Altered spreading of fast aperiodic brain waves relates to disease duration in Amyotrophic Lateral Sclerosis.

OBJECTIVE: To test the hypothesis that patients affected by Amyotrophic Lateral Sclerosis (ALS) show an altered spatio-temporal spreading of neuronal avalanches in the brain, and that this may related to the clinical picture. METHODS: We obtained the source-reconstructed magnetoencephalography (MEG) signals from thirty-six ALS patients and forty-two healthy controls. Then, we used the construct of the avalanche transition matrix (ATM) and the corresponding network parameter nodal strength to quantify the changes in each region, since this parameter provides key information about which brain regions are mostly involved in the spreading avalanches. RESULTS: ALS patients presented higher values of the nodal strength in both cortical and sub-cortical brain areas. This parameter correlated directly with disease duration. CONCLUSIONS: In this work, we provide a deeper characterization of neuronal avalanches propagation in ALS, describing their spatio-temporal trajectories and identifying the brain regions most likely to be involved in the process. This makes it possible to recognize the brain areas that take part in the pathogenic mechanisms of ALS. Furthermore, the nodal strength of the involved regions correlates directly with disease duration. SIGNIFICANCE: Our results corroborate the clinical relevance of aperiodic, fast large-scale brain activity as a biomarker of microscopic changes induced by neurophysiological processes.

ChatGPT vs. neurologists: a cross-sectional study investigating preference, satisfaction ratings and perceived empathy in responses among people living with multiple sclerosis.

BACKGROUND: ChatGPT is an open-source natural language processing software that replies to users' queries. We conducted a cross-sectional study to assess people living with Multiple Sclerosis' (PwMS) preferences, satisfaction, and empathy toward two alternate responses to four frequently-asked questions, one authored by a group of neurologists, the other by ChatGPT. METHODS: An online form was sent through digital communication platforms. PwMS were blind to the author of each response and were asked to express their preference for each alternate response to the four questions. The overall satisfaction was assessed using a Likert scale (1-5); the Consultation and Relational Empathy scale was employed to assess perceived empathy. RESULTS: We included 1133 PwMS (age, 45.26 ± 11.50 years; females, 68.49%). ChatGPT's responses showed significantly higher empathy scores (Coeff = 1.38; 95% CI = 0.65, 2.11; p > z < 0.01), when compared with neurologists' responses. No association was found between ChatGPT' responses and mean satisfaction (Coeff = 0.03; 95% CI = - 0.01, 0.07; p = 0.157). College graduate, when compared with high school education responder, had significantly lower likelihood to prefer ChatGPT response (IRR = 0.87; 95% CI = 0.79, 0.95; p < 0.01). CONCLUSIONS: ChatGPT-authored responses provided higher empathy than neurologists. Although AI holds potential, physicians should prepare to interact with increasingly digitized patients and guide them on responsible AI use. Future development should consider tailoring AIs' responses to individual characteristics. Within the progressive digitalization of the population, ChatGPT could emerge as a helpful support in healthcare management rather than an alternative.

Dihydroergotamine mesylate nasal spray: an acute treatment option for migraine in adults.

INTRODUCTION: Although the landscape of migraine symptomatic treatment has been enriched by novel effective drugs, it is mandatory to critically reappraise older molecules to ascertain whether they could still represent reliable alternatives in specific endophenotypes of patients or migraine attacks. Among these, dihydroergotamine (DHE) nasal spray has been shown to be effective and is characterized by greater tolerability and manageability than the parenteral DHE formulation. AREAS COVERED: In this narrative review, the authors describe the pharmacodynamic and pharmacokinetic properties of DHE nasal spray and explore the results of the trials which explored its efficacy, safety and tolerability as migraine symptomatic treatment. They also discuss the limitations of the classically used device and the attempts that several companies are carrying out to generate devices warranting a more reproducible drug absorption. EXPERT OPINION: DHE nasal spray could be considered as rescue treatment in patients who have failed other symptomatic therapeutic strategies. Nevertheless, in the perspective of tailored therapy, the intranasal route of administration and the consequent rapid onset of action may represent benefits putatively making DHE a treatment of choice for challenging migraine attacks such as those with nocturnal onset or quickly reaching the climax of both headache and neurovegetative associated symptoms.

Repetitive Transcranial Magnetic Stimulation (rTMS) in Mild Cognitive Impairment: Effects on Cognitive Functions-A Systematic Review.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique also used as a non-pharmacological intervention against cognitive impairment. The purpose of the present review was to summarize what is currently known about the effectiveness of rTMS intervention on different cognitive domains in patients with mild cognitive impairment (MCI) and to address potential neuromodulation approaches in combination with electroencephalography (EEG) and neuroimaging, especially functional magnetic resonance imaging (fMRI). In this systematic review, we consulted three main databases (PubMed, Science Direct, and Scopus), and Google Scholar was selected for the gray literature search. The PRISMA flowchart drove the studies' inclusion. The selection process ensured that only high-quality studies were included; after removing duplicate papers, explicit ratings were given based on the quality classification as high (A), moderate (B), or low (C), considering factors such as risks of bias, inaccuracies, inconsistencies, lack of direction, and publication bias. Seven full-text articles fulfilled the stated inclusion, reporting five double-blind, randomized, sham-controlled studies, a case study, and a randomized crossover trial. The results of the reviewed studies suggested that rTMS in MCI patients is safe and effective for enhancing cognitive functions, thus making it a potential therapeutic approach for MCI patients. Changes in functional connectivity within the default mode network (DMN) after targeted rTMS could represent a valuable indicator of treatment response. Finally, high-frequency rTMS over the dorsolateral prefrontal cortex (DLPFC) has been shown to significantly enhance cognitive functions, such as executive performance, together with the increase of functional connectivity within frontoparietal networks. The main limitations were the number of included studies and the exclusion of studies using intermittent theta-burst stimulation, used in studies on Alzheimer's disease. Therefore, neuroimaging techniques in combination with rTMS have been shown to be useful for future network-based, fMRI-guided therapeutic approaches.

Retrospective observational study on the use of acetyl-L-carnitine in ALS.

ALCAR (Acetyl-L-carnitine) is a donor of acetyl groups and increases the intracellular levels of carnitine, the primary transporter of fatty acids across the mitochondrial membranes. In vivo studies showed that ALCAR decrease oxidative stress markers and pro-inflammatory cytokines. In a previous double-blind placebo-controlled phase II trial showed positive effects on self-sufficiency (defined as a score of 3+ on the ALSFRS-R items for swallowing, cutting food and handling utensils, and walking) ALSFRS-R total score and FVC. We conducted an observational, retrospective, multicentre, case-control study to provide additional data on the effects of ALCAR in subjects with ALS in Italy. Subjects treated with ALCAR 1.5 g/day or 3 g/day were included and matched with not treated subjects by sex, age at diagnosis, site of onset, and time from diagnosis to baseline, (45 subjects per group). ALCAR 3 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 23 (51.1%) treated subjects (adj. OR 1.18, 95% CI 0.46-3.02). No statistically significant differences were detected in ALSFRS nor FVC nor self-sufficiency. ALCAR 1.5 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 32 (71.1%) treated subjects (adj. OR 0.27, 95% CI 0.10-0.71). For ALSFRS-R, a mean slope of - 1.0 was observed in treated subjects compared to - 1.4 in those not treated (p = 0.0575). No statistically significant difference was detected in the FVC nor self-sufficiency. Additional evidence should be provided to confirm the efficacy of the drug and provide a rationale for the dosage.

Iron and Ferroptosis More than a Suspect: Beyond the Most Common Mechanisms of Neurodegeneration for New Therapeutic Approaches to Cognitive Decline and Dementia.

Neurodegeneration is a multifactorial process that involves multiple mechanisms. Examples of neurodegenerative diseases are Parkinson's disease, multiple sclerosis, Alzheimer's disease, prion diseases such as Creutzfeldt-Jakob's disease, and amyotrophic lateral sclerosis. These are progressive and irreversible pathologies, characterized by neuron vulnerability, loss of structure or function of neurons, and even neuron demise in the brain, leading to clinical, functional, and cognitive dysfunction and movement disorders. However, iron overload can cause neurodegeneration. Dysregulation of iron metabolism associated with cellular damage and oxidative stress is reported as a common event in several neurodegenerative diseases. Uncontrolled oxidation of membrane fatty acids triggers a programmed cell death involving iron, ROS, and ferroptosis, promoting cell death. In Alzheimer's disease, the iron content in the brain is significantly increased in vulnerable regions, resulting in a lack of antioxidant defenses and mitochondrial alterations. Iron interacts with glucose metabolism reciprocally. Overall, iron metabolism and accumulation and ferroptosis play a significant role, particularly in the context of diabetes-induced cognitive decline. Iron chelators improve cognitive performance, meaning that brain iron metabolism control reduces neuronal ferroptosis, promising a novel therapeutic approach to cognitive impairment.

Cognitive, behavioral, and brain functional connectivity correlates of fatigue in amyotrophic lateral sclerosis.

INTRODUCTION: Fatigue is defined as a symptom of exhaustion unexplained by drug effects or psychiatric disorders and comprises two main components (i.e., central or "mental" and peripheral or "physical" components), both influencing global disability in amyotrophic lateral sclerosis (ALS). We aim at investigating the clinical correlations between "physical" and "mental" components of fatigue, measured by the Multidimensional Fatigue Inventory scale, and motor and cognitive/behavioral disability in a large sample of patients with ALS. We also investigated the correlations between these measures of fatigue and resting-state functional connectivity of brain functional magnetic resonance imaging (RS-fMRI) large-scale networks in a subset of patients. METHODS: One hundred and thirty ALS patients were assessed for motor disability, cognitive and behavioral dysfunctions, fatigue, anxiety, apathy, and daytime sleepiness. Moreover, the collected clinical parameters were correlated with RS-fMRI functional connectivity changes in the large-scale brain networks of 30 ALS patients who underwent MRI. RESULTS: Multivariate correlation analysis revealed that "physical" fatigue was related to anxiety and respiratory dysfunction, while "mental" fatigue was related to memory impairment and apathy. Moreover, the mental fatigue score was directly related to functional connectivity in the right and left insula (within the salience network), and inversely related to functional connectivity in the left middle temporal gyrus (within the default mode network). CONCLUSIONS: Although the "physical" component of fatigue may be influenced by the disease itself, in ALS the "mental" component of fatigue correlates with cognitive and behavioral impairment, as well as with alterations of functional connectivity in extra-motor networks.

Emerging drugs for the preventive treatment of migraine: a review of CGRP monoclonal antibodies and gepants trials.

INTRODUCTION: Migraine is a leading cause of years lived with disability and preventive strategies represent a mainstay to reduce health-related disability and improve quality of life of migraine patients. Until a few years ago, migraine prevention was based on drugs developed for other clinical indications and relocated in the migraine therapeutic armamentarium, characterized by unfavorable tolerability profiles. The advent of monoclonal antibodies against Calcitonin Gene-Related Peptide (CGRP) and gepants, CGRP receptor antagonists, has been a turning point in migraine prevention owing to advantageous efficacy, safety and tolerability profiles.Nevertheless, while in an ideal scenario a drug characterized by significant greater efficacy and tolerability compared to existing therapeutic strategies should be adopted as a first-line treatment, cost-effectiveness analyses available for monoclonal antibodies against CGRP pathway tend to limit their administration to more severe migraine phenotypes. AREAS COVERED: The present narrative review aims to provide a critical appraisal of phase II and III CGRP-mAbs and gepants trials to analyze their use in clinical practice. EXPERT OPINION: Despite monoclonal antibodies against CGRP pathway and gepants can be undoubtedly considered top-of-the-range treatments, there are still issues deserving to be addressed in the coming years as the risk of off-target effects as well as their economic sustainability based on the considerable migraine burden.

The HFE p.H63D (p.His63Asp) Polymorphism Is a Modifier of ALS Outcome in Italian and French Patients with SOD1 Mutations.

Background: Data from published studies about the effect of HFE polymorphisms on ALS risk, phenotype, and survival are still inconclusive. We aimed at evaluating whether the p.H63D polymorphism is a modifier of phenotype and survival in SOD1-mutated patients. Methods: We included 183 SOD1-mutated ALS patients. Mutations were classified as severe or mild according to the median survival of the study population. Patients were screened for the HFE p.H63D polymorphism. Survival was calculated using the Kaplan-Meier modeling, and differences were measured by the log-rank test. Multivariable analysis was performed with the Cox proportional hazards model (stepwise backward). Results: SOD1 severe mutation carriers show more frequent familial history for ALS and shorter survival compared to mild mutation carriers. Carriers and non-carriers of the p.H63D polymorphism did not differ in terms of sex ratio, frequency of positive familial history, age at onset, and bulbar/spinal ratio. In univariate and in Cox multivariable analysis using sex, age at onset, site of onset, family history, country of origin, and mutation severity as covariates, p.H63D carriers had a longer survival (p = 0.034 and p = 0.004). Conclusions: We found that SOD1-mutated ALS patients carrying the p.H63D HFE polymorphism have a longer survival compared to non-carriers, independently of sex, age and site of onset, family history, nation of origin, and severity of mutations, suggesting a possible role as disease progression modifier for the p.H63D HFE polymorphism in SOD1-ALS.

Long-Term Neuromodulatory Effects of Repetitive Transcranial Magnetic Stimulation (rTMS) on Plasmatic Matrix Metalloproteinases (MMPs) Levels and Visuospatial Abilities in Mild Cognitive Impairment (MCI).

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that is used against cognitive impairment in mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, the neurobiological mechanisms underlying the rTMS therapeutic effects are still only partially investigated. Maladaptive plasticity, glial activation, and neuroinflammation, including metalloproteases (MMPs) activation, might represent new potential targets of the neurodegenerative process and progression from MCI to AD. In this study, we aimed to evaluate the effects of bilateral rTMS over the dorsolateral prefrontal cortex (DLPFC) on plasmatic levels of MMP1, -2, -9, and -10; MMPs-related tissue inhibitors TIMP1 and TIMP2; and cognitive performances in MCI patients. Patients received high-frequency (10 Hz) rTMS (MCI-TMS, n = 9) or sham stimulation (MCI-C, n = 9) daily for four weeks, and they were monitored for six months after TMS. The plasmatic levels of MMPs and TIMPs and the cognitive and behavioral scores, based on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Beck Depression Inventory II, Beck Anxiety Inventory, and Apathy Evaluation Scale, were assessed at baseline (T0) and after 1 month (T1) and 6 months (T2) since rTMS. In the MCI-TMS group, at T2, plasmatic levels of MMP1, -9, and -10 were reduced and paralleled by increased plasmatic levels of TIMP1 and TIMP2 and improvement of visuospatial performances. In conclusion, our findings suggest that targeting DLPFC by rTMS might result in the long-term modulation of the MMPs/TIMPs system in MCI patients and the neurobiological mechanisms associated with MCI progression to dementia.

Infodemiology of cluster headache seasonality: A proof of concept by a Google Trends analysis.

BACKGROUND: Cluster headache is commonly reported to follow an annual pattern with a peak in the spring and a second peak in autumn. Patients with headache frequently use search engines, such as Google, to look for terms related to their disease, creating trend data that can be analyzed with Google Trends. Indeed, Google Trends has been used for surveillance studies and can provide indirect estimates of the burden of diseases and symptoms. The present cross-sectional study investigated the seasonality of searches for "cluster headache" in the northern and southern hemispheres using 10 years of Google Trends data. METHODS: The term "cluster headache" or its translation in the 10 most spoken languages in the world was searched on Google Trends to obtain relative search volumes (from 0 to 100), in order to compare variations in searches across periods. Twenty-eight countries were selected according to the following criteria: (1) a relative search volume of >40 for the term for cluster headache; and (2) a population of at least 5 million inhabitants. For statistical purposes, countries were grouped in relation to hemisphere (northern or southern). Relative search volumes were extracted from January 2012 to January 2022 and analyzed according to two subgroups based on meteorological seasons (summer and winter vs. spring and autumn). RESULTS: A seasonal trend for in searches for cluster headache was found worldwide exhibiting higher relative search volumes in spring and autumn compared with summer and winter (17 [0, 39] vs. 13 [0, 37]; p = 0.016). CONCLUSION: Higher search volumes for the term during the meteorological seasons of spring and autumn clearly reflect a circannual pattern of cluster headache occurrence, representing new evidence for its seasonality.

Levels of 24-hydroxycholesteryl esters in cerebrospinal fluid and plasma from patients with amyotrophic lateral sclerosis.

OBJECTIVE: In this context, our study aimed to ascertain whether the esterification of 24-hydroxycholesterol, a process heavily affected by oxidative stress, is altered in ALS. METHODS: The study examined the level of 24-hydroxycholesteryl esters in cerebrospinal fluid and plasma of 18 ALS patients by spectroscopic technique as Ultra-high performance liquid chromatography mass spectrometry (UPLC-MS). RESULTS: The level of 24-hydroxycholesteryl esters in cerebrospinal fluid was found to be lower as the brain-blood barrier was damaged. Such a level was positively correlated with the level of esters in plasma. Both cerebrospinal fluid (CSF) level and plasma level were lower in ALS patients (60.05 ± 4.24 % and 54.07 ± 20.37 % respectively) than in controls (79.51 ± 2.47 % and 80.07 ± 10.02 % respectively). CONCLUSIONS: The data suggest that the level 24-hydroxycholesteryl esters might be a new biomarker of ALS and can be measured for monitoring the disease progression.

Telemedicine in Neuromuscular Diseases During Covid-19 Pandemic: ERN-NMD European Survey.

BACKGROUND: Telemedicine (TM) contributes to bridge the gap between healthcare facilities and patients' homes with neuromuscular disease (NMD) because of mobility issues. However, its deployment is limited due to difficulties evaluating subtle neurological signs such as mild weakness or sensory deficits. The COVID-19 pandemic has disrupted healthcare delivery worldwide, necessitating rapid measures implementation by health care providers (HCPs) to protect patients from acquiring SARS-CoV-2 while maintaining the best care and treatment. OBJECTIVES: Given the challenges faced by remote healthcare assistance of NMD patients, we aim to evaluate the use of TM in NMD during the COVID-19 pandemic. METHODS: Based on the Model for Assessment-of-Telemedicine-Applications (MAST), we conducted a survey amongst clinicians of the ERN EURO NMD (European-Reference-Network-for-Rare-Neuromuscular-Diseases). RESULTS: Based on 42 responses over 76 expected ones, our results show that the COVID-19 pandemic significantly increased the number of HCPs using TM (from 60% to 100%). The TM types most used during the COVID-19 period are teleconsultation and consultation by phone, particularly in the context of symptoms worsening in NMD patients with COVID-19 infection. Most European HCPs were satisfied when using TM but as a complementary option to physical consultations. Many responses addressed the issue of technical aspects needing improvement, particularly for elderly patients who need caregivers' assistance for accessing the TM platform. CONCLUSIONS: TM has been essential during COVID-19, but its use still presents some limitations for NMD patients with cognitive deficits or for first-time diagnosis. Thus, TM should be used as complement to, rather than substitute, for face-to-face consultations.

Effect of RNS60 in amyotrophic lateral sclerosis: a phase II multicentre, randomized, double-blind, placebo-controlled trial.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. RNS60 is an immunomodulatory and neuroprotective investigational product that has shown efficacy in animal models of ALS and other neurodegenerative diseases. Its administration has been safe and well tolerated in ALS subjects in previous early phase trials. METHODS: This was a phase II, multicentre, randomized, double-blind, placebo-controlled, parallel-group trial. Participants diagnosed with definite, probable or probable laboratory-supported ALS were assigned to receive RNS60 or placebo administered for 24 weeks intravenously (375 ml) once a week and via nebulization (4 ml/day) on non-infusion days, followed by an additional 24 weeks off-treatment. The primary objective was to measure the effects of RNS60 treatment on selected biomarkers of inflammation and neurodegeneration in peripheral blood. Secondary objectives were to measure the effect of RNS60 on functional impairment (ALS Functional Rating Scale-Revised), a measure of self-sufficiency, respiratory function (forced vital capacity, FVC), quality of life (ALS Assessment Questionnaire-40, ALSAQ-40) and survival. Tolerability and safety were assessed. RESULTS: Seventy-four participants were assigned to RNS60 and 73 to placebo. Assessed biomarkers did not differ between arms. The mean rate of decline in FVC and the eating and drinking domain of ALSAQ-40 was slower in the RNS60 arm (FVC, difference 0.41 per week, standard error 0.16, p = 0.0101; ALSAQ-40, difference -0.19 per week, standard error 0.10, p = 0.0319). Adverse events were similar in the two arms. In a post hoc analysis, neurofilament light chain increased over time in bulbar onset placebo participants whilst remaining stable in those treated with RNS60. CONCLUSIONS: The positive effects of RNS60 on selected measures of respiratory and bulbar function warrant further investigation.

Resting state fMRI analysis of pseudobulbar affect in Amyotrophic Lateral Sclerosis (ALS): motor dysfunction of emotional expression.

Pseudobulbar affect (PBA), referring to exaggerated or inappropriate episodes of laughing and/or crying without an apparent motivating stimulus, has been mainly attributed to bilateral degeneration of corticobulbar tracts. We aimed at exploring brain functional connectivity (FC) correlates of PBA in patients with amyotrophic lateral sclerosis (ALS), the most common motor neuron disease, frequently associated with PBA. Resting state functional MRI (RS-fMRI) independent component (ICA) and seed-based analyses and voxel-based morphometry (VBM) whole-brain analysis were performed on 27 ALS patients (13 with PBA; 14 without PBA) and 26 healthy controls (HC), for investigating functional and structural abnormalities in ALS patients compared to HC and in patients with PBA compared to patients without PBA. Between-patient analysis revealed different FC patterns, especially regarding decreased FC in several areas of cognitive (default mode, frontoparietal, salience) and sensory-motor networks in patients with PBA compared to those without PBA. However, no significant differences were found in gray matter atrophy. Seed-based analysis showed increased FC between middle cerebellar peduncles and posterior cingulate cortex and decreased FC between middle cerebellar peduncles and left middle frontal gyrus in patients with PBA compared to patients without PBA. Our findings suggest that some alterations of fronto-tempo-parietal-cerebellar circuits could be related to PBA in ALS. In particular, the abnormal FC between cerebellum and posterior cingulate cortex and left middle frontal gyrus in patients with PBA compared to patients without PBA highlights a crucial role of the cerebellum in regulating emotion expression in patients with ALS.

Neurophysiological Hallmarks of Axonal Degeneration in CIDP Patients: A Pilot Analysis.

In this work, we aim to identify sensitive neurophysiological biomarkers of axonal degeneration in CIDP patients. A total of 16 CIDP patients, fulfilling the clinical and neurophysiological criteria for typical CIDP, treated with subcutaneous immunoglobulin (ScIg) (0.4 g/kg/week) were evaluated at baseline (before ScIg treatment) and after long-term treatment with ScIg (24 months) by clinical assessment scales, nerve conduction studies (NCS) and electromyography (EMG). Conventional and non-conventional neurophysiological parameters: motor unit potential (MUP) analysis, MUP thickness and size index (SI)] and interference pattern (IP) features were evaluated after long-term treatment (24 months) and compared with a population of 16 healthy controls (HC). An increase of distal motor latency (DML) and reduced compound motor action potential (CMAP) amplitude and area in CIDP patients suggest axonal damage of motor fibers, together with a significant increase of MUP amplitude, duration and area. Analysis of non-conventional MUP parameters shows no difference for MUP thickness; however, in CIDP patients, SI is increased and IP area and amplitude values are lower than HC. Despite clinical and neurophysiological improvement after ScIg treatment, neurophysiological analysis revealed axonal degeneration of motor fibers and motor unit remodeling. Correlation analysis shows that the axonal degeneration process is related to the diagnostic and therapeutic delay. MUP area and SI parameters can detect early signs of axonal degeneration, and their introduction in clinical practice may help to identify patients with the worst outcome.

Adults with spinal muscular atrophy: a large-scale natural history study shows gender effect on disease.

BACKGROUND: Natural history of spinal muscular atrophy (SMA) in adult age has not been fully elucidated yet, including factors predicting disease progression and response to treatments. Aim of this retrospective, cross-sectional study, is to investigate motor function across different ages, disease patterns and gender in adult SMA untreated patients. METHODS: Inclusion criteria were as follows: (1) clinical and molecular diagnosis of SMA2, SMA3 or SMA4 and (2) clinical assessments performed in adult age (>18 years). RESULTS: We included 64 (38.8%) females and 101 (61.2%) males (p=0.0025), among which 21 (12.7%) SMA2, 141 (85.5%) SMA3 and 3 (1.8%) SMA4. Ratio of sitters/walkers within the SMA3 subgroup was significantly (p=0.016) higher in males (46/38) than in females (19/38). Median age at onset was significantly (p=0.0071) earlier in females (3 years; range 0-16) than in males (4 years; range 0.3-28), especially in patients carrying 4 SMN2 copies. Median Hammersmith Functional Rating Scale Expanded scores were significantly (p=0.0040) lower in males (16, range 0-64) than in females (40, range 0-62); median revised upper limb module scores were not significantly (p=0.059) different between males (24, 0-38) and females (33, range 0-38), although a trend towards worse performance in males was observed. In SMA3 patients carrying three or four SMN2 copies, an effect of female sex in prolonging ambulation was statistically significant (p=0.034). CONCLUSIONS: Our data showed a relevant gender effect on SMA motor function with higher disease severity in males especially in the young adult age and in SMA3 patients.

Flexibility of Fast Brain Dynamics and Disease Severity in Amyotrophic Lateral Sclerosis.

BACKGROUND AND OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a multisystem disorder, as supported by clinical, molecular, and neuroimaging evidence. As a consequence, predicting clinical features requires a description of large-scale neuronal dynamics. Normally, brain activity dynamically reconfigures over time, recruiting different brain areas. Brain pathologies induce stereotyped dynamics which, in turn, are linked to clinical impairment. Hence, based on recent evidence showing that brain functional networks become hyperconnected as ALS progresses, we hypothesized that the loss of flexible dynamics in ALS would predict the symptoms severity. METHODS: To test this hypothesis, we quantified flexibility using the "functional repertoire" (i.e., the number of configurations of active brain areas) as measured from source-reconstructed magnetoencephalography (MEG) in patients with ALS and healthy controls. The activity of brain areas was reconstructed in the classic frequency bands, and the functional repertoire was estimated to quantify spatiotemporal fluctuations of brain activity. Finally, we built a k-fold cross-validated multilinear model to predict the individual clinical impairment from the size of the functional repertoire. RESULTS: Comparing 42 patients with ALS and 42 healthy controls, we found a more stereotyped brain dynamics in patients with ALS (p < 0.05), as conveyed by the smaller functional repertoire. The relationship between the size of the functional repertoire and the clinical scores in the ALS group showed significant correlations in both the delta and the theta frequency bands. Furthermore, through a k-fold cross-validated multilinear regression model, we found that the functional repertoire predicted both clinical staging (p < 0.001 and p < 0.01, in the delta and theta bands, respectively) and symptoms severity (p < 0.001, in both the delta and theta bands). DISCUSSION: Our work shows that (1) ALS pathology reduces the flexibility of large-scale brain dynamics, (2) subcortical regions play a key role in determining brain dynamics, and (3) reduced brain flexibility predicts disease stage and symptoms severity. Our approach provides a noninvasive tool to quantify alterations in brain dynamics in ALS (and, possibly, other neurodegenerative diseases), thus opening new opportunities in disease management and a framework to test, in the near future, the effects of disease-modifying interventions at the whole-brain level.