Down-sampling in diffusion MRI: a bundle-specific DTI and NODDI study.

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.

Clinical value of neuroimaging indicators of intracranial hypertension in patients with cerebral venous thrombosis.

PURPOSE: Intracranial hypertension (IH) frequently complicates cerebral venous thrombosis (CVT). Distinct neuroimaging findings are associated with IH, yet their discriminative power, reversibility and factors favoring normalization in prospective CVT patients are unknown. We determined test performance measures of neuroimaging signs in acute CVT patients, their longitudinal change under anticoagulation, association with IH at baseline and with recanalization at follow-up. METHODS: We included 26 consecutive acute CVT patients and 26 healthy controls. Patients were classified as having IH based on CSF pressure > 25 cmH2O and/or papilledema on ophthalmological examination or ocular MRI. We assessed optic nerve sheath diameter (ONSD), optic nerve tortuousity, bulbar flattening, lateral and IVth ventricle size, pituitary configuration at baseline and follow-up, and their association with IH and venous recanalization. RESULTS: 46% of CVT patients had IH. ONSD enlargement > 5.8 mm, optic nerve tortuousity and pituitary grade ≥ III had highest sensitivity, ocular bulb flattening and pituitary grade ≥ III highest specificity for IH. Only ONSD reliably discriminated IH at baseline. Recanalization was significantly associated with regressive ONSD and pituitary grade. Other neuroimaging signs tended to regress with recanalization. After treatment, 184.9 ± 44.7 days after diagnosis, bulbar flattening resolved, whereas compared with controls ONSD enlargement (p < 0.001) and partially empty sella (p = 0.017), among other indicators, persisted. CONCLUSION: ONSD and pituitary grading have a high diagnostic value in diagnosing and monitoring CVT-associated IH. Given their limited sensitivity during early CVT and potentially persistent alterations following IH, neuroimaging indicators can neither replace CSF pressure measurement in diagnosing IH, nor determine the duration of anticoagulation.

A novel imaging marker of cortical "cellularity" in multiple sclerosis patients.

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.

Cervical and thoracic spinal cord gray matter atrophy is associated with disability in patients with amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: In amyotrophic lateral sclerosis (ALS), there is an unmet need for more precise patient characterization through quantitative, ideally operator-independent, assessments of disease extent and severity. Radially sampled averaged magnetization inversion recovery acquisitions (rAMIRA) magnetic resonance imaging enables gray matter (GM) and white matter (WM) area quantitation in the cervical and thoracic spinal cord (SC) with optimized contrast. We aimed to investigate rAMIRA-derived SC GM and SC WM areas and their association with clinical phenotype and disability in ALS. METHODS: A total of 36 patients with ALS (mean [SD] age 61.7 [12.6] years, 14 women) and 36 healthy, age- and sex-matched controls (HCs; mean [SD] age 63.1 [12.1] years, 14 women) underwent two-dimensional axial rAMIRA imaging at the inter-vertebral disc levels C2/3-C5/C6 and the lumbar enlargement level Tmax. ALS Functional Rating Scale-revised (ALSFRS-R) score, muscle strength, and sniff nasal inspiratory pressure (SNIP) were assessed. RESULTS: Compared to HCs, GM and WM areas were reduced in patients at all cervical levels (p < 0.0001). GM area (p = 0.0001), but not WM area, was reduced at Tmax. Patients with King's Stage 3 showed significant GM atrophy at all levels, while patients with King's Stage 1 showed significant GM atrophy selectively at Tmax. SC GM area was significantly associated with muscle force at corresponding myotomes. GM area at C3/C4 was associated with ALSFRS-R (p < 0.001) and SNIP (p = 0.0016). CONCLUSION: Patients with ALS assessed by rAMIRA imaging show significant cervical and thoracic SC GM and SC WM atrophy. SC GM area correlates with muscle strength and clinical disability. GM area reduction at Tmax may be an early disease sign. Longitudinal studies are warranted.

Association of Spinal Cord Atrophy and Brain Paramagnetic Rim Lesions With Progression Independent of Relapse Activity in People With MS.

BACKGROUND AND OBJECTIVES: Progression independent of relapse activity (PIRA) is a crucial determinant of overall disability accumulation in multiple sclerosis (MS). Accelerated brain atrophy has been shown in patients experiencing PIRA. In this study, we assessed the relation between PIRA and neurodegenerative processes reflected by (1) longitudinal spinal cord atrophy and (2) brain paramagnetic rim lesions (PRLs). Besides, the same relationship was investigated in progressive MS (PMS). Last, we explored the value of cross-sectional brain and spinal cord volumetric measurements in predicting PIRA. METHODS: From an ongoing multicentric cohort study, we selected patients with MS with (1) availability of a susceptibility-based MRI scan and (2) regular clinical and conventional MRI follow-up in the 4 years before the susceptibility-based MRI. Comparisons in spinal cord atrophy rates (explored with linear mixed-effect models) and PRL count (explored with negative binomial regression models) were performed between: (1) relapsing-remitting (RRMS) and PMS phenotypes and (2) patients experiencing PIRA and patients without confirmed disability accumulation (CDA) during follow-up (both considering the entire cohort and the subgroup of patients with RRMS). Associations between baseline MRI volumetric measurements and time to PIRA were explored with multivariable Cox regression analyses. RESULTS: In total, 445 patients with MS (64.9% female; mean [SD] age at baseline 45.0 [11.4] years; 11.2% with PMS) were enrolled. Compared with patients with RRMS, those with PMS had accelerated cervical cord atrophy (mean difference in annual percentage volume change [MD-APC] -1.41; p = 0.004) and higher PRL load (incidence rate ratio [IRR] 1.93; p = 0.005). Increased spinal cord atrophy (MD-APC -1.39; p = 0.0008) and PRL burden (IRR 1.95; p = 0.0008) were measured in patients with PIRA compared with patients without CDA; such differences were also confirmed when restricting the analysis to patients with RRMS. Baseline volumetric measurements of the cervical cord, whole brain, and cerebral cortex significantly predicted time to PIRA (all p ≤ 0.002). DISCUSSION: Our results show that PIRA is associated with both increased spinal cord atrophy and PRL burden, and this association is evident also in patients with RRMS. These findings further point to the need to develop targeted treatment strategies for PIRA to prevent irreversible neuroaxonal loss and optimize long-term outcomes of patients with MS.

Characteristics, Prevalence, and Clinical Relevance of Juxtacortical Paramagnetic Rims in Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: A subgroup of patients with multiple sclerosis (MS) presents focal paramagnetic rims at the border between cortex and white matter (juxtacortical paramagnetic rims [JPRs]). We investigated the presence of this finding in our in vivo MS cohort and explored its potential clinical relevance. Moreover, we exploited postmortem MRI of fixed whole MS brains to (1) detect those rims and (2) investigate their histologic correlation. METHODS: Quantitative susceptibility mapping (QSM) and magnetization-prepared 2 rapid acquisition gradient-echo (MP2RAGE) images at 3T-MRI of 165 patients with MS from the in vivo cohort were screened for JPRs and the presence of cortical lesions. Five postmortem brains from patients with MS were imaged with 3T-MRI to obtain QSM and MP2RAGE sequences. Tissue blocks containing JPRs were excised and paraffin-embedded slices stained by immunohistochemistry for myelin basic protein (for myelin) and anti-CR3/43 (for major histocompatibility complex II-positive microglia/macrophages). DAB-Turnbull stain was performed to detect iron. RESULTS: JPRs are present in approximately 10% of in vivo patients and are associated with increased cortical lesion load. One of the 5 postmortem brains showed JPRs. Histologically, JPRs correspond to an accumulation of activated iron-laden phagocytes and are associated with demyelination of the whole overlying cortical ribbon. DISCUSSION: JPRs are a novel potential MRI biomarker of focal cortical demyelination, which seems related to global cortical pathology and might be useful for diagnostic and stratification purposes in a clinical setting.

An investigation of the association between focal damage and global network properties in cognitively impaired and cognitively preserved patients with multiple sclerosis.

Introduction: The presence of focal cortical and white matter damage in patients with multiple sclerosis (pwMS) might lead to specific alterations in brain networks that are associated with cognitive impairment. We applied microstructure-weighted connectomes to investigate (i) the relationship between global network metrics and information processing speed in pwMS, and (ii) whether the disruption provoked by focal lesions on global network metrics is associated to patients' information processing speed. Materials and methods: Sixty-eight pwMS and 92 healthy controls (HC) underwent neuropsychological examination and 3T brain MRI including multishell diffusion (dMRI), 3D FLAIR, and MP2RAGE. Whole-brain deterministic tractography and connectometry were performed on dMRI. Connectomes were obtained using the Spherical Mean Technique and were weighted for the intracellular fraction. We identified white matter lesions and cortical lesions on 3D FLAIR and MP2RAGE images, respectively. PwMS were subdivided into cognitively preserved (CPMS) and cognitively impaired (CIMS) using the Symbol Digit Modalities Test (SDMT) z-score at cut-off value of -1.5 standard deviations. Statistical analyses were performed using robust linear models with age, gender, and years of education as covariates, followed by correction for multiple testing. Results: Out of 68 pwMS, 18 were CIMS and 50 were CPMS. We found significant changes in all global network metrics in pwMS vs HC (p < 0.05), except for modularity. All global network metrics were positively correlated with SDMT, except for modularity which showed an inverse correlation. Cortical, leukocortical, and periventricular lesion volumes significantly influenced the relationship between (i) network density and information processing speed and (ii) modularity and information processing speed in pwMS. Interestingly, this was not the case, when an exploratory analysis was performed in the subgroup of CIMS patients. Discussion: Our study showed that cortical (especially leukocortical) and periventricular lesions affect the relationship between global network metrics and information processing speed in pwMS. Our data also suggest that in CIMS patients increased focal cortical and periventricular damage does not linearly affect the relationship between network properties and SDMT, suggesting that other mechanisms (e.g. disruption of local networks, loss of compensatory processes) might be responsible for the development of processing speed deficits.

Personalized maps of T1 relaxometry abnormalities provide correlates of disability in multiple sclerosis patients.

OBJECTIVES AND AIMS: Quantitative MRI (qMRI) has greatly improved the sensitivity and specificity of microstructural brain pathology in multiple sclerosis (MS) when compared to conventional MRI (cMRI). More than cMRI, qMRI also provides means to assess pathology within the normal-appearing and lesion tissue. In this work, we further developed a method providing personalized quantitative T1 (qT1) abnormality maps in individual MS patients by modeling the age dependence of qT1 alterations. In addition, we assessed the relationship between qT1 abnormality maps and patients' disability, in order to evaluate the potential value of this measurement in clinical practice. METHODS: We included 119 MS patients (64 relapsing-remitting MS (RRMS), 34 secondary progressive MS (SPMS), 21 primary progressive MS (PPMS)), and 98 Healthy Controls (HC). All individuals underwent 3T MRI examinations, including Magnetization Prepared 2 Rapid Acquisition Gradient Echoes (MP2RAGE) for qT1 maps and High-Resolution 3D Fluid Attenuated Inversion Recovery (FLAIR) imaging. To calculate personalized qT1 abnormality maps, we compared qT1 in each brain voxel in MS patients to the average qT1 obtained in the same tissue (grey/white matter) and region of interest (ROI) in healthy controls, hereby providing individual voxel-based Z-score maps. The age dependence of qT1 in HC was modeled using linear polynomial regression. We computed the average qT1 Z-scores in white matter lesions (WMLs), normal-appearing white matter (NAWM), cortical grey matter lesions (GMcLs) and normal-appearing cortical grey matter (NAcGM). Lastly, a multiple linear regression (MLR) model with the backward selection including age, sex, disease duration, phenotype, lesion number, lesion volume and average Z-score (NAWM/NAcGM/WMLs/GMcLs) was used to assess the relationship between qT1 measures and clinical disability (evaluated with EDSS). RESULTS: The average qT1 Z-score was higher in WMLs than in NAWM. (WMLs: 1.366 ± 0.409, NAWM: -0.133 ± 0.288, [mean ± SD], p < 0.001). The average Z-score in NAWM in RRMS patients was significantly lower than in PPMS patients (p = 0.010). The MLR model showed a strong association between average qT1 Z-scores in white matter lesions (WMLs) and EDSS (R2 = 0.549, ß = 0.178, 97.5 % CI = 0.030 to 0.326, p = 0.019). Specifically, we measured a 26.9 % increase in EDSS per unit of qT1 Z-score in WMLs in RRMS patients (R2 = 0.099, ß = 0.269, 97.5 % CI = 0.078 to 0.461, p = 0.007). CONCLUSIONS: We showed that personalized qT1 abnormality maps in MS patients provide measures related to clinical disability, supporting the use of those maps in clinical practice.

Longitudinal assessment of cervical spinal cord compartments in multiple sclerosis.

BACKGROUND: Although cervical spinal cord (cSC) area is an established biomarker in MS, there is currently a lack of longitudinal assessments of cSC gray and white matter areas. OBJECTIVE: We conducted an explorative analysis of longitudinal changes of cSC gray and white matter areas in MS patients. METHODS: 65 MS patients (33 relapsing-remitting; 20 secondary progressive and 12 primary progressive) and 20 healthy controls (HC) received clinical and upper cSC MRI assessments over 1.10±0.28 years. cSC compartments were quantified on MRI using the novel averaged magnetization inversion recovery acquisitions sequence (in-plane resolution=0.67 × 0.67mm2), and in-house developed post-processing methods. Patients were stratified regarding clinical progression. RESULTS: Patients with clinical progression showed faster reduction of cSC areas over time at the level of cSC enlargement (approximate vertebral level C4-C5) compared to stable patients (p<0.05). In addition, when compared to the rostral-cSC (approximate vertebral level C2-C3), a preferential reduction of cSC and white matter areas over time at the level of cSC enlargement (p<0.05 and p<0.01, respectively) was demonstrated only in patients with clinical progression, but not in stable MS patients and HC. Compared to HC, MS patients showed comparable changes over time in all cSC compartments. CONCLUSIONS: MS patients with clinical disease progression demonstrate subtle signs of a more pronounced tissue loss at the level of cSC enlargement. Future studies should consider larger sample sizes and more extended observation periods.

A Multicenter Longitudinal MRI Study Assessing LeMan-PV Software Accuracy in the Detection of White Matter Lesions in Multiple Sclerosis Patients.

BACKGROUND: Detecting new and enlarged lesions in multiple sclerosis (MS) patients is needed to determine their disease activity. LeMan-PV is a software embedded in the scanner reconstruction system of one vendor, which automatically assesses new and enlarged white matter lesions (NELs) in the follow-up of MS patients; however, multicenter validation studies are lacking. PURPOSE: To assess the accuracy of LeMan-PV for the longitudinal detection NEL white-matter MS lesions in a multicenter clinical setting. STUDY TYPE: Retrospective, longitudinal. SUBJECTS: A total of 206 patients with a definitive MS diagnosis and at least two follow-up MRI studies from five centers participating in the Swiss Multiple Sclerosis Cohort study. Mean age at first follow-up = 45.2 years (range: 36.9-52.8 years); 70 males. FIELD STRENGTH/SEQUENCE: Fluid attenuated inversion recovery (FLAIR) and T1-weighted magnetization prepared rapid gradient echo (T1-MPRAGE) sequences at 1.5 T and 3 T. ASSESSMENT: The study included 313 MRI pairs of datasets. Data were analyzed with LeMan-PV and compared with a manual "reference standard" provided by a neuroradiologist. A second rater (neurologist) performed the same analysis in a subset of MRI pairs to evaluate the rating-accuracy. The Sensitivity (Se), Specificity (Sp), Accuracy (Acc), F1-score, lesion-wise False-Positive-Rate (aFPR), and other measures were used to assess LeMan-PV performance for the detection of NEL at 1.5 T and 3 T. The performance was also evaluated in the subgroup of 123 MRI pairs at 3 T. STATISTICAL TESTS: Intraclass correlation coefficient (ICC) and Cohen's kappa (CK) were used to evaluate the agreement between readers. RESULTS: The interreader agreement was high for detecting new lesions (ICC = 0.97, Pvalue < 10-20 , CK = 0.82, P value = 0) and good (ICC = 0.75, P value < 10-12 , CK = 0.68, P value = 0) for detecting enlarged lesions. Across all centers, scanner field strengths (1.5 T, 3 T), and for NEL, LeMan-PV achieved: Acc = 61%, Se = 65%, Sp = 60%, F1-score = 0.44, aFPR = 1.31. When both follow-ups were acquired at 3 T, LeMan-PV accuracy was higher (Acc = 66%, Se = 66%, Sp = 66%, F1-score = 0.28, aFPR = 3.03). DATA CONCLUSION: In this multicenter study using clinical data settings acquired at 1.5 T and 3 T, and variations in MRI protocols, LeMan-PV showed similar sensitivity in detecting NEL with respect to other recent 3 T multicentric studies based on neural networks. While LeMan-PV performance is not optimal, its main advantage is that it provides automated clinical decision support integrated into the radiological-routine flow. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Anterior horn atrophy in the cervical spinal cord: A new biomarker in progressive multiple sclerosis.

BACKGROUND: Spinal cord (SC) gray and white matter pathology plays a central role in multiple sclerosis (MS). OBJECTIVE: We aimed to investigate the extent, pattern, and clinical relevance of SC gray and white matter atrophy in vivo. METHODS: 39 relapsing-remitting patients (RRMS), 40 progressive MS patients (PMS), and 24 healthy controls (HC) were imaged at 3T using the averaged magnetization inversion recovery acquisitions sequence. Total and lesional cervical gray and white matter, and posterior (SCPH) and anterior horn (SCAH) areas were automatically quantified. Clinical assessment included the expanded disability status scale, timed 25-foot walk test, nine-hole peg test, and the 12-item MS walking scale. RESULTS: PMS patients had significantly reduced cervical SCAH - but not SCPH - areas compared with HC and RRMS (both p < 0.001). In RRMS and PMS, the cervical SCAH areas increased significantly less in the region of cervical SC enlargement compared with HC (all p < 0.001). This reduction was more pronounced in PMS compared with RRMS (both p < 0.001). In PMS, a lower cervical SCAH area was the most important magnetic resonance imaging (MRI)-variable for higher disability scores. CONCLUSION: MS patients show clinically relevant cervical SCAH atrophy, which is more pronounced in PMS and at the level of cervical SC enlargement.

Postmortem quantitative MRI disentangles histological lesion types in multiple sclerosis.

Quantitative MRI (qMRI) probes the microstructural properties of the central nervous system (CNS) by providing biophysical measures of tissue characteristics. In this work, we aimed to (i) identify qMRI measures that distinguish histological lesion types in postmortem multiple sclerosis (MS) brains, especially the remyelinated ones; and to (ii) investigate the relationship between those measures and quantitative histological markers of myelin, axons, and astrocytes in the same experimental setting. Three fixed MS whole brains were imaged with qMRI at 3T to obtain magnetization transfer ratio (MTR), myelin water fraction (MWF), quantitative T1 (qT1), quantitative susceptibility mapping (QSM), fractional anisotropy (FA) and radial diffusivity (RD) maps. The identification of lesion types (active, inactive, chronic active, or remyelinated) and quantification of tissue components were performed using histological staining methods as well as immunohistochemistry and immunofluorescence. Pairwise logistic and LASSO regression models were used to identify the best qMRI discriminators of lesion types. The association between qMRI and quantitative histological measures was performed using Spearman's correlations and linear mixed-effect models. We identified a total of 65 lesions. MTR and MWF best predicted the chance of a lesion to be remyelinated, whereas RD and QSM were useful in the discrimination of active lesions. The measurement of microstructural properties through qMRI did not show any difference between chronic active and inactive lesions. MWF and RD were associated with myelin content in both lesions and normal-appearing white matter (NAWM), FA was the measure most associated with axon content in both locations, while MWF was associated with astrocyte immunoreactivity only in lesions. Moreover, we provided evidence of extensive astrogliosis in remyelinated lesions. Our study provides new information on the discriminative power of qMRI in differentiating MS lesions -especially remyelinated ones- as well as on the relative association between multiple qMRI measures and myelin, axon and astrocytes.

Evaluation of tractography-based myelin-weighted connectivity across the lifespan.

Introduction: Recent studies showed that the myelin of the brain changes in the life span, and demyelination contributes to the loss of brain plasticity during normal aging. Diffusion-weighted magnetic resonance imaging (dMRI) allows studying brain connectivity in vivo by mapping axons in white matter with tractography algorithms. However, dMRI does not provide insight into myelin; thus, combining tractography with myelin-sensitive maps is necessary to investigate myelin-weighted brain connectivity. Tractometry is designated for this purpose, but it suffers from some serious limitations. Our study assessed the effectiveness of the recently proposed Myelin Streamlines Decomposition (MySD) method in estimating myelin-weighted connectomes and its capacity to detect changes in myelin network architecture during the process of normal aging. This approach opens up new possibilities compared to traditional Tractometry. Methods: In a group of 85 healthy controls aged between 18 and 68 years, we estimated myelin-weighted connectomes using Tractometry and MySD, and compared their modulation with age by means of three well-known global network metrics. Results: Following the literature, our results show that myelin development continues until brain maturation (40 years old), after which degeneration begins. In particular, mean connectivity strength and efficiency show an increasing trend up to 40 years, after which the process reverses. Both Tractometry and MySD are sensitive to these changes, but MySD turned out to be more accurate. Conclusion: After regressing the known predictors, MySD results in lower residual error, indicating that MySD provides more accurate estimates of myelin-weighted connectivity than Tractometry.

A comparative assessment of myelin-sensitive measures in multiple sclerosis patients and healthy subjects.

INTRODUCTION: Multiple Sclerosis (MS) is a common neurological disease primarily characterized by myelin damage in lesions and in normal - appearing white and gray matter (NAWM, NAGM). Several quantitative MRI (qMRI) methods are sensitive to myelin characteristics by measuring specific tissue biophysical properties. However, there are currently few studies assessing the relative reproducibility and sensitivity of qMRI measures to MS pathology in vivo in patients. METHODS: We performed two studies. The first study assessed of the sensitivity of qMRI measures to MS pathology: in this work, we recruited 150 MS and 100 healthy subjects, who underwent brain MRI at 3 T including quantitative T1 mapping (qT1), quantitative susceptibility mapping (QSM), magnetization transfer saturation imaging (MTsat) and myelin water imaging for myelin water fraction (MWF). The sensitivity of qMRIs to MS focal pathology (MS lesions vs peri-plaque white/gray matter (PPWM/PPGM)) was studied lesion-wise; the sensitivity to diffuse normal appearing (NA) pathology was measured using voxel-wise threshold-free cluster enhancement (TFCE) in NAWM and vertex-wise inflated cortex analysis in NAGM. Furthermore, the sensitivity of qMRI to the identification of lesion tissue was investigated using a voxel-wise logistic regression analysis to distinguish MS lesion and PP voxels. The second study assessed the reproducibility of myelin-sensitive qMRI measures in a single scanner. To evaluate the intra-session and inter-session reproducibility of qMRI measures, we have investigated 10 healthy subjects, who underwent two brain 3 T MRIs within the same day (without repositioning), and one after 1-week interval. Five region of interest (ROIs) in white and deep grey matter areas were segmented, and inter- and intra- session reproducibility was studied using the intra-class correlation coefficient (ICC). Further, we also investigated the voxel-wise reproducibility of qMRI measures in NAWM and NAGM. RESULTS: qT1 and QSM showed the highest sensitivity to distinguish MS focal WM and cortical pathology from peri-plaque WM (P < 0.0001), although QSM also showed the highest variance when applied to lesions. MWF and MTsat exhibited the highest sensitivity to NAWM pathology (P < 0.01). On the other hand, qT1 appeared to be the most sensitive measure to NAGM pathology (P < 0.01). All myelin-sensitive qMRI measures exhibited high inter/intra sessional ICCs in various WM and deep GM ROIs, in NAWM and in NAGM (ICC 0.82 ± 0.12). CONCLUSION: This work shows that the applied qT1, MWF, MTsat and QSM are highly reproducible and exhibit differential sensitivity to focal and diffuse WM and GM pathology in MS patients.

A New Advanced MRI Biomarker for Remyelinated Lesions in Multiple Sclerosis.

OBJECTIVES: Neuropathological studies have shown that multiple sclerosis (MS) lesions are heterogeneous in terms of myelin/axon damage and repair as well as iron content. However, it remains a challenge to identify specific chronic lesion types, especially remyelinated lesions, in vivo in patients with MS. METHODS: We performed 3 studies: (1) a cross-sectional study in a prospective cohort of 115 patients with MS and 76 healthy controls, who underwent 3 T magnetic resonance imaging (MRI) for quantitative susceptibility mapping (QSM), myelin water fraction (MWF), and neurite density index (NDI) maps. White matter (WM) lesions in QSM were classified into 5 QSM lesion types (iso-intense, hypo-intense, hyperintense, lesions with hypo-intense rims, and lesions with paramagnetic rim legions [PRLs]); (2) a longitudinal study of 40 patients with MS to study the evolution of lesions over 2 years; (3) a postmortem histopathology-QSM validation study in 3 brains of patients with MS to assess the accuracy of QSM classification to identify neuropathological lesion types in 63 WM lesions. RESULTS: At baseline, hypo- and isointense lesions showed higher mean MWF and NDI values compared to other QSM lesion types (p < 0.0001). Further, at 2-year follow-up, hypo-/iso-intense lesions showed an increase in MWF. Postmortem analyses revealed that QSM highly accurately identifies (1) fully remyelinated areas as hypo-/iso-intense (sensitivity = 88.89% and specificity = 100%), (2) chronic inactive lesions as hyperintense (sensitivity = 71.43% and specificity = 92.00%), and (3) chronic active/smoldering lesions as PRLs (sensitivity = 92.86% and specificity = 86.36%). INTERPRETATION: These results provide the first evidence that it is possible to distinguish chronic MS lesions in a clinical setting, hereby supporting with new biomarkers to develop and assess remyelinating treatments. ANN NEUROL 2022;92:486-502.

Association of Brain Atrophy With Disease Progression Independent of Relapse Activity in Patients With Relapsing Multiple Sclerosis.

Importance: The mechanisms driving neurodegeneration and brain atrophy in relapsing multiple sclerosis (RMS) are not completely understood. Objective: To determine whether disability progression independent of relapse activity (PIRA) in patients with RMS is associated with accelerated brain tissue loss. Design, Setting, and Participants: In this observational, longitudinal cohort study with median (IQR) follow-up of 3.2 years (2.0-4.9), data were acquired from January 2012 to September 2019 in a consortium of tertiary university and nonuniversity referral hospitals. Patients were included if they had regular clinical follow-up and at least 2 brain magnetic resonance imaging (MRI) scans suitable for volumetric analysis. Data were analyzed between January 2020 and March 2021. Exposures: According to the clinical evolution during the entire observation, patients were classified as those presenting (1) relapse activity only, (2) PIRA episodes only, (3) mixed activity, or (4) clinical stability. Main Outcomes and Measures: Mean difference in annual percentage change (MD-APC) in brain volume/cortical thickness between groups, calculated after propensity score matching. Brain atrophy rates, and their association with the variables of interest, were explored with linear mixed-effect models. Results: Included were 1904 brain MRI scans from 516 patients with RMS (67.4% female; mean [SD] age, 41.4 [11.1] years; median [IQR] Expanded Disability Status Scale score, 2.0 [1.5-3.0]). Scans with insufficient quality were excluded (n = 19). Radiological inflammatory activity was associated with increased atrophy rates in several brain compartments, while an increased annualized relapse rate was linked to accelerated deep gray matter (GM) volume loss. When compared with clinically stable patients, patients with PIRA had an increased rate of brain volume loss (MD-APC, -0.36; 95% CI, -0.60 to -0.12; P = .02), mainly driven by GM loss in the cerebral cortex. Patients who were relapsing presented increased whole brain atrophy (MD-APC, -0.18; 95% CI, -0.34 to -0.02; P = .04) with respect to clinically stable patients, with accelerated GM loss in both cerebral cortex and deep GM. No differences in brain atrophy rates were measured between patients with PIRA and those presenting relapse activity. Conclusions and Relevance: Our study shows that patients with RMS and PIRA exhibit accelerated brain atrophy, especially in the cerebral cortex. These results point to the need to recognize the insidious manifestations of PIRA in clinical practice and to further evaluate treatment strategies for patients with PIRA in clinical trials.

Fluid and White Matter Suppression: New Sensitive 3 T Magnetic Resonance Imaging Contrasts for Cortical Lesion Detection in Multiple Sclerosis.

OBJECTIVE: Cortical lesions are common in multiple sclerosis (MS), but their visualization is challenging on conventional magnetic resonance imaging. The uniform image derived from magnetization prepared 2 rapid acquisition gradient echoes (MP2RAGE uni ) detects cortical lesions with a similar rate as the criterion standard sequence, double inversion recovery. Fluid and white matter suppression (FLAWS) provides multiple reconstructed contrasts acquired during a single acquisition. These contrasts include FLAWS minimum image (FLAWS min ), which provides an exquisite sensitivity to the gray matter signal and therefore may facilitate cortical lesion identification, as well as high contrast FLAWS (FLAWS hco ), which gives a contrast that is similar to one of MP2RAGE uni . In this study, we compared the manual detection rate of cortical lesions on MP2RAGE uni , FLAWS min , and FLAWS hco in MS patients. Furthermore, we assessed whether the combined detection rate on FLAWS min and FLAWS hco was superior to MP2RAGE uni for cortical lesions identification. Last, we compared quantitative T1 maps (qT1) provided by both MP2RAGE and FLAWS in MS lesions. MATERIALS AND METHODS: We included 30 relapsing-remitting MS patients who underwent MP2RAGE and FLAWS magnetic resonance imaging with isotropic spatial resolution of 1 mm at 3 T. Cortical lesions were manually segmented by consensus of 3 trained raters and classified as intracortical or leukocortical lesions on (1) MP2RAGE uniform/flat images, (2) FLAWS min , and (3) FLAWS hco . In addition, segmented lesions on FLAWS min and FLAWS hco were merged to produce a union lesion map (FLAWS min + hco ). Number and volume of all cortical, intracortical, and leukocortical lesions were compared among MP2RAGE uni , FLAWS min , and FLAWS hco using Friedman test and between MP2RAGE uni and FLAWS min + hco using Wilcoxon signed rank test. The FLAWS T1 maps were then compared with the reference MP2RAGE T1 maps using relative differences in percentage. In an exploratory analysis, individual cortical lesion counts of the 3 raters were compared, and interrater variability was quantified using Fleiss Ï°. RESULTS: In total, 633 segmentations were made on the 3 contrasts, corresponding to 355 cortical lesions. The median number and volume of single cortical, intracortical, and leukocortical lesions were comparable among MP2RAGE uni , FLAWS min , and FLAWS hco . In patients with cortical lesions (22/30), median cumulative lesion volume was larger on FLAWS min (587 µL; IQR, 1405 µL) than on MP2RAGE uni (490 µL; IQR, 990 µL; P = 0.04), whereas there was no difference between FLAWS min and FLAWS hco , or FLAWS hco and MP2RAGE uni . FLAWS min + hco showed significantly greater numbers of cortical (median, 4.5; IQR, 15) and leukocortical (median, 3.5; IQR, 12) lesions than MP2RAGE uni (median, 3; IQR, 10; median, 2.5; IQR, 7; both P < 0.001). Interrater agreement was moderate on MP2RAGE uni (Ï° = 0.582) and FLAWS hco (Ï° = 0.584), but substantial on FLAWS min (Ï° = 0.614). qT1 in lesions was similar between MP2RAGE and FLAWS. CONCLUSIONS: Cortical lesions identification in FLAWS min and FLAWS hco was comparable to MP2RAGE uni . The combination of FLAWS min and FLAWS hco allowed to identify a higher number of cortical lesions than MP2RAGE uni , whereas qT1 maps did not differ between the 2 acquisition schemes.

Spinal cord gray matter atrophy is associated with functional decline in post-polio syndrome.

OBJECTIVE: To determine if patients with post-polio syndrome (PPS) show spinal cord gray matter (SCGM) atrophy and to assess associations between SCGM atrophy, muscle strength and patient-reported functional decline. METHODS: Twenty patients diagnosed with PPS (March of Dimes criteria) and 20 age- and sex-matched healthy controls (HC) underwent 3T axial 2D-rAMIRA magnetic resonance imaging at the intervertebral disc levels C2/C3-C6/C7, T9/T10 and the lumbar enlargement level (Tmax ) (0.5 × 0.5 mm2 in-plane resolution). SCGM areas were segmented manually by two independent raters. Muscle strength, self-reported fatigue, depression and pain measures were assessed. RESULTS: Post-polio syndrome patients showed significantly and preferentially reduced SCGM areas at C2/C3 (p = 0.048), C3/C4 (p = 0.001), C4/C5 (p < 0.001), C5/C6 (p = 0.004) and Tmax (p = 0.041) compared to HC. SCGM areas were significantly associated with muscle strength in corresponding myotomes even after adjustment for fatigue, pain and depression. SCGM areaTmax together with age and sex explained 68% of ankle dorsiflexion strength variance. No associations were found with age at or time since infection. Patients reporting PPS-related decline in arm function showed significant cervical SCGM atrophy compared to stable patients adjusted for initial disease severity. CONCLUSIONS: Patients with PPS show significant SCGM atrophy that correlates with muscle strength and is associated with PPS-related functional decline. Our findings suggest a secondary neurodegenerative process underlying SCGM atrophy in PPS that is not explained by aging or residua of the initial infection alone. Confirmation by longitudinal studies is needed. The described imaging methodology is promising for developing novel imaging surrogates for SCGM diseases.

Bundle myelin fraction (BMF) mapping of different white matter connections using microstructure informed tractography.

To date, we have scarce information about the relative myelination level of different fiber bundles in the human brain. Indirect evidence comes from postmortem histology data but histological stainings are unable to follow a specific bundle and determine its intrinsic myelination. In this context, quantitative MRI, and diffusion MRI tractography may offer a viable solution by providing, respectively, voxel-wise myelin sensitive maps and the pathways of the major tracts of the brain. Then, "tractometry" can be used to combine these two pieces of information by averaging tissue features (obtained from any voxel-wise map) along the streamlines recovered with diffusion tractography. Although this method has been widely used in the literature, in cases of voxels containing multiple fiber populations (each with different levels of myelination), tractometry provides biased results because the same value will be attributed to any bundle passing through the voxel. To overcome this bias, we propose a new method - named "myelin streamline decomposition" (MySD) - which extends convex optimization modeling for microstructure informed tractography (COMMIT) allowing the actual value measured by a microstructural map to be deconvolved on each individual streamline, thereby recovering unique bundle-specific myelin fractions (BMFs). We demonstrate the advantage of our method with respect to tractometry in well-studied bundles and compare the cortical projection of the obtained bundle-wise myelin values of both methods. We also prove the stability of our approach across different subjects and different MRI sensitive myelin mapping approaches. This work provides a proof-of-concept of in vivo investigations of entire neuronal pathways that, to date, are not possible.