Search

Objective: To validate an Italian version of the Rasch-Built Overall ALS Disability Scale (ROADS) in a broad population of patients and assess its longitudinal performance over time. Methods: 270 ALS patients referring to the Motor Neuron Disease Clinic of the University of Padova and Modena (Italy) accepted to compile the Italian version of the ROADS and results were correlated with the ALSFRSr and ALSAQ-40 scores, FVC values, and creatinine or albumin blood levels. To verify test–retest reliability, patients were asked to fill in a second copy of the scale within 5–7 days. Thirty-nine patients compiled a further copy of questionnaire during the follow up visit (after 133 days on average) which allowed us a longitudinal assessment of the scale. Results: We found a good external construct validity between ROADS and either ALSFRS-R (correlation coefficient = 0.85) or ALSAQ-40 (correlation coefficient = − 0.84). Test–retest reliability was excellent with a concordance-correlation coefficient of 0.93. Yet, we observed a significant correlation between changes over time of the ROADS normalised sum score (− 2.18 point loss per month) and those of both the ALSFRS-R (positive correlation; Rho = 0.64, p ≤ 0.0001) or the ALSAQ-40 (negative correlation; Rho = − 0.60, p = 0.014). Conclusions: The Italian version of ROADS proved to be a reliable marker to monitor overall disability in ALS patients. Further studies are necessary to assess its longitudinal performance. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a multifactorial, multisystem motor neuron disease for which currently there is no effective treatment. There is an urgent need to identify biomarkers to tackle the disease's complexity and help in early diagnosis, prognosis, and therapy. Extracellular vesicles (EVs) are nanostructures released by any cell type into body fluids. Their biophysical and biochemical characteristics vary with the parent cell's physiological and pathological state and make them an attractive source of multidimensional data for patient classification and stratification. Methods: We analyzed plasma-derived EVs of ALS patients (n = 106) and controls (n = 96), and SOD1G93A and TDP-43Q331K mouse models of ALS. We purified plasma EVs by nickel-based isolation, characterized their EV size distribution and morphology respectively by nanotracking analysis and transmission electron microscopy, and analyzed EV markers and protein cargos by Western blot and proteomics. We used machine learning techniques to predict diagnosis and prognosis. Results: Our procedure resulted in high-yield isolation of intact and polydisperse plasma EVs, with minimal lipoprotein contamination. EVs in the plasma of ALS patients and the two mouse models of ALS had a distinctive size distribution and lower HSP90 levels compared to the controls. In terms of disease progression, the levels of cyclophilin A with the EV size distribution distinguished fast and slow disease progressors, a possibly new means for patient stratification. Immuno-electron microscopy also suggested that phosphorylated TDP-43 is not an intravesicular cargo of plasma-derived EVs. Conclusions: Our analysis unmasked features in plasma EVs of ALS patients with potential straightforward clinical application. We conceived an innovative mathematical model based on machine learning which, by integrating EV size distribution data with protein cargoes, gave very high prediction rates for disease diagnosis and prognosis. [ABSTRACT FROM AUTHOR]

Peripherin (PRPH), a type III intermediate filament, assembles with neurofilaments in neurons of the peripheral nervous system, including lower motor neurons (LMN). To evaluate the role of PRPH in LMN degeneration, we assessed PRPH and neurofilament light chain (NfL) in cerebrospinal fluid (CSF) and serum of 91 patients with motor neuron diseases (MND) and 69 controls. Overall, we found PRPH to be more concentrated in serum than in CSF. Serum PRPH resulted significantly increased in MND patients but it was unrelated to CSF‐NfL or survival in the amyotrophic lateral sclerosis (ALS) subset. PRPH might represent a marker of LMN involvement. [ABSTRACT FROM AUTHOR]

Background: Kennedy's disease (KD), also known as spinal and bulbar muscular atrophy (SBMA), is a rare, adult-onset, X-linked recessive neuromuscular disease caused by CAG expansions in exon 1 of the androgen receptor gene (AR). The objective of the French national diagnostic and management protocol is to provide evidence-based best practice recommendations and outline an optimised care pathway for patients with KD, based on a systematic literature review and consensus multidisciplinary observations.Results: The initial evaluation, confirmation of the diagnosis, and management should ideally take place in a tertiary referral centre for motor neuron diseases, and involve an experienced multidisciplinary team of neurologists, endocrinologists, cardiologists and allied healthcare professionals. The diagnosis should be suspected in an adult male presenting with slowly progressive lower motor neuron symptoms, typically affecting the lower limbs at onset. Bulbar involvement (dysarthria and dysphagia) is often a later manifestation of the disease. Gynecomastia is not a constant feature, but is suggestive of a suspected diagnosis, which is further supported by electromyography showing diffuse motor neuron involvement often with asymptomatic sensory changes. A suspected diagnosis is confirmed by genetic testing. The multidisciplinary assessment should ascertain extra-neurological involvement such as cardiac repolarisation abnormalities (Brugada syndrome), signs of androgen resistance, genitourinary abnormalities, endocrine and metabolic changes (glucose intolerance, hyperlipidemia). In the absence of effective disease modifying therapies, the mainstay of management is symptomatic support using rehabilitation strategies (physiotherapy and speech therapy). Nutritional evaluation by an expert dietician is essential, and enteral nutrition (gastrostomy) may be required. Respiratory management centres on the detection and treatment of bronchial obstructions, as well as screening for aspiration pneumonia (chest physiotherapy, drainage, positioning, breath stacking, mechanical insufflation-exsufflation, cough assist machnie, antibiotics). Non-invasive mechanical ventilation is seldom needed. Symptomatic pharmaceutical therapy includes pain management, endocrine and metabolic interventions. There is no evidence for androgen substitution therapy.Conclusion: The French national Kennedy's disease protocol provides management recommendations for patients with KD. In a low-incidence condition, sharing and integrating regional expertise, multidisciplinary experience and defining consensus best-practice recommendations is particularly important. Well-coordinated collaborative efforts will ultimately pave the way to the development of evidence-based international guidelines. [ABSTRACT FROM AUTHOR]

The extent of central nervous system involvement in Kennedy's disease (KD) relative to other motor neuron disease (MND) phenotypes still needs to be clarified. In this study, we investigated cortical and white matter (WM) MRI alterations in 25 patients with KD, compared with 24 healthy subjects, 25 patients with sporadic amyotrophic lateral sclerosis (ALS), and 35 cases with lower motor neuron‐predominant disease (LMND). LMND patients were clinically differentiated into 24 fast and 11 slow progressors. Whole‐brain cortical thickness, WM tract‐based spatial statistics and corticospinal tract (CST) tractography analyses were performed. No significant difference in terms of cortical thickness was found between groups. ALS patients showed widespread decreased fractional anisotropy and increased mean (MD) and radial diffusivity (radD) in the CST, corpus callosum and fronto‐temporal extra‐motor tracts, compared with healthy controls and other patient groups. CST tractography showed significant alterations of DT MRI metrics in ALS and LMND‐fast patients whereas KD and LMND‐slow patients were comparable with healthy controls. Our study demonstrated the absence of WM abnormalities in patients with KD and LMND‐slow, in contrast with diffuse WM damage in ALS and focal CST degeneration in LMND‐fast, supporting the use of DT MRI measures as powerful tools to differentiate fast‐ and slow‐progressing MND syndromes, including KD. [ABSTRACT FROM AUTHOR]

Owing to the frequent observation of poverty of movements, facial hypomimia and balance impairment, amyotrophic lateral sclerosis (ALS) variant with predominance of upper motor neuron involvement (UMN-ALS) is prone to be diagnosed with Parkinsonism. A clinical assessment, including the velocity-dependent stretch response test to differentiate between pyramidal and extrapyramidal stiffness; the Unified Parkinson's Disease Rating Scale and the Berg Balance Scale to assess degree of bradykinesia and postural instability; and 123I-FP-CIT scintigraphy evaluation to investigate the nigrostriatal circuit involvement, were carried out to characterize Parkinson-like features in UMN-ALS patients. Sixteen UMN-ALS patients were included in the study. The velocity-dependent stretch response indicated spasticity in all the muscles tested. The degree of stiffness was found to be related to bradykinesia and postural instability. Eleven patients (70%) showed a reduction in striatal 123I-FP-CIT uptake found to be related to disease duration and patients' ages but not to scores of the functional scales. Slowness of movements and postural instability noted in our patients could be mostly attributed to spasticity. The lack of any correlation between UPDRS or BBS scores and the degree of nigrostriatal impairment on DaTSCAN seems to disprove nigrostriatal circuit involvement in these extrapyramidal-like features. [ABSTRACT FROM AUTHOR]

A new amyotrophic lateral sclerosis (ALS) category named ‘UMN-dominant ALS’ and defined as ‘due predominantly to UMN signs but with minor electromyogram (EMG) denervation or LMN signs on examination’ has been proposed. The clinical and laboratory features of 20 patients with UMN-dominant ALS are described here, their disease course is analysed longitudinally according to their disability progression, and all these parameters are compared with those of typical ALS patients. Ten women and 10 men diagnosed with UMN-dominant ALS were evaluated. Their mean age at disease onset was 58.6 years. At the most recent evaluation, after a mean disease duration of 7.7 years, all patients progressed to a tetrapyramidal syndrome with pseudobulbar features of varying degree. No patient had respiratory problems. Cognitive impairment was observed in eight patients. The differences in disease progression between the UMN-dominant ALS and typical ALS patients proved significant ( p <0.02) both with regard to the total ALSFRS-R score at six months and to each single region subscore at 12 months. Our findings suggest that there is both a different pattern of disability and longer survival in UMN-dominant ALS compared to classic ALS patients. [ABSTRACT FROM AUTHOR]

Objective: To assess whether phosphorylated neurofilament heavy chain (pNfH) can discriminate different upper motor neuron (UMN) syndromes, namely, ALS, UMN-predominant ALS, primary lateral sclerosis (PLS) and hereditary spastic paraparesis (hSP) and to test the prognostic value of pNfH in UMN diseases. Methods: CSF and serum pNfH were measured in 143 patients presenting with signs of UMN and later diagnosed with classic/bulbar ALS, UMNp-ALS, hSP, and PLS. Between-group comparisons were drawn by ANOVA and receiver operating characteristic (ROC) analysis was performed. The prognostic value of pNfH was tested by the Cox regression model. Results: ALS and UMNp-ALS patients had higher CSF pNfH compared to PLS and hSP (p < 0.001). ROC analysis showed that CSF pNfH could differentiate ALS, UMNp-ALS included, from PLS and hSP (AUC = 0.75 and 0.95, respectively), while serum did not perform as well. In multivariable survival analysis among the totality of UMN patients and classic/bulbar ALS, CSF pNfH independently predicted survival. Among UMNp-ALS patients, only the progression rate (HR4.71, p = 0.01) and presence of multifocal fasciculations (HR 15.69, p = 0.02) were independent prognostic factors. Conclusions: CSF pNfH is significantly higher in classic and UMNp-ALS compared to UMN diseases with a better prognosis such as PLS and hSP. Its prognostic role is confirmed in classic and bulbar ALS, but not among UMNp, where clinical signs remained the only independent prognostic factors. [ABSTRACT FROM AUTHOR]

Motor neuron diseases (MNDs) are etiologically and biologically heterogeneous diseases. The pathobiology of motor neuron degeneration is still largely unknown, and no effective therapy is available. Heterogeneity and lack of specific disease biomarkers have been appointed as leading reasons for past clinical trial failure, and biomarker discovery is pivotal in today's MND research agenda. In the last decade, neurofilaments (NFs) have emerged as promising biomarkers for the clinical assessment of neurodegeneration. NFs are scaffolding proteins with predominant structural functions contributing to the axonal cytoskeleton of myelinated axons. NFs are released in CSF and peripheral blood as a consequence of axonal degeneration, irrespective of the primary causal event. Due to the current availability of highly-sensitive automated technologies capable of precisely quantify proteins in biofluids in the femtomolar range, it is now possible to reliably measure NFs not only in CSF but also in blood. In this review, we will discuss how NFs are impacting research and clinical management in ALS and other MNDs. Besides contributing to the diagnosis at early stages by differentiating between MNDs with different clinical evolution and severity, NFs may provide a useful tool for the early enrolment of patients in clinical trials. Due to their stability across the disease, NFs convey prognostic information and, on a larger scale, help to stratify patients in homogenous groups. Shortcomings of NFs assessment in biofluids will also be discussed according to the available literature in the attempt to predict the most appropriate use of the biomarker in the MND clinic. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disease due to motor neuron loss variably associated with frontotemporal dementia (FTD). Next generation sequencing technology revealed an increasing number of rare and novel genetic variants and interpretation of their pathogenicity represents a major challange in the diagnosis of ALS. We selected 213 consecutive patients with sporadic or familial (16%) ALS, tested negative for SOD1, FUS, TARDBP, and C9orf72 mutations. To reveal rare forms of genetic ALS, we performed a comprehensive multi-gene panel screening including 46 genes associated with ALS, hereditary motor neuronopathies, spastic paraplegia, and FTD. Our study allowed the identification of pathogenic or likely pathogenic variants in 4.2% of patients. The genes with the highest percentage of pathogenic variants were OPTN (1%), VCP (1%) SQSTM1(1%), SETX (0.4%), FIG4 (0.4%), and GARS1 (0.4%) genes. We also found 49 novel or rare gene variants of unknown significance in 30 patients (14%), 44 unlikely pathogenic variants (39%), and 48 variants in ALS susceptibility genes. The results of our study suggest the screening of OPTN, VCP, and SQSTM1 genes in routine diagnostic investigations for both sporadic and familial cases, and confirm the importance of diagnosis and couselling for patients and their relative family members. [ABSTRACT FROM AUTHOR]

The article presents an overview of a study on the therapeutic use of clenbuterol in the treatment of amyotrophic lateral sclerosis patients who are already taking riluzole. The anabolic effect of clenbuterol on skeletal muscle is discussed. The methodology used in the study is described. The key factors included in clenbuterol safety assessment are outlined.

Background: Spasticity is a major determinant of disability and decline in quality of life in patients with motor neuron disease. Cannabinoids have been approved for symptomatic treatment of spasticity in multiple sclerosis. We investigated whether cannabinoids might also reduce spasticity in patients with motor neuron disease.Methods: We did an investigator-initiated, randomised, double-blind, placebo-controlled, phase 2 clinical trial at four tertiary motor neuron disease centres in Italy. Eligible patients were aged 18-80 years; had possible, laboratory-supported probable, probable, or definite amyotrophic lateral sclerosis as defined by revised El Escorial criteria, or primary lateral sclerosis according to Pringle's criteria; had spasticity symptoms due to motor neuron disease for at least 3 months; had spasticity scores of 1 or greater in at least two muscle groups on the Modified Ashworth Scale; and were taking an antispasticity regimen that was maintained at a stable dose for 30 days before enrolment. Participants were assigned (1:1) by an independent statistician via a computer-generated randomisation sequence to a standardised oromucosal spray (nabiximols) containing a defined combination of delta-9-tetrahydrocannabinol and cannabidiol (each 100 μL actuation contained 2·7 mg delta-9-tetrahydrocannabinol and 2·5 mg cannabidiol) or to placebo for 6 weeks. Participants self-titrated during the first 14 treatment days according to a predefined escalation scheme (maximum 12 actuations per 24 h), then maintained that dose for 4 weeks. The primary endpoint was the change in the score on the Modified Ashworth Scale, which was assessed at baseline and after 6 weeks. Safety and tolerability were also monitored. Participants, investigators, site personnel, and the study statistician were masked to treatment allocation. All randomised participants who received at least one dose of study drug were included in the analysis. This trial is registered with ClinicalTrials.gov, number NCT01776970. The trial is closed to new participants with follow-up completed.Findings: Between Jan 19, 2013, and Dec 15, 2014, 60 participants were randomly assigned, and 59 participants were included in the final analysis (29 in the nabiximols group and 30 in the placebo group). Modified Ashworth Scale scores improved by a mean of 0·11 (SD 0·48) in the nabiximols group and deteriorated by a mean of 0·16 (0·47) in the placebo group (adjusted effect estimate -0·32 [95% CI -0·57 to -0·069]; p=0·013). Nabiximols was well tolerated, and no participants withdrew from the double-blind phase of the study. No serious adverse effects occurred.Interpretation: In this proof-of-concept trial, nabiximols had a positive effect on spasticity symptoms in patients with motor neuron disease and had an acceptable safety and tolerability profile. These findings should be investigated further in larger clinical trials.Funding: Italian Research Foundation for Amyotrophic Lateral Sclerosis. [ABSTRACT FROM AUTHOR]

Abstract: Amyotrophic lateral sclerosis (ALS) is as an adult-onset neurodegenerative disorder involving both upper and lower motor neurons. About 5% of all cases exhibit signs of frontotemporal degeneration (FTD). We established the mutation frequency of C9ORF72, SOD1, TARDBP, and FUS genes in 307 patients with sporadic ALS, 46 patients with familial ALS (FALS), and 73 patients affected with FTD, all originating from the northeastern part of Italy. C9ORF72 pathogenic expansion was found on 22% of familial ALS, 5% of sporadic ALS, and 14% of FTD patients, resulting the most frequently genetic determinant in our cohort. Sequence analysis of ALS cohort identified 2 novel variants on SOD1 (p.Glu41Gly) and FUS (p.Gly496Glyfs*31). Interestingly, the single base deletion on FUS was observed in an homozygous state, suggesting a recessive pattern of inheritance. No point mutations were identified on FTD cohort. Although useful to direct genetic testing, this study results expand the current knowledge of ALS genetics. [Copyright &y& Elsevier]