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The organization of brain functional connectivity (FC) has been shown to differ between sexes. Amyotrophic lateral sclerosis (ALS) is characterized by sexual dimorphism, showing sex-specific trends in site of onset, phenotypes, and prognosis. Here, we explored resting state (RS) FC differences within major large-scale functional networks between women and men in a sample of ALS patients, in comparison to healthy controls (HCs). A group-level independent component analysis (ICA) was performed on RS-fMRI time-series enabling spatial and spectral analyses of large-scale RS FC networks in 45 patients with ALS (20 F; 25 M) and 31 HCs (15 F; 16 M) with a focus on sex-related differences. A whole-brain voxel-based morphometry (VBM) was also performed to highlight atrophy differences. Between-sex comparisons showed: decreased FC in the right middle frontal gyrus and in the precuneus within the default mode network (DMN), in affected men compared to affected women; decreased FC in the right post-central gyrus (sensorimotor network), in the right inferior parietal gyrus (right fronto-parietal network) and increased FC in the anterior cingulate cortex and right insula (salience network), in both affected and non-affected men compared to women. When comparing affected men to affected women, VBM analysis revealed atrophy in men in the right lateral occipital cortex. Our results suggest that in ALS sex-related trends of brain functional and structural changes are more heavily represented in DMN and in the occipital cortex, suggesting that sex is an additional dimension of functional and structural heterogeneity in ALS.

Introduction Covid-19 has been sweeping over the world for more than a year. People with Multiple Sclerosis (MS) might be particularly vulnerable either for the disease iteself or for the ongoing immune treatment. The aim of this review is to understand the impact of the Covid-19 pandemic and lockdown on patients with MS and to provide evidence-based advice to ensure them a high standard of care even during the pandemic. Areas covered Literature search was conducted in the Scopus, Web of Science, Pubmed electronic databases, and articles reference lists to investigate the effect of Covid-19 on MS patients' treatment, access to health-care services and mental-health.The search terms 'multiple sclerosis' AND 'Covid-19' were combined with each of the following term 'disease modifying treatment,' 'steroids,' 'vaccination,' 'mental health,' 'stress,' 'quality of life,' 'management,' 'impact,' 'recommendations,'. Expert opinion To ensure MS control during the pandemic, minimizing the risk of Covid-19 contagion, face-to-face visits may be implemented with televisits. Management of relapses and DMTs schedule should be adapted based on the specific benefit/risk ratio for each patient, considering disease activity, disability, comorbidities. Vaccination should be strongly recommended. Telerehabilitation and online psychological support programs should be encouraged to preserve motor performances and mental health.

Emerging evidence suggests that memory deficit in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease with varying impairment of motor abilities and cognitive profile, may be independent from executive dysfunction. Our multimodal magnetic resonance imaging (MRI) approach, including resting state functional MRI (RS-fMRI), diffusion tensor imaging (DTI) and voxel-based morphometry (VBM), aimed to investigate structural and functional changes within and beyond the Papez circuit in non-demented ALS patients (n = 32) compared with healthy controls (HCs, n = 21), and whether these changes correlated with neuropsychological measures of verbal and non-verbal memory. We revealed a decreased functional connectivity between bilateral hippocampus, bilateral parahippocampal gyri and cerebellum in ALS patients compared with HCs. Between-group comparisons revealed white matter abnormalities in the genu and body of the corpus callosum and bilateral cortico-spinal tracts, superior longitudinal and uncinate fasciculi in ALS patients (p

Objective: Advanced neuroimaging techniques may offer the potential to monitor disease spreading in amyotrophic lateral sclerosis (ALS). We aim to investigate brain functional and structural magnetic resonance imaging (MRI) changes in a cohort of ALS patients, examined at diagnosis and clinically monitored over 18 months, in order to early discriminate fast progressors (FPs) from slow progressors (SPs). Methods: Resting state functional MRI (RS-fMRI), diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) analyses were performed at baseline in 54 patients with ALS and 22 HCs. ALS patients were classified a posteriori into FPs (n = 25) and SPs (n = 29) based on changes in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score from baseline to the 18-month assessment (ΔALSFRS-R), applying a k-means clustering algorithm. Results: At diagnosis, when compared to HCs, ALS patients showed reduced functional connectivity in both motor and extra-motor networks. When compared to SPs, at baseline, FPs showed decreased function connectivity in paracentral lobule (sensorimotor network), precuneus (in the default mode network), middle frontal gyri (frontoparietal networks) and increased functional connectivity in insular cortices (salience network). Structural analyses did not reveal significant differences in gray and white matter damage by comparing FPs to SPs. Receiver operating characteristic (ROC) curve analysis showed that functional connectivity increase in the left insula at baseline best discriminated FPs and SPs (area under the curve 78%). Conclusions: Impairment of extra-motor networks may appear early in ALS patients with faster disease progression, suggesting that a more widespread functional connectivity damage may be an indicator of poorer prognosis.

Introduction Blood coagulation constituents might exert immunomodulatory functions in the CNS and may trigger neuroinflammation and demyelination. We evaluated whether particular single-nucleotide polymorphisms (SNPs), thought to be involved in fibrinogen-mediated hemostatic pathways, are overrepresented in patients with MS compared with controls. Methods The case–control study consisted of 119 MS patients recruited consecutively at our clinic, and 68 healthy controls. Afterwards, we created a cumulative genetic risk score (CGRS) which included the 5 selected hemostatic risk alleles (Beta-Fibrinogen 455G/A, Glycoprotein IIIa P1A2, Factor V Leiden, Factor V H2R, and Prothrombin 20210G/A). Multivariate ordinal logistic regression and multivariate multinomial logistic regression were applied to evaluate the effect of CGRS on MS susceptibility. Results The FGB 455 G/A and Factor V H1299R variants might be associated with MS status, in the recessive and dominant model, respectively. A cumulative association of the five SNPs investigated with the disease was observed. Discussion We found that MS patients carried more pro-hemostatic variants than healthy controls. An increasing number of unfavorable alleles might increase the likelihood of being in the MS group, in the cumulative analysis. Our findings encourage to evaluating these variants in a larger population-based cohort.

Background In the past decades a plethora of studies has been conducted to explore resting-state functional connectivity (RS-FC) of the brain networks in migraine with conflicting results probably due to the variability and susceptibility of signal fluctuations across the course of RS-FC scan. On the other hand, the structural substrates enabling the functional communications among the brain connectome, characterized by higher stability and reproducibility, have not been widely investigated in migraine by means of graph analysis approach. We hypothesize a rearrangement of the brain connectome with an increase of both strength and density of connections between cortical areas specifically involved in pain perception, processing and modulation in migraine patients. Moreover, such connectome rearrangement, inducing an imbalance between the competing parameters of network efficiency and segregation, may underpin a mismatch between energy resources and demand representing the neuronal correlate of the energetically dysfunctional migraine brain. Methods We investigated, using diffusion-weighted MRI imaging tractography-based graph analysis, the graph-topological indices of the brain “connectome”, a set of grey matter regions (nodes) structurally connected by white matter paths (edges) in 94 patients with migraine without aura compared to 91 healthy controls. Results We observed in migraine patients compared to healthy controls: i) higher local and global network efficiency (p p p Conclusion The imbalance between the need of investing resources to promote network efficiency and the need of minimizing the metabolic cost of wiring probably represents the mechanism underlying migraine patients’ susceptibility to triggers. Such changes in connectome topography suggest an intriguing pathophysiological model of migraine as brain “connectopathy”.

BACKGROUND AND PURPOSE Although the majority of migraine with aura (MwA) patients experience simple visual aura, a discrete percentage also report somatosensory, dysphasic or motor symptoms (the so-called complex auras). The wide aura clinical spectrum led to an investigation of whether the heterogeneity of the aura phenomenon could be produced by different neural correlates, suggesting an increased visual cortical excitability in complex MwA. The aim was to explore whether complex MwA patients are characterized by more pronounced connectivity changes of the visual network and whether functional abnormalities may extend beyond the visual network encompassing also the sensorimotor network in complex MwA patients compared to simple visual MwA patients. METHODS By using a resting-state functional magnetic resonance imaging approach, the resting-state functional connectivity (RS-Fc) of both visual and sensorimotor networks in 20 complex MwA patients was compared with 20 simple visual MwA patients and 20 migraine without aura patients. RESULTS Complex MwA patients showed a significantly higher RS-Fc of the left lingual gyrus, within the visual network, and of the right anterior insula, within the sensorimotor network, compared to both simple visual MwA and migraine without aura patients (p < 0.001). The abnormal right anterior insula RS-Fc was able to discriminate complex MwA patients from simple aura MwA patients as demonstrated by logistic regression analysis (area under the curve 0.83). CONCLUSION Our findings suggest that higher extrastriate RS-Fc might promote cortical spreading depression onset representing the neural correlate of simple visual aura that can propagate to sensorimotor regions if an increased insula RS-Fc coexists, leading to complex aura phenotypes.

Objective To assess the performance of a combination of three quantitative MRI markers (iron deposition, basal neuronal metabolism, and regional atrophy) for differential diagnosis between amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS). Methods In total, 33 ALS, 12 PLS, and 28 healthy control (HC) subjects underwent a 3T MRI study including single‐ and multi‐echo sequences for gray matter (GM) volumetry and quantitative susceptibility mapping (QSM) and a pseudo‐continuous arterial spin labeling (ASL) sequence for cerebral blood flow (CBF) measurement. Mean values of QSM, CBF, and GM volumes were extracted in the motor cortex, basal ganglia, thalamus, amygdala, and hippocampus. A generalized linear model was applied to the three measures to binary discriminate between groups. The diagnostic performances were evaluated via receiver operating characteristic analyses. Results A significant discrimination was obtained: between ALS and HCs in the left and right motor cortex, where QSM increases were respectively associated with disability scores and disease duration; between PLS and ALS in the left motor cortex, where PLS patients resulted significantly more atrophic; between ALS and HC in the right motor cortex, where GM volumes were associated with upper motor neuron scores. Significant discrimination between ALS and HC was achieved in subcortical structures only combining all three parameters. Interpretation While increased QSM values in the motor cortex of ALS patients is a consolidated finding, combining QSM, CBF, and GM volumetry shows higher diagnostic potential for differentiating ALS patients from HC subjects and, in the motor cortex, between ALS and PLS.

Objectives: To investigate the effects of cholecalciferol supplementation on the progression of motor disability in a cohort of amyotrophic lateral sclerosis (ALS) patients with low blood 25-hydroxyvitamin D3 [25(OH)D] levels, on the basis of the hypothesis of potential neuroprotective effects of vitamin D supplementation. Methods: Forty-eight ALS patients, 34 with deficient ( 0.05) and UMN (p > 0.05) among the patient groups who underwent 3 different doses of cholecalciferol. Conversely, the treatment with 75.000 IU/month or 100.000 IU/month induced a significant increase in serum levels of 25(OH)D in comparison with the supplementation with 50.000 IU/month; no significant differences were found between 75.000 IU/month and 100.000 IU/month. Conclusions: Our findings highlighted that 6-month supplementation of vitamin D in ALS patients had no significant effects on motor dysfunction. However, it is recommended to prevent medical complications of vitamin D deficiency in ALS patients as well as in other populations of neurodegenerative patients, characterized by low mobility and decreased sun exposure.

Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was designed for testing patients with amyotrophic lateral sclerosis (ALS), a multi-system neurodegenerative disease characterized by progressive physical disability. In this study, we aim to explore the potential brain microstructural substrates associated with performance on ECAS in the early stages of ALS, using a whole-brain tract-based spatial statistics diffusion tensor imaging approach. Thirty-six non-demented ALS patients, assessed using ECAS, and 35 age-, sex- and education-matched healthy controls underwent magnetic resonance imaging at 3 Tesla. The ALS patients showed decreased fractional anisotropy (FA) in the cortico-spinal tracts and corpus callosum (CC) and significant association between verbal fluency score, among ALS-specific ECAS scores, and FA measures in several long association fiber tracts in the frontal, temporal and parietal lobes. Furthermore, the ALS non-specific total score was inversely related to axial diffusivity (AD) in the mediodorsal nucleus of the thalamus, with more extended areas of correlation in the CC, when considering only the memory subscore. Our results point towards microstructural degeneration across motor and extra-motor areas in ALS, underlining that alterations in verbal fluency performances may be related to impairment of frontotemporal connectivity, while alterations of memory may be associated with damage of thalamocortical circuits.

Introduction COVID-19 pandemic radically transformed our daily clinical practice, raising the need not to lose close contact with patients without being able to see them face-to-face. These issues are even more felt and evident in fragile patients, as those affected by neuromuscular disease. An important help came from new digital technologies that allow clinicians to remotely monitor health status and any deterioration of chronically ill patients. Methods In this mini-review, an initiative of the “Digital Technologies, Web and Social Media Study Group” of the Italian Society of Neurology, we propose to analyze the approach to neuromuscular patients by looking over raising evidence on the main cornerstones of Telemedicine (TM): clinician-patient interaction, remote clinical assessment, remote monitoring, and digital therapeutics. In particular, we explored the strategies developed by researchers and their impact on the physical and emotional status of the patients, with particular focusing on their adherence to the program of virtual monitoring. Results TM plays an important role in each of four stages of approach to neuromuscular disease, having demonstrated validity in keep close clinical patient interaction, clinical assessment, remote monitoring, and telerehabilitation. Nevertheless, there is no remote alternative to electrophysiological testing neither validate tools to assess disability. Conclusion The role of TM in neuromuscular care is yet underestimated but is crucial, beyond the pandemic era. Further development of TM is advisable, through making specific apps, remotely controlled by clinicians, and making more engaging clinicians-patients interaction. Last, it is necessary to ensure adequate internet access to everyone.

Background: Public engagement (PE) is defined as the involvement of “specialists who listen, develop their understanding, and interact with non-specialists in non-profit activities of educational, cultural, and social nature to engage the public in science-related matters”. The public health relevance of PE consists in building up a scientifically literate society, able to participate in and support scientific and technological developments and their implications for educational settings. Neurological disorders account for 35% of all diseases. PE could have a positive impact on the lives of people affected by neurological diseases. Method: This review evaluates the role of PE in dementia, stroke, epilepsy, multiple sclerosis, Parkinson’s disease, migraine, neurogenetics, and amyotrophic lateral sclerosis. Results and Conclusions: PE can provide accessible information, support research activities and prevention through appropriate lifestyles, and increase knowledge and awareness of neurological disorders, improving their diagnosis and treatment.

Objectives To evaluate the concordance between Google Maps® application (GM®) and clinical practice measurements of ambulatory function (e.g., Ambulation Score (AS) and respective Expanded Disability Status Scale (EDSS)) in people with multiple sclerosis (pwMS). Materials and methods This is a cross-sectional multicenter study. AS and EDSS were calculated using GM® and routine clinical methods; the correspondence between the two methods was assessed. A multinomial logistic model is investigated which demographic (age, sex) and clinical features (e.g., disease subtype, fatigue, depression) might have influenced discrepancies between the two methods. Results Two hundred forty-three pwMS were included; discrepancies in AS and in EDDS assessments between GM® and routine clinical methods were found in 81/243 (33.3%) and 74/243 (30.4%) pwMS, respectively. Progressive phenotype (odds ratio [OR] = 2.8; 95% confidence interval [CI] 1.1–7.11, p = 0.03), worse fatigue (OR = 1.03; 95% CI 1.01–1.06, p = 0.01), and more severe depression (OR = 1.1; 95% CI 1.04–1.17, p = 0.002) were associated with discrepancies between GM® and routine clinical scoring. Conclusion GM® could easily be used in a real-life clinical setting to calculate the AS and the related EDSS scores. GM® should be considered for validation in further clinical studies. Supplementary Information The online version contains supplementary material available at 10.1007/s10072-021-05389-7.

Digital therapeutics (DTx) is a section of digital health defined by the DTx Alliance as “delivering evidence-based therapeutic interventions to patients that are driven by software to prevent, manage, or treat a medical disorder or disease. They are used independently or in concert with medications, devices, or other therapies to optimize patient care and health outcomes”. Chronic disabling diseases could greatly benefit from DTx. In this narrative review, we provide an overview of DTx in the care of patients with neurological dysfunctions.

Background/objectives Several studies supported the beneficial effects of the Mediterranean diet (MeDi) on chronic diseases. In Multiple Sclerosis (MS), the MeDi might interfere with systemic inflammatory state, gut microbiota, and comorbidities. The Med Diet Score (MDS) estimates the adherence to the MeDi and the cardiovascular (CV) risk. Aims of our study were i) to photograph lifestyle and diet habits of a southern Italy cohort of people with MS (pwMS), and ii) to investigate the impact of the MeDi on MS clinical outcomes. Subjects/methods We conducted a multi-center, cross-sectional study, enrolling 435 consecutive consenting pwMS, attending the outpatient clinics for routine follow-up visits. Participants underwent a clinical examination and a 29-item self-administered questionnaire on life and dietary habits. Disease phenotype, Expanded Disability Status Scale (EDSS), MS Severity Score (MSSS), waist circumference (WC), Body Mass Index (BMI), therapies, and comorbidities, were updated. MDS was assessed and correlated with current and retrospective clinical data. Results 75.8% of respondents were interested in nutrition, 72.8% were non-smokers, 52.9% performed physical activity, and 45.6% used food supplements. MDS was higher in pwMS with normal WC (p = 0.031), and inversely correlated with MSSS (p = 0.013) and EDSS (p = 0.012) at survey time. MDS did not correlate with the total number of relapses (before and after diagnosis) (p = 0.372). Metabolic comorbidities were associated with an increased 10-year CV risk (r = 0.85, p = 0.002). Conclusion Our findings suggest a putative beneficial effect of the MeDi on WC, MS course and disability. Given the role of chronic systemic inflammation in maintenance of autoimmunity and secondary neurodegeneration, both involved in long-term disability, we may suppose a beneficial effect of the MeDi on MS long-term disability outcomes, probably mediated by a modulation of the gut microbiota and the low-grade chronic systemic inflammation.

Physical disability impacts psychosocial wellbeing in people with multiple sclerosis. However, the role of physical activity in this context is still debated. By taking advantage of a previous survey, conducted online from 22 April to 7 May 2020, we performed a post-hoc analysis with the aim to assess the associations between disability, physical exercise, and mental health in multiple sclerosis. We retrieved the following data: (i) sociodemographic information, (ii) changes in lifestyle (including exercise), (iii) physical disability, as measured with the Patient-Determined Disease Steps scale, and (iv) anxiety feelings and depressive symptoms assessed via the items included in the Quality of Life in Neurological Disorders measurement system. Examination of the interaction plot showed that the effect of disability on depression, but not on anxious symptoms, was significant for all levels of physical exercise (low: b = 1.22, 95% C.I. 0.85, 1.58, p &lt, 0.001, moderate: b = 0.95, 95% C.I. 0.66, 1.24, p &lt, and high: b = 0.68, 95% C.I. 0.24, 1.13, p = 0.003). Based on these data, we can conclude that disability significantly impacted depression during the COVID-19 pandemic, with physical activity playing a moderating role. Our results suggest that favoring exercise in multiple sclerosis (MS) would ameliorate psychological wellbeing regardless of the level of physical disability.

COVID-19 pandemic has induced an urgent reorganization of the healthcare system to ensure continuity of care for patients affected by chronic neurological diseases including myasthenia gravis (MG). Due to the fluctuating nature of the disease, early detection of disease worsening, adverse events, and possibly life-threatening complications is mandatory. This work analyzes the main unresolved issues in the management of the myasthenic patient, the possibilities offered so far by digital technologies, and proposes an online evaluation protocol based on 4 simple tests to improve MG management. Telemedicine and Digital Technology might help neurologists in the clinical decision-making process of MG management, avoiding unnecessary in presence consultations and allowing a rational use of the time and space reduced by the pandemic.

Background: Digital health, including telemedicine, is increasingly recommended for the management of chronic neurological disorders, and it has changed the roles of patients and clinicians. Methods: In this cross-sectional study we aimed to investigate the digital work engagement of Italian neurologists through a survey collected between September 2020 and January 2021. Questionnaires were anonymous and collected demographic characteristics, attitudes towards digital devices and social media, and details about the clinician–patient relationship. We used logistic-regression models to identify characteristics associated with the propensity to communicate with patients using social media. Results: Among the 553 neurologists who participated to the study, smartphones and computers were widely preferred compared with tablets; wearable devices were not common, although some neurologists desired them. A total of 48% of participants reported communicating with patients using social media but only a few were in favor of social friendship with patients; WhatsApp was the social media most popular for professional (86%) and personal (98%) purposes. Propensity to communicate with social media was significantly higher among those who were older ( p Conclusions: The preferred social media were those which were rapid and which safeguard privacy more effectively; neurologists made many efforts to disprove fake news circulating online, providing help to patients in various ways. This analysis can help direct future interventions for the management of chronic neurological disorders.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no known cure. Approximately 90% of ALS cases are sporadic, although multiple genetic risk factors have been recently revealed also in sporadic ALS (SALS). The pathological expansion of a hexanucleotide repeat in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic mutation identified in familial ALS, detected also in 5–10% of SALS patients. C9orf72-related ALS phenotype appears to be dependent on several modifiers, including demographic factors. Sex has been reported as an independent factor influencing ALS development, with men found to be more susceptible than women. Exposure to both female and male sex hormones have been shown to influence disease risk or progression. Moreover, interplay between genetics and sex has been widely investigated in ALS preclinical models and in large populations of ALS patients carrying C9orf72 repeat expansion. In light of the current need for reclassifying ALS patients into pathologically homogenous subgroups potentially responsive to targeted personalized therapies, we aimed to review the recent literature on the role of genetics and sex as both independent and synergic factors, in the pathophysiology, clinical presentation, and prognosis of ALS. Sex-dependent outcomes may lead to optimizing clinical trials for developing patient-specific therapies for ALS.

ObjectiveAdvanced neuroimaging techniques may offer the potential to monitor disease progression in amyotrophic lateral sclerosis (ALS), a neurodegenerative, multisystem disease that still lacks therapeutic outcome measures. We aim to investigate longitudinal functional and structural magnetic resonance imaging (MRI) changes in a cohort of patients with ALS monitored for one year after diagnosis.MethodsResting state functional MRI, diffusion tensor imaging (DTI), and voxel-based morphometry analyses were performed in 22 patients with ALS examined by six-monthly MRI scans over one year.ResultsDuring the follow-up period, patients with ALS showed reduced functional connectivity only in some extramotor areas, such as the middle temporal gyrus in the left frontoparietal network after six months and in the left middle frontal gyrus in the default mode network after one year without showing longitudinal changes of cognitive functions. Moreover, after six months, we reported in the ALS group a decreased fractional anisotropy (P = .003, Bonferroni corrected) in the right uncinate fasciculus. Conversely, we did not reveal significant longitudinal changes of functional connectivity in the sensorimotor network, as well as of gray matter (GM) atrophy or of DTI metrics in motor areas, although clinical measures of motor disability showed significant decline throughout the three time points.ConclusionOur findings highlighted that progressive impairment of extramotor frontotemporal networks may precede the appearance of executive and language dysfunctions and GM changes in ALS. Functional connectivity changes in cognitive resting state networks might represent candidate radiological markers of disease progression.

Besides the prominent motor syndrome, some patients affected by amyotrophic lateral sclerosis (ALS) complain of many non-motor symptoms during the disease course, in particular chronic pain that significantly reduces the patients' quality of life. Complex regional pain syndrome (CRPS) is a rare painful condition, rarely described in ALS patients. We present the clinical case of a patient affected by spinal-onset ALS, who developed a type I CRPS (CRPS-I) at the upper limbs. To the best of our knowledge, only five cases of ALS-CRPS-I have been reported and they share some peculiar features: ALS spinal-onset with classic phenotype, rapid deterioration of quality of life, and a poor prognosis. Different mechanisms have been supposed in the pathogenesis of both CRPS and ALS, resulting in distinctive clinical presentations. Altered plasticity of brain sensory and motor areas might represent a common feature that seems to influence negatively ALS progression and prognosis.

Motor neuron disease (MND) is a heterogeneous group of neurodegenerative disorders defined by a progressive upper motor neuron (UMN) and lower motor neuron (LMN) loss in a varying combination, encompassing a heterogeneous clinical spectrum depending on a different body region involvement at onset, extent and rate of motor neuron (MN) loss and disease spread. Amyotrophic lateral sclerosis (ALS) is the most common and severe form of MND, leading to death in approximately 4 years from symptoms onset. To date, the mainstay neuroprotective therapy is riluzole, despite its limited efficacy, while the role of edaravon is still debated. Phenotypic heterogeneity is increasingly recognised within the MND spectrum, ranging from selective UMN or LMN involvement, to classic ALS, when widespread combination of UMN and LMN dysfunction occurs.1 The clinical spectrum of MND has been further detailed with the recognition of flail arm (FA), flail leg (FL) and pure lower motor neuron (PLMN) phenotypes, considered to be restricted MND phenotypes characterised by a predominant or selective LMN disease (LMND), when UMN dysfunction is absent or marginal.1 2 Furthermore, patients with MND can show an extra-motor involvement such as cognitive impairment with the development, in approximately 10%–15% of cases, of frontotemporal dementia. Few studies have previously focused on these LMN-restricted phenotypes, therefore, the aim of the present study is to retrospectively investigate the differentiating features of FA, FL and PLMN phenotypes in a large Italian MND cohort. 2648 patients with MND were recruited in 13 Italian ALS referral centres from January 2009 to December 2013 and data collected in a common database, which was cleaned before data analysis. To highlight the distinguishing features of patients with FA, FL and PLMN, the classic and bulbar phenotypes were used as controls. The final dataset consisted of 1944 patients. ALS diagnosis was established in accordance with …

Objectives: The aim of the study is to analyze the ALS disease progression and respiratory function of Italian patients treated with edaravone (EVN), as well as the adherence to, and the effects of, the therapy. Methods: We performed an observational study of patients treated with EVN from May 2017 to May 2019, in 39 Italian ALS Centers. Taking into account ALS patients with at least 12months of EVN treatment, we compared the decline of ALSFRS-R and FVC with a group of matched historical controls from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, using both descriptive and survival analysis approaches. Results: A total of 331 ALS Italian patients treated with EVN and 290 matched historical controls were recruited in this study. No significant differences on disease progression or respiratory function were found comparing the two cohorts in both descriptive and survival analyses. The EVN treatment was overall well tolerated. Conclusions: The study showed that EVN treatment was well tolerated. No significant differences were reported in ALS patients treated and not treated with EVN, in terms of both disease progression and respiratory function. These findings prove that further studies are required to better clarify whether EVN could be considered an effective treatment for ALS disease.

ObjectiveTo retrospectively investigate safety and efficacy of nusinersen in a large cohort of adult Italian patients with spinal muscular atrophy (SMA).MethodsInclusion criteria were: (1) clinical and molecular diagnosis of SMA2 or SMA3; (2) nusinersen treatment started in adult age (>18 years); (3) clinical data available at least at baseline (T0-beginning of treatment) and 6 months (T6).ResultsWe included 116 patients (13 SMA2 and 103 SMA3) with median age at first administration of 34 years (range 18–72). The Hammersmith Functional Rating Scale Expanded (HFMSE) in patients with SMA3 increased significantly from baseline to T6 (median change +1 point, pConclusionsOur data provide further evidence of nusinersen safety and efficacy in adult SMA2 and SMA3, with the latter appearing to be cumulative over time. In patients with extremely advanced disease, effects on residual motor function are less clear.

Social cognition includes mental operations essential for functional social interactions, and several studies revealed an impairment of social cognition abilities in patients with Multiple Sclerosis (MS). These deficits have been related to global and focal gray matter atrophy as well as microstructural white matter damage. Although some studies reveal a correlation between social cognition and task-based functional magnetic resonance imaging (MRI), no studies to date have explored the association between brain resting-state functional connectivity (RS-FC) abnormalities and several measures of social cognition in MS. The aim of this explorative study was to assess the contribution of RS-FC abnormalities of major brain networks to social cognition in MS patients. Clinical, neuropsychological, and MRI data were collected from 41 non-depressed and cognitively preserved relapsing-remitting MS patients (mean disease duration = 8.8 ± 8.2 years; median Expanded Disability Status Scale = 1.5, range 0–6.5) and 25 matched healthy controls (HCs). The ToM Pictures Sequencing Task (TMPS) and the Reading the Mind in the Eyes Task were employed to evaluate social cognition. All participants underwent a structural MRI and RS functional MRI 3T protocol. Regional gray matter atrophy was measured, and FCs of the default mode (DMN), right and left fronto-parietal, executive (EN), salience, cerebellar, and limbic (LN) networks were evaluated by independent component analysis (ICA). Differences on TMPS were found between MS patients and HC (MS < HC). In the MS group, associations were found between right middle temporal gyrus FC (in the DMN) and reciprocity subscale of TMPS, posterior cingulate cortex (PCC) FC (in the DMN) and first-order false-belief subscale of TMPS, cingulate gyrus FC (in the EN) and TMPS as well as reciprocity subscale of TMPS, and right superior temporal gyrus (in the LN) and reciprocity subscale of TMPS. All detected RS-FC changes did not co-localize with regional gray matter atrophy. The results suggest an association between social cognition and RS-FC changes of DMN, EN, and LN in MS. Future studies should further explore the possible adaptive or maladaptive mechanisms of these FC abnormalities in MS.

Background erenumab was safe and effective in clinical trials for the prevention of migraine. However, real-life data are still lacking. Here we report the clinical experience from an Italian real-world setting using erenumab in patients with chronic migraine experiencing previous unsuccessful preventive treatments. Methods Seventy patients with chronic migraine and failure to ≥4 migraine preventive medication classes initially received monthly erenumab 70 mg s.c. Patients without a clinically meaningful improvement, considered as a > 30% reduction in headache days per month, after ≥3 months of therapy switched to monthly erenumab 140 mg. At the first administration and after 3 and 6 months, patients underwent extensive interviews to assess clinical parameters of disease severity and migraine-related disability and impact, and validated questionnaires to explore depression/anxiety, sleep, and quality of life (QoL). Finally, the Pain Catastrophizing Scale, Allodynia Symptom Checklist-12 and MIGraine attacks-Subjective COGnitive impairments scale (MIG-SCOG) were administered. Results 70% of patients were “responders” after the third administration of erenumab 70 mg, whereas 30% switched to erenumab 140 mg; 29% (6 pts) responded after the sixth administration. The headache-day frequency was reduced from 21.1 ± 0.7 to 11.4 ± 0.9 days after the third administration (p p Also improved were headache pain severity, migraine-related disability, and impact on daily living, QoL, pain catastrophizing and allodynia (all p p Conclusion These real-world data support monthly erenumab 70 or 140 mg s.c. as a safe and effective preventive treatment to reduce headache frequency and severity in chronic migraine patients experiencing previous unsuccessful preventive treatments.

Aim: The present study aims at investigating the possible correlation between peripheral markers of inflammation and brain networks. Introduction: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease dominated by progressive motor impairment. Among the complex mechanisms contributing to the pathogenesis of the disease, neuroinflammation, which is associated with altered circulating cytokine levels, is suggested to play a prominent role. Methods: Based on magnetoencephalography data, we estimated topological properties of the brain networks in ALS patients and healthy controls. Subsequently, the blood levels of a subset of cytokines were assayed. Finally, we modeled the brain topological features in the function of the cytokine levels. Results: Significant differences were found in the levels of the cytokines interleukin (IL)-4, IL-1β, and interferon-gamma (IFN-γ) between patients and controls. In particular, IL-4 and IL-1β levels increased in ALS patients, while the IFN-γ level was higher in healthy controls. We also detected modifications in brain global topological parameters in terms of hyperconnectedness. Despite both blood cytokines and brain topology being altered in ALS patients, such changes do not appear to be in a direct relationship. Conclusion: Our results would be in line with the idea that topological changes relate to neurodegenerative processes. However, the absence of correlation between blood cytokines and topological parameters of brain networks does not preclude that inflammatory processes contribute to the alterations of the brain networks. Impact statement The progression of amyotrophic lateral sclerosis entails both neurodegenerative and inflammatory processes. Furthermore, disease progression induces global modifications of the brain networks, with advanced stages showing a more compact, hyperconnected network topology. The pathophysiological processes underlying topological changes are unknown. In this article, we hypothesized that the global inflammatory profile would relate to the topological alterations. Our results showed that this is not the case, as modeling the topological properties as a function of the inflammatory state did not yield good predictions. Hence, our results suggest that topological changes might directly relate to neurodegenerative processes instead.

PURPOSE: Advances in computational network analysis have enabled the characterization of topological properties of human brain networks (connectomics) from high angular resolution diffusion imaging (HARDI) MRI structural measurements. In this study, the effect of changing the diffusion weighting (b value) and sampling (number of gradient directions) was investigated in ten healthy volunteers, with specific focus on graph theoretical network metrics used to characterize the human connectome.METHODS: Probabilistic tractography based on the Q-ball reconstruction of HARDI MRI measurements was performed and structural connections between all pairs of regions from the automated anatomical labeling (AAL) atlas were estimated, to compare two HARDI schemes: low b value (b = 1000) and low direction number (n = 32) (LBLD); high b value (b = 3000) and high number (n = 54) of directions (HBHD).RESULTS: LBLD and HBHD data sets produced connectome images with highly overlapping hub structure. Overall, the HBHD scheme yielded significantly higher connection probabilities between cortical and subcortical sites and allowed detecting more connections. Small worldness and modularity were reduced in HBHD data. The clustering coefficient was significantly higher in HBHD data indicating a higher level of segregation in the resulting connectome for the HBHD scheme.CONCLUSION: Our results demonstrate that the HARDI scheme as an impact on structural connectome measures which is not automatically implied by the tractography outcome. As the number of gradient directions and b values applied may introduce a bias in the assessment of network properties, the choice of a given HARDI protocol must be carefully considered when comparing results across connectomic studies.

This study hypothesizes that the brain shows hyper connectedness as amyotrophic lateral sclerosis (ALS) progresses. 54 patients (classified as “early stage” or “advanced stage”) and 25 controls underwent magnetoencephalography and MRI recordings. The activity of the brain areas was reconstructed, and the synchronization between them was estimated in the classical frequency bands using the phase lag index. Brain topological metrics such as the leaf fraction (number of nodes with degree of 1), the degree divergence (a measure of the scale-freeness) and the degree correlation (a measure of disassortativity) were estimated. Betweenness centrality was used to estimate the centrality of the brain areas. In all frequency bands, it was evident that, the more advanced the disease, the more connected, scale-free and disassortative the brain networks. No differences were evident in specific brain areas. Such modified brain topology is sub-optimal as compared to controls. Within this framework, our study shows that brain networks become more connected according to disease staging in ALS patients., Highlights • Brain networks grow more connected as amyotrophic lateral sclerosis progresses. • Such changes affect the brain globally, they are not focal. • The topology of brain networks reaches a suboptimal configuration as amyotrophic lateral sclerosis progresses. • Brain networks modifications involve multiple frequency bands. • Brain networks become more scale-free and more disassortative as disease progresses.

Theory of Mind (ToM), the ability to recognize thoughts and emotions of another, may be one of the cognitive domains affected in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease now recognized as a multi-system disorder. The present study aimed to identify early dysfunctions of brain resting state functional magnetic resonance imaging (RS-fMRI) networks in a group of ALS patients longitudinally explored for impairment of “cognitive” and “affective” ToM subcomponents. RS-fMRI connectivity was investigated in a group of 21 patients with ALS (i.e., 9 with bulbar-onset or ALS-B and 12 with limb-onset or ALS-L) in early stages of disease and 15 healthy controls (HCs). The same subjects were assessed, at baseline and after six months, for neuropsychological performances, including cognitive and affective ToM and multi-domain cognitive functions. The RS-fMRI study showed a decreased connectivity in frontotemporal areas within the main cognitive resting state networks, including the default mode (DMN), the right and left fronto-parietal (R-, L-FPN), and the salience (SLN) networks, in the entire ALS group. As exploratory results, comparing the ALS-B subgroup to the ALS-L one, we revealed a widespread decrease of RS-fMRI signals in the left middle frontal gyrus for L-FPN and SLN and in the left superior frontal gyrus for SLN. At baseline, no ToM or other cognitive abnormalities were reported in the entire group of ALS patients compared to HCs, although, after six months, the ALS-B subset exhibited a significant impairment of both affective and cognitive ToM subcomponents, whereas the ALS-L group showed significant impairment of the cognitive subcomponent alone. Our findings provide original evidence of the deficit of both ToM subcomponents during the ALS course, supporting the hypothesis of a biologically more aggressive character of ALS-B. Moreover, early RS-fMRI abnormalities in cognitive networks may underlie and precede the clinical appearance of ToM alterations in ALS.

Background and aims: In 2018 we surveyed the use of social media and digital devices among Italian neurologists. In the present study, we evaluated whether major changes had occurred in a short time-frame and indirectly assessed the impact of the Sars-COV-2 virus and the related COronaVIrus Disease 19 (COVID-19) pandemic. Methods: Online survey (September 2020 to January 2021) to collect information on attitude toward digital health of members of the Italian Society of Neurology (SIN). The outline of the survey was the same as the prior study. Results: One hundred and nine neurologists participated in the survey. Some major changes were found compared to 2018: fewer participants reported using the tablet (23% versus 43%;p < 0.001) and Facebook (18% versus 32%;p = 0.006) for professional purposes. More participants reported that social media had worsened the doctor-patient relationship, and were against a friendship with their patients in social media. There was a trend towards higher use of WhatsApp (92% versus 82%;p = 0.018), and a significant reduction in active involvement in personal websites, blogs, or online forums. Conclusions: Dramatic changes in the attitudes towards social media have occurred in Italy in a very short timeframe, probably due to the concurrent pandemic and its impact on daily practice, and the dissemination of online misinformation.

Objective Using magnetic resonance (MR) high angular resolution diffusion imaging (HARDI), we aimed at revealing possible microstructural alterations in the early stage of amyotrophic lateral sclerosis (ALS), still not completely elucidated. Methods We studied 22 patients with ALS, in stages 1 or 2 according to the King's staging system, compared to 18 healthy controls (HCs). Statistical mapping of HARDI-derived parameters and tractography measures were performed using the Q-ball imaging diffusion data model. Results When compared to HCs, the ALS group showed a highly significant decrease of generalized fractional anisotropy (GFA) and fiber length and density in the corticospinal tracts (CSTs) and in the corpus callosum (CC) (pÂ

OBJECTIVES Apathy is associated with cognitive decline and worse survival in amyotrophic lateral sclerosis (ALS); an accurate evaluation of this aspect is relevant in clinical settings. The aims of this study are to evaluate the prevalence of apathy in a large ALS sample, using published diagnostic criteria, and to explore the psychometric properties, the sensitivity and the specificity of the Dimensional Apathy Scale (DAS) as a screening tool for apathy. METHODS One hundred and thirty-one patients underwent clinical interview based on diagnostic criteria for apathy, DAS, Apathy Evaluation Scale, and assessment of depression, global cognitive functioning, and non-verbal intelligence. RESULTS According to diagnostic criteria, apathy occurred in 28.2% of the patients. The DAS showed high consistency, convergent, and discriminant validities. Apathetic and non-apathetic patients significantly differed on total DAS and executive and Behavioral/Cognitive Initiation subscales, indicating good criterion validity. Receiver operating characteristics analysis, considering diagnostic criteria for apathy as gold standard, revealed that a score of 26/27 was an optimal cut-off score for the identification of apathy. CONCLUSIONS The DAS is a valid screening tool for apathy and its aspects in ALS through limiting the impact of physical disability. Executive and behavioral/cognitive aspects of apathy, rather than emotional aspects, are more frequent in ALS.

Background: Although migraine is recognized as one of the most common and disabling diseases in the world, it is nonetheless still underestimated, underdiagnosed, and undertreated. The fact that migraine patients often tend to access the Web to search for headache-related information hinderspatient-doctor relationships and one should also bear in mind that, unfortunately, text readability and medical literacyin the overall population may be the reason why patients' understanding of health information is compromised. Aim: We aimed to assess the readability of the home page of the top 10 patient – oriented migraine-related websites and the educational level required to be in a position to broach them. Methods: On April 15, 2018, we conducted a descriptive study on the international version of Google by entering the words “headache” and “migraine.” We then analyzed the overall level of readability of texts of the home pages of the top 10 patient-oriented websites, by means of the Simple Measure of Gobbledygook Readability Calculator. Results: Entering “headache” on the home pages of the top 10 patient-oriented websites on Google we found that to understand these particular websites with ease, an average grade level of 12.4 (±1.5 standard deviation, SD) and an average 13.3 years of formal education (±1.7 SD) were required. Similarly, typing “migraine” on Google we found an average grade level of 10.8 (±1.2 SD) and an average of 12.5 years of formal education (±1.9 SD) were required. The most frequently viewed websites all failed to meet the USA National Institutes of Health guidelines, which recommend a range between 6th and 7th grade level readability. Discussion: The present study shows the low readability level resulting from the top 10 patient-oriented headache/migraine websites and the consequent barrier this creates in the dissemination of headache/migraine-related medical information. Although the actual physicians, both primary care physicians and headache specialists are the principal source of understandable headache-related information, only a minority of people consult these professionals. Given the foregoing, the majority of migraine patients is, therefore, unable to obtain adequate comprehensible health information on the Web. Furthermore, the existing gap between migraine-related website content readability and the unmet need for migraine patients to obtain pertinent and correct information might well contribute to the worldwide neglect of migraine as a major public health problem. Conclusion: Physician experts in headache and migraine should actively cooperate in planning informative material to establish what information patients need to know, how they should use it, and how readable that material actually is. Readability ought to be established before the final website publication. Plain language ought to be used and written messages should be supplemented with visual content such as simple drawings. We recommend the setting up of a new dynamic, modern, plain-talking, and efficient approach in communication aimed at catching the public’s attention with its readability and thus satisfying a migraine and headache web scenario.

We investigated whether the C9orf72 repeat expansion is associated with specific clinical features, comorbidities, and prognosis in patients with amyotrophic lateral sclerosis (ALS). A cohort of 1417 ALS patients, diagnosed between January 1, 2009 and December 31, 2013 by 13 Italian ALS Referral Centers, was screened for the C9orf72 repeat expansion, and the analyses were performed comparing patients carrying this expansion (ALS-C9Pos) to those negative for this and other explored ALS-related mutations (ALS without genetic mutations, ALSwoGM). Compared to the ALSwoGM group, ALS-C9Pos patients (n = 84) were younger at disease onset, at the first clinical observation and at diagnosis (p < 0.001). After correcting for these differences, we found that ALS-C9Pos patients had higher odds of bulbar onset, diagnosis of frontotemporal dementia (FTD) and family history of ALS, FTD, and Alzheimer's disease and had lower odds of spinal onset, non-invasive ventilation, hypertension and psychiatric diseases than ALSwoGM patients. Among these variables, those related to shorter survival time were: bulbar onset, presence of FTD, hypertension, psychiatric disease, and family history of ALS (p < 0.05). Cox proportional hazards regression multivariate analysis suggested that carrying the C9orf72 repeat expansion was an independent factor negatively impacting on survival time in men (HR 1.58, 95% CI 1.07-2.33, p = 0.021), but not in women (p > 0.05) as well as in the whole sample (p > 0.05). When compared to ALSwoGM, ALS-C9Pos showed an earlier disease onset, no significant diagnostic delay and a higher odds of bulbar onset, FTD and family history of ALS and dementia. Moreover, male sex drove the negative effect of expanded variant on survival, confirming the hypothesis that sex is likely to be a crucial factor in the biology of C9orf72-related disease.