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Impairment of cardiovascular control is common in multiple sclerosis (MS), possibly due to damage of strategic brain regions such as the insula. Aerobic training (AT) targets cardiopulmonary system and may represent a neuroprotective strategy.To investigate whether insular damage (T2-hyperintense lesions and volume) is associated with cardiovascular fitness (CF) and influences AT effects in MS.Sixty-one MS patients were randomized to an AT intervention group (MS-AT) and a motor training control group (MS-C). At baseline and after training (24 sessions over 2-3 months), peak of oxygen consumption (VO2max), heart rate reserve (HRR), 6-min walk test (6MWT) and whole brain and insula MRI data were collected. Two healthy control (HC) groups were enrolled for CF and MRI data analysis.At baseline, MS patients vs HC showed impaired VO2max, HRR and 6MWT (p 0.001) and widespread gray matter atrophy, including bilateral insula. In MS patients, left insula T2-lesion volume correlated with HRR (r = 0.27, p = 0.042). After training, MS-AT, especially those without insular T2-hyperintense lesions, showed 6MWT improvement (p 0.05) and a stable insular volume, whereas MS-C showed left insular volume loss (p 0.001).By increasing 6MWT performance, our results suggest that AT may improve walking capacity and submaximal measure of CF in MS patients. Such beneficial effect may be modulated by insula integrity.

ObjectiveTo investigate monoaminergic network abnormalities in patients with multiple sclerosis (MS) according to their fatigue and depressive status through a positron emission tomography (PET)-based constrained independent component analysis (ICA) on resting state (RS) functional MRI (fMRI).MethodsIn this prospective study, 213 patients with MS (mean age=40.6±12.5 years; 94/119 men/women; 153 relapsing-remitting; 60 progressive) and 62 healthy controls (HCs, mean age=39.0±10.4 years; 30/32 men/women) underwent neurological, fatigue, depression and RS fMRI assessment. Patterns of dopamine, norepinephrine-related and serotonin-related RS functional connectivity (FC) were derived by ICA, constrained to PET atlases for dopamine, norepinephrine and serotonin transporters, obtained in HCs’ brain.ResultsCompared with HCs, patients with MS showed abnormalities in all three explored monoaminergic networks, mostly with decreased RS FC within PET-guided monoaminergic networks in frontal regions and subcortical areas including the cerebellum and thalamus, and increased RS FC in temporo-parieto-occipital cortical areas, including bilateral precunei.MS-related fatigue was associated with decreased RS FC within the PET-guided dopamine network in the left thalamus and left cerebellum, and with increased RS FC within the PET-guided serotonin network in the left middle occipital gyrus. MS-related depression was associated with more distributed abnormalities involving the three explored monoaminergic networks, resulting in overall reduced RS FC in the frontal lobe, limbic areas and the precuneus.ConclusionsPatients with MS present diffuse dysregulation in the monoaminergic networks. Specific alterations in these networks were associated with fatigue and depression, providing a pathological marker for these bothersome symptoms and putative targets for their treatment.

Soma and neurite density imaging (SANDI) is a new biophysical model that incorporates soma in addition to neurite density, thus possibly providing more specific information about the complex pathological processes of multiple sclerosis (MS).To discriminate the pathological abnormalities of MS white matter (WM) lesions, normal-appearing (NA) WM and cortex and to evaluate the associations among SANDI-derived measures, clinical disability, and conventional MRI variables.Twenty healthy controls (HC) and 23 MS underwent a 3 T brain MRI. Using SANDI on diffusion-weighted sequence, the fractions of neurite (fCompared to HC WM, MS NAWM showed lower fSANDI may represent a clinically relevant model to discriminate different neurodegenerative phenomena that gradually accumulate through MS disease course.

Fatigue is a common and debilitating symptom among multiple sclerosis (MS) patients with a prevalence up to 81% and with a considerable impact on quality of life. However, its subjective nature makes it difficult to define and quantify in clinical practice. Research aimed at a more precise definition and knowledge of this construct is thus continuously growing.This review summarizes the most relevant updates available on PubMed up to 1 July 2022 regarding: the assessment methods that aim to measure the concept of fatigue (as opposed to fatigability), the possible treatment pathways currently available to clinicians, interconnection with the pathophysiological substrates and with the common comorbidities of MS, such as depression and mood disorders.The in-depth study of fatigue can help to better understand its actual impact on MS patients and can stimulate clinicians toward a more valid approach, through a targeted analysis of this symptom. Considering fatigue from a multidimensional perspective allows the use of patient-tailored methods for its identification and subsequent treatment by different professional figures. Better identification of methods and treatment pathways would reduce the extremely negative impact of fatigue on MS patients' quality of life.

Introduction Cladribine is approved for the treatment of active relapsing MS (RRMS), but its positioning in MS therapeutic scenario still needs to be fully elucidated. Methods This is a monocentric, observational, real-world study on RRMS patients treated with cladribine. Relapses, magnetic resonance imaging (MRI) activity, disability worsening, and loss of no-evidence-of-disease-activity-3 (NEDA-3) status were assessed as outcomes. White blood cell, lymphocyte counts and side effects were also evaluated. Patients were analyzed overall and in subgroups according to the last treatment before cladribine. The relationship between baseline characteristics and outcomes was tested to identify predictors of response. Results Among the 114 patients included, 74.9% were NEDA-3 at 24 months. We observed a reduction of relapses and MRI activity, along with a stabilization of disability. A higher number of gadolinium-enhancing lesions at baseline was the only risk factor for loss of NEDA-3 during follow-up. Cladribine was more efficacious in switchers from first-line therapies or naïves. Grade I lymphopenia was more frequent at month 3 and 15. No grade IV lymphopenia cases were observed. Independent predictors of grade III lymphopenia were a lower baseline lymphocyte count and a higher number of previous treatments. Sixty-two patients presented at least one side effect and globally 111 adverse events were recorded, none of them was serious. Conclusions Our study confirms previous data on cladribine effectiveness and safety. Cladribine is more effective when placed early in the treatment algorithm. Real-world data on larger populations with longer follow-up are needed to confirm our findings.

Fig S2. Technical validation using NuGEN's Ovation System. The scatter plot shows the fold change consistency of genes differentially expressed using WG-DASL and NuGEN methods. Only 6 out of the 509 DE genes were found discordant, confirming the WG-DASL patterns. Data are plotted as log2 fold change (FC) expression long/short PFS; positive log2(FC) values stand for genes up-regulated in long-PFS cases, while negative values stand for up-regulation in short-PFS cases. Statistical significance was tested through Monte Carlo test (1000 interactions) yielding p-value

Fig S1. Volcano plot for the 17,378 genes detected by microarray analysis. The x-axis is the fold-change, and the y-axis is log10 p value. A total of 509 probes (blue dots) were differentially expressed in long-PFS patients (14) compared with short-PFS patients (26), imposing a FDR < 15%. Probability of finding by chance 509 significant DE genes between the classes: p = 0.016.

FigS3: Biasogram representing the influence of tissue origin on outcome. Y axes indicate the outcome vector (long- versus short- PFS), while B indicates the nuisance variable (tissue origin; primary versus recurrence/metastatic). The colorgram represents a bivariate histogram of all the 17,378 detected genes; the green circles indicate the genes present in our signature.

Purpose: To identify the tumor portrait of the minority of head and neck squamous cell carcinoma (HNSCC) patients with recurrent–metastatic (RM) disease who upon treatment with platinum-based chemotherapy plus cetuximab present a long-lasting response.Experimental Design: The gene expression of pretreatment samples from 40 HNSCC-RM patients, divided in two groups [14 long-progression-free survival (PFS) and 26 short-PFS (median = 19 and 3 months, respectively)], was associated with PFS and was challenged against a dataset from metastatic colon cancer patients treated with cetuximab. For biologic analysis, we performed functional and subtype association using gene set enrichment analysis, associated biology across all currently available HNSCC signatures, and inferred drug sensitivity using data from the Cancer Genomic Project.Results: The identified genomic profile exhibited a significant predictive value that was essentially confirmed in the single publicly available dataset of cetuximab-treated patients. The main divergence between long- and short-PFS groups was based on developmental/differentiation status. The long-PFS patients are characterized by basal subtype traits such as strong EGFR signaling phenotype and hypoxic differentiation, further validated by the significantly higher association with the hypoxia metagene. The short-PFS patients presented a strong activation of RAS signaling confirmed in an in vitro model of two isogenic HNSCC cell lines sensitive or resistant to cetuximab. The predicted drug sensitivity for all four EGFR inhibitors was higher in long- versus short-PFS patients (P range: Conclusions: Our data uncover the biology behind response to platinum-based chemotherapy plus cetuximab in RM-HNSCC cancer and may have translational implications improving treatment selection. Clin Cancer Res; 22(15); 3961–70. ©2016 AACR.See related commentary by Chau and Hammerman, p. 3710

Fig S4. Ability of existing gene signatures to predict outcome following cetuximab treatment. Five available prognostic gene-expression based signatures were taken into account: i) the hypoxia metagene (Winter, 2007); ii) the 13-gene OSCC signature (Lohavanichbutr, 2013); iii) the RSI-index (Eschrich, 2009); iv) the 42-gene Chung's high risk signature (Chung, 2006); v) the 172-gene signature (De Cecco, 2014). A score was assessed for each sample entering into our study following the model developed by the authors and compared among long- and short PFS cases. The boxplots depicts the data in the two groups. Green: long-PFS; Red: short-PFS.

Supplementary Table S2 Gene sets associated to long- and short-PFS patients

ObjectiveSince astrocytes at the blood–brain barrier are targeted by neuromyelitis optica spectrum disorder (NMOSD), this study aims to assess whether patients with NMOSD have a subclinical accumulation of brain water and if it differs according to disease activity.MethodsSeventy-seven aquaporin-4-positive patients with NMOSD and 105 healthy controls were enrolled at two European centres. Brain dual-echo turbo spin-echo MR images were evaluated and maps of T2 relaxation time (T2rt) in the normal-appearing white matter (NAWM), grey matter and basal ganglia were obtained. Patients with a clinical relapse within 1 month before or after MRI acquisition were defined ‘active’. Differences between patients and controls were assessed using z-scores of T2rt obtained with age-adjusted and sex-adjusted linear models from each site. A stepwise binary logistic regression was run on clinical and MRI variables to identify independent predictors of disease activity.ResultsPatients had increased T2rt in both white and grey matter structures (p range: 0.014 to 2=0.46, pConclusionsIn line with the research hypothesis, patients with NMOSD have increased brain T2rt. The magnitude of this alteration might be useful for identifying those patients with active disease.

Background and purpose: To investigate the relationship between the functional connectivity (FC) of the sensorimotor and cognitive cerebellum and measures of structural damage in patients with multiple sclerosis (MS) and no physical disability. Methods: We selected 144 relapsing-remitting MS patients with an Expanded Disability Status Scale score of ≤1.5 and 98 healthy controls from the Italian Neuroimaging Network Initiative database. From multimodal 3T magnetic resonance imaging (MRI), including functional MRI at rest, we calculated lesion load, cortical thickness, and white matter, cortical gray matter, and caudate, putamen, thalamic, and cerebellar volumes. Voxel-wise FC of the sensorimotor and cognitive cerebellum was assessed with seed-based analysis, and multiple regression analysis was used to evaluate the relationship between FC and structural damage. Results: Whole brain, white matter, caudate, putamen, and thalamic volumes were reduced in patients compared to controls, whereas cortical gray matter was not significantly different in patients versus controls. Both the sensorimotor and cognitive cerebellum showed a widespread pattern of increased and decreased FC that were negatively associated with structural measures, indicating that the lower the FC, the greater the tissue loss. Lastly, among multiple structural measures, cortical gray matter and white matter volumes were the best predictors of cerebellar FC alterations. Conclusions: Increased and decreased cerebellar FC with several brain areas coexist in MS patients with no disability. Our data suggest that white matter loss hampers FC, whereas, in the absence of atrophy, cortical volume represents the framework for FC to increase.

Background: Previous studies demonstrated an association between motor and cognitive performance in multiple sclerosis (MS). However, disease-related brain damage might represent a common substrate to both phenomena, which was not considered before. Objective: Aim of this study is to investigate whether the association between cognition and motor function is beyond structural damage in patients with MS. Methods: Eighty-one healthy controls and 106 relapsing–remitting (RR) MS patients underwent a 3.0T MRI with quantification of T2-lesion volumes, T1-lesion volumes and normalized brain volumes. A functional examination [Nine-Hole Peg Test (9-HPT), Timed 25-Foot Walk test (T25FW) and Expanded Disability Status Scale] and a neuropsychological evaluation (Brief Repeatable Battery of Neuropsychological Tests) were also administered. Association between demographic, clinical, cognitive, MRI and functional measures were analysed with univariate analyses and hierarchical linear regression. Results: In RRMS patients, Spatial Recall Test and Symbol Digit Modalities Test were positively correlated with 9-HPT (p < 0.001) and T25FW (p ≤ 0.035); Paced Auditory Serial Addition Test (PASAT) correlated with 9-HPT (p ≤ 0.009). 9-HPT and T25FW were significantly associated with normalized brain volumes (p ≤ 0.016), T2- and T1-lesion volumes (p ≤ 0.009). Hierarchical regression models selected age and normalized deep gray matter volume as predictors of T25FW (adjusted-R2 = 0.109). Younger age, female sex, higher normalized gray matter volume and higher PASAT 2″ scores predicted higher 9-HPT scores (adjusted-R2 = 0.337). Conclusions: In RRMS patients, deficit in information processing speed and executive function may contribute to hand motor dysfunction beyond the effect of structural disease-related burden, supporting the integration of motor and cognitive assessment in clinical settings.

Background Altered callosal integrity has been associated with motor deficits in patients with multiple sclerosis (MS), but its contribution to disability has, to the knowledge of the authors, not been investigated by using multiparametric MRI approaches. Purpose To investigate structural and functional interhemispheric MRI substrates of global disability at different milestones and upper limb motor impairment in MS. Materials and Methods In this cross-sectional study, healthy control patients and patients with MS (between January 1, 2008, and December 31, 2016) were retrospectively selected from our hospital database. Clinical assessment included Expanded Disability Status Scale (EDSS), nine-hole peg test, and digital finger tapping test. By using structural and resting-state functional MRI sequences, probabilistic tractography of hand corticospinal tract fibers, and transcallosal fibers between hand-motor cortices (hereafter, referred to as hand-M1), supplementary motor areas (SMAs), premotor cortices (PMCs), and voxel-mirror homotopic connectivity (VMHC) were analyzed. Random forest analyses identified the MRI predictors of clinical disability at different milestones (EDSS scores of 3.0, 4.0, 6.0) and upper limb motor impairment (nine-hole peg test and finger tapping test z scores < healthy control patients 5th percentile). Results One-hundred thirty healthy control patients (median age, 39 years; interquartile range, 31-50 years; 70 women) and 340 patients with MS (median age, 43 years; interquartile range, 33-51 years; 213 women) were studied. EDSS 3.0 predictors (n = 159) were global measures of atrophy and lesions together with damage measures of corticospinal tracts and transcallosal fibers between PMCs and SMAs (accuracy, 86%; P = .001-.01). For EDSS 4.0 (n = 131), similar predictors were found in addition to damage in transcallosal fibers between hand-M1 (accuracy, 89%; P = .001-.049). No MRI predictors were found for EDSS 6.0 (n = 70). Nine-hole peg test (right, n = 161; left, n = 166) and finger tapping test (right, n = 117; left, n = 111) impairments were predicted by damage in transcallosal fibers between SMAs and PMCs (accuracy range, 69%-77%; P = .001-.049). VMHC abnormalities did not explain clinical outcomes. Conclusion Structural, not functional, abnormalities at MRI in transcallosal premotor and motor white matter fibers predicted severity of global disability and upper limb motor impairment in patients with multiple sclerosis. The informative role of such predictors appeared less evident at higher disability levels. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Barkhof and Pontillo in this issue.

We aimed to investigate abnormal time-varying functional connectivity (FC) for thalamic sub-regions in multiple sclerosis (MS) and their clinical, cognitive and MRI correlates. Eighty-nine MS patients (49 relapsing-remitting [RR] MS; 40 progressive [P] MS) and 53 matched healthy controls underwent neurological, neuropsychological and resting state fMRI assessment. Time-varying connectivity (TVC) was quantified using sliding-window seed-voxel correlation analysis. Standard deviation of FC across windows was taken as measure of TVC, while mean connectivity across windows expressed static FC. MS patients showed reduced TVC vs controls between most of thalamic sub-regions and fronto-temporo-occipital regions. At the same time, they showed increased static FC between all thalamic sub-regions and structurally connected cortico-subcortical regions. TVC reduction was mainly driven by RRMS; while PMS exhibited a variable pattern of TVC abnormalities, characterized by reduced TVC between frontal/motor thalamic seeds and default-mode network areas and increased TVC vs controls/RRMS between posterior thalamic sub-regions and occipito-temporo-insular cortices, associated with severity of clinical disability. Compared with controls, both cognitively preserved and impaired patients showed reduced TVC between anterior thalamic sub-regions and frontal cortex. Cognitively impaired patients also showed increased TVC of the right postcentral thalamic sub-region with the cingulate cortex and postcentral gyrus vs both controls and cognitively preserved patients. Divergent patterns of TVC thalamic abnormalities were found between RRMS and PMS patients. TVC reduction in RRMS may represent the attempt of thalamic network to keep with stable connections. Conversely, increased TVC of posterior thalamic sub-regions characterized PMS and cognitively impaired MS, possibly reflecting maladaptive mechanisms.

Recent evidence has shown the existence of a CNS ‘waste clearance’ system, defined as the glymphatic system. Glymphatic abnormalities have been described in several neurodegenerative conditions, including Alzheimer’s and Parkinson’s disease. Glymphatic function has not been thoroughly explored in multiple sclerosis, where neurodegenerative processes are intermingled with inflammatory processes. We aimed to investigate glymphatic system function in multiple sclerosis and to evaluate its association with clinical disability, disease course, demyelination and neurodegeneration, quantified using different MRI techniques. In this retrospective study, we enrolled 71 multiple sclerosis patients (49 relapsing-remitting and 22 progressive multiple sclerosis) and 32 age- and sex-matched healthy control subjects. All subjects underwent neurological and MRI assessment including high-resolution T1, T2 and double inversion recovery sequences, diffusion and susceptibility weighted imaging. We calculated the diffusion along perivascular space index, a proxy for glymphatic function, cortical and deep grey matter volume, white and cortical grey matter lesion volume and normal-appearing white matter microstructural damage. Multiple sclerosis patients showed an overall lower diffusion along perivascular space index versus healthy controls (estimated mean difference: −0.09, P = 0.01). Both relapsing-remitting and progressive multiple sclerosis patients had lower diffusion along perivascular space index versus healthy controls (estimated mean difference: −0.06, P = 0.04 for relapsing-remitting and −0.19, P = 0.001 for progressive multiple sclerosis patients). Progressive multiple sclerosis patients showed lower diffusion along perivascular space index versus relapsing-remitting multiple sclerosis patients (estimated mean difference: −0.09, P = 0.03). In multiple sclerosis patients, lower diffusion along perivascular space index was associated with more severe clinical disability (r = −0.45, P = 0.001) and longer disease duration (r = −0.37, P = 0.002). Interestingly, we detected a negative association between diffusion along perivascular space index and disease duration in the first 4.13 years of the disease course (r = −0.38, P = 0.04) without any association thereafter (up to 34 years of disease duration). Lower diffusion along perivascular space index was associated with higher white (r = −0.36, P = 0.003) and cortical (r = −0.41, P = 0.001) lesion volume, more severe cortical (r = 0.30, P = 0.007) and deep (r = 0.42, P = 0.001) grey matter atrophy, reduced fractional anisotropy (r = 0.42, P = 0.001) and increased mean diffusivity (r = −0.45, P = 0.001) in the normal-appearing white matter. Our results suggest that the glymphatic system is impaired in multiple sclerosis, especially in progressive stages. Impaired glymphatic function was associated with measures of both demyelination and neurodegeneration and reflects a more severe clinical disability. These findings suggest that glymphatic impairment may be a pathological mechanism underpinning multiple sclerosis. The dynamic interplay with other pathological substrates of the disease deserves further investigation.

The adult brain retains over life endogenous neural stem/precursor cells (eNPCs) within the subventricular zone (SVZ). Whether or not these cells exert physiological functions is still unclear. In the present work, we provide evidence that SVZ-eNPCs tune structural, electrophysiological, and behavioural aspects of striatal function via secretion of insulin-like growth factor binding protein-like 1 (IGFBPL1). In mice, selective ablation of SVZ-eNPCs or selective abrogation of IGFBPL1 determined an impairment of striatal medium spiny neuron morphology, a higher failure rate in GABAergic transmission mediated by fast-spiking interneurons, and striatum-related behavioural dysfunctions. We also found IGFBPL1 expression in the human SVZ, foetal and induced-pluripotent stem cell-derived NPCs. Finally, we found a significant correlation between SVZ damage, reduction of striatum volume, and impairment of information processing speed in neurological patients. Our results highlight the physiological role of adult SVZ-eNPCs in supporting cognitive functions by regulating striatal neuronal activity.

ObjectiveTo characterise in vivo the microstructural abnormalities of multiple sclerosis (MS) normal-appearing (NA) cortex and cortical lesions (CLs) and their relations with clinical phenotypes and disability using neurite orientation dispersion and density imaging (NODDI).MethodsOne hundred and seventy-two patients with MS (101 relapsing–remitting multiple sclerosis (RRMS), 71 progressive multiple sclerosis (PMS)) and 62 healthy controls (HCs) underwent a brain 3T MRI. Brain cortex and CLs were segmented from three-dimensional T1-weighted and double inversion recovery sequences. Using NODDI on diffusion-weighted sequence, intracellular volume fraction (ICV_f) and Orientation Dispersion Index (ODI) were assessed in NA cortex and CLs with default or optimised parallel diffusivity for the cortex (D//=1.7 or 1.2 µm2/ms, respectively).ResultsThe NA cortex of patients with MS had significantly lower ICV_f versus HCs’ cortex with both D// values (false discovery rate (FDR)-p 2/ms. No CL microstructural differences were found between MS clinical phenotypes. MS NA cortex ICV_f and ODI were significantly correlated with disease duration, clinical disability, lesion burden and global and regional brain atrophy (r from −0.51 to 0.71, FDR-p from ConclusionsA significant neurite loss occurs in MS NA cortex. CLs show a further neurite density reduction and a reduced ODI suggesting a simplification of neurite complexity. NODDI is relevant to investigate in vivo the heterogeneous pathology affecting the MS cortex.

Objective To elucidate the hypothalamic involvement in episodic migraine and investigate the association between hypothalamic resting state functional connectivity changes and migraine patients’ clinical characteristics and disease progression over the years. Methods Ninety-one patients with episodic migraine and 73 controls underwent interictal resting state functional magnetic resonance imaging. Twenty-three patients and controls were re-examined after a median of 4.5 years. Hypothalamic resting state functional connectivity changes were investigated using a seed-based correlation approach. Results At baseline, a decreased functional interaction between the hypothalamus and the parahippocampus, cerebellum, temporal, lingual and orbitofrontal gyrus was found in migraine patients versus controls. Increased resting state functional connectivity between the hypothalamus and bilateral orbitofrontal gyrus was demonstrated in migraine patients at follow-up versus baseline. Migraine patients also experienced decreased right hypothalamic resting state functional connectivity with ipsilateral lingual gyrus. A higher migraine attack frequency was associated with decreased hypothalamic-lingual gyrus resting state functional connectivity at baseline, while greater headache impact at follow-up correlated with decreased hypothalamic-orbitofrontal gyrus resting state functional connectivity at baseline. At follow-up, a lower frequency of migraine attacks was associated with higher hypothalamic-orbitofrontal gyrus resting state functional connectivity. Conclusions During the interictal phase, the hypothalamus modulates the activity of pain and visual processing areas in episodic migraine patients. The hypothalamic-cortical interplay changes dynamically over time according to patients’ clinical features.

In multiple sclerosis (MS), paramagnetic rim lesions (PRLs) on MRI identify a subset of chronic active lesions (CALs), which have been linked through clinical and pathological studies to more severe disease course and greater disability accumulation. Beside their prognostic relevance, increasing evidence supports the use of PRL as a diagnostic biomarker.This review summarizes the most recent updates regarding the MRI pathophysiology of PRL, their prevalence in MS (by clinical phenotypes) vs mimicking conditions, and their potential role as diagnostic MS biomarkers. We searched PubMed with terms including 'multiple sclerosis' AND 'paramagnetic rim lesions' OR 'iron rim lesions' OR 'rim lesions' for manuscripts published between January 2008 and July 2022.Current research suggests that PRL can improve the diagnostic specificity and the overall accuracy of MS diagnosis when used together with the dissemination in space MRI criteria and the central vein sign. Nevertheless, future prospective multicenter studies should further define the real-world prevalence and specificity of PRL. International guidelines are needed to establish methodological criteria for PRL identification before its implementation into clinical practice.

Spinal cord involvement can be observed in the course of immune-mediated disorders. Although multiple sclerosis (MS) represents the leading cause of inflammatory myelopathy, an increasing number of alternative etiologies must be now considered in the diagnostic work-up of patients presenting with myelitis. These include antibody-mediated disorders and cytotoxic T cell-mediated diseases targeting central nervous system (CNS) antigens, and systemic autoimmune conditions with secondary CNS involvement. Even though clinical features are helpful to orient the diagnostic suspicion (e.g., timing and severity of myelopathy symptoms), the differential diagnosis of inflammatory myelopathies is often challenging due to overlapping features. Moreover, noninflammatory etiologies can sometimes mimic an inflammatory process. In this setting, magnetic resonance imaging (MRI) is becoming a fundamental tool for the characterization of spinal cord damage, revealing a pictorial scenario which is wider than the clinical manifestations. The characterization of spinal cord lesions in terms of longitudinal extension, location on axial plane, involvement of the white matter and/or gray matter, and specific patterns of contrast enhancement, often allows a proper differentiation of these diseases. For instance, besides classical features, such as the presence of longitudinally extensive spinal cord lesions in patients with aquaporin-4-IgG positive neuromyelitis optica spectrum disorder (AQP4+NMOSD), novel radiological signs (e.g., H sign, trident sign) have been recently proposed and successfully applied for the differential diagnosis of inflammatory myelopathies. In this review article, we will discuss the radiological features of spinal cord involvement in autoimmune disorders such as MS, AQP4+NMOSD, myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and other recently characterized immune-mediated diseases. The identification of imaging pitfalls and mimics that can lead to misdiagnosis will also be examined. Since spinal cord damage is a major cause of irreversible clinical disability, the recognition of these radiological aspects will help clinicians achieve a correct and prompt diagnosis, treat early with disease-specific treatment and improve patient outcomes.

BACKGROUND: Frontal cortico-subcortical dysfunction may contribute to fatigue and dual-task impairment of walking and cognition in progressive multiple sclerosis (PMS).PURPOSE: To explore the associations among fatigue, dual-task performance and structural and functional abnormalities of frontal cortico-subcortical network in PMS.METHODS: Brain 3 T structural and functional MRI sequences, Modified Fatigue Impact Scale (MFIS), dual-task motor and cognitive performances were obtained from 57 PMS patients and 10 healthy controls (HC). The associations of thalamic, caudate nucleus and dorsolateral prefrontal cortex (DLPFC) atrophy, microstructural abnormalities of their connections and their resting state effective connectivity (RS-EC) with fatigue and dual-task performance were investigated using random forest.RESULTS: Thirty-seven PMS patients were fatigued (F) (MFIS ≥ 38). Compared to HC, non-fatigued (nF) and F-PMS patients had significantly worse dual-task performance (p ≤ 0.002). Predictors of fatigue (out-of-bag [OOB]-accuracy = 0.754) and its severity (OOB-R2 = 0.247) were higher Expanded Disability Status scale (EDSS) score, lower RS-EC from left-caudate nucleus to left-DLPFC, lower fractional anisotropy between left-caudate nucleus and left-thalamus, higher mean diffusivity between right-caudate nucleus and right-thalamus, and longer disease duration. Microstructural abnormalities in connections among thalami, caudate nuclei and DLPFC, mainly left-lateralized in nF-PMS and more bilateral in F-PMS, higher RS-EC from left-DLPFC to right-DLPFC in nF-PMS and lower RS-EC from left-caudate nucleus to left-DLPFC in F-PMS, higher EDSS score, higher WM lesion volume, and lower cortical volume predicted worse dual-task performances (OOB-R2 from 0.426 to 0.530).CONCLUSIONS: In PMS, structural and functional frontal cortico-subcortical abnormalities contribute to fatigue and worse dual-task performance, with different patterns according to the presence of fatigue.

Context Mutations in the androgen receptor (AR) gene might be associated with infertility mainly because they cause various degrees of androgen insensitivity. Objective The aim of the study was to evaluate the frequency and type of AR variants in a large cohort of infertile males. Methods A total of 8224 males of Italian idiopathic infertile couples were referred to the University Hospital of Padova. The main outcome measures were mutational screening of AR, computational, and functional analyses. Results We found 131 patients (1.6%) harboring 45 variants in AR gene, of which 18 were novel missense AR variants. Patients with AR gene variants had lower sperm count (P = .048), higher testosterone (T) concentration (P < .0001), and higher androgen sensitivity index (ASI) (luteinizing hormone × T, P < .001) than patients without variants. Statistical analyses found T ≥ 15.38 nmol/L and ASI ≥ 180 IU × nmol/L2 as the threshold values to discriminate with good accuracy patients with AR variants. Patients with oligozoospermia and T ≥ 15.38 nmol/L had a 9-fold increased risk of harboring mutations compared with patients with normal sperm count and T < 15.38 nmol/L (odds ratio 9.29, 95% CI 5.07-17.02). Using computational and functional approaches, we identified 2 novel variants, L595P and L791I, as potentially pathogenic. Conclusion This is the largest study screening AR gene variants in men of idiopathic infertile couples. We found that the prevalence of variants increased to 3.4% in oligozoospermic subjects with T ≥ 15.38 nmol/L. Conversely, more than 80% of men with AR gene variants had low sperm count and high T levels. Based on our findings, we suggest AR sequencing as a routine genetic test in cases of idiopathic oligozoospermia with T ≥ 15.38 nmol/L.

BackgroundChoroid plexus (CP) enlargement has been suggested as a reliable marker of neuroinflammation in adult multiple sclerosis (MS). We investigated CP volume in patients with paediatric MS compared with matched healthy controls (HC), possible sex-related effect, and the associations with clinical and structural MRI variables.MethodsBrain 3.0 T dual-echo and three-dimensional (3D) T1-weighted sequences were selected retrospectively from 69 patients with paediatric MS and 23 age-matched and sex-matched HC. CP volume was manually obtained from 3D T1-weighted scans by two expert raters.ResultsCP segmentation was highly reproducible (intraobserver agreement: rater I=0.963, rater II=0.958; interobserver agreement=0.968). Compared with HC, patients with paediatric MS showed higher normalised CP volume (pConclusionsCP enlargement occurs in paediatric MS, suggesting its early involvement in the pathophysiology of the disease. The higher CP volume, which is found especially in female patients, supports the hypothesis of sex-related differences occurring already in paediatric MS.

BACKGROUND Aquaporin-4 (AQP4) water channel is involved in hippocampal plasticity and is the target of neuromyelitis optica spectrum disorders (NMOSD) autoimmunity. We measured volumes of hippocampal subfields and their association with cognitive performance in AQP4-seropositive NMOSD patients. METHODS Global and regional hippocampal volumes were derived from 28 AQP4-seropositive NMOSD patients and 101 healthy controls (HC) from 3D-T1-weighted images. Normalized brain volumes were also calculated. A neuropsychological evaluation, including the Brief Repeatable Battery of Neuropsychological Tests, was performed in patients. Based on HC data, we estimated mean z-scores of volumes in the whole NMOSD group and compared them according to the status of global and domain-selective cognitive impairment. RESULTS Global cognitive impairment was detected in 46.4% of NMOSD patients, with attentive (60.7%) and executive (21.4%) domains being the most affected. NMOSD patients had left hippocampal atrophy at global (p = 0.012) and regional level (fimbria, Cornu Ammonis [CA] 3, molecular layer, dentate gyrus [DG], and subicular complex, p values ranging between 0.033 and

Background Cognitive impairment frequently affects multiple sclerosis (MS) patients. However, its neuroanatomical correlates still need to be fully explored. We investigated the contribution of structural and functional magnetic resonance imaging (MRI) abnormalities in explaining cognitive impairment in MS. Methods Brain dual-echo, diffusion tensor, 3D T1-weighted and resting-state (RS) MRI sequences were acquired from 276 MS patients and 102 healthy controls. Using random forest analysis, the contribution of regional white matter (WM) lesions, WM fractional anisotropy (FA) abnormalities, gray matter (GM) atrophy and RS functional connectivity (FC) alterations to cognitive impairment in MS patients was investigated. Results Eighty-four MS patients (30.4%) were cognitively impaired. The best MRI predictors of cognitive impairment (relative importance [%]) (out-of-bag area under the curve [AUC]=0.795) were (a) WM lesions in the right superior longitudinal fasciculus (100%), left anterior thalamic radiation (93.4%), left posterior corona radiata (78.5%), left medial lemniscus (74.2%), left inferior longitudinal fasciculus (70.4%), left optic radiation (68.7%), right middle cerebellar peduncle (60.6%) and right optic radiation (53.5%); (b) decreased FA in the splenium of the corpus callosum (64.3%), left optic radiation (61.0%), body of the corpus callosum (51.9%), and fornix (50.9%); (c) atrophy of the left precuneus (91.4%), right cerebellum crus I (84.4%), right caudate nucleus (78.6%), left thalamus (76.2%) and left supplementary motor area (59.8%). The relevance of these MRI measures in explaining cognitive impairment was confirmed in a cross-validation analysis (AUC=0.765). Conclusions Structural damage in strategic WM and GM regions more than RS FC abnormalities explains cognitive impairment in MS patients.

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS) characterized by the accumulation of focal white matter (WM) lesio...

BACKGROUND AND PURPOSE Multiple sclerosis (MS) susceptibility is influenced by genetics; however, little is known about genetic determinants of disease expression. We aimed at assessing genetic factors influencing quantitative neuroimaging measures in two cohorts of progressive MS (PMS) and relapsing-remitting MS (RRMS) patients. METHODS Ninety-nine PMS and 214 RRMS patients underwent a 3-T brain magnetic resonance imaging (MRI) scan, with the measurement of five MRI metrics including T2 lesion volumes and measures of white matter, grey matter, deep grey matter, and hippocampal volumes. A candidate pathway strategy was adopted; gene set analysis was carried out to estimate cumulative contribution of genes to MRI phenotypes, adjusting for relevant confounders, followed by single nucleotide polymorphism (SNP) regression analysis. RESULTS Seventeen Kyoto Encyclopedia of Genes and Genomes pathways and 42 Gene Ontology (GO) terms were tested. We additionally included in the analysis genes with enriched expression in brain cells. Gene set analysis revealed a differential pattern of association across the two cohorts, with processes related to sodium homeostasis being associated with grey matter volume in PMS (p = 0.002), whereas inflammatory-related GO terms such as adaptive immune response and regulation of inflammatory response appeared to be associated with T2 lesion volume in RRMS (p = 0.004 and p = 0.008, respectively). As for SNPs, the rs7104613T mapping to SPON1 gene was associated with reduced deep grey matter volume (β = -0.731, p = 3.2*10-7 ) in PMS, whereas we found evidence of association between white matter volume and rs740948A mapping to SEMA3A gene (β = 22.04, p = 5.5*10-6 ) in RRMS. CONCLUSIONS Our data suggest a different pattern of associations between MRI metrics and functional processes across MS disease courses, suggesting different phenomena implicated in MS.

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

This study aims to provide real-world data on oncologic and functional outcomes of the most modern surgical and non-surgical treatments of locally advanced HPV-positive oropharyngeal cancer.We reviewed data on patients treated for stage III and IV HPV-positive oropharyngeal squamous cell carcinoma with either endoscopic surgery (Transoral Robotic Surgery, TORS; Transoral Laser Microsurgery, TLM - group A) or intensity-modulated radiotherapy (IMRT - group B). The minimum follow-up required was 6 months. Survival outcomes and toxicities of treatments were evaluated.30 patients in group A and 66 in group B were eligible for the analysis. 28% of patients in group A underwent a unimodal treatment, while 42% needed trimodal treatment. 90% of patients in group B underwent concurrent chemoradiation. We found no statistically significant difference in survival outcomes (group A: overall survival 97%, progression-free survival 83%; group B: OS 98%, PFS 86%) or toxicities between groups.Both transoral surgery and IMRT provide excellent outcomes in HPV-positive oropharyngeal cancer. Because of the good prognosis, treatments need to be refined to reduce toxicities while preserving oncologic soundness.Confronto tra chirurgia transorale e radioterapia a intensità modulata nel carcinoma orofaringeo HPV-positivo.Questo studio presenta dati di pratica clinica sui risultati oncologici e funzionali dei più moderni trattamenti chirurgici e non chirurgici del carcinoma orofaringeo HPV-positivo in stadio localmente avanzato.Abbiamo revisionato i dati dei pazienti affetti da carcinoma squamocellulare dell’orofaringe HPV-positivo in stadio III e IV e trattati con chirurgia endoscopica (Chirurgia Robotica Transorale; Microchirurgia Laser Transorale – gruppo A) o radioterapia a intensità modulata (IMRT – gruppo B). Il follow-up minimo era di 6 mesi. Sono state valutate e confrontate sopravvivenze e tossicità.Sono stati inclusi nell’analisi 30 pazienti nel gruppo A e 66 pazienti nel gruppo B. il 28% dei pazienti del gruppo A ha ricevuto un trattamento unimodale, mentre il 42% un trattamento trimodale. Nel gruppo B il 90% è stato sottoposto a chemioradioterapia concomitante. Non abbiamo rilevato differenze statisticamente significative nelle sopravvivenze (gruppo A: overall survival 97%, progression-free survival 83%; gruppo B: OS 98%, PFS 86%) e nelle tossicità.TORS e IMRT forniscono risultanti eccellenti nel cancro orofaringeo HPV-positivo. Alla luce della buona prognosi, i trattamenti devono essere perfezionati per ridurre le tossicità preservando l’efficacia oncologica.

ObjectivesTo assess the effectiveness of Neuroaspis plp10 nutritional supplement when added to interferon (IFN)-β treatment in patients with relapsing-remitting multiple sclerosis (RRMS).DesignA 30-month phase III multicentre, randomised, double-blind, placebo-controlled trial. Randomisation stratified by centre using a computer-generated procedure with Neuroaspis plp10 versus placebo in 1:1 ratio. The first 6 months were used as both the pre-entry and normalisation period.Setting3 teaching hospitals in Greece and 1 Neurology Institute in Cyprus.Participants61 patients with RRMS on IFN-β were randomly assigned to receive Neuroaspis plp10 (n=32) or placebo (n=29), 20 mL, orally, once daily, for 30 months.InterventionNeuroaspis plp10, a cocktail mixture, containing specific PUFA (12 150 mg) and γ-tocopherol (760 mg) versus virgin olive oil (placebo).Main outcome measureThe primary end point was the annual relapse rate (ARR) whereas the secondary ones were the rate of sustained progression of disability, as measured by the Expanded Disability Status Scale (EDSS) and the brain T2 and gadolinium-enhancing lesions, at 2 years.ResultsFor the intention-to-treat analyses Neuroaspis plp10 significantly reduced the ARR by 80%, (RRR, 0.20; 95% CI: 0.09 to 0.45; p=0.0001) and the risk of sustained progression of disability by 73% (HR, 0.27; 95% CI: 0.09 to 0.83; p=0.022) versus placebo, at 2 years. The number of T1 gadolinium-enhancing lesions and the number of new/enlarged T2-hyperintense lesions were significantly reduced (p=0.01 and pConclusionsNeuroaspis plp10 added to IFN-β was significantly more effective than IFN-β alone in patients with RRMS.Trial registration numberISRCTN06166891.

Quantitative MRI provides biophysical measures of the microstructural integrity of the CNS, which can be compared across CNS regions, patients, and centres. In patients with multiple sclerosis, quantitative MRI techniques such as relaxometry, myelin imaging, magnetization transfer, diffusion MRI, quantitative susceptibility mapping, and perfusion MRI, complement conventional MRI techniques by providing insight into disease mechanisms. These include: (i) presence and extent of diffuse damage in CNS tissue outside lesions (normal-appearing tissue); (ii) heterogeneity of damage and repair in focal lesions; and (iii) specific damage to CNS tissue components. This review summarizes recent technical advances in quantitative MRI, existing pathological validation of quantitative MRI techniques, and emerging applications of quantitative MRI to patients with multiple sclerosis in both research and clinical settings. The current level of clinical maturity of each quantitative MRI technique, especially regarding its integration into clinical routine, is discussed. We aim to provide a better understanding of how quantitative MRI may help clinical practice by improving stratification of patients with multiple sclerosis, and assessment of disease progression, and evaluation of treatment response., Quantitative MRI techniques provide biophysical measures of the microstructural integrity of the CNS. Granziera et al. review the information provided by qMRI in the field of multiple sclerosis research and the potential for translation of qMRI techniques into clinical practice.

Purpose of review To summarize recent evidence from the application of susceptibility-based MRI sequences to investigate the 'central vein sign' (CVS) and 'iron rim' as biomarkers to improve the diagnostic work-up of multiple sclerosis (MS) and predict disease severity. Recent findings The CVS is a specific biomarker for MS being detectable from the earliest phase of the disease. A threshold of 40% of lesions with the CVS can be optimal to distinguish MS from non-MS patients. Iron rim lesions, reflecting chronic active lesions, develop in relapsing-remitting MS patients and persist in progressive MS. They increase in size in the first few years after their formation and then stabilize. Iron rim lesions can distinguish MS from non-MS patients but not the different MS phenotypes. The presence of at least four iron rim lesions is associated with an earlier clinical disability, higher prevalence of clinically progressive MS and more severe brain atrophy. Automated methods for CVS and iron rim lesion detection are under development to facilitate their quantification. Summary The assessment of the CVS and iron rim lesions is feasible in the clinical scenario and provides MRI measures specific to MS pathological substrates, improving diagnosis and prognosis of these patients.

Multiple sclerosis (MS) is a chronic neurological disorder characterized by inflammation in the central nervous system (CNS) that leads to neurodegeneration. The clinical course is highly variable, but its prevalence is rising worldwide, partly thanks to novel disease-modifying therapies. Additionally, the lifespan of people with MS is increasing, and for this reason, it is fundamental to have a multidisciplinary approach to MS. MS may be associated with cardiovascular diseases (CVD), but there is scarce attention on this issue. In particular, CNS is essential in regulating the autonomic system and heart activity. Moreover, cardiovascular risk factors show a higher prevalence in MS patients. On the other hand, conditions like Takotsubo syndrome are rare complications of MS. The parallelism between MS and myocarditis is also interesting. Finally, cardiac toxicity represents a not infrequent adverse reaction to MS drugs. This narrative review aims to provide an overview of cardiovascular complications in MS and their management to prompt further clinical and pre-clinical research on this topic.

Introduction Pediatric-onset (PO) multiple sclerosis (MS) accounts for about 2-10% of the total MS cases. Recently, a greater attention has been given to POMS, with substantial improvements in the understanding of its pathophysiology, in the diagnostic work-up and in the identification of reliable prognosticators associated with long-term disability in these patients. Areas covered This review summarizes the most recent updates regarding the pathophysiology of POMS, the current diagnostic criteria and the clinical, neuroradiological and laboratoristic markers that have been associated with disease progression (i.e. occurrence of a second clinical attack at disease onset and accumulation of disability in definite MS). Expert opinion The study of POMS, where the clinical onset is closer to the biological onset of MS, may contribute to better understand how the different pathological processes impact brain maturation and contribute to disease progression, but also how brain plasticity may counterbalance structural damage accumulation. Although rare, POMS is a severe disease, characterized by a prominent clinical and radiological activity at disease onset and by the accumulation of physical and cognitive disability at a younger age compared to the adult counterpart, with significant detrimental consequences at long-term. Early and accurate diagnosis, together with early treatment, is highly warranted.

OBJECTIVES The aims of this study were to present a deep learning approach for the automated classification of multiple sclerosis and its mimics and compare model performance with that of 2 expert neuroradiologists. MATERIALS AND METHODS A total of 268 T2-weighted and T1-weighted brain magnetic resonance imagin scans were retrospectively collected from patients with migraine (n = 56), multiple sclerosis (n = 70), neuromyelitis optica spectrum disorders (n = 91), and central nervous system vasculitis (n = 51). The neural network architecture, trained on 178 scans, was based on a cascade of 4 three-dimensional convolutional layers, followed by a fully dense layer after feature extraction. The ability of the final algorithm to correctly classify the diseases in an independent test set of 90 scans was compared with that of the neuroradiologists. RESULTS The interrater agreement was 84.9% (Cohen κ = 0.78, P < 0.001). In the test set, deep learning and expert raters reached the highest diagnostic accuracy in multiple sclerosis (98.8% vs 72.8%, P < 0.001, for rater 1; and 81.8%, P < 0.001, for rater 2) and the lowest in neuromyelitis optica spectrum disorders (88.6% vs 4.4%, P < 0.001, for both raters), whereas they achieved intermediate values for migraine (92.2% vs 53%, P = 0.03, for rater 1; and 64.8%, P = 0.01, for rater 2) and vasculitis (92.1% vs 54.6%, P = 0.3, for rater 1; and 45.5%, P = 0.2, for rater 2). The overall performance of the automated method exceeded that of expert raters, with the worst misdiagnosis when discriminating between neuromyelitis optica spectrum disorders and vasculitis or migraine. CONCLUSIONS A neural network performed better than expert raters in terms of accuracy in classifying white matter disorders from magnetic resonance imaging and may help in their diagnostic work-up.