis for DTI parameters and automated voxel brain morphometry and segmentation was done for all study groups. Statistical comparison between the two patient groups and between them and the control group was performed regarding DTI indices (fractional anisotropy [FA], mean diffusivity [MD], and relative anisotropy [RA]) and brain morphometry parameters (including white matter volume (WMV), grey matter volume (GMV), cerebrospinal fluid volume (CSFV), T2 lesion load and deep grey matter volume).ResultsA statistically significant difference was observed between the MD, FA, and RA values of the patients and control groups. The MD values were significantly higher in the MS than in its mimics with a cut-off value of > 1.058 × 10−3 mm2/s (p < 0.001). Compared to the mimics group, the MS patients showed significantly lower WMV (33.31 ± 4.40 versus 35.71 ± 4.58; p = 0.047) and higher CSFV (16.38 ± 5.93 versus 13.06 ± 3.09; p = 0.012) with no significant difference regarding the GMV.ConclusionsMD analysis of DTI, WMV, and CSFV are useful quantitative measurements in confirming the diagnosis of MS and differentiating it from its imaging mimics.

Baseline predictors of disability worsening among patients wth a Clinically Isolated Syndrome. (P5-3.015)

Baseline predictors of disability worsening among patients wth a Clinically Isolated Syndrome. (P5-3.015)

High serum neurofilament light chain levels correlate with brain atrophy and physical disability in multiple sclerosis.

Serum neurofilament light chain (sNfL) is a promising biomarker of neuroaxonal damage in persons with multiple sclerosis (pwMS). In cross-sectional studies, sNfL has been associated with disease activity and brain magnetic resonance imaging (MRI) changes; however, it is still unclear to what extent in particular high sNfL levels impact on subsequent disease evolution. sNfL was quantified by an ultrasensitive single molecule array (Simoa) in 199 pwMS (median age=34.2 years, 64.3% female) and 49 controls. All pwMS underwent 3-T MRI to assess global and compartmental normalized brain volumes, T2-lesion load, and cortical mean thickness. Follow-up data and serum samples were available in 144 pwMS (median follow-up time=3.8 years). Linear and binary logistic models were used to estimate the independent contribution of sNfL for changes in MRI and Expanded Disability Status Scale (EDSS). Age-corrected sNfL z-scores from a normative database of healthy controls were used for sensitivity analyses. High sNfL levels at baseline were associated with atrophy measures of the whole brain (standardized beta coefficient βj= -0.352, p< 0.001), white matter (βj= -0.229, p= 0.007), thalamus (βj= -0.372, p= 0.004), and putamen (βj= -1.687, p= 0.012). pwMS with high levels of sNfL at baseline and follow-up had a greater risk of EDSS worsening (p= 0.007). Already single time point elevation of sNfL has a distinct effect on brain volume changes over a short-term period, and repeated high levels of sNfL indicate accumulating physical disability. Serial assessment of sNfL may provide added value in the clinical management of pwMS.

Graph theoretical approach to brain remodeling in multiple sclerosis.

Multiple sclerosis (MS) is a neuroinflammatory disorder damaging structural connectivity. Natural remodeling processes of the nervous system can, to some extent, restore the damage caused. However, there is a lack of biomarkers to evaluate remodeling in MS. Our objective is to evaluate graph theory metrics (especially modularity) as a biomarker of remodeling and cognition in MS. We recruited 60 relapsing-remitting MS and 26 healthy controls. Structural and diffusion MRI, plus cognitive and disability evaluations, were done. We calculated modularity and global efficiency from the tractography-derived connectivity matrices. Association of graph metrics with T2 lesion load, cognition, and disability was evaluated using general linear models adjusting for age, gender, and disease duration wherever applicable. We showed that MS subjects had higher modularity and lower global efficiency compared with controls. In the MS group, modularity was inversely associated with cognitive performance but positively associated with T2 lesion load. Our results indicate that modularity increase is due to the disruption of intermodular connections in MS because of the lesions, with no improvement or preserving of cognitive functions.

Fatigue in Multiple Sclerosis Is Associated with Reduced Expression of Interleukin-10 and Worse Prospective Disease Activity.

In multiple sclerosis (MS), fatigue is a frequent symptom that negatively affects quality of life. The pathogenesis of fatigue is multifactorial and inflammation may play a specific role. To explore the association between fatigue, central inflammation and disease course in MS in 106 relapsing-remitting (RR)-MS patients, clinical characteristics, including fatigue and mood, were explored at the time of diagnosis. NEDA (no evidence of disease activity)-3 status after one-year follow up was calculated. Cerebrospinal fluid (CSF) levels of a set of proinflammatory and anti-inflammatory molecules and peripheral blood markers of inflammation were also analyzed. MRI structural measures were explored in 35 patients. A significant negative correlation was found at diagnosis between fatigue measured with the Modified Fatigue Impact Scale (MFIS) and the CSF levels of interleukin (IL)-10. Conversely, no significant associations were found with peripheral markers of inflammation. Higher MFIS scores were associated with reduced probability to reach NEDA-3 status after 1-year follow up. Finally, T2 lesion load showed a positive correlation with MFIS scores and a negative correlation with CSF IL-10 levels at diagnosis. CSF inflammation, and particularly the reduced expression of the anti-inflammatory molecule IL-10, may exacerbate fatigue. Fatigue in MS may reflect subclinical CSF inflammation, predisposing to greater disease activity.

Minocycline treatment in clinically isolated syndrome and serum NfL, GFAP, and metalloproteinase levels

Background: In the trial of Minocycline in Clinically Isolated Syndrome (MinoCIS), minocycline significantly reduced the risk of conversion to clinically definite multiple sclerosis (CDMS). Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are emerging biomarkers in MS, and minocycline modulates matrix metalloproteinases (MMPs). Objective: To assess the value of blood NfL and GFAP as a biomarker of baseline and future disease activity and its utility to monitor treatment response in minocycline-treated patients with clinically isolated syndrome (CIS). Methods: We measured NfL, GFAP, and MMPs in blood samples from 96 patients with CIS from the MinoCIS study and compared biomarkers with clinical and radiologic characteristics and outcome. Results: At baseline, NfL levels correlated with T2 lesion load and number of gadolinium-enhancing lesions. Baseline NfL levels predicted conversion into CDMS at month 6. GFAP levels at baseline were correlated with T2 lesion volume. Minocycline treatment significantly increased NfL levels at 3 months but not at 6 months, and decreased GFAP levels at month 6. Minocycline decreased MMP-7 concentrations at month 1. Discussion: Blood NfL levels are associated with measures of disease activity in CIS and have prognostic value. Minocycline increased NfL levels at month 3, but reduced GFAP and MMP-7 levels.

Blood Neurofilament Light in Progressive Multiple Sclerosis: Post Hoc Analysis of 2 Randomized Controlled Trials.

To investigate the potential of plasma neurofilament light (pNfL) as a biomarker of disease progression and treatment response in progressive multiple sclerosis (PMS) with and without acute disease activity. A post hoc blinded analysis of pNfL levels in 2 placebo-controlled, phase 3 studies in secondary progressive multiple sclerosis (SPMS; EXPAND) and primary progressive multiple sclerosis (PPMS; INFORMS) using siponimod and fingolimod, respectively, as active compounds was performed. pNfL levels were quantified using a single molecule array (Homebrew Simoa) immunoassay from stored ethylenediaminetetraacetic acid (EDTA) plasma samples of all patients who consented for exploratory biomarker analysis in either study; pNfL levels were divided into high (≥30 pg/mL) and low (<30 pg/mL) at baseline. We investigated the association of pNfL levels with disability progression, cognitive decline, and brain atrophy and their sensitivity to indicate treatment response through clinical measures. We analyzed pNfL in 4,185 samples from 1,452 patients with SPMS and 1,172 samples from 378 patients with PPMS. Baseline pNfL levels were higher in SPMS (geomean 32.1 pg/mL) than in PPMS (22.0 pg/mL; p < 0.0001). In both studies, higher baseline pNfL levels were associated with older age, higher Expanded Disability Status Scale score, more Gd+ lesions, and higher T2 lesion load (all p < 0.05). Independent of treatment, high vs low baseline pNfL levels were associated with significantly higher risks of confirmed 3-month (SPMS [32%], hazard ratio [95% CI] 1.32 [1.09-1.61]; PPMS [49%], 1.49 [1.05-2.12]) and 6-month disability progression (SPMS [26%], 1.26 [1.01-1.57]; PPMS [48%], 1.48 [1.01-2.17]), earlier wheelchair dependence (SPMS [50%], 1.50 [0.96-2.34]; PPMS [197%], 2.97 [1.44-6.10]), cognitive decline (SPMS [41%], 1.41 [1.09-1.84]), and higher rates of brain atrophy (mean change at month 24: SPMS, -0.92; PPMS, -1.39). Baseline pNfL levels were associated with future disability progression and the degree of brain atrophy regardless of presence or absence of acute disease activity (gadolinium-enhancing lesions or recent occurrence of relapses before baseline). pNfL levels were lower in patients treated with siponimod or fingolimod vs placebo-treated patients and higher in those having experienced disability progression. pNfL was associated with future clinical and radiologic disability progression features at the group level. pNfL was reduced by treatment and may be a meaningful outcome measure in PMS studies. EXPAND (ClinicalTrials.gov identifier: NCT01665144) and INFORMS (ClinicalTrials.gov identifier: NCT00731692).

Neuroinflammation Is Associated with GFAP and sTREM2 Levels in Multiple Sclerosis.

Background: Astrocytes and microglia play an important role in the inflammatory process of multiple sclerosis (MS). We investigated the associations between the cerebrospinal fluid (CSF) levels of glial fibrillary acid protein (GFAP) and soluble triggering receptors expressed on myeloid cells-2 (sTREM-2), inflammatory molecules, and clinical characteristics in a group of patients with relapsing-remitting MS (RRMS). Methods: Fifty-one RRMS patients participated in the study. Clinical evaluation and CSF collection were performed at the time of diagnosis. The CSF levels of GFAP, sTREM-2, and of a large set of inflammatory and anti-inflammatory molecules were determined. MRI structural measures (cortical thickness, T2 lesion load, cerebellar volume) were examined. Results: The CSF levels of GFAP and sTREM-2 showed significant correlations with inflammatory cytokines IL-8, G-CSF, and IL-5. Both GFAP and sTREM-2 CSF levels positively correlated with age at diagnosis. GFAP was also higher in male MS patients, and was associated with an increased risk of MS progression, as evidenced by higher BREMS at the onset. Finally, a negative association was found between GFAP CSF levels and cerebellar volume in RRMS at diagnosis. Conclusions: GFAP and sTREM-2 represent suitable biomarkers of central inflammation in MS. Our results suggest that enhanced CSF expression of GFAP may characterize patients with a higher risk of progression.

Cortical morphology predicts placebo response in multiple sclerosis

Despite significant insights into the neural mechanisms of acute placebo responses, less is known about longer-term placebo responses, such as those seen in clinical trials, or their interactions with brain disease. We examined brain correlates of placebo responses in a randomized trial of a then controversial and now disproved endovascular treatment for multiple sclerosis. Patients received either balloon or sham extracranial venoplasty and were followed for 48 weeks. Venoplasty had no therapeutic effect, but a subset of both venoplasty- and sham-treated patients reported a transient improvement in health-related quality of life, suggesting a placebo response. Placebo responders did not differ from non-responders in total MRI T2 lesion load, count or location, nor were there differences in normalized brain volume, regional grey or white matter volume or cortical thickness (CT). However, responders had higher lesion activity. Graph theoretical analysis of CT covariance showed that non-responders had a more small-world-like CT architecture. In non-responders, lesion load was inversely associated with CT in somatosensory, motor and association areas, precuneus, and insula, primarily in the right hemisphere. In responders, lesion load was unrelated to CT. The neuropathological process in MS may produce in some a cortical configuration less capable of generating sustained placebo responses.

Leptomeningeal enhancement in multiple sclerosis and other neurological diseases: A systematic review and Meta-Analysis

BackgroundThe lack of systematic evidence on leptomeningeal enhancement (LME) on MRI in neurological diseases, including multiple sclerosis (MS), hampers its interpretation in clinical routine and research settings. PurposeTo perform a systematic review and meta-analysis of MRI LME in MS and other neurological diseases. Materials and MethodsIn a comprehensive literature search in Medline, Scopus, and Embase, out of 2292 publications, 459 records assessing LME in neurological diseases were eligible for qualitative synthesis. Of these, 135 were included in a random-effects model meta-analysis with subgroup analyses for MS. ResultsOf eligible publications, 161 investigated LME in neoplastic neurological (n = 2392), 91 in neuroinfectious (n = 1890), and 75 in primary neuroinflammatory diseases (n = 4038). The LME-proportions for these disease classes were 0.47 [95%-CI: 0.37–0.57], 0.59 [95%-CI: 0.47–0.69], and 0.26 [95%-CI: 0.20–0.35], respectively. In a subgroup analysis comprising 1605 MS cases, LME proportion was 0.30 [95%-CI 0.21–0.42] with lower proportions in relapsing-remitting (0.19 [95%-CI 0.13–0.27]) compared to progressive MS (0.39 [95%-CI 0.30–0.49], p = 0.002) and higher proportions in studies imaging at 7 T (0.79 [95%-CI 0.64–0.89]) compared to lower field strengths (0.21 [95%-CI 0.15–0.29], p < 0.001). LME in MS was associated with longer disease duration (mean difference 2.2 years [95%-CI 0.2–4.2], p = 0.03), higher Expanded Disability Status Scale (mean difference 0.6 points [95%-CI 0.2–1.0], p = 0.006), higher T1 (mean difference 1.6 ml [95%-CI 0.1–3.0], p = 0.04) and T2 lesion load (mean difference 5.9 ml [95%-CI 3.2–8.6], p < 0.001), and lower cortical volume (mean difference −21.3 ml [95%-CI −34.7–-7.9], p = 0.002). ConclusionsOur study provides high-grade evidence for the substantial presence of LME in MS and a comprehensive panel of other neurological diseases. Our data could facilitate differential diagnosis of LME in clinical settings. Additionally, our meta-analysis corroborates that LME is associated with key clinical and imaging features of MS.PROSPERO No: CRD42021235026.

Signs of neuroinflammation outweigh neurodegeneration as predictors for early conversion to MS

BackgroundThe pathophysiological mechanisms underlying multiple sclerosis include both inflammatory and degenerative processes. We aimed to study and compare markers of neuroinflammation and neurodegeneration in patients with first presentation of demyelinating disorder and to prospectively identify which of the studied markers serve as predictors for early conversion to multiple sclerosis. Thus, 42 patients with first clinical manifestations suggestive of demyelinating disease were included in a prospective study. Subjects underwent thorough history taking and clinical evaluation. Laboratory studies involved analysis of cerebrospinal fluid (CSF) and serum chitinase 3-like 1 levels. Brain imaging included MRI and ultrasonographic assessment.ResultsT1 black holes, elevated oligoclonal bands (OCB), high baseline T2 lesion load, and enhanced MRI lesions were significantly higher in patients with 1st attack multiple sclerosis. Significantly higher CSF-OCB and serum chitinase 3-like 1 protein was detected in patients with multiple sclerosis (MS) compared to clinically isolated syndrome, and higher levels in MS convertors than non-convertors. Cognitive dysfunction evaluated by MoCA test and brain atrophy assessed using transcranial sonography did not show significant difference among the studied groups. Logistic regression analysis showed that heavy T2 lesion load served as the only predictor of conversion to MS.ConclusionEarly conversion to MS after first attack of demyelination is related to detection of signs of neuroinflammation rather than neurodegeneration.

Diagnostic value of gadolinium contrast administration for spinal cord magnetic resonance imaging in multiple sclerosis patients and correlative markers of lesion enhancement

BackgroundMagnetic resonance imaging is essential for monitoring people with multiple sclerosis, but the diagnostic value of gadolinium contrast administration in spine magnetic resonance imaging is unclear.ObjectiveTo assess the diagnostic value of gadolinium contrast administration in spine magnetic resonance imaging follow-up examinations and identify imaging markers correlating with lesion enhancement.MethodsA total of 65 multiple sclerosis patients with at least 2 spinal magnetic resonance imaging follow-up examinations were included. Spine magnetic resonance imaging was performed at 3 Tesla with a standardized protocol (sagittal and axial T2-weighted turbo spin echo and T1-weighted post-contrast sequences). T2 lesion load and enhancing lesions were assessed by two independent neuroradiologists for lesion size, localization, and T2 signal ratio (T2 signallesion/T2 signalnormal appearing spinal cord).ResultsA total of 68 new spinal T2 lesions and 20 new contrast-enhancing lesions developed during follow-up. All enhancing lesions had a discernable correlate as a new T2 lesion. Lesion enhancement correlated with a higher T2 signal ratio compared to non-enhancing lesions (T2 signal ratio: 2.0 ± 0.4 vs. 1.4 ± 0.2, ****p < 0.001). Receiver operating characteristics analysis showed an optimal cutoff value of signal ratio 1.78 to predict lesion enhancement (82% sensitivity and 97% specificity).ConclusionGadolinium contrast administration is dispensable in follow-up spine magnetic resonance imaging if no new T2 lesions are present. Probability of enhancement correlates with the T2 signal ratio.

Correlation between vitamin D and lipid profile in multiple sclerosis patients

Abstract Background Studies have suggested that vitamin D and lipid profile have been linked to the etiology of multiple sclerosis and have an impact on the activity and progression of the disease. Objectives The aim of the present study was to determine correlation between vitamin D level and lipid profile in multiple sclerosis (MS) patients and their effect on disease activity and progression for better management and control of risk factors. Patients and Methods It is a cross-sectional hospital based study carried on clinically definite 111 Relapsing Remitting MS (RRMS) patients according to McDonald criteria 2010 recruited from Multiple sclerosis unit at Ain Shams University Hospitals, both genders included and aged from 18 to 50 years old. All subjects were assessed regarding their basic demographic data, serum vitamin D level and lipid profile and correlated these data with their state of disease activity and degree of disability. Results The mean level of serum vitamin D was 18.93 ± 9.85 ng/mL. Serum vitamin D level was insufficient (&amp;lt; 30 ng/mL) in 81.08% of patients and sufficient (≥ 30 ng/mL) in 18.92% of patients. The mean level of total cholesterol (TC) was 204.9 ± 50.9 mg/dL, of tri-glycerides (TG) was 105.4 ± 44.6 mg/dL, of low density lipoprotein (LDL) was 122.2 ± 38.8 mg/dL and of high density lipoprotein (HDL) level was 56.2 ± 16.6 mg/dL. High relapse frequency was found to be significantly related to low serum vitamin D level with P-value 0.005. Near all lipid related variables were positively correlated to disease duration. TC and TG were positively related to EDSS while HDL was negatively related with it. Number of brain T2 lesions was significantly correlated with TC and TG levels with P-value 0.001 and 0.002 respectively. Fingolimod was found to be associated with dyslipidemia. We found that each 1 ng/mL increase in vitamin D was associated with decrease in TC of 1.48 mg/dL (95% CI: -2.42 to -0.54, P-value 0.002) and increase in HDL of 0.35 mg/dL (95% CI: 0.04 to -0.66, P-value 0.028). Conclusion Vitamin D deficiency is predominant among Egyptian MS patients. Patients with insufficient vitamin D were found to have higher annualized relapse rate (ARR). Patients with dyslipidemia found to have longer duration, more disability and higher brain T2 lesion load. Vitamin D was correlated positively with HDL and negatively with TC.

Brain Atrophy and Physical and Cognitive Disability in Multiple Sclerosis.

Brain atrophy is associated with physical disability in multiple sclerosis (MS), but there is a great variability between different studies and methodologies, and its use is still limited to research projects. We aimed to analyze the relationship between several volumetric measurements and physical disability and cognitive functioning in MS patients in a clinical practice setting. This is a cross-sectional study. A total of 41 patients (31 relapsing-remitting MS, 6 secondary-progressive MS, and 4 primary-progressive MS) were included. Whole brain volume (WBV), gray matter volume (GMV), and T2 lesion load (T2L) were obtained using Icometrix® software. Physical disability was measured with the Expanded Disability Status Scale (EDSS), and cognitive status was evaluated with the brief repeatable battery of neuropsychological tests (BRB-N). The relationship between brain volumes and EDSS was analyzed through linear multivariate regression. The association between volumetry measurements and the number of affected cognitive domains was studied with negative binomial regression. GMV was associated with age (b=-1.7, P=0.014) and with EDSS (b=-7.55, P=0.013). T2L was associated with EDSS (b=2.29, P=0.032). The number of affected cognitive domains was associated with clinical phenotype, worse in primary progressive MS (PPMS). There was not correlations between cognitive impairment and cerebral volumes. Brain atrophy measurement is feasible in clinical practice setting, and it is helpful in monitoring the EDSS progression. Primary progressive phenotype is associated with greater risk of cognitive dysfunction. The T2 lesion load is associated with physical disability in patients with multiple sclerosis (MS).The gray matter volume is associated with age and physical disability in patients with MS.There is no significant correlation between cognitive impairment and cerebral volumes in patients with MS. Conventional magnetic resonance imaging (MRI) is still used for diagnosing and monitoring multiple sclerosis (MS). Analysis of Brain volumes including Whole brain volume (WBV), gray matter volume (GMV), and T2 lesion load (T2L) allows the evaluation of its neurodegenerative mechanisms. Robust evidence links brain atrophy with disability in MS. This study aims to analyze the relationship between advanced MRI sequences and physical disability and cognitive functioning in MS patients. According to the results, T2L was associated with physical disability and GMV was associated with age and physical disability. There was no significant correlation between cognitive impairment and cerebral volumes in patients with MS.

Chronic White Matter Inflammation and Serum Neurofilament Levels in Multiple Sclerosis.

ObjectiveTo assess whether chronic white matter inflammation in patients with multiple sclerosis (MS) as detected in vivo by paramagnetic rim MRI lesions (PRLs) is associated with higher serum neurofilament light chain (sNfL) levels, a marker of neuroaxonal damage.MethodsIn 118 patients with MS with no gadolinium-enhancing lesions or recent relapses, we analyzed 3D-submillimeter phase MRI and sNfL levels. Histopathologic evaluation was performed in 25 MS lesions from 20 additional autopsy MS cases.ResultsIn univariable analyses, participants with ≥2 PRLs (n = 43) compared to those with ≤1 PRL (n = 75) had higher age-adjusted sNfL percentiles (median, 91 and 68; p < 0.001) and higher Multiple Sclerosis Severity Scale scores (MSSS median, 4.3 and 2.4; p = 0.003). In multivariable analyses, sNfL percentile levels were higher in PRLs ≥2 cases (βadd, 16.3; 95% confidence interval [CI], 4.6–28.0; p < 0.01), whereas disease-modifying treatment (DMT), Expanded Disability Status Scale (EDSS) score, and T2 lesion load did not affect sNfL. In a similar model, sNfL percentile levels were highest in cases with ≥4 PRLs (n = 30; βadd, 30.4; 95% CI, 15.6–45.2; p < 0.01). Subsequent multivariable analysis revealed that PRLs ≥2 cases also had higher MSSS (βadd, 1.1; 95% CI, 0.3–1.9; p < 0.01), whereas MSSS was not affected by DMT or T2 lesion load. On histopathology, both chronic active and smoldering lesions exhibited more severe acute axonal damage at the lesion edge than in the lesion center (edge vs center: p = 0.004 and p = 0.0002, respectively).ConclusionChronic white matter inflammation was associated with increased levels of sNfL and disease severity in nonacute MS, suggesting that PRL contribute to clinically relevant, inflammation-driven neurodegeneration.

Tract-specific MRI measures explain learning and recall differences in multiple sclerosis.

Cognitive difficulties are common and a key concern for people with multiple sclerosis. Advancing knowledge of the role of white matter pathology in multiple sclerosis-related cognitive impairment is essential as both occur early in the disease with implications for early intervention. Consequently, this cross-sectional study asked whether quantifying the relationships between lesions and specific white matter structures could better explain co-existing cognitive differences than whole brain imaging measures. Forty participants with relapse-onset multiple sclerosis underwent cognitive testing and MRI at 3 Tesla. They were classified as cognitively impaired (n = 24) or unimpaired (n = 16) and differed across verbal fluency, learning and recall tasks corrected for intelligence and education (corrected P-values = 0.007–0.04). The relationships between lesions and white matter were characterized across six measures: conventional voxel-based T2 lesion load, whole brain tractogram load (lesioned volume/whole tractogram volume), whole bundle volume, bundle load (lesioned volume/whole bundle volume), Tractometry (diffusion-tensor and high angular resolution diffusion measures sampled from all bundle streamlines) and lesionometry (diffusion measures sampled from streamlines traversing lesions only). The tract-specific measures were extracted from corpus callosum segments (genu and isthmus), striato-prefrontal and -parietal pathways, and the superior longitudinal fasciculi (sections I, II and III). White matter measure-task associations demonstrating at least moderate evidence against the null hypothesis (Bayes Factor threshold < 0.2) were examined using independent t-tests and covariate analyses (significance level P < 0.05). Tract-specific measures were significant predictors (all P-values < 0.05) of task-specific clinical scores and diminished the significant effect of group as a categorical predictor in Story Recall (isthmus bundle load), Figure Recall (right striato-parietal lesionometry) and Design Learning (left superior longitudinal fasciculus III volume). Lesion load explained the difference in List Learning, whereas Letter Fluency was not associated with any of the imaging measures. Overall, tract-specific measures outperformed the global lesion and tractogram load measures. Variation in regional lesion burden translated to group differences in tract-specific measures, which in turn, attenuated differences in individual cognitive tasks. The structural differences converged in temporo-parietal regions with particular influence on tasks requiring visuospatial-constructional processing. We highlight that measures quantifying the relationships between tract-specific structure and multiple sclerosis lesions uncovered associations with cognition masked by overall tract volumes and global lesion and tractogram loads. These tract-specific white matter quantifications show promise for elucidating the relationships between neuropathology and cognition in multiple sclerosis.

Is disease activity prior to fingolimod initiation predictive of response? Fingolimod as a "common" first line treatment.

In countries where fingolimod is available as first-line therapy without restrictions, we have an opportunity to observe long-term efficacy profile of this drug in treatment-naive patients according to their initial disease activity. We retrospectively analysed the data of RRMS patients treated with FTY, focusing on 2 groups: 17 highly active patients (HA) defined as follows: ≥2 relapses in the year before treatment initiation and either≥1 Gd-enhancing T1 lesion or a significant increase in T2 lesion load from a baseline MRI; and 37 "not highly active" (NHA). We reviewed treatment efficacy (defined as NEDA-3), reasons for discontinuation and treatment tolerance in both groups. Mean follow-up duration was 48.2 months, SD 18.4. Fingolimod efficiently reduced relapses (NHA 90.3% reduction, P<0.001, HA 84.9%, P<0.001), and new Gd enhancing lesions (NHA 85.4% reduction, P=0.019, HA 92.3%, P=0.043). The proportion of patients reaching NEDA-3 status was higher in the NHA group (NHA: 80% at 2 years and 66% at 4 years, HA: 58% at 2 years and 38% at 4 years, P=0.042). Fingolimod was discontinued in 20 cases, mainly because of lack of efficacy (n=15). FTY is efficient in reducing relapses and new Gd enhancing lesions in both HA and NHA patients although the probability of achieving NEDA-3 over time is higher in early-treated treatment-naive NHA patients.