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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., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

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.

Background: In multiple sclerosis (MS), imaging biomarkers play a crucial role in characterizing the disease at the time of diagnosis. MRI and optical coherence tomography (OCT) provide readily available biomarkers that may help to define the patient's clinical profile. However, the evaluation of cortical and paramagnetic rim lesions (CL, PRL), as well as retinal atrophy, is not routinely performed in clinic., Objective: To identify the most significant MRI and OCT biomarkers associated with early clinical disability in MS., Methods: Brain, spinal cord (SC) MRI, and OCT scans were acquired from 45 patients at MS diagnosis to obtain: brain PRL and non-PRL, CL, SC lesion volumes and counts, brain volumetric metrics, SC C2-C3 cross-sectional area, and retinal layer thickness. Regression models assessed relationships with physical disability (Expanded Disability Status Scale [EDSS]) and cognitive performance (Brief International Cognitive Assessment for Multiple Sclerosis [BICAMS])., Results: In a stepwise regression (R 2  = 0.526), PRL (β = 0.001, p = 0.023) and SC lesion volumes (β = 0.001, p = 0.017) were the most significant predictors of EDSS, while CL volume and age were strongly associated with BICAMS scores. Moreover, in a model where PRL and non-PRL were pooled, only the contribution of SC lesion volume was retained in EDSS prediction. OCT measures did not show associations with disability at the onset., Conclusion: At MS onset, PRL and SC lesions exhibit the strongest association with physical disability, while CL strongly contribute to cognitive performance. Incorporating the evaluation of PRL and CL into the initial MS patient assessment could help define their clinical profile, thus supporting the treatment choice., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Objectives: Conventional magnetic resonance imaging (MRI) used for detecting possible antibody-negative autoimmune encephalitis (AIE) often fails to meet the diagnostic requirements of this disease. Positron emission tomography (PET) with a translocator protein radioligand can help visualize microglia distribution density in inflammation-related diseases, thereby offering potentially incremental value to conventional MRI for the in vivo assessment of possible antibody-negative AIE., Methods: In this prospective study, 15 participants diagnosed with possible antibody-negative AIE and 10 healthy controls were enrolled (ClinicalTrials.gov: NCT05293405, dated March 15, 2022). All participants underwent hybrid 18 F-DPA714 PET/MRI and evaluation for modified Rankin scale (mRS) score, clinical assessment scale for AIE (CASE), and appropriate antibodies. A positive finding was defined as the intensity of 18 F-DPA714 uptake that was above a threshold of mean standardized uptake value ratio (SUVR) + two standard deviations of SUVR within the corresponding brain regions of healthy controls., Results: The positive detection rate of 18 F-DPA714 PET for possible antibody-negative AIE was significantly higher than that of brain MRI (10/15 [67%] vs. 3/15 [20%]; P = 0.039). In addition, both the intensity and extent of 18 F-DPA714 uptake were significantly associated with the CASE score (P = 0.002 and 0.001). Meanwhile, SUVR levels in the cerebellar region were significantly higher in patients with ataxia than in those without ataxia (P = 0.006). Furthermore, 18 F-DPA714 uptake decreased in 5/10 [50%] patients who underwent follow-up PET/MRI, which mirrored their symptom relief., Conclusion: 18 F-DPA714 PET demonstrated its potentially incremental value to conventional MRI for detecting possible antibody-negative AIE., Competing Interests: Declarations. Conflicts of interest: Meng HY, He L, Chunyu HX, Zhou QM, Wang J, Qu Q, Hai WX, Zhang Y, Li B, Zhang M and Chen S declare that they have no conflict of interest. Ethical standard statement: This single-center prospective study was approved by the Ethics Committee of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (2021CER375) (ClinicalTrials.gov: NCT05293405)., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Deep gray matter (DGM) atrophy and lesions are found in multiple sclerosis (MS)., Objective: To optimize automated segmentation for 7 T DGM volumetrics and assess sensitivity to atrophy and relationship to DGM lesions and disability in relapsing-remitting (RR) MS., Methods: 30 RRMS subjects [mean age 44.0 years, median Expanded Disability Status Scale (EDSS) score 2] and 14 healthy controls underwent 7 T MRI with 3D magnetization-prepared 2 rapid gradient-echoes (MP2RAGE) and fluid-attenuated inversion recovery. Customizing an automated pipeline to assess DGM structure volumes required pre-processing combining two MP2RAGE inversion times and uniform T1 images, and noise-suppressed reconstruction. DGM volumes were normalized. Brain DGM lesions and white matter T2 lesion volume (T2LV) were expert-quantified. Spearman correlations and Wilcoxon rank-sum tests were assessed., Results: DGM lesions were found in 77% (n = 23) of MS subjects and no controls, with thalamic lesions most prevalent (73%). An average of 3.6 DGM lesions was found per person with MS. Total DGM volumes were lower in MS vs. controls (p = 0.034), varying by region, most pronounced in the caudate (p = 0.008). DGM volumes inversely correlated with EDSS (total DGM: r = - 0.45, p = 0.014; globus pallidus: r =  - 0.42, p = 0.023; putamen: r = - 0.44, p = 0.016; caudate: r = - 0.37, p = 0.047) and T2LV (total DGM: r = - 0.53, p = 0.003; putamen: r = - 0.40, p = 0.030; thalamus: r = - 0.63, p < 0.001). DGM atrophy was most closely linked to disability among all MRI measures. Thalamic lesion volume correlated inversely with thalamic volume (r = - 0.38, p = 0.045)., Conclusion: 7 T MRI shows a link between DGM atrophy and both white matter lesions and physical disability in RRMS. Thalamic lesions are associated with thalamic atrophy., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: While many studies have examined relationships of neuroimaging variables to cognitive measures in multiple sclerosis (MS), longitudinal studies are lacking. The relationship of cognitive changes to neuroradiological changes in MS is thus incompletely understood. The present study systematically reviews all studies reporting a relationship between MRI changes and cognitive changes after at least one year of follow-up., Method: An extensive and methodical search of online databases was conducted to identify qualified studies until August 2023. Among various cognitive tests and magnetic resonance imaging (MRI) measures, Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT), verbal fluency, T2 lesion volume (T2LV), white matter lesion volume (WML), and grey matter volume (GMV) qualified for inclusion in a meta-analysis investigating the association of cognitive changes to neuroradiological changes., Results: We identified 35 studies that explored the link between MRI changes and changes in cognitive outcomes. Of these, twenty studies (57.14%) investigated the association between SDMT/PASAT and MRI metrics. Eleven studies (31.42%) focused on the relationship between MRI metrics and verbal learning and memory, while ten studies (28.57%) reported associations with visuospatial learning and memory. Furthermore, eight studies (22.85%) analyzed the correlation between verbal fluency and MRI measures. Only 5 were eligible for inclusion in the meta-analysis. The meta-analysis evaluated correlations between SDMT/PASAT and GMV (r s  = 0.67, 95% CI 0.44-0.91), and verbal fluency and T2LV (r s  = 0.35, 95% CI 0.09-0.60)., Conclusion: In this rigorously conducted systematic review, we found a significant association of cognitive changes, specifically SDMT/PASAT and verbal fluency, to changes in T2LV and atrophy in individuals with MS. Findings should be interpreted cautiously due to the limited amount of high-quality research, small sample sizes, and variability in study methodologies., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The in vivo relation between microglia activation and demyelination in multiple sclerosis is still unclear. Objective: We combined 11C-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: 11C-PBR28 standardized uptake values normalized by a pseudo-reference region (SUVR) were used to measure activated microglia. A voxelwise analysis compared 11C-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: 11C-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. [ABSTRACT FROM AUTHOR]

Background: Cognitive impairment, a common and debilitating symptom in people with multiple sclerosis (MS), is especially related to cortical damage. However, the impact of regional cortical damage remains poorly understood. Our aim was to evaluate structural (network) integrity in lesional and non-lesional cortex in people with MS, and its relationship with cognitive dysfunction., Methods: In this cross-sectional study, 176 people with MS and 48 healthy controls underwent MRI, including double inversion recovery and diffusion-weighted scans, and neuropsychological assessment. Cortical integrity was assessed based on fractional anisotropy (FA) and mean diffusivity (MD) within 212 regions split into lesional or non-lesional cortex, and grouped into seven cortical networks. Integrity was compared between people with MS and controls, and across cognitive groups: cognitively-impaired (CI; ≥ two domains at Z ≤ - 2 below controls), mildly CI (≥ two at - 2 < Z ≤ - 1.5), or cognitively-preserved (CP)., Results: Cortical lesions were observed in 87.5% of people with MS, mainly in ventral attention network, followed by limbic and default mode networks. Compared to controls, in non-lesional cortex, MD was increased in people with MS, but mean FA did not differ. Within the same individual, MD and FA were increased in lesional compared to non-lesional cortex. CI-MS exhibited higher MD than CP-MS in non-lesional cortex of default mode, frontoparietal and sensorimotor networks, of which the default mode network could best explain cognitive performance., Conclusion: Diffusion differences in lesional cortex were more severe than in non-lesional cortex. However, while most people with MS had cortical lesions, diffusion differences in CI-MS were more prominent in non-lesional cortex than lesional cortex, especially within default mode, frontoparietal and sensorimotor networks., (© 2024. The Author(s).)

In recent years, the use of magnetic resonance imaging (MRI) for the diagnostic work-up of multiple sclerosis (MS) has evolved considerably. The 2017 McDonald criteria show high sensitivity and accuracy in predicting a second clinical attack in patients with a typical clinically isolated syndrome and allow an earlier diagnosis of MS. They have been validated, are evidence-based, simplify the clinical use of MRI criteria and improve MS patients' management. However, to limit the risk of misdiagnosis, they should be applied by expert clinicians only after the careful exclusion of alternative diagnoses. Recently, new MRI markers have been proposed to improve diagnostic specificity for MS and reduce the risk of misdiagnosis. The central vein sign and chronic active lesions (i.e., paramagnetic rim lesions) may increase the specificity of MS diagnostic criteria, but further effort is necessary to validate and standardize their assessment before implementing them in the clinical setting. The feasibility of subpial demyelination assessment and the clinical relevance of leptomeningeal enhancement evaluation in the diagnostic work-up of MS appear more limited. Artificial intelligence tools may capture MRI attributes that are beyond the human perception, and, in the future, artificial intelligence may complement human assessment to further ameliorate the diagnostic work-up and patients' classification. However, guidelines that ensure reliability, interpretability, and validity of findings obtained from artificial intelligence approaches are still needed to implement them in the clinical scenario. This review provides a summary of the most recent updates regarding the application of MRI for the diagnosis of MS. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease associated with axonal injury, and neurofilament light chains in serum (sNfL) are considered a biomarker for this damage. We aimed to investigate the relationship between sNfL and the axonal damage in early MS lesions in a special cohort of biopsied patients. sNfL from 106 biopsied patients with 26 follow-up samples were analyzed using single-molecule array (SiMoA) technology. Findings were correlated with clinical parameters and histological findings of acute axonal damage (APP-positive spheroids) and axonal loss in different lesion stages. A median of 59 pg/ml sNfL was found (range 8–3101 pg/ml). sNfL levels correlated with APP-positive spheroids in early active demyelinating lesions that represent the earliest lesion stages (p < 0.01). A significant negative correlation between sNfL levels in follow-up blood samples and axonal density in normal-appearing white matter was also observed (p = 0.02). sNfL levels correlated with the Expanded Disability Status Score at biopsy (p < 0.01, r = 0.49) and at last clinical follow-up (p < 0.01, r = 0.66). In conclusion, sNfL likely represent a compound measure of recent and ongoing neuroaxonal damage. We found that sNfL in biopsied MS patients correlate with acute axonal damage in the earliest MS lesion stages. Determination of sNfL levels thus allows insight into brain pathology and underlines the relevance of relapse-associated lesional pathology. Axonal loss in normal-appearing white matter contributes to sNfL levels independent of relapses. Since sNfL levels correlate with clinical disability, they may predict the future disability of patients and help with individual treatment decisions. [ABSTRACT FROM AUTHOR]

Background: Pathologically specific MRI measures may elucidate in-vivo the heterogeneous processes contributing to cognitive impairment in multiple sclerosis (MS). Purpose: Using diffusion tensor and neurite orientation dispersion and density imaging (NODDI), we explored the contribution of focal lesions and normal-appearing (NA) tissue microstructural abnormalities to cognitive impairment in MS. Methods: One hundred and fifty-two MS patients underwent 3 T brain MRI and a neuropsychological evaluation. Forty-eight healthy controls (HC) were also scanned. Fractional anisotropy (FA), mean diffusivity (MD), intracellular volume fraction (ICV_f) and orientation dispersion index (ODI) were assessed in cortical and white matter (WM) lesions, thalamus, NA cortex and NAWM. Predictors of cognitive impairment were identified using random forest. Results: Fifty-two MS patients were cognitively impaired. Compared to cognitively preserved, impaired MS patients had higher WM lesion volume (LV), lower normalized brain volume (NBV), cortical volume (NCV), thalamic volume (NTV), and WM volume (p ≤ 0.021). They also showed lower NAWM FA, higher NAWM, NA cortex and thalamic MD, lower NAWM ICV_f, lower WM lesion ODI, and higher NAWM ODI (false discovery rate-p ≤ 0.026). Cortical lesion number and microstructural abnormalities were not significantly different. The best MRI predictors of cognitive impairment (relative importance) (out-of-bag area under the curve = 0.727) were NAWM FA (100%), NTV (96.0%), NBV (84.7%), thalamic MD (43.4%), NCV (40.6%), NA cortex MD (26.0%), WM LV (23.2%) and WM lesion ODI (17.9%). Conclusions: Our multiparametric MRI study including NODDI measures suggested that neuro-axonal damage and loss of microarchitecture integrity in focal WM lesions, NAWM, and GM contribute to cognitive impairment in MS. [ABSTRACT FROM AUTHOR]

Background: White matter (WM) atrophy is relevant in multiple sclerosis (MS), but the methods of analysis currently used are not specific for microstructural changes. The aims of this study were to assess the use of advanced diffusion-weighted imaging (DWI) techniques proposed as measures of baseline and longitudinal WM atrophy in MS and to analyze whether these measures helped explain MS clinical disability (including cognitive impairment) better than volumetric and diffusion tensor (DT)-derived measures. Methods: 3DT1-weighted and DWI sequences were applied to 86 MS and 55 healthy controls (HC) at baseline and after one-year. Intra-cellular volume (vic) maps were computed from neurite orientation dispersion and density imaging model. Voxel-wise fiber-bundle cross-section (FCS) atrophy in MS compared to HC was estimated. Maps of fractional anisotropy and mean diffusivity were also obtained from DWI for a comparison with the proposed advanced DW-derived measures (vic and FCS). Results: Both at baseline and after 1-year, only FCS measure showed a significant atrophy in relapsing–remitting (RR) MS compared to HC and in progressive MS compared to RRMS, mainly located in specific WM tracts (corticospinal tract, splenium of the corpus callosum, left optic radiation, bilateral cingulum, middle cerebellar peduncle and anterior commissure, p value < 0.05). Global baseline FCS and vic were the selected predictors of clinical (R-sq = 0.33, p = 0.007) and cognitive scores (R-sq = 0.29, p = 0.0014) in a linear regression model. Conclusion: Voxel-based FCS was able to detect WM tracts atrophy in MS clinical phenotypes with greater anatomical specificity compared to other measures (volumetric and DT-derived measures of WM damage). FCS and vic measured at baseline in the WM were the best predictors of clinical disability and cognitive impairment. [ABSTRACT FROM AUTHOR]

Background: Cognitive impairment (CI) is a frequent and debilitating symptom in MS. To better understand the neural bases of CI in MS, this magnetic resonance imaging (MRI) study aimed to identify and quantify related structural brain changes and to investigate their relation to each other. Methods: We studied 51 patients with CI and 391 patients with cognitive preservation (CP). We analyzed three-dimensional T1-weighted and FLAIR scans at 3 Tesla. We determined mean cortical thickness as well as volumes of cortical grey matter (GM), deep GM including thalamus, cerebellar cortex, white matter, corpus callosum, and white matter lesions (WML). We also analyzed GM across the whole brain by voxel-wise and surface-based techniques. Results: Mean disease duration was 5 years. Comparing MS patients with CI and CP, we found higher volumes of WML, lower volumes of deep and cortical GM structures, and lower volumes of the corpus callosum (all corrected p values < 0.05). Effect sizes were largest for WML and thalamic volume (standardized ß values 0.25 and − 0.25). By logistic regression analysis including both WML and thalamic volume, we found a significant effect only for WML volume. Inclusion of the interaction term of WML and thalamic volume increased the model fit and revealed a highly significant interaction of WML and thalamic volume. Moreover, voxel-wise and surface-based comparisons of MS patients with CI and CP showed regional atrophy of both deep and cortical GM independent of WML volume and overall disability, but effect sizes were lower. Conclusion: Although several mechanisms contribute to CI already in the early stage of MS, WML seem to be the main driver with thalamic atrophy primarily intensifying this effect. [ABSTRACT FROM AUTHOR]

Background: Atrophied T2-lesion volume (LV) is a novel MRI marker representing brain-lesion loss due to atrophy, able to predict long-term disability progression and conversion to secondary-progressive multiple sclerosis (MS). Objective: To better characterize atrophied T2-LV via comparison with other multidisciplinary markers of MS progression. Methods: We studied 127 MS patients (85 relapsing–remitting, RRMS and 42 progressive, PMS) and 20 clinically isolated syndrome (CIS) utilizing MRI, optical coherence tomography, and serum neurofilament light chain (sNfL) at baseline and at 5-year follow-up. Symbol Digit Modalities Test (SDMT) was obtained at follow-up. Atrophied T2-LV was calculated by combining baseline lesion masks with follow-up CSF partial-volume maps. Measures were compared between MS patients who developed or not disease progression (DP). Partial correlations between atrophied T2-LV and other biomarkers were performed, and corrected for multiple comparisons. Results: Atrophied T2-LV was the only biomarker that significantly differentiated DP from non-DP patients over the follow-up (p = 0.007). In both DP and non-DP groups, atrophied T2-LV was associated with baseline T2-LV and T1-LV (both p = 0.003), absolute change of T1-LV (DP p = 0.038; non-DP p = 0.003) and percentage of brain volume change (both p = 0.003). Furthermore, in the DP group, atrophied T2-LV was related to baseline brain parenchymal (p = 0.017) and thalamic (p = 0.003) volumes, thalamic volume change and follow-up SDMT (both p = 0.003). In non-DP patients, atrophied T2-LV was significantly related to baseline sNfL (p = 0.008), contrast-enhancing LV (p = 0.02) and percentage ventricular volume change (p = 0.003). Conclusion: Atrophied T2-LV is associated with disability accrual in MS, and to several multimodal markers of disease evolution. [ABSTRACT FROM AUTHOR]

A telestroke system was established between a community hospital lacking an on-call neurologist and a comprehensive stroke center only 13 km away. Our goal was to analyze the impact of telestroke on the number of intravenous thrombolysis (IVT), door-to-needle times and stroke outcomes. An observational before-and-after study of patients with acute ischemic stroke (IS) who were attended in a community hospital during the 2 years before the telestroke system was implemented (pre-telestroke group) and the first 2 years after telestroke was established (telestroke group). The number of IVT, the door-to-needle time (min), the outcomes [modified Rankin Scale (mRS)] and the safety (mortality and hemorrhagic transformations) were compared between groups. During the pre-telestroke years, 259 patients with IS were attended (28 phone activations), 12 of whom received IVT (4.7 %). During the telestroke years, 225 patients with IS were attended (42 telestroke activations), of whom 18 (8 %) received IVT. The door-to-needle times were lower in the telestroke group [median interquartile range: 66 (54) vs. 143.5 (48) min, P < 0.0001]. The safety was similar in both groups; however, the 3-month mRS scores were lower in the telestroke group ( P = 0.049). The multiple linear regression analysis showed a negative association between telestroke and door-to-needle time [ β-coefficient (SE) = −59.089 (14.461)], adjusted for confounders. In conclusion, telestroke systems are effective, even between nearby hospitals, shortening door-to-needle time and improving stroke outcomes. [ABSTRACT FROM AUTHOR]