Background and Aims:

Covid-19 pandemic has boosted telemedicine in clinical practice. It could be crucial in the care of neurological patients with chronic disease. However there is a lack of specific disease tools to evaluate patients in telemedicine. The aim of our study was to validate the Myasthenia Gravis TeleScore (MGTS), a scale for the evaluation of MG patients in telemedicine.

Methods:

The MGTS included ten items divided in four districts: ocular, generalized muscular strength, bulbar, respiratory. Patients were assessed with two different scales: the MGTS, and the INCB-MG chosen as gold standard and from whom MGTS was partially derived. Visit in presence with INCB-MG and televisit with MGTS were performed consecutively. Televisit was conducted by another neurologist between two rooms. A blind method was adopted. The strength of correlation was determined by the correlation coefficient (r); analysis of covariance (ANOVA-Kruskal Wallis test) was used to compare subgroups. Significance was set to p<0,05.

Results:

131 patients were included in the study, 71 females, 60 males. The Spearman correlation coefficient between the INCB-MG scale and the MGTS was 0.825 (p < 0.001), indicating a very strong correlation between them. Different items showed different correlations from low to high (0,32 to 0,80). As expected correlation was lower between items with different evaluation modality (anamnestic vs clinical).

Conclusions:

The MGTS demonstrated a good correlation with INCB. It is reliable and has demonstrated construct validity.

Background and Aims:

Axonal sensorimotor neuropathy with a chronic, indolent course is a frequent occurrence in middle-aged and older adults, often in the absence of a definite diagnosis after thorough investigations. Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome (CANVAS) is an ataxic disorder recently associated with Replication Factor C subunit 1 (RFC1) repeat expansion mutation, presenting as a slowly evolving sensory neuro(no)pathy at onset in many cases.

We described clinical and pathological findings in RFC1-mutated patients identified in a biopsy-investigated Chronic Idiopathic Axonal Polyneuropathy (CIAP) population.

Methods:

We abstracted clinical, instrumental and pathology characteristics from 234 CIAP cases identified out of 594 consecutive patients with peripheral neuropathy evaluated at a single tertiary-care referral center for sural nerve biopsy. Patients were classified as pure sensory, predominantly sensory or sensorimotor according to clinical examination and screened for biallelic RFC1 AAGGG expansion.

Results:

A biallelic RFC1 AAGGG expansion was common in patients with pure sensory neuropathy (21/40, 53%) and more frequent compared to both predominantly sensory (10/56, 18%, P<0.001) and sensorimotor cases (3/138, 2%, P<0.001). Compared to non-mutated patients, RFC1-positive cases presented with greater sensory ataxia and autonomic disturbances, but often retained deep tendon reflexes. Cerebellar or vestibular involvement, on the other hand, was infrequent. On pathology, mutated patients showed scant regenerative changes and loss of both myelinated and unmyelinated nerve fibers, suggestive for sensory neuronopathy.

Conclusions:

RFC1 AAGGG expansion is frequently detected in patients with slowly progressive sensory axonal neuropathy of unknown cause. Specific clinical characteristics should prompt genetic testing in thoroughly investigated patients.

Background and Aims:

The complex genetic landscape in ALS presents a significant challenge. Despite the increasing number of pathogenic/risk mutations reported in ALS, the true proportion of cases that can be attributed to genetic factors remains unclear, and the actual role of genome-wide screening in clinical practice is still undetermined. Here we provide a comprehensive analysis of the spectrum of genetic risk in ALS patients and assess the clinical utility of performing whole-genome sequencing (WGS).

Methods:

WGS was performed on 1050 ALS cases and 675 controls from an Italian population-based ALS cohort. We screened for coding single-nucleotide variants, indels and repeated expansions in 40 ALS-related genes. Variants were classified according to a pipeline that accounted for allele frequency, absence from the control cohort, and integrated pathogenicity scores.

Results:

We identified 62 pathogenic variants, 32 loss-of-function variants and 61 variants classified as deleterious according to our pipeline. These variants were observed in 188 patients (17.9% of our cohort). Furthermore, WGS correctly identified 79 patients (7.5%) who carried the C9ORF72 expansion. Overall, 25.4% of our cohort carried a pathogenic mutation, and 3% of cases were found to carry multiple pathogenic variants. Age at onset (p<0.0252) and family history (p< 0.00001) predicted the likelihood of finding an underlying genetic factor.

Conclusions:

We conclusively show that genetic mutations and risk factors in ALS patients are more common than previously thought, thus highlighting that genetics play a central role in ALS pathogenesis. Whole-genome testing should be offered to all patients diagnosed with ALS for both diagnostic and prognostic purposes.

Background and Aims:

Motor neuron diseases (MNDs), including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and spinal and bulbar muscular atrophy (SBMA), are a heterogeneous group of neurodegenerative disorders characterized by motor neuron loss. Despite variability in onset, progression and genetic causes, these disorders share a common involvement of skeletal muscle that is suspected to have a relevant role in MND pathogenesis.

Due to the key role of muscle-specific microRNAs (myomiRs) in muscle development, here we investigated the expression of miR-206, miR-133a, miR-133b and miR-1 myomiRs, and their target genes, in G93A-SOD1 ALS, Δ7SMA and KI-SBMA mouse muscle during disease progression.

Methods:

MyomiRs and their putative target genes, PAX7, MYOD, MYOG, and MEF2, were analyzed by qPCR in ALS-G93A-SOD1, Δ7SMA-SMA and AR113Q-SBMA mice during disease progression. Sperman’s correlation analyses were performed to examine the myomiR/mRNA relationships. The corresponding myomiR target proteins were analysed by western blot. By qPCR, myomiRs were assessed in serum of 14 ALS-SOD1, 23 SMA pediatric, 10 SBMA patients, and 30 controls, including 19 pediatric patients with encephalitis.

Results:

We revealed myomiRs/mRNA target gene dysregulation as common pathogenic feature of the three MNDs. A similar myomiR signature was observed in serum from SOD1-mutated ALS, SMA and SBMA patients, with miR-206 up-regulation being identified in both animal muscle tissues and patients’sera.

Conclusions:

Our findings highlight the role of myomiRs as contributing factors and promising non-invasive biomarkers in ALS, SMA and SBMA, laying the groundwork for further investigations to explore myomiR potential as future therapeutic targets for MNDs.

Background and Aims:

Neurofilament light chain (NFL) has been proposed as a reliable and validated prognostic biomarker for amyotrophic lateral sclerosis (ALS). Usually, fast and slow progressors (FP and SP respectively) of disease were identified according to the slopes of the revised ALS functional rating scale. We aim to evaluate the prognostic value of King’s stage progression rate (KPR) through cerebrospinal fluid (CSF) neurofilament light chain (NFL) assessment.

Methods:

The KPR was calculated as the following formula: (0 – King’s clinical stage at first visit)/disease duration from onset to first visit. CSF NFL levels were measured at the time of diagnosis in 58 ALS patients. The whole cohort was divided in FP and SP according to the median value of KPR. Linear regression analysis was performed to evaluate how changes in NFL levels were reflected in KPR modifications.

Results:

Clinical and demographic characteristics were summarized in Figure 1. The NFL levels differed in the two groups (p=0.014). High concentrations of CSF NFL significantly correlated with more negative KPR (r_s = -0.357; p < 0.0003). Multivariate linear regression analysis (adjusted for sex and age) showed that every increase of 1000 ng/l in NFL was associated with a reduction in KPR of 0.02 points/month (p= 0.012).

Conclusions:

This study suggests that KPR could be a valid prognostic marker of disease mirroring levels of NFL, an ascertained reliable biomarker of ALS progression. Indeed, higher NFL levels were associated with more negative KPR reflecting a wider extension of the disease process.

Background and Aims:

Psychological status has already been related to clinical outcome in ALS, as well as in other neurological disease, without considering the specific role of anxiety and depression.

Methods:

We collected all Hospital Anxiety and Depression scale (HADS) questionnaires administered to patients at diagnosis from 2008 to 2018 in the Turin ALS Centre during a full neuropsychological evaluation. We analyzed the frequency of both anxiety and depression in ALS patients, their association to clinical features and their prognostic role, adjusting for different motor and cognitive confounders, using Cox proportional hazard models and Kaplan-Maier curves.

Results:

Data from 569 patients were collected. HADS-A and HADS-D scores showed moderate correlation (0.485, p<0.001). HADS Severity scores are showed in Figure 1.

Depression was significantly correlated to age, total ALSFRS-R score and cognitive impairment, while anxiety showed only a minimal correlation to ALSFRS-R score (-0.108, p=0.022). Cox proportional hazard model showed that HADS-A was related to overall survival, but not HADS-D (HADS-A: HR 1.040, CI 1.012-1.069, p=0.005; HADS-D: HR 1.013, CI 0.976-1.052, p=0.497). The best discriminating cut-off for both HADS-A was 6 (HR HADS-A>6 1.453, CI 1.151-1.835, p=0.002; log-rank test p=0.012, see Figure 2 for KM curves).

Interestingly, HADS-D raw scores resulted to be prognostic only in patients with comorbid anxiety (Figure 3).

Conclusions:

Anxiety is more frequent than depression in ALS patients at diagnosis and, unlike depression, seems not to be related to motor and cognitive features and to disease duration. Anxiety is also an independent prognostic factor, similarly to what happens in other non-neurological disease.

Background and Aims:

Increasing evidence indicates that up to 50 % of patients affected by amyotrophic lateral sclerosis (ALS) displays cognitive (ALSci) or behavioral (ALSbi) impairment, or both (ALScbi). The aim of our study is to assess whether the burden of upper (UMN) and lower motor neuron (LMN) involvement is associated to the presence of cognitive and behavioral impairment.

Methods:

A retrospective cohort of 110 Italian ALS patients has been evaluated to assess correlations between motor and cognitive/behavioral phenotypes. UMN regional involvement was measured with the Penn Upper Motor Neuron Score (PUMNS), while LMN signs were assessed using the Lower Motor Neuron Score (LMNS). The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) - Italian version and Frontal Behavior Inventory (FBI) were used to perform an evaluation of both cognitive and behavioral profile.

Results:

PUMNS scores at first visit were significantly higher in behaviorally impaired patients (ALSbi and ALScbi) compared to unimpaired individuals (ALS and ALSci) (9.90 vs 6.97, p=0.014). With regard to the different FBI subdomains, higher PUMNS scores correlated with the presence of Apathy, Emotive Indifference, Inflexibility, Inattention, Perseveration and Aggressiveness.

Conclusions:

To our knowledge, this is the first study suggesting that a prominent UMN dysfunction is associated with a more significant behavioral impairment in ALS patients, rising the hypothesis of a preferential spreading of the pathology from the motor cortex to the ventromedial prefrontal and orbitofrontal cortex in this group of patients

Background and Aims:

The aim of this study was to analyze whether ALS patients with C9orf72 expansion showed a different profile of cognitive and behavioral domains compared to patients without C9orf72 expansion.

Methods:

Patients were diagnosed according to El Escorial's revised criteria. Kings’ staging and genetic analysis at the time of cognitive testing were collected for all patients. ALS patients underwent a neuropsychological battery selected according to the ALS-FTD Consensus Criteria.

Comparisons were performed for King’s stage, independently from their level of cognitive status; for cognitive tests merging the intermediate cognitive categories, and for the number of ALSC9+ vs. ALSC9- cases who showed impairment in each neuropsychological domain.

Results:

Of 741 ALS patients (2010-2018) ALSC9+ patients had significantly lower scores in tests exploring executive functions and verbal memory both when classified as cognitively normal and when diagnosed in the intermediate cognitive categories. Considering the clinical perspective, ALSC9+ patients showed significantly lower scores compared to ALSC9- patients at King’s stage 1 and 3 in almost all the examined neuropsychological domains, while at King’s stage 2 ALSC9+ patients were more severely affected only in the verbal memory domain. The behavioral function was comparably impaired in the two cohorts.

Conclusions:

According to our data, it is conceivable that in some ALSC9+ patients a poor cognitive performance is already present in the early motor stages of the disease. Longitudinal studies are necessary to clarify whether this subclinical cognitive impairment in ALSC9+ patients will evolve to clinically overt dementia over time.