Background and Objectives Progression independent of relapse activity (PIRA) is associated with worse outcomes in people with multiple sclerosis (pwMS). Although previous research has linked PIRA to accelerated brain and spinal cord atrophy and compartmentalized chronic inflammation, the role of white matter (WM) tract degeneration remains unclear. This study aimed to explore the relationship between PIRA and the integrity of major WM tracts using diffusion tensor imaging (DTI). Methods A cohort of 258 pwMS was stratified based on the presence or absence of PIRA over a 4-year follow-up period. At the end of follow-up, DTI metrics were compared between groups using propensity score–weighted linear regression models to account for potential confounders. Results PwMS with ≥1 PIRA event (n = 39) exhibited significant reductions in fractional anisotropy and increases in radial, axial, and mean diffusivity within the corpus callosum and motor tracts (false discovery rate–adjusted p ≤ 0.04) compared with those without PIRA, indicating more pronounced WM damage. Discussion Our findings highlight an association between PIRA and microstructural damage in key WM tracts. The observed DTI changes likely reflect processes such as Wallerian degeneration and contribute to the growing evidence linking PIRA to neurodegeneration.

Remyelination of cortical lesions in people with multiple sclerosis (pwMS) has been shown to be extensive. In this work, we aimed to assess whether postmortem quantitative MRI (qMRI) can help detect those areas. We imaged six fixed whole brains of deceased pwMS by 3T-MRI using magnetization transfer ratio (MTR, 570 μm isotropic), myelin water fraction (MWF, 1000 μm isotropic), quantitative T1 (qT1, 670 μm isotropic), quantitative susceptibility mapping (QSM, 330 μm isotropic) and radial diffusivity (RD, 1300 or 1400 μm isotropic) maps. Immunohistochemistry for myelin proteins was performed in 129 tissue blocks including the cortex and enabled the detection of cortical demyelination (DM), cortical remyelination (RM), and normal-appearing cortex (NAC). We identified 25 DM, 25 RM, and for each of these areas, a corresponding NAC near the lesion. Wilcoxon paired tests showed that: (a) qT1 and RD were higher and QSM lower in DM versus NAC (all p < 0.001), whereas RD was higher and QSM lower in RM versus NAC (p = 0.048 and p < 0.01 respectively); (b) mean qT1 in RM did not differ from mean qT1 in NAC (p = 0.074); (c) MWF and MTR were not different between DM and RM. We compared the delta between DM versus NAC (∆DM) and the delta between RM versus NAC (∆RM) using a Mann-Whitney test, in which RM showed a partial recovery of qT1 only (∆qT1 DM > ∆qT1 RM, p = 0.045). Mixed-effect models confirmed the findings obtained using univariate analyses. qT1 and QSM, but not RD, correlated with MBP intensity (r = -0.28, p < 0.01 and r = 0.29, p < 0.01 respectively). A Bonferroni correction was performed for multiple testing. Our data show that qT1 is altered in demyelinated but not in remyelinated cortical areas, while QSM and RD are affected by any cortical abnormalities. Accordingly, qT1 might be considered a potential imaging biomarker of cortical RM.

Traditional Diffusion Tensor Imaging (DTI) metrics are affected by crossing fibers and lesions. Most of the previous tractometry works use the single diffusion tensor, which leads to limited sensitivity and challenging interpretation of the results in crossing fiber regions. In this work, we propose a tractometry pipeline that combines white matter tractography with multi-tensor fixel-based metrics. These multi-tensors are estimated using the stable, accurate and robust to noise Multi-Resolution Discrete Search method (MRDS). The spatial coherence of the multi-tensor field estimated with MRDS, which includes up to three anisotropic and one isotropic tensors, is tractography-regularized using the Track Orientation Density Imaging method. Our end-to-end tractometry pipeline goes from raw data to track-specific multi-tensor-metrics tract profiles that are robust to noise and crossing fibers. A comprehensive evaluation conducted in a phantom simulating healthy and damaged tissue with the standard model, as well as in a healthy cohort of 20 individuals scanned along 5 time points, demonstrates the advantages of using multi-tensor metrics over traditional single-tensor metrics in tractometry. Qualitative assessment in a cohort of patients with relapsing-remitting multiple sclerosis reveals that the pipeline effectively detects white matter anomalies in the presence of crossing fibers and lesions.

Pathological studies suggest that multiple sclerosis (MS) lesions endure multiple waves of damage and repair; however, the dynamics and characteristics of these processes are poorly understood in patients living with MS.

Background and Objectives In patients with multiple sclerosis (PwMS), thalamic atrophy occurs during the disease course. However, there is little understanding of the mechanisms leading to volume loss and of the relationship between microstructural thalamic pathology and disease progression. This cross-sectional and longitudinal study aimed to comprehensively characterize in vivo pathologic changes within thalamic microstructure in PwMS using advanced multiparametric quantitative MRI (qMRI). Methods Thalamic microstructural integrity was evaluated using quantitative T1, magnetization transfer saturation, multishell diffusion, and quantitative susceptibility mapping (QSM) in 183 PwMS and 105 healthy controls (HCs). The same qMRI protocol was available for 127 PwMS and 73 HCs after a 2-year follow-up period. Inclusion criteria for PwMS encompassed either an active relapsing-remitting MS (RRMS) or inactive progressive MS (PMS) disease course. Thalamic alterations were compared between PwMS and HCs and among disease phenotypes. In addition, the study investigated the relationship between thalamic damage and clinical and conventional MRI measures of disease severity. Results Compared with HCs, PwMS exhibited substantial thalamic alterations, indicative of microstructural and macrostructural damage, demyelination, and disruption in iron homeostasis. These alterations extended beyond focal thalamic lesions, affecting normal-appearing thalamic tissue diffusely. Over the follow-up period, PwMS displayed an accelerated decrease in myelin volume fraction [mean difference in annualized percentage change (MD-ApC) = −1.50; p = 0.041] and increase in quantitative T1 (MD-ApC = 0.92; p < 0.0001) values, indicating heightened demyelinating and neurodegenerative processes. The observed differences between PwMS and HCs were substantially driven by the subgroup with PMS, wherein thalamic degeneration was significantly accelerated, even in comparison with patients with RRMS. Thalamic qMRI alterations showed extensive correlations with conventional MRI, clinical, and cognitive disease burden measures. Disability progression over follow-up was associated with accelerated thalamic degeneration, as reflected by enhanced diffusion (β = −0.067; p = 0.039) and QSM (β = −0.077; p = 0.027) changes. Thalamic qMRI metrics emerged as significant predictors of neurologic and cognitive disability even when accounting for other established markers including white matter lesion load and brain and thalamic atrophy. Discussion These findings offer deeper insights into thalamic pathology in PwMS, emphasizing the clinical relevance of thalamic damage and its link to disease progression. Advanced qMRI biomarkers show promising potential in guiding interventions aimed at mitigating thalamic neurodegenerative processes.

Background and Objectives Myelin and iron play essential roles in remyelination processes of multiple sclerosis (MS) lesions. χ-separation, a novel biophysical model applied to multiecho T2*-data and T2-data, estimates the contribution of myelin and iron to the obtained susceptibility signal. We used this method to investigate myelin and iron levels in lesion and nonlesion brain areas in patients with MS and healthy individuals. Methods This prospective MS cohort study included patients with MS fulfilling the McDonald Criteria 2017 and healthy individuals, aged 18 years or older, with no other neurologic comorbidities. Participants underwent MRI at baseline and after 2 years, including multiecho GRE-(T2*) and FAST-(T2) sequences. Using χ-separation, we generated myelin-sensitive and iron-sensitive susceptibility maps. White matter lesions (WMLs), cortical lesions (CLs), surrounding normal-appearing white matter (NAWM), and normal-appearing gray matter were segmented on fluid-attenuated inversion recovery and magnetization-prepared 2 rapid gradient echo images, respectively. Cross-sectional group comparisons used Wilcoxon rank-sum tests, longitudinal analyses applied Wilcoxon signed-rank tests. Associations with clinical outcomes (disease phenotype, age, sex, disease duration, disability measured by Expanded Disability Status Scale [EDSS], neurofilament light chain levels, and T2-lesion number and volume) were assessed using linear regression models. Results Of 168 patients with MS (median [interquartile range (IQR)] age 47.0 [21.7] years; 101 women; 6,898 WMLs, 775 CLs) and 103 healthy individuals (age 33.0 [10.5] years, 57 women), 108 and 62 were followed for a median of 2 years, respectively (IQR 0.1; 5,030 WMLs, 485 CLs). At baseline, WMLs had lower myelin (median 0.025 [IQR 0.015] parts per million [ppm]) and iron (0.017 [0.015] ppm) than the corresponding NAWM (myelin 0.030 [0.012]; iron 0.019 [0.011] ppm; both p < 0.001). After 2 years, both myelin (0.027 [0.014] ppm) and iron had increased (0.018 [0.015] ppm; both p < 0.001). Younger age (p < 0.001, b = −5.111 × 10−5), lower disability (p = 0.04, b = −2.352 × 10−5), and relapsing-remitting phenotype (RRMS, 0.003 [0.01] vs primary progressive 0.002 [IQR 0.01], p < 0.001; vs secondary progressive 0.0004 [IQR 0.01], p < 0.001) at baseline were associated with remyelination. Increment of myelin correlated with clinical improvement measured by EDSS (p = 0.015, b = −6.686 × 10−4). Discussion χ-separation, a novel mathematical model applied to multiecho T2*-images and T2-images shows that young RRMS patients with low disability exhibit higher remyelination capacity, which correlated with clinical disability over a 2-year follow-up.

To fully characterize the orientation dependence of magnetization transfer (MT) and inhomogeneous MT (ihMT) measures in the whole white matter (WM), for both single‐fiber and crossing‐fiber voxels.

Pathological data showed focal inflammation and regions of diffuse neuronal loss in the cortex of people with multiple sclerosis (MS). In this work, we applied a novel model ("soma and neurite density imaging (SANDI)") to multishell diffusion-weighted MRI data acquired in healthy subjects and people with multiple sclerosis (pwMS), in order to investigate inflammation and degeneration-related changes in the cortical tissue of pwMS. We aimed to (i) establish whether SANDI is applicable in vivo clinical data; (ii) investigate inflammatory and degenerative changes using SANDI soma fraction (fsoma)-a marker of cellularity-in both cortical lesions and in the normal-appearing-cortex and (iii) correlate SANDI fsoma with clinical and biological measures in pwMS. We applied a simplified version of SANDI to a clinical scanners. We then provided evidence that pwMS exhibited an overall decrease in cortical SANDI fsoma compared to healthy subjects, suggesting global degenerative processes compatible with neuronal loss. On the other hand, we have found that progressive pwMS showed a higher SANDI fsoma in the outer part of the cortex compared to relapsing-remitting pwMS, possibly supporting current pathological knowledge of increased innate inflammatory cells in these regions. A similar finding was obtained in subpial lesions in relapsing-remitting patients, reflecting existing pathological data in these lesion types. A significant correlation was found between SANDI fsoma and serum neurofilament light chain-a biomarker of inflammatory axonal damage-suggesting a relationship between SANDI soma fraction and inflammatory processes in pwMS again. Overall, our data show that SANDI fsoma is a promising biomarker to monitor changes in cellularity compatible with neurodegeneration and neuroinflammation in the cortex of MS patients.

Introduction Multi-shell diffusion Magnetic Resonance Imaging (dMRI) data has been widely used to characterise white matter microstructure in several neurodegenerative diseases. The lack of standardised dMRI protocols often implies the acquisition of redundant measurements, resulting in prolonged acquisition times. In this study, we investigate the impact of the number of gradient directions on Diffusion Tensor Imaging (DTI) and on Neurite Orientation Dispersion and Density Imaging (NODDI) metrics. Methods Data from 124 healthy controls collected in three different longitudinal studies were included. Using an in-house algorithm, we reduced the number of gradient directions in each data shell. We estimated DTI and NODDI measures on six white matter bundles clinically relevant for neurodegenerative diseases. Results Fractional Anisotropy (FA) measures on bundles where data were sampled at the 30% rate, showed a median L1 distance of up to 3.92% and a 95% CI of (1.74, 8.97)% when compared to those obtained at reference sampling. Mean Diffusivity (MD) reached up to 4.31% and a 95% CI of (1.60, 16.98)% on the same premises. At a sampling rate of 50%, we obtained a median of 3.90% and a 95% CI of (1.99, 16.65)% in FA, and 5.49% with a 95% CI of (2.14, 21.68)% in MD. The Intra-Cellular volume fraction (ICvf) median L1 distance was up to 2.83% with a 95% CI of (1.98, 4.82)% at a 30% sampling rate and 3.95% with a 95% CI of (2.39, 7.81)% at a 50% sampling rate. The volume difference of the reconstructed white matter at reference and 50% sampling reached a maximum of (2.09 ± 0.81)%. Discussion In conclusion, DTI and NODDI measures reported at reference sampling were comparable to those obtained when the number of dMRI volumes was reduced by up to 30%. Close to reference DTI and NODDI metrics were estimated with a significant reduction in acquisition time using three shells, respectively with: 4 directions at a b value of 700 s/mm2, 14 at 1000 s/mm2, and 32 at 2000 s/mm2. The study revealed aspects that can be important for large-scale clinical studies on bundle-specific diffusion MRI.