Assessing brain involvement in Fabry disease with deep learning and the brain-age paradigm.

While neurological manifestations are core features of Fabry disease (FD), quantitative neuroimaging biomarkers allowing to measure brain involvement are lacking. We used deep learning and the brain-age paradigm to assess whether FD patients' brains appear older than normal and to validate brain-predicted age difference (brain-PAD) as a possible disease severity biomarker. MRI scans of FD patients and healthy controls (HCs) from a single Institution were, retrospectively, studied. The Fabry stabilization index (FASTEX) was recorded as a measure of disease severity. Using minimally preprocessed 3D T1-weighted brain scans of healthy subjects from eight publicly available sources (N = 2160; mean age = 33 years [range 4-86]), we trained a model predicting chronological age based on a DenseNet architecture and used it to generate brain-age predictions in the internal cohort. Within a linear modeling framework, brain-PAD was tested for age/sex-adjusted associations with diagnostic group (FD vs. HC), FASTEX score, and both global and voxel-level neuroimaging measures. We studied 52 FD patients (40.6 ± 12.6 years; 28F) and 58 HC (38.4 ± 13.4 years; 28F). The brain-age model achieved accurate out-of-sample performance (mean absolute error = 4.01 years, R2 = .90). FD patients had significantly higher brain-PAD than HC (estimated marginal means: 3.1 vs. -0.1, p = .01). Brain-PAD was associated with FASTEX score (B = 0.10, p = .02), brain parenchymal fraction (B = -153.50, p = .001), white matter hyperintensities load (B = 0.85, p = .01), and tissue volume reduction throughout the brain. We demonstrated that FD patients' brains appear older than normal. Brain-PAD correlates with FD-related multi-organ damage and is influenced by both global brain volume and white matter hyperintensities, offering a comprehensive biomarker of (neurological) disease severity.

Ocrelizumab in MS patients with persistence of disease activity after alemtuzumab: A multi-center Italian study.

BACKGROUND: The reason why some multiple sclerosis (MS) patients show disease activity after alemtuzumab (ALM) is still unclear, but ocrelizumab (OCR) could represent an interesting sequential therapeutic approach. OBJECTIVES: To investigate safety and efficacy of OCR in MS patients with disease activity after two ALM courses. METHODS: Observational retrospective multi-centers Italian cohort study. RESULTS: Seventy-two subjects were included. Mean follow-up (FU) was 2.4 (±1) years. Forty-five patients (62.5%) experienced at least one adverse event (AE), with infections accounting for 96.7% of cases. A reduction in total lymphocytes was observed between OCR start and 6 months FU, driven by BCD19+ lymphocytes depletion (p < 0.001). Immunoglobulin M (IgM) levels decreased between OCR start and 6 months FU (p < 0.001). At 2-year FU, relapse, magnetic resonance imaging (MRI) activity and disability worsening-free survival were 92.1%, 90.8%, and 89.2%. The evidence of inflammatory activity between the two ALM courses was associated with higher risk of relapse, MRI activity, and NEDA-3 status loss in relapsing-remitting multiple sclerosis (RRMS; p = 0.02, p = 0.05, p = 0.01, respectively). CONCLUSIONS: OCR after two ALM courses seemed to be safe and effective. Early IgM hypogammaglobulinemia occurred in a high proportion of patients. The evidence of inflammatory activity between ALM courses seemed to increase the risk of MS re-activation on OCR treatment.

The impact of image contrast, resolution and reader expertise on black hole identification in Multiple Sclerosis.

OBJECTIVES: In the neuroradiological work-up of Multiple Sclerosis (MS), the detection of "black holes" (BH) represent an information of undeniable importance. Nevertheless, different sequences can be used in clinical practice to evaluate BH in MS. Aim of this study was to investigate the possible impact of different sequences, resolutions, and levels of expertise on the intra- and inter-rater reliability identification of BH in MS. METHODS: Brain MRI scans of 85 MS patients (M/F = 22/63; mean age = 36.0 ± 10.2 years) were evaluated in this prospective single-center study. The acquisition protocol included a 3 mm SE-T1w sequence, a 1 mm 3D-GrE-T1w sequence from which a resliced 3 mm sequence was also obtained. Images were evaluated independently by two readers of different expertise at baseline and after a wash-out period of 30 days. The intraclass correlation coefficient (ICC) was calculated as an index of intra and inter-reader reliability. RESULTS: For both readers, the intra-reader ICC analysis showed that the 3 mm SE-T1w and 3 mm resliced GrE-T1w images achieved an excellent performance (both with an ICC ≥ 0.95), while 1 mm 3D-GrE-T1w scans achieved a moderate one (ICC < 0.90). The inter-reader analysis showed that each of the three sequences achieved a moderate performance (all ICCs < 0.90). CONCLUSIONS: The 1 mm 3D-GrE-T1w sequence seems to be prone to a greater intra-reader variability compared to the 3 mm SE-T1w, with this effect being driven by the higher spatial resolution of the first sequence. To ensure reliability levels comparable with the standard SE-T1w in BH count, an assessment on a 3 mm resliced GrE-T1w sequence should be recommended.

Using The Virtual Brain to study the relationship between structural and functional connectivity in patients with multiple sclerosis: a multicenter study.

The relationship between structural connectivity (SC) and functional connectivity (FC) captured from magnetic resonance imaging, as well as its interaction with disability and cognitive impairment, is not well understood in people with multiple sclerosis (pwMS). The Virtual Brain (TVB) is an open-source brain simulator for creating personalized brain models using SC and FC. The aim of this study was to explore SC-FC relationship in MS using TVB. Two different model regimes have been studied: stable and oscillatory, with the latter including conduction delays in the brain. The models were applied to 513 pwMS and 208 healthy controls (HC) from 7 different centers. Models were analyzed using structural damage, global diffusion properties, clinical disability, cognitive scores, and graph-derived metrics from both simulated and empirical FC. For the stable model, higher SC-FC coupling was associated with pwMS with low Single Digit Modalities Test (SDMT) score (F=3.48, P$\lt$0.05), suggesting that cognitive impairment in pwMS is associated with a higher SC-FC coupling. Differences in entropy of the simulated FC between HC, high and low SDMT groups (F=31.57, P$\lt$1e-5), show that the model captures subtle differences not detected in the empirical FC, suggesting the existence of compensatory and maladaptive mechanisms between SC and FC in MS.

Integration of the expanded disability status scale with ambulation, visual and cognitive tests.

INTRODUCTION: The Expanded Disability Status Scale (EDSS) is usually calculated through a neurological examination with self-reported performance. This may lead to incorrect assessment of Functional System scores (FSs). Aim of our study was to estimate the difference between EDSS obtained during routine visits, or after specific tests. METHODS: We enrolled 670 MS patients that underwent a regular neurology consultation, and visual evaluation using optotype tables, ambulation evaluation with a rodometer, and cognitive assessment with the Brief International Cognitive assessment for MS (BICAMS). We calculated a new integrated EDSS (iEDSS) using the refined values of the FS and compared it to the standard EDSS. RESULTS: Visual, cerebral and ambulation FSs were significantly higher compared with the self-reported counterpart [+ 1.169 (95%CI 1.077, 1.262; p < 0.001), + 0.727 (95%CI 0.653, 0.801; p < 0.001) and + 0.822 (95%CI 0.705, 0.939; p < 0.001), respectively]. Mean iEDSS was higher than EDSS (+ 0.642; p < 0.001). Visual acuity tests worsened the EDSS in 31% of cases, cognitive tests in 10%, ambulation measurement in 35%, all three measurements in 59% of cases. CONCLUSIONS: Objective measurement of FSs results in a more accurate EDSS score in almost two-thirds of cases. This could lead to a more thorough evaluation of patients in the transition or progressive phase.

Fertility, pregnancy and childbirth in women with multiple sclerosis: a population-based study from 2018 to 2020.

BACKGROUND: We aim to evaluate whether fertility, pregnancy, delivery and breastfeeding have been actually improving in women with multiple sclerosis (MS), compared with general population, and in relation to treatment features. METHODS: We included 2018-2020 population-level healthcare data on women with MS living in the Campania region (Italy). Fertility, pregnancy and delivery outcomes were obtained from Certificate of Delivery Assistance; breastfeeding was collected up to 6 months after delivery by trained personnel. RESULTS: Out of 2748 women with MS in childbearing age, 151 women delivered 156 babies. Fertility rate was 0.58 live births per woman with MS, compared with 1.29 in Campania region and 1.25 in Italy. Disease-modifying treatment (DMT) continuation during pregnancy was associated with lower birth weight (coeff -107.09; 95% CI -207.91 to -6.26; p=0.03). Exposure to DMTs with unknown/negative effects on pregnancy was associated with birth defects (OR 8.88; 95% CI 1.35 to 58.41; p=0.02). Birth defects occurred in pregnancies exposed to dimethyl fumarate (2/21 exposed pregnancies), fingolimod (1/11 exposed pregnancies) and natalizumab (2/30 exposed pregnancies). After delivery, 18.8% of women with MS were escalated of DMT efficacy, while 50.7% started on same/similar-efficacy DMTs, and 30.5% did not receive DMT. The probability of breastfeeding was higher in women who were treated with breastfeeding-safe DMTs (OR 5.57; 95% CI 1.09 to 28.55; p=0.03). CONCLUSIONS: Fertility rate in women with MS remains below the general population. Family planning and subsequent DMT decisions should aim to achieve successful pregnancy, delivery and breastfeeding outcomes, while controlling disease activity.

Consensus Paper: Ataxic Gait.

The aim of this consensus paper is to discuss the roles of the cerebellum in human gait, as well as its assessment and therapy. Cerebellar vermis is critical for postural control. The cerebellum ensures the mapping of sensory information into temporally relevant motor commands. Mental imagery of gait involves intrinsically connected fronto-parietal networks comprising the cerebellum. Muscular activities in cerebellar patients show impaired timing of discharges, affecting the patterning of the synergies subserving locomotion. Ataxia of stance/gait is amongst the first cerebellar deficits in cerebellar disorders such as degenerative ataxias and is a disabling symptom with a high risk of falls. Prolonged discharges and increased muscle coactivation may be related to compensatory mechanisms and enhanced body sway, respectively. Essential tremor is frequently associated with mild gait ataxia. There is growing evidence for an important role of the cerebellar cortex in the pathogenesis of essential tremor. In multiple sclerosis, balance and gait are affected due to cerebellar and spinal cord involvement, as a result of disseminated demyelination and neurodegeneration impairing proprioception. In orthostatic tremor, patients often show mild-to-moderate limb and gait ataxia. The tremor generator is likely located in the posterior fossa. Tandem gait is impaired in the early stages of cerebellar disorders and may be particularly useful in the evaluation of pre-ataxic stages of progressive ataxias. Impaired inter-joint coordination and enhanced variability of gait temporal and kinetic parameters can be grasped by wearable devices such as accelerometers. Kinect is a promising low cost technology to obtain reliable measurements and remote assessments of gait. Deep learning methods are being developed in order to help clinicians in the diagnosis and decision-making process. Locomotor adaptation is impaired in cerebellar patients. Coordinative training aims to improve the coordinative strategy and foot placements across strides, cerebellar patients benefiting from intense rehabilitation therapies. Robotic training is a promising approach to complement conventional rehabilitation and neuromodulation of the cerebellum. Wearable dynamic orthoses represent a potential aid to assist gait. The panel of experts agree that the understanding of the cerebellar contribution to gait control will lead to a better management of cerebellar ataxias in general and will likely contribute to use gait parameters as robust biomarkers of future clinical trials.

Clinical correlates of R1 relaxometry and magnetic susceptibility changes in multiple sclerosis: a multi-parameter quantitative MRI study of brain iron and myelin.

OBJECTIVES: The clinical impact of brain microstructural abnormalities in multiple sclerosis (MS) remains elusive. We aimed to characterize the topography of longitudinal relaxation rate (R1) and quantitative susceptibility (χ) changes, as indices of iron and myelin, together with brain atrophy, and to clarify their contribution to cognitive and motor disability in MS. METHODS: In this cross-sectional study, voxel-based morphometry, and voxel-based quantification analyses of R1 and χ maps were conducted in gray matter (GM) and white matter (WM) of 117 MS patients and 53 healthy controls. Voxel-wise between-group differences were assessed with nonparametric permutation tests, while correlations between MRI metrics and clinical variables (global disability, cognitive and motor performance) were assessed both globally and voxel-wise within clusters emerging from the between-group comparisons. RESULTS: MS patients showed widespread R1 decrease associated with more limited modifications of χ, with atrophy mainly involving deep GM, posterior and infratentorial regions (p < 0.02). While R1 and χ showed a parallel reduction in several WM tracts (p < 0.001), reduced GM R1 values (p < 0.001) were associated with decreased thalamic χ (p < 0.001) and small clusters of increased χ in the caudate nucleus and prefrontal cortex (p < 0.02). In addition to the atrophy, χ values in the cingulum and corona radiata correlated with global disability and motor performance, while focal demyelination correlated with cognitive performance (p < 0.04). CONCLUSIONS: We confirmed the presence of widespread R1 changes, involving both GM and WM, and atrophy in MS, with less extensive modifications of tissue χ. While atrophy and χ changes are related to global and motor disability, R1 changes are meaningful correlates of cognition. KEY POINTS: • Compared to healthy controls, multiple sclerosis patients showed R1 and χ changes suggestive of iron increase within the basal ganglia and reduced iron and myelin content within (subnuclei of) the thalamus. • Thalamic volume and χ changes significantly predicted clinical disability, as well as pulvinar R1 and χ changes, independently from atrophy. • Atrophy-independent R1 and χ changes, suggestive of thalamic iron and myelin depletion, may represent a sensitive marker of subclinical inflammation.

Altered anterior default mode network dynamics in progressive multiple sclerosis.

BACKGROUND: Modifications in brain function remain relatively unexplored in progressive multiple sclerosis (PMS), despite their potential to provide new insights into the pathophysiology of the disease at this stage. OBJECTIVES: To characterize the dynamics of functional networks at rest in patients with PMS, and the relation with clinical disability. METHODS: Thirty-two patients with PMS underwent clinical and cognitive assessment. The dynamic properties of functional networks, retrieved from transient brain activity, were obtained from patients and 25 healthy controls (HCs). Sixteen HCs and 19 patients underwent a 1-year follow-up (FU) clinical and imaging assessment. Differences in the dynamic metrics between groups, their longitudinal changes, and the correlation with clinical disability were explored. RESULTS: PMS patients, compared to HCs, showed a reduced dynamic functional activation of the anterior default mode network (aDMN) and a decrease in its opposite-signed co-activation with the executive control network (ECN), at baseline and FU. Processing speed and visuo-spatial memory negatively correlated to aDMN dynamic activity. The anti-couplings between aDMN and auditory/sensory-motor network, temporal-pole/amygdala, or salience networks were differently associated with separate cognitive domains. CONCLUSION: Patients with PMS presented an altered aDMN functional recruitment and anti-correlation with ECN. The aDMN dynamic functional activity and interaction with other networks explained cognitive disability.

Emergency medical care for multiple sclerosis: A five-year population study in the Campania Region (South Italy).

BACKGROUND: Emergency hospital admissions are common in multiple sclerosis (MS), and can highlight unmet medical needs. OBJECTIVES: To evaluate burden, predictors and outcomes of MS emergency admissions. METHODS: This is a population-based study, conducted in the Campania Region (South Italy) from 2015 to 2019, using hospital discharge records, drug prescriptions and outpatients. The risk of emergency hospital admissions and the likelihood of worse outcomes were evaluated using the Cox regression and multinomial logistic regression models, respectively, in relation to age, sex, disease-modifying treatments (DMTs), comorbidities and adherence. RESULTS: We recorded 1225 emergency admissions for 1001 patients (out of 5765 prevalent MS patients), overall costing 4,143,764.67 EUR. The risk of emergency admissions increased with age (hazard ratio (HR) = 1.02; 95% confidence interval (CI) = 1.01, 1.03; p < 0.01) and comorbidities (HR = 1.62; p < 0.01), and decreased in patients using DMTs (interferon beta/peg-interferon beta/glatiramer acetate HR = 0.19; p < 0.01; teriflunomide/dimethyl-fumarate/fingolimod HR = 0.18; p < 0.01, and alemtuzumab/cladribine/natalizumab/ocrelizumab HR = 0.21; p < 0.01), and with higher adherence (HR = 0.18; 95% CI = 0.13, 0.26; p < 0.01). Following emergency admission, older age was associated with probability of death (n = 63) (odds ratio (OR) = 1.06; p < 0.01) and discharge to long-term facility (n = 65) (OR = 1.03; p = 0.01). CONCLUSION: With 17% people with MS requiring emergency medical care over 5 years, improved management of DMTs and comorbidities could potentially reduce their medical, social and financial burden.

The central vein sign helps in differentiating multiple sclerosis from its mimickers: lessons from Fabry disease.

OBJECTIVES: Although the use of specific MRI criteria has significantly increased the diagnostic accuracy of multiple sclerosis (MS), reaching a correct neuroradiological diagnosis remains a challenging task, and therefore the search for new imaging biomarkers is crucial. This study aims to evaluate the incidence of one of the emerging neuroradiological signs highly suggestive of MS, the central vein sign (CVS), using data from Fabry disease (FD) patients as an index of microvascular disorder that could mimic MS. METHODS: In this retrospective study, after the application of inclusion and exclusion criteria, MRI scans of 36 FD patients and 73 relapsing-remitting (RR) MS patients were evaluated. Among the RRMS participants, 32 subjects with a disease duration inferior to 5 years (early MS) were also analyzed. For all subjects, a Fazekas score (FS) was recorded, excluding patients with FS = 0. Different neuroradiological signs, including CVS, were evaluated on FLAIR T2-weighted and spoiled gradient recalled echo sequences. RESULTS: Among all the recorded neuroradiological signs, the most striking difference was found for the CVS, with a detectable prevalence of 78.1% (57/73) in RRMS and of 71.4% (25/32) in early MS patients, while this sign was absent in FD (0/36). CONCLUSIONS: Our results confirm the high incidence of CVS in MS, also in the early phases of the disease, while it seems to be absent in conditions with a different etiology. These results corroborate the possible role of CVS as a useful neuroradiological sign highly suggestive of MS. KEY POINTS: • The search for new imaging biomarkers is crucial to achieve a correct neuroradiological diagnosis of MS. • The CVS shows an incidence superior to 70% in MS patients, even in the early phases of the disease, while it appears to be absent in FD. • These findings further corroborate the possible future central role of CVS in distinguishing between MS and its mimickers.

Stratification of multiple sclerosis patients using unsupervised machine learning: a single-visit MRI-driven approach.

OBJECTIVES: To stratify patients with multiple sclerosis (pwMS) based on brain MRI-derived volumetric features using unsupervised machine learning. METHODS: The 3-T brain MRIs of relapsing-remitting pwMS including 3D-T1w and FLAIR-T2w sequences were retrospectively collected, along with Expanded Disability Status Scale (EDSS) scores and long-term (10 ± 2 years) clinical outcomes (EDSS, cognition, and progressive course). From the MRIs, volumes of demyelinating lesions and 116 atlas-defined gray matter regions were automatically segmented and expressed as z-scores referenced to external populations. Following feature selection, baseline MRI-derived biomarkers entered the Subtype and Stage Inference (SuStaIn) algorithm, which estimates subgroups characterized by distinct patterns of biomarker evolution and stages within subgroups. The trained model was then applied to longitudinal MRIs. Stability of subtypes and stage change over time were assessed via Krippendorf's α and multilevel linear regression models, respectively. The prognostic relevance of SuStaIn classification was assessed with ordinal/logistic regression analyses. RESULTS: We selected 425 pwMS (35.9 ± 9.9 years; F/M: 301/124), corresponding to 1129 MRI scans, along with healthy controls (N = 148; 35.9 ± 13.0 years; F/M: 77/71) and external pwMS (N = 80; 40.4 ± 11.9 years; F/M: 56/24) as reference populations. Based on 11 biomarkers surviving feature selection, two subtypes were identified, designated as "deep gray matter (DGM)-first" subtype (N = 238) and "cortex-first" subtype (N = 187) according to the atrophy pattern. Subtypes were consistent over time (α = 0.806), with significant annual stage increase (b = 0.20; p < 0.001). EDSS was associated with stage and DGM-first subtype (p ≤ 0.02). Baseline stage predicted long-term disability, transition to progressive course, and cognitive impairment (p ≤ 0.03), with the latter also associated with DGM-first subtype (p = 0.005). CONCLUSIONS: Unsupervised learning modelling of brain MRI-derived volumetric features provides a biologically reliable and prognostically meaningful stratification of pwMS. KEY POINTS: • The unsupervised modelling of brain MRI-derived volumetric features can provide a single-visit stratification of multiple sclerosis patients. • The so-obtained classification tends to be consistent over time and captures disease-related brain damage progression, supporting the biological reliability of the model. • Baseline stratification predicts long-term clinical disability, cognition, and transition to secondary progressive course.

Cerebellar pathology and disability worsening in relapsing-remitting multiple sclerosis: A retrospective analysis from the CombiRx trial.

BACKGROUND AND PURPOSE: Cerebellar damage is a valuable predictor of disability, particularly in progressive multiple sclerosis. It is not clear if it could be an equally useful predictor of motor disability worsening in the relapsing-remitting phenotype. AIM: We aimed to determine whether cerebellar damage is an equally useful predictor of motor disability worsening in the relapsing-remitting phenotype. METHODS: Cerebellar lesion loads and volumes were estimated using baseline magnetic resonance imaging from the CombiRx trial (n = 838). The relationship between cerebellar damage and time to disability worsening (confirmed disability progression [CDP], timed 25-foot walk test [T25FWT] score worsening, nine-hole peg test [9HPT] score worsening) was tested in stagewise and stepwise Cox proportional hazards models, accounting for demographics and supratentorial damage. RESULTS: Shorter time to 9HPT score worsening was associated with higher baseline Expanded Disability Status Scale (EDSS) score (hazard ratio [HR] 1.408, p = 0.0042) and higher volume of supratentorial and cerebellar T2 lesions (HR 1.005 p = 0.0196 and HR 2.211, p = 0.0002, respectively). Shorter time to T25FWT score worsening was associated with higher baseline EDSS (HR 1.232, p = 0.0006). Shorter time to CDP was associated with older age (HR 1.026, p = 0.0010), lower baseline EDSS score (HR 0.428, p < 0.0001) and higher volume of supratentorial T2 lesions (HR 1.024, p < 0.0001). CONCLUSION: Among the explored outcomes, single time-point evaluation of cerebellar damage only allows the prediction of manual dexterity worsening. In clinical studies the selection of imaging biomarkers should be informed by the outcome of interest.

Non-invasive quantification of inflammation, axonal and myelin injury in multiple sclerosis.

The aim of this study was to determine the feasibility of diffusion basis spectrum imaging in multiple sclerosis at 7 T and to investigate the pathological substrates of tissue damage in lesions and normal-appearing white matter. To this end, 43 patients with multiple sclerosis (24 relapsing-remitting, 19 progressive), and 21 healthy control subjects were enrolled. White matter lesions were classified in T1-isointense, T1-hypointense and black holes. Mean values of diffusion basis spectrum imaging metrics (fibres, restricted and non-restricted fractions, axial and radial diffusivities and fractional anisotropy) were measured from whole brain white matter lesions and from both lesions and normal appearing white matter of the corpus callosum. Significant differences were found between T1-isointense and black holes (P ranging from 0.005 to <0.001) and between lesions' centre and rim (P < 0.001) for all the metrics. When comparing the three subject groups in terms of metrics derived from corpus callosum normal appearing white matter and T2-hyperintense lesions, a significant difference was found between healthy controls and relapsing-remitting patients for all metrics except restricted fraction and fractional anisotropy; between healthy controls and progressive patients for all metrics except restricted fraction and between relapsing-remitting and progressive multiple sclerosis patients for all metrics except fibres and restricted fractions (P ranging from 0.05 to <0.001 for all). Significant associations were found between corpus callosum normal-appearing white matter fibres fraction/non-restricted fraction and the Symbol Digit Modality Test (respectively, r = 0.35, P = 0.043; r = -0.35, P = 0.046), and between black holes radial diffusivity and Expanded Disability Status Score (r = 0.59, P = 0.002). We showed the feasibility of diffusion basis spectrum imaging metrics at 7 T, confirmed the role of the derived metrics in the characterization of lesions and normal appearing white matter tissue in different stages of the disease and demonstrated their clinical relevance. Thus, suggesting that diffusion basis spectrum imaging is a promising tool to investigate multiple sclerosis pathophysiology, monitor disease progression and treatment response.

Cognitive trajectories in multiple sclerosis: a long-term follow-up study.

BACKGROUND: Cognitive impairment occurs in multiple sclerosis (MS) and undergoes a progressive worsening over disease course. However, clinicians still struggle to predict the course of cognitive function. To evaluate baseline clinical and imaging predictors of cognitive abilities worsening over time, we performed a latent trajectory analysis for cognitive performances in MS patients, up to 15 years from disease onset. METHODS: We collected age, sex, education, dominant and non-dominant 9-hole peg test (9HP) and timed 25-foot walk (T25-FW) as well as MRI measures (grey matter volume and lesion load) within 6 months from disease diagnosis for relapsing-remitting MS (RR-MS) patients. At diagnosis and over the follow-up, we also assessed cognitive status through the symbol digit modalities test (SDMT). Cognitive impairment was defined by applying age-, gender- and education-adjusted normative values. Group-based trajectory analysis was performed to determine trajectories, and the predictive value of clinical and imaging variables at baseline was assessed through multinomial logistic regression. RESULTS: We included 148 RR-MS (98 females and 50 males). Over 11 ± 4 year follow-up, 51.4% remained cognitively stable whereas 48.6% cognitively worsened. Cognitively worsening patients had a higher T25FW time (p = 0.004) and a reduced hippocampal volume at baseline (p = 0.04). CONCLUSION: Physical disability as well as hippocampal atrophy might depict patients at risk of cognitive worsening over the disease course. Therefore, using such predictors, clinicians may select patients to carefully evaluate for cognitive impairment as to eventually introduce cognitive rehabilitation treatments.

Evaluation of Disability Progression in Multiple Sclerosis via Magnetic-Resonance-Based Deep Learning Techniques.

Short-term disability progression was predicted from a baseline evaluation in patients with multiple sclerosis (MS) using their three-dimensional T1-weighted (3DT1) magnetic resonance images (MRI). One-hundred-and-eighty-one subjects diagnosed with MS underwent 3T-MRI and were followed up for two to six years at two sites, with disability progression defined according to the expanded-disability-status-scale (EDSS) increment at the follow-up. The patients' 3DT1 images were bias-corrected, brain-extracted, registered onto MNI space, and divided into slices along coronal, sagittal, and axial projections. Deep learning image classification models were applied on slices and devised as ResNet50 fine-tuned adaptations at first on a large independent dataset and secondly on the study sample. The final classifiers' performance was evaluated via the area under the curve (AUC) of the false versus true positive diagram. Each model was also tested against its null model, obtained by reshuffling patients' labels in the training set. Informative areas were found by intersecting slices corresponding to models fulfilling the disability progression prediction criteria. At follow-up, 34% of patients had disability progression. Five coronal and five sagittal slices had one classifier surviving the AUC evaluation and null test and predicted disability progression (AUC > 0.72 and AUC > 0.81, respectively). Likewise, fifteen combinations of classifiers and axial slices predicted disability progression in patients (AUC > 0.69). Informative areas were the frontal areas, mainly within the grey matter. Briefly, 3DT1 images may give hints on disability progression in MS patients, exploiting the information hidden in the MRI of specific areas of the brain.

AQP4-MOG Double-Positive Neuromyelitis Optica Spectrum Disorder: Case Report with Central and Peripheral Nervous System Involvement and Review of Literature.

(1) The co-occurrence of AQP4 and myelin oligodendrocyte glycoprotein (MOG) antibodies in patients with demyelinating disorders is extremely rare. In addition, a concomitant involvement of the peripheral nervous system (PNS) has been described either in association with AQP4 antibodies-positive neuromyelitis optica spectrum disorder (NMOSD), or MOG-associated disease. We report on a case of NMOSD with co-occurrence of AQP4 and MOG antibodies and concomitant central and peripheral nervous system involvement. We also reviewed available cases of AQP4-MOG double-positive patients. (2) Brain and spine MRI, cerebrospinal fluid studies, and electrophysiological test were performed. Serum AQP4 and MOG positivity was assessed with live cell-based assay. (3) A 62-year-old woman presented with recurrent optic neuritis, myelitis, and radiculitis, tested positive for AQP4 and MOG antibodies, and was treated successfully with rituximab. (4) Although few cases of AQP4-MOG double-positive patients were already described mostly affecting females with a concomitant spinal cord and optical nerve involvement, we describe the first case of double-positive NMOSD with the peculiar involvement of both central and peripheral nervous system.

Mental Health in Multiple Sclerosis During the COVID-19 Outbreak: A Delicate Balance between Fear of Contagion and Resilience.

The current study aimed at exploring the relationship between objective disability, illness perceptions, resilience, fear of COVID-19, and psychological distress (i.e., anxiety, depression, and stress) in people with multiple sclerosis (pwMS) during the second wave of the COVID-19 outbreak. A group of 122 pwMS recruited in an Italian university hospital took part in this cross-sectional monocentric study. Hierarchical multiple linear regression analyses were performed to assess the strength of the hypothesized associations. Results indicated that, differently from cognitive impairment, motor disability was positively associated with anxiety. However, accounting for subjective illness perception, such association was no longer significant. Moreover, accounting for both protective and risk factors in the models, even illness perception was no longer significant, highlighting the central role of resilience and fear of COVID-19 in explaining the negative emotional outcomes. Implications for clinical interventions and psychoeducational trainings are discussed.

Tractography dissection variability: What happens when 42 groups dissect 14 white matter bundles on the same dataset?

White matter bundle segmentation using diffusion MRI fiber tractography has become the method of choice to identify white matter fiber pathways in vivo in human brains. However, like other analyses of complex data, there is considerable variability in segmentation protocols and techniques. This can result in different reconstructions of the same intended white matter pathways, which directly affects tractography results, quantification, and interpretation. In this study, we aim to evaluate and quantify the variability that arises from different protocols for bundle segmentation. Through an open call to users of fiber tractography, including anatomists, clinicians, and algorithm developers, 42 independent teams were given processed sets of human whole-brain streamlines and asked to segment 14 white matter fascicles on six subjects. In total, we received 57 different bundle segmentation protocols, which enabled detailed volume-based and streamline-based analyses of agreement and disagreement among protocols for each fiber pathway. Results show that even when given the exact same sets of underlying streamlines, the variability across protocols for bundle segmentation is greater than all other sources of variability in the virtual dissection process, including variability within protocols and variability across subjects. In order to foster the use of tractography bundle dissection in routine clinical settings, and as a fundamental analytical tool, future endeavors must aim to resolve and reduce this heterogeneity. Although external validation is needed to verify the anatomical accuracy of bundle dissections, reducing heterogeneity is a step towards reproducible research and may be achieved through the use of standard nomenclature and definitions of white matter bundles and well-chosen constraints and decisions in the dissection process.

Depression is associated with disconnection of neurotransmitter-related nuclei in multiple sclerosis.

BACKGROUND: Depression is frequently associated with multiple sclerosis (MS). However, the biological background underlying such association is poorly understood. OBJECTIVE: Investigating the functional connections of neurotransmitter-related brainstem nuclei, along with their relationship with white matter (WM) microstructure, in MS patients with depressive symptomatology (MS-D) and without depressive symptomatology (MS-nD). METHODS: Combined resting-state functional magnetic resonance imaging (fMRI) and diffusion-weighted MRI (dMRI) study on 50 MS patients, including 19 MS-D and 31 MS-nD patients, along with 37 healthy controls (HC). Main analyses performed are (1) comparison between groups of raphe nuclei (RN)-related functional connectivity (FC); (2) correlation between RN-related FC and whole brain dMRI-derived fractional anisotropy (FA) map; and (3) comparison between groups of FA in the RN-related WM area. RESULTS: (1) RN-related FC was reduced in MS-D when compared to MS-nD and HC; (2) RN-related FC positively correlated with FA in a WM cluster mainly encompassing thalamic/basal ganglia regions, including the fornix; and (3) FA in such WM area was reduced in MS-D. CONCLUSION: Depressive symptomatology in MS is specifically associated to a functional disconnection of neurotransmitter-related nuclei, which in turn may be traced to a distinct spatial pattern of WM alterations mainly involving the limbic network.