Widespread Structural and Functional Connectivity Changes in Amyotrophic Lateral Sclerosis: Insights from Advanced Neuroimaging Research

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease principally affecting motor neurons. Besides motor symptoms, a subset of patients develop cognitive disturbances or even frontotemporal dementia (FTD), indicating that ALS may also involve extramotor brain regions. Both neuropathological and neuroimaging findings have provided further insight on the widespread effect of the neurodegeneration on brain connectivity and the underlying neurobiology of motor neurons degeneration. However, associated effects on motor and extramotor brain networks are largely unknown. Particularly, neuropathological findings suggest that ALS not only affects the frontotemporal network but rather is part of a wide clinicopathological spectrum of brain disorders known as TAR-DNA binding protein 43 (TDP-43) proteinopathies. This paper reviews the current state of knowledge concerning the neuropsychological and neuropathological sequelae of TDP-43 proteinopathies, with special focus on the neuroimaging findings associated with cognitive change in ALS

Amyotrophic Lateral Sclerosis and Multiple Sclerosis Overlap: A Case Report

The concurrence of amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) is extremely rare. We reported the case of a 33-year-old woman with a past history of paresthesias at the right hand, who developed progressive quadriparesis with muscular atrophy of limbs and, finally, bulbar signs and dyspnea. Clinical and neurophysiologic investigations revealed upper and lower motor neuron signs in the bulbar region and extremities, suggesting the diagnosis of ALS. Moreover, magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis demonstrated 3 periventricular and juxtacortical lesions, hyperintense in T2 and FLAIR sequences, and 3 liquoral immunoglobulin G (IgG) oligoclonal bands, consistent with diagnosis of primary progressive MS (PPMS). This unusual overlap of ALS and MS leads to the discussion of a hypothetical common pathological process of immunological dysfunction in these two disorders, although the role of immune response in ALS remains ambivalent and unclear

Clinical features and lifestyle of patients with amyotrophic lateral sclerosis in Campania: brief overview of an Italian database

Background. Physical activity and occupational exposures appeared to play a relevant role in pathogenesis of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease of unknown origin. Materials and methods. We aimed to make an overview of the clinical characteristics and life - style (occupation and sport) of a population of 395 patients with ALS from campania, in southern Italy. Results. ALS onset resulted anticipated of about 11 years in industry workers, whilst the more frequent site of onset among farmers was upper limbs. compared to non-athletes, athletes, particu- larly soccer players, showed a 7 years anticipation of ALS onset, with higher mortality after 5 years. Discussion and conclusions. We suggest that subjects genetically prone to abnormal response to hy - poxia during strenuous physical activity or exposed to neurotoxic agents, such as athletes, farmers or industry workers, might present increased risk to develop ALS. Future case-control and follow-up studies on our population should be implemented to deepen the present results. Riassunto (Caratteristiche cliniche e stile di vita di pazienti con sclerosi laterale amiotrofica in Campania: breve panoramica di un database italiano). Introduzione. Attivita fisica ed esposizione professionale a sostanze tossiche sembrano svolgere un ruolo rilevante nella patogenesi della sclerosi laterale amiotrofica (SLA), una malattia neurodegenerativa di origine sconosciuta. Materiali e metodi. ci siamo proposti di effettuare una panoramica delle caratteristiche cliniche e dello stile di vita (attivita lavorativa e sport) di una popolazione di 395 pazienti affetti da SLA provenienti dalla regione campania, in Italia meridionale. Risultati. L'insorgenza della SLA e risultata anticipata di circa 11 anni nei lavoratori dell'industria, mentre il sito piu frequente di insorgenza tra i contadini era caratterizzato dagli arti superiori. Rispetto ai non- sportivi, gli sportivi, soprattutto i calciatori, hanno mostrato un'anticipazione di 7 anni nell'insorgenza della SLA, con maggiore mortalita a 5 anni. Discussione e conclusioni. Abbiamo ipotizzato che i soggetti geneticamente predisposti a risposte anomale all'ipossia durante l'attivita fisica intensa o esposti ad agenti neurotossici, come gli sportivi, gli agricoltori o i lavoratori dell'industria, possano presentare un aumen - tato rischio di sviluppare la SLA. Futuri studi caso-controllo e di follow-up sulla nostra popolazione dovrebbero essere effettuati per approfondire i risultati attuali

Sporadic ALS is not associated with VAPB gene mutations in Southern Italy

Mutations in the Cu/Zn superoxide dismutase (Sod1) gene have been reported to cause adult-onset autosomal dominant Amyotrophic Lateral Sclerosis (FALS). In sporadic cases (SALS) de novo mutations in the Sod1 gene have occasionally been observed. The recent finding of a mutation in the VAMP/synaptobrevin-associated membrane protein B (VAPB) gene as the cause of amyotrophic lateral sclerosis (ALS8), prompted us to investigate the entire coding region of this gene in SALS patients. One hundred twenty-five unrelated patients with adult-onset ALS and 150 healthy sex-age-matched subjects with the same genetic background were analyzed. Genetic analysis for all exons of the VAPB gene by DHPLC revealed 5 variant profiles in 83 out of 125 SALS patients. Direct sequencing of these PCR products revealed 3 nucleotide substitutions. Two of these were found within intron 3 of the gene, harbouring 4 variant DHPLC profiles. The third nucleotide variation (Asp130Glu) was the only substitution present in the coding region of the VAPB gene, and it occurred within exon 4. It was found in three patients out of 125. The frequency of the detected exon variation in the VAPB gene was not significantly different between patients and controls. In conclusion, our study suggests that VAPB mutations are not a common cause of adult-onset SALS

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

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

An Italian kindred with FALS due to c.149T>C mutation in the SOD1 gene: case report of an affected family member

We report the first Italian kindred with Familial Amyotrophic Lateral Sclerosis (FALS) due to c.149T>C mutation in the exon 5 of superoxide dismutase-1 (SOD1) gene. The proband was a 49-year-old woman who came to our observation because of an history of progressive limbs weakness and gait impairment. She belonged to a family of 24 affected members. The prevalent phenotype of the affected members was characterized by slowly progressive spinal impairment with proximal distribution of weakness, and bulbar involvement in advanced stages. We briefly reviewed the few previous reports about the same SOD1 mutation and discussed the hypothesis that structural instability of the mutant codon 149 protein may underlie some toxic effects significantly involved in FALS pathogenesis

Motor and extramotor neurodegeneration in amyotrophic lateral sclerosis: A 3T high angular resolution diffusion imaging (HARDI) study

In amyotrophic lateral sclerosis (ALS), diffusion weighted magnetic resonance imaging (DW-MRI) has produced mounting evidence of a widespread white matter (WM) damage within motor and extramotor pathways. To provide novel information about the degenerative process in ALS, overcoming some of the limitations imposed by diffusion tensor imaging (DTI), we performed a high angular resolution diffusion imaging (HARDI) analysis of DW-MRI data. Generalized fractional anisotropy (GFA) was evaluated in 19 patients with ALS and 19 matched control subjects, and was correlated with clinical scores of disability, pyramidal impairment by upper motor neuron (UMN) score and frontal dysfunction by the Frontal Systems Behaviour (FrSBe) scale. Results demonstrated that ALS patients showed a significant decrease of GFA in the WM tracts underneath the left and right precentral gyri and the body of the corpus callosum (p < 0.05, corrected), where GFA was significantly related to UMN scores (p < 0.001, uncorrected); and in the left superior longitudinal fasciculus (p < 0.05, corrected), where GFA was significantly related to FrSBe scale scores (p < 0.01, uncorrected). In conclusion, this study revealed a pattern of motor and extramotor frontal diffusivity abnormalities (probably related to behavioural and cognitive dysfunctions) showing a spatial distribution similar to what was previously described in ALS-frontotemporal dementia continuum

Earliest videofluoromanometric pharyngeal signs of dysphagia in ALS patients

The aim of this study was to find whether there are manometric pharyngeal changes that may have diagnostic and prognostic relevance in the amyotrophic lateral sclerosis (ALS) patient who does not show changes in contrast-medium oropharyngeal transit in a videofluoroscopic swallowing study. Ten ALS patients, with an ALS Severity Scale Score of at least 7, no need to change dietary habit, no aspiration and/or penetration, and no other changes in contrast-medium oropharyngeal transit, were collected from our institution's database of videofluoromanometric swallowing studies. They were included in the study together with a group of 11 healthy volunteers. For each subject, 12 manometric items-7 for the pharyngeal phase and 5 for UES functionality-were evaluated. Statistically significant differences between the ALS patients and the healthy volunteers were found for pharyngeal contraction time of the upper region (median = 1,120, range = 880-1,420 vs. median = 970, range = 800-1,140), pharyngeal contraction time of the intermediate region (median = 1140, range = 960-1,360 vs. median = 770, range = 280-1,180), pharyngeal contraction time of the lower region (median = 1,320, range = 920-1,760 vs. median = 800, range = 620-1,780), and residual pressure after the relaxation of the UES (median = 2.2, range = -20.2 to 27.8 vs. median = -5.7, range = -2.9 to 8.4). A videofluoromanometric swallowing study may show an increase in the pharyngeal contraction time and in residual pressure after relaxation of the UES in ALS patients without videofluoroscopic changes in contrast-medium oropharyngeal transit

Coping strategies and psychological distress in caregivers of patients with Amyotrophic Lateral Sclerosis (ALS)

Background: Amyotrophic lateral sclerosis (ALS) causes distress in caregivers. The present study aims to examine the association between coping strategies and psychological distress in caregivers of ALS patients. Methods: Coping strategies were assessed in 96 ALS informal caregivers by means of the Coping Inventory for Stressful Situations. Data about caregivers’ demographic characteristics, levels of burden, depression and anxiety (psychological distress) were also gathered by standardised questionnaires. Patients’ clinical, cognitive and behavioural disturbances were evaluated by ALS specific assessment tools. Results: Sequential logistic regression analysis showed that emotion-oriented coping strategy was significantly associated with high levels of depressive (p < 0.01) and anxiety (p < 0.05) symptoms and high levels of burden (p < 0.05), after controlling for all other variables. Moreover, a significant relationship of patients’ functional dependence levels with burden experienced by caregivers was observed. No relationships were detected between task-oriented and avoidance-oriented coping strategies and caregivers’ levels of psychological distress. Conclusions: The present study supported the mediating effects of coping strategies on intensity of burden, depression and anxiety experienced by ALS caregivers. These findings suggest that interventions aimed at reducing utilisation of maladaptive coping strategies may improve well-being in ALS caregivers, and, possibly, management of symptoms in ALS patients