Determinants and Biomarkers of Progression Independent of Relapses in Multiple Sclerosis.

Clinical, pathological, and imaging evidence in multiple sclerosis (MS) suggests that a smoldering inflammatory activity is present from the earliest stages of the disease and underlies the progression of disability, which proceeds relentlessly and independently of clinical and radiological relapses (PIRA). The complex system of pathological events driving "chronic" worsening is likely linked with the early accumulation of compartmentalized inflammation within the central nervous system as well as insufficient repair phenomena and mitochondrial failure. These mechanisms are partially lesion-independent and differ from those causing clinical relapses and the formation of new focal demyelinating lesions; they lead to neuroaxonal dysfunction and death, myelin loss, glia alterations, and finally, a neuronal network dysfunction outweighing central nervous system (CNS) compensatory mechanisms. This review aims to provide an overview of the state of the art of neuropathological, immunological, and imaging knowledge about the mechanisms underlying the smoldering disease activity, focusing on possible early biomarkers and their translation into clinical practice. ANN NEUROL 2024.

Resting state functional connectivity modifications in monoaminergic circuits underpin fatigue development in patients with multiple sclerosis.

Dysregulation of monoaminergic networks might have a role in the pathogenesis of fatigue in multiple sclerosis (MS). We investigated longitudinal changes of resting state (RS) functional connectivity (FC) in monoaminergic networks and their association with the development of fatigue in MS. Eighty-nine MS patients and 49 age- and sex-matched healthy controls (HC) underwent neurological, fatigue, and RS functional MRI assessment at baseline and after a median follow-up of 1.3 years (interquartile range = 1.01-2.01 years). Monoaminergic-related RS FC was estimated with an independent component analysis constrained to PET atlases for dopamine (DA), noradrenaline (NA), and serotonin (5-HT) transporters. At baseline, 24 (27%) MS patients were fatigued (F) and 65 were not fatigued (NF). Of these, 22 (34%) developed fatigue (DEV-FAT) at follow-up and 43 remained not fatigued (NO-FAT). At baseline, F-MS patients showed increased monoaminergic-related RS FC in the caudate nucleus vs NF-MS and in the hippocampal, postcentral, temporal, and occipital cortices vs NF-MS and HC. Moreover, F-MS patients exhibited decreased RS FC in the frontal cortex vs NF-MS and HC, and in the thalamus vs NF-MS. During the follow-up, no RS FC changes were observed in HC. NO-FAT patients showed limited DA-related RS FC modifications, whereas DEV-FAT MS patients showed increased DA-related RS FC in the left hippocampus, significant at time-by-group interaction analysis. In the NA-related network, NO-FAT patients showed decreased RS FC over time in the left superior frontal gyrus. This region showed increased RS FC in both DEV-FAT and F-MS patients; this divergent behavior was significant at time-by-group interaction analysis. Finally, DEV-FAT MS patients presented increased 5-HT-related RS FC in the angular and middle occipital gyri, while this latter region showed decreased 5-HT-related RS FC during the follow-up in F-MS patients. In MS patients, distinct patterns of alterations were observed in monoaminergic networks based on their fatigue status. Fatigue was closely linked to specific changes in the basal ganglia and hippocampal, superior frontal, and middle occipital cortices.

Radiologically isolated syndromes: to treat or not to treat?

The widespread use of magnetic resonance imaging (MRI) has led to increased detection of individuals exhibiting asymptomatic brain and spinal cord lesions suggestive of multiple sclerosis (MS), defined as "radiologically isolated syndrome" (RIS). Specific criteria have been proposed and updated over time to identify individuals with RIS. Moreover, a younger age, the presence of infratentorial, spinal cord or gadolinium-enhancing lesions, as well as of cerebrospinal fluid-specific oligoclonal bands have been recognized as relevant risk factors for the occurrence of a first clinical event. Recent randomized controlled trials conducted in individuals with RIS have shown that dimethyl fumarate and teriflunomide significantly reduce the occurrence of clinical events in this population. These findings support the notion that early treatment initiation may positively influence the prognosis of these patients. However, several aspects should be taken into account before treating individuals with RIS in the real-world clinical setting, including an accurate identification of individuals with RIS to avoid misdiagnosis, a precise stratification of their risk of experiencing a first clinical event and further data supporting favorable balance between benefits and risks, even in the long term. This commentary provides an overview of the latest updates in RIS diagnosis, prognosis, and emerging treatment evidence.

Thalamic nuclei volume partially mediates the effects of aerobic capacity on fatigue in people with multiple sclerosis.

BACKGROUND: Fatigue is frequent in people with multiple sclerosis (pwMS) impacting physical and cognitive functions. Lower aerobic capacity and regional thalamic volume may be involved in the pathophysiology of fatigue in pwMS. OBJECTIVES: To identify associations between thalamic nuclei volumes, aerobic capacity and fatigue and to investigate whether the influence of aerobic capacity on fatigue in pwMS is mediated by thalamic integrity. METHODS: Eighty-three pwMS underwent a clinical evaluation with assessment of fatigue (Modified Fatigue Impact Scale [MFIS]), including physical (pMFIS) and cognitive (cMFIS) components, and peak of oxygen uptake (VO2peak). PwMS and 63 sex- and age-matched healthy controls (HC) underwent a 3 T brain MRI to quantify volume of the whole thalamus and its nuclei. RESULTS: Compared to HC, pwMS showed higher global MFIS, pMFIS and cMFIS scores, and lower VO2peak and thalamic volumes (p < 0.001). In pwMS, higher VO2peak was significantly associated with lower MFIS and pMFIS scores (r value = - 0.326 and - 0.356; pFDR ≤ 0.046) and higher laterodorsal thalamic nucleus (Dor) cluster volume (r value = 0.300; pFDR = 0.047). Moreover, lower Dor thalamic cluster volume was significantly associated with higher MFIS, pMFIS and cMFIS scores (r value range = - 0.305; - 0.293; pFDR ≤ 0.049). The volume of Dor thalamic cluster partially mediated the positive effects of VO2peak on both MFIS and cMFIS, with relative indirect effects of 21% and 32% respectively. No mediation was found for pMFIS. CONCLUSIONS: Higher VO2peak is associated with lower fatigue in pwMS, likely acting on Dor thalamic cluster volume integrity. Such an effect might be different according to the type of fatigue (cognitive or physical).

Cognitive Impairment Is Related to Glymphatic System Dysfunction in Pediatric Multiple Sclerosis.

OBJECTIVE: The aim of this study was to investigate whether, compared to pediatric healthy controls (HCs), the glymphatic system is impaired in pediatric multiple sclerosis (MS) patients according to their cognitive status, and to assess its association with clinical disability and MRI measures of brain structural damage. METHODS: Sixty-five pediatric MS patients (females = 62%; median age = 15.5 [interquartile range, IQR = 14.5;17.0] years) and 23 age- and sex-matched HCs (females = 44%; median age = 14.1 [IQR = 11.8;16.2] years) underwent neurological, neuropsychological and 3.0 Tesla MRI assessment, including conventional and diffusion tensor imaging (DTI). We calculated the diffusion along the perivascular space (DTI-ALPS) index, a proxy of glymphatic function. Cognitive impairment (Co-I) was defined as impairment in at least 2 cognitive domains. RESULTS: No significant differences in DTI-ALPS index were found between HCs and cognitively preserved (Co-P) pediatric MS patients (estimated mean difference [EMD] = -0.002 [95% confidence interval = -0.069; 0.065], FDR-p = 0.956). Compared to HCs and Co-P patients, Co-I pediatric MS patients (n = 20) showed significantly lower DTI-ALPS index (EMD = -0.136 [95% confidence interval = -0.214; -0.058], FDR-p ≤ 0.004). In HCs, no associations were observed between DTI-ALPS index and normalized brain, cortical and thalamic volumes, and normal-appearing white matter (NAWM) fractional anisotropy (FA) and mean diffusivity (MD) (FDR-p ≥ 0.348). In pediatric MS patients, higher brain WM lesion volume (LV), higher NAWM MD, lower normalized thalamic volume, and lower NAWM FA were associated with lower DTI-ALPS index (FDR-p ≤ 0.016). Random Forest selected lower DTI-ALPS index (relative importance [RI] = 100%), higher brain WM LV (RI = 59.5%) NAWM MD (RI = 57.1%) and intelligence quotient (RI = 51.3%) as informative predictors of cognitive impairment (out-of-bag area under the curve = 0.762). INTERPRETATION: Glymphatic system dysfunction occurs in pediatric MS, is associated with brain focal lesions, irreversible tissue loss accumulation and cognitive impairment. ANN NEUROL 2024.

Chronic Active Lesions and Larger Choroid Plexus Explain Cognition and Fatigue in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Chronic inflammation may contribute to cognitive dysfunction and fatigue in patients with multiple sclerosis (MS). Paramagnetic rim lesions (PRLs) and choroid plexus (CP) enlargement have been proposed as markers of chronic inflammation in MS being associated with a more severe disease course. However, their relation with cognitive impairment and fatigue has not been fully explored yet. Here, we investigated the contribution of PRL number and volume and CP enlargement to cognitive impairment and fatigue in patients with MS. METHODS: Brain 3T MRI, neurologic evaluation, and neuropsychological assessment, including the Brief Repeatable Battery of Neuropsychological Tests and Modified Fatigue Impact Scale, were obtained from 129 patients with MS and 73 age-matched and sex-matched healthy controls (HC). PRLs were identified on phase images of susceptibility-weighted imaging, whereas CP volume was quantified using a fully automatic method on brain three-dimensional T1-weighted and fluid-attenuated inversion recovery MRI sequences. Predictors of cognitive impairment and fatigue were identified using random forest. RESULTS: Thirty-six (27.9%) patients with MS were cognitively impaired, and 31/113 (27.4%) patients had fatigue. Fifty-nine (45.7%) patients with MS had ≥1 PRLs (median = 0, interquartile range = 0;2). Compared with HC, patients with MS showed significantly higher T2-hyperintense white matter lesion (WM) volume; lower normalized brain, thalamic, hippocampal, caudate, cortical, and WM volumes; and higher normalized CP volume (p from <0.001 to 0.040). The predictors of cognitive impairment (relative importance) (out-of-bag area under the curve [OOB-AUC] = 0.707) were normalized brain volume (100%), normalized caudate volume (89.1%), normalized CP volume (80.3%), normalized cortical volume (70.3%), number (67.3%) and volume (66.7%) of PRLs, and T2-hyperintense WM lesion volume (64.0%). Normalized CP volume was the only predictor of the presence of fatigue (OOB-AUC = 0.563). DISCUSSION: Chronic inflammation, with higher number and volume of PRLs and enlarged CP, may contribute to cognitive impairment in MS in addition to gray matter atrophy. The contribution of enlarged CP in explaining fatigue supports the relevance of immune-related processes in determining this manifestation independently of disease severity. PRLs and CP enlargement may contribute to the pathophysiology of cognitive impairment and fatigue in MS, and they may represent clinically relevant therapeutic targets to limit the impact of these clinical manifestations in MS.

Spatial correspondence among regional gene expressions and gray matter volume loss in multiple sclerosis.

In multiple sclerosis (MS), a non-random and clinically relevant pattern of gray matter (GM) volume loss has been described. Whether differences in regional gene expression might underlay distinctive pathological processes contributing to this regional variability has not been explored yet. Two hundred eighty-six MS patients and 172 healthy controls (HC) underwent a brain 3T MRI, a complete neurological evaluation and a neuropsychological assessment. Using Allen Human Brain Atlas, voxel-based morphometry and MENGA platform, we integrated brain transcriptome and neuroimaging data to explore the spatial cross-correlations between regional GM volume loss and expressions of 2710 genes involved in MS (p < 0.05, family-wise error-corrected). Enrichment analyses were performed to evaluate overrepresented molecular functions, biological processes and cellular components involving genes significantly associated with voxel-based morphometry-derived GM maps (p < 0.05, Bonferroni-corrected). A diffuse GM volume loss was found in MS patients compared to HC and it was spatially correlated with 74 genes involved in GABA neurotransmission and mitochondrial oxidoreductase activity mainly expressed in neurons and astrocytes. A more severe GM volume loss was spatially associated, in more disabled MS patients, with 44 genes involved in mitochondrial integrity of all resident cells of the central nervous system (CNS) and, in cognitively impaired MS patients, with 64 genes involved in mitochondrial protein heterodimerization and oxidoreductase activities expressed also in microglia and endothelial cells. Specific differences in the expressions of genes involved in synaptic GABA receptor activities and mitochondrial functions in resident CNS cells may influence regional susceptibility to MS-related excitatory/inhibitory imbalance and oxidative stress, and subsequently, to GM volume loss.

Juxtacortical Paramagnetic Rim: A New MRI Marker to Characterize Focal Cortical Pathology in Multiple Sclerosis?

The accumulation of focal white matter and cortical inflammatory demyelinating lesions represents the pathologic hallmark of multiple sclerosis (MS).1 Typically, acute white matter lesions are characterized by an increased blood-brain barrier (BBB) permeability, an inflammatory infiltrate, and ongoing demyelination and axonal transection.2 In the chronic phase, a substantial proportion of white matter lesions, known as chronic active lesions, exhibit a hypocellular core with a rim of iron-laden activated microglia/macrophages, with no abnormal BBB permeability.2 Some of these lesions can be identified on susceptibility-based MRI as exhibiting a paramagnetic rim, and they are, therefore, referred to as "paramagnetic rim lesions" (PRLs).3.

Assessing treatment response to oral drugs for multiple sclerosis in real-world setting: a MAGNIMS Study.

BACKGROUND: The assessment of treatment response is a crucial step for patients with relapsing-remitting multiple sclerosis on disease-modifying therapies (DMTs). We explored whether a scoring system developed within the MAGNIMS (MRI in Multiple Sclerosis) network to evaluate treatment response to injectable drugs can be adopted also to oral DMTs. METHODS: A multicentre dataset of 1200 patients who started three oral DMTs (fingolimod, teriflunomide and dimethyl fumarate) was collected within the MAGNIMS network. Disease activity after the first year was classified by the 'MAGNIMS' score based on the combination of relapses (0-≥2) and/or new T2 lesions (<3 or ≥3) on brain MRI. We explored the association of this score with the following 3-year outcomes: (1) confirmed disability worsening (CDW); (2) treatment failure (TFL); (3) relapse count between years 1 and 3. The additional value of contrast-enhancing lesions (CELs) and lesion location was explored. RESULTS: At 3 years, 160 patients experienced CDW: 12% of them scored '0' (reference), 18% scored '1' (HR=1.82, 95% CI 1.20 to 2.76, p=0.005) and 37% scored '2' (HR=2.74, 95% CI 1.41 to 5.36, p=0.003) at 1 year. The analysis of other outcomes provided similar findings. Considering the location of new T2 lesions (supratentorial vs infratentorial/spinal cord) and the presence of CELs improved the prediction of CDW and TFL, respectively, in patients with minimal MRI activity alone (one or two new T2 lesions). CONCLUSIONS: Early relapses and substantial MRI activity in the first year of treatment are associated with worse short-term outcomes in patients treated with some of the oral DMTs.

Choroid plexus and perivascular space enlargement in neuropsychiatric systemic lupus erythematosus.

Choroid plexus (CP) enlargement is proposed as a marker of neuroinflammation in immune-mediated conditions. CP involvement has also been hypothesized in the immunopathology of systemic lupus erythematosus (SLE). We investigated whether CP enlargement occurs in SLE patients and its association with neuropsychiatric involvement. Additionally, we explored abnormalities along the glymphatic system in SLE patients through enlarged perivascular space (PVS) quantification. Clinical assessment and 3 Tesla brain dual-echo and T1-weighted MRI scans were obtained from 32 SLE patients and 32 sex and age-matched healthy controls (HC). CPs were manually segmented on 3D T1-weighted sequence and enlarged PVS (ePVS) were assessed through Potter's score. Compared to HC, SLE patients showed higher normalized CP volume (nCPV) (p = 0.023), with higher CP enlargement in neuropsychiatric SLE (NPSLE) (n = 12) vs. non-NPSLE (p = 0.027) patients. SLE patients with antiphospholipid antibodies (APA) positivity (n = 18) had higher nCPV compared to HC (p = 0.012), while APA negative ones did not. SLE patients also had higher Potter's score than HC (p < 0.001), with a tendency towards a higher number of basal ganglia ePVS in NPSLE vs. non-NPSLE patients. Using a random forest analysis, nCPV emerged as a significant predictor of NPSLE, together with T2-hyperintense white matter (WM) lesion volume (LV) and APA positivity (out-of-bag AUC 0.81). Our findings support the hypothesis of a role exerted by the CP in SLE physiopathology, especially in patients with neuropsychiatric involvement. The higher prevalence of ePVS in SLE patients, compared to HC, suggests the presence of glymphatic system impairment in this population.

Sex-related differences in upper limb motor function in healthy subjects and multiple sclerosis patients: a multiparametric MRI study.

BACKGROUND: We investigated sex-related differences in upper limb motor performance tested with the 9-Hole Peg Test (9HPT) in healthy controls (HC) and multiple sclerosis (MS) patients and their MRI substrates. MATERIALS AND METHODS: We enrolled 94 HC and 133 MS patients, who underwent neurological examination, 9HPT and brain 3T MRI, with sequences for regional grey matter volume (GMV), white matter (WM) fractional anisotropy (FA) and resting state (RS) functional connectivity (FC) analysis. Associations between MRI variables and 9HPT performance were analyzed with general linear models. RESULTS: 9HPT performance was better in HC vs MS patients, and in female vs male HC. Regional GMV analysis showed: associations between better 9HPT performance and higher GMV in motor and cognitive cortical areas in HC, with stronger positive correlations in females vs males. In MS, worse 9HPT performance correlated with lower volume in motor and cognitive areas. Sex-related differences were minimal and mostly found in cerebellar areas. WM FA analysis disclosed neither associations with 9HPT performance in HC, nor sex-related differences in MS. RS FC analysis showed: in the sensorimotor network, stronger associations of RS FC with 9HPT performance in female vs male HC and no sex-related differences in MS; in the cerebellar network, no sex-related differences in HC but stronger negative correlation in left cerebellum in male vs female MS patients. CONCLUSIONS: Sex influences 9HPT performance in HC, mainly through differences in volume and RS FC of motor and cognitive areas. Sex-related effects on motor performance become secondary but still present in MS.

Influence of cardiorespiratory fitness and MRI measures of neuroinflammation on hippocampal volume in multiple sclerosis.

BACKGROUND: The hippocampus is a clinically relevant region where neurogenesis and neuroplasticity occur throughout the whole lifespan. Neuroinflammation and cardiorespiratory fitness (CRF) may influence hippocampal integrity by modulating the processes promoting neurogenesis and neuroprotection that contribute to the preservation of functions. This study aimed to investigate the effects of neuroinflammation and CRF on hippocampal volume in multiple sclerosis (MS) patients with relapsing-remitting (RR) and progressive (P) clinical phenotypes. The influence of neuroinflammation and CRF on brain, grey matter (GM) and thalamic volumes was also assessed to determine whether the effects were specific for the hippocampus. METHOD: Brain 3T structural MRI scans and maximum oxygen consumption (VO2max), a proxy of CRF, were acquired from 81 MS patients (27 RR and 54 P) and 45 age-matched and sex-matched healthy controls. T2-hyperintense white matter lesion volume (T2-LV) and choroid plexuses volume (CPV) were quantified as neuroinflammatory measures. Associations of demographic, clinical, neuroinflammatory and CRF measures with normalised brain, GM, hippocampal and thalamic volumes in relapsing-remitting MS (RRMS) and progressive MS patients were assessed using Shapley and best subset selection regression. RESULTS: For most volumetric measures, the largest portions of variance were explained by T2-LV (variable importance (VI)=9.4-39.4) and CPV (VI=4.5-26.2). VO2max explained the largest portion of variance of normalised hippocampal volume only in RRMS patients (VI=16.9) and was retained as relevant predictor (standardised ß=0.374, p=0.023) with T2-LV (standardised ß=-0.330, p=0.016). CONCLUSIONS: A higher CRF may play a specific neuroprotective role on MS patients' hippocampal integrity, but only in the RR phase of the disease.

Depressive symptoms, anxiety and cognitive impairment: emerging evidence in multiple sclerosis.

Neuropsychiatric abnormalities may be broadly divided in two categories: disorders of mood, affect, and behavior and abnormalities affecting cognition. Among these conditions, clinical depression, anxiety and neurocognitive disorders are the most common in multiple sclerosis (MS), with a substantial impact on patients' quality of life and adherence to treatments. Such manifestations may occur from the earliest phases of the disease but become more frequent in MS patients with a progressive disease course and more severe clinical disability. Although the pathogenesis of these neuropsychiatric manifestations has not been fully defined yet, brain structural and functional abnormalities, consistently observed with magnetic resonance imaging (MRI), together with genetic and immunologic factors, have been suggested to be key players. Even though the detrimental clinical impact of such manifestations in MS patients is a matter of crucial importance, at present, they are often overlooked in the clinical setting. Moreover, the efficacy of pharmacologic and non-pharmacologic approaches for their amelioration has been poorly investigated, with the majority of studies showing marginal or no beneficial effect of different therapeutic approaches, possibly due to the presence of multiple and heterogeneous underlying pathological mechanisms and intrinsic methodological limitations. A better evaluation of these manifestations in the clinical setting and improvements in the understanding of their pathophysiology may offer the potential to develop tools for differentiating these mechanisms in individual patients and ultimately provide a principled basis for treatment selection. This review provides an updated overview regarding the pathophysiology of the most common neuropsychiatric symptoms in MS, the clinical and MRI characteristics that have been associated with mood disorders (i.e., depression and anxiety) and cognitive impairment, and the treatment approaches currently available or under investigation.

Emerging Perspectives on MRI Application in Multiple Sclerosis: Moving from Pathophysiology to Clinical Practice.

MRI plays a central role in the diagnosis of multiple sclerosis (MS) and in the monitoring of disease course and treatment response. Advanced MRI techniques have shed light on MS biology and facilitated the search for neuroimaging markers that may be applicable in clinical practice. MRI has led to improvements in the accuracy of MS diagnosis and a deeper understanding of disease progression. This has also resulted in a plethora of potential MRI markers, the importance and validity of which remain to be proven. Here, five recent emerging perspectives arising from the use of MRI in MS, from pathophysiology to clinical application, will be discussed. These are the feasibility of noninvasive MRI-based approaches to measure glymphatic function and its impairment; T1-weighted to T2-weighted intensity ratio to quantify myelin content; classification of MS phenotypes based on their MRI features rather than on their clinical features; clinical relevance of gray matter atrophy versus white matter atrophy; and time-varying versus static resting-state functional connectivity in evaluating brain functional organization. These topics are critically discussed, which may guide future applications in the field.

Functional and structural brain MRI changes associated with cognitive worsening in multiple sclerosis: a 3-year longitudinal study.

BACKGROUND: Heterogeneous processes may contribute to cognitive impairment in multiple sclerosis (MS). OBJECTIVE: To apply a longitudinal multiparametric MRI approach to identify mechanisms associated with cognitive worsening in MS patients. METHODS: 3 T brain functional and structural MRI scans were acquired at baseline and after a median follow-up of 3.4 years in 35 MS patients and 22 healthy controls (HC). Associations between cognitive worsening (reliable change index score < - 1.25 at the Rao's battery) and longitudinal changes in regional T2-hyperintense white matter (WM) lesions, diffusion tensor microstructural WM damage, gray matter (GM) atrophy and resting state (RS) functional connectivity (FC) were explored. RESULTS: At follow-up, HC showed no clusters of significant microstructural WM damage progression, GM atrophy or changes in RS FC. At follow-up, 10 MS patients (29%) showed cognitive worsening. Compared to cognitively stable, cognitively worsened MS patients showed more severe GM atrophy of the right anterior cingulate cortex and bilateral supplementary motor area (p < 0.001). Cognitively worsened vs cognitively stable MS patients showed also decreased RS FC in the right hippocampus of the right working memory network and in the right insula of the default mode network. Increased RS FC in the left insula of the executive control network was found in the opposite comparison (p < 0.001). No significant regional accumulation of focal WM lesions nor microstructural WM abnormalities occurred in both patients' groups. CONCLUSIONS: GM atrophy progression in cognitively relevant brain regions combined with functional impoverishment in networks involved in cognitive functions may represent the substrates underlying cognitive worsening in MS.

Unraveling the heterogeneous pathological substrates of relapse-onset multiple sclerosis: a multiparametric voxel-wise 3 T MRI study.

BACKGROUND: In multiple sclerosis (MS), pathological processes affecting brain gray (GM) and white matter (WM) are heterogeneous. OBJECTIVE: To apply a multimodal MRI approach to investigate the regional distribution of the different pathological processes occurring in the brain WM and GM of relapse-onset MS patients. METHODS: Fifty-seven MS patients (forty-two relapsing remitting [RR], fifteen secondary progressive [SP]) and forty-seven age- and sex-matched healthy controls (HC) underwent a multimodal 3 T MRI acquisition. Between-group voxel-wise differences of brain WM and GM volumes, magnetization transfer ratio (MTR), T1-weighted(w)/T2w ratio, intracellular volume fraction (ICV_f), and quantitative susceptibility mapping (QSM) maps were investigated. RESULTS: Compared to HC, RRMS showed significant WM, deep GM and cortical atrophy, significantly lower MTR and T1w/T2w ratio of periventricular and infratentorial WM, deep GM and several cortical areas, lower ICV_f in supratentorial and cerebellar WM and in some cortical areas, and lower QSM values in bilateral periventricular WM (p < 0.001). Compared to RRMS, SPMS patients showed significant deep GM and widespread cortical atrophy, significantly lower MTR of periventricular WM, deep GM and cerebellum, lower T1w/T2w ratio of fronto-temporal WM regions, lower ICV_f of some fronto-tempo-occipital WM and cortical areas. They also had increased QSM and T1w/T2w ratio in the pallidum, bilaterally (p < 0.001). CONCLUSION: A periventricular pattern of demyelination and widespread GM and WM neuro-axonal loss are detectable in RRMS and are more severe in SPMS. Higher T1w/T2w ratio and QSM in the pallidum, possibly reflecting iron accumulation and neurodegeneration, may represent a relevant MRI marker to differentiate SPMS from RRMS.

Regional white matter and gray matter damage and cognitive performances in multiple sclerosis according to sex.

In this study, we investigated whether regional distribution of white matter (WM) lesions, normal-appearing [NA] WM microstructural abnormalities and gray matter (GM) atrophy may differently contribute to cognitive performance in multiple sclerosis (MS) patients according to sex. Using the same scanner, brain 3.0T MRI was acquired for 287 MS patients (females = 173; mean age = 42.1 [standard deviation, SD = 12.7] years; relapsing-remitting = 196, progressive = 91; median Expanded Disability Status Scale = 2.5 [interquartile range, IQR = 1.5-5.0]; median disease duration = 12.1 [IQR = 6.3-19.0] years; treatment: none = 70, first-line = 130, second-line = 87) and 172 healthy controls (HC) (females = 92; mean age = 39.3 [SD = 14.8] years). MS patients underwent also Rao's neuropsychological battery. Using voxel-wise analyses, we investigated in patients sex-related differences in the association of cognitive performances with WM lesions, NAWM fractional anisotropy (FA) and GM volumes (p < 0.01, family-wise error [FWE]). Sixty-six female (38%) and 48 male (42%) MS patients were cognitively impaired, with no significant between-group difference (p = 0.704). However, verbal memory performance was worse in males (p = 0.001), whereas verbal fluency performance was worse in females (p = 0.004). In both sexes, a higher T2-hyperintense lesion prevalence in cognitively-relevant WM tracts was significantly associated with worse cognitive performance (p ≤ 0.006), with stronger associations in females than males in global cognition (p ≤ 0.004). Compared to sex-matched HC, male and female MS patients had widespread lower NAWM FA and GM volume (p < 0.01). In both sexes, worse cognitive performance was associated with widespread reduced NAWM FA (p < 0.01), with stronger associations in females than males in global cognition and verbal memory (p ≤ 0.009). Worse cognitive performance was significantly associated with clusters of cortical GM atrophy in males (p ≤ 0.007) and mainly with deep GM atrophy in females (p ≤ 0.006). In this study, only limited differences in cognitive performances were found between male and female MS patients. A disconnection syndrome due to focal WM lesions and diffuse NAWM microstructural abnormalities seems to be more relevant in female MS patients to explain cognitive impairment.

Multicenter Evaluation of AI-generated DIR and PSIR for Cortical and Juxtacortical Multiple Sclerosis Lesion Detection.

Background Cortical multiple sclerosis lesions are clinically relevant but inconspicuous at conventional clinical MRI. Double inversion recovery (DIR) and phase-sensitive inversion recovery (PSIR) are more sensitive but often unavailable. In the past 2 years, artificial intelligence (AI) was used to generate DIR and PSIR from standard clinical sequences (eg, T1-weighted, T2-weighted, and fluid-attenuated inversion-recovery sequences), but multicenter validation is crucial for further implementation. Purpose To evaluate cortical and juxtacortical multiple sclerosis lesion detection for diagnostic and disease monitoring purposes on AI-generated DIR and PSIR images compared with MRI-acquired DIR and PSIR images in a multicenter setting. Materials and Methods Generative adversarial networks were used to generate AI-based DIR (n = 50) and PSIR (n = 43) images. The number of detected lesions between AI-generated images and MRI-acquired (reference) images was compared by randomized blinded scoring by seven readers (all with >10 years of experience in lesion assessment). Reliability was expressed as the intraclass correlation coefficient (ICC). Differences in lesion subtype were determined using Wilcoxon signed-rank tests. Results MRI scans of 202 patients with multiple sclerosis (mean age, 46 years ± 11 [SD]; 127 women) were retrospectively collected from seven centers (February 2020 to January 2021). In total, 1154 lesions were detected on AI-generated DIR images versus 855 on MRI-acquired DIR images (mean difference per reader, 35.0% ± 22.8; P < .001). On AI-generated PSIR images, 803 lesions were detected versus 814 on MRI-acquired PSIR images (98.9% ± 19.4; P = .87). Reliability was good for both DIR (ICC, 0.81) and PSIR (ICC, 0.75) across centers. Regionally, more juxtacortical lesions were detected on AI-generated DIR images than on MRI-acquired DIR images (495 [42.9%] vs 338 [39.5%]; P < .001). On AI-generated PSIR images, fewer juxtacortical lesions were detected than on MRI-acquired PSIR images (232 [28.9%] vs 282 [34.6%]; P = .02). Conclusion Artificial intelligence-generated double inversion-recovery and phase-sensitive inversion-recovery images performed well compared with their MRI-acquired counterparts and can be considered reliable in a multicenter setting, with good between-reader and between-center interpretative agreement. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Zivadinov and Dwyer in this issue.