Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.

BACKGROUND: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis. METHODS: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed. FINDINGS: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI -0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]). INTERPRETATION: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated. FUNDING: Orphazyme.

European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).

BACKGROUND: This update of the guideline on the management of amyotrophic lateral sclerosis (ALS) was commissioned by the European Academy of Neurology (EAN) and prepared in collaboration with the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD) and the support of the European Network for the Cure ALS (ENCALS) and the European Organization for Professionals and Patients with ALS (EUpALS). METHODS: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the effectiveness of interventions for ALS. Two systematic reviewers from Cochrane Response supported the guideline panel. The working group identified a total of 26 research questions, performed systematic reviews, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available. RESULTS: A guideline mapping effort revealed only one other ALS guideline that used GRADE methodology (a National Institute for Health and Care Excellence [NICE] guideline). The available evidence was scarce for many research questions. Of the 26 research questions evaluated, the NICE recommendations could be adapted for 8 questions. Other recommendations required updates of existing systematic reviews or de novo reviews. Recommendations were made on currently available disease-modifying treatments, multidisciplinary care, nutritional and respiratory support, communication aids, psychological support, treatments for common ALS symptoms (e.g., muscle cramps, spasticity, pseudobulbar affect, thick mucus, sialorrhea, pain), and end-of-life management. CONCLUSIONS: This update of the guideline using GRADE methodology provides a framework for the management of ALS. The treatment landscape is changing rapidly, and further updates will be prepared when additional evidence becomes available.

One third of physicians discuss exit strategies with patients with amyotrophic lateral sclerosis: Results from nationwide surveys among German and Polish neurologists.

OBJECTIVE: This paper examines neurologists' approaches to exit strategies (ESs), such as euthanasia and physician-assisted suicide, in patients with amyotrophic lateral sclerosis (PALS) in two European countries. METHODS: In a nationwide anonymous survey, we collected responses from 237 Polish and 228 German neurologists, focusing on their practices and beliefs about ESs, as well as their viewpoints on life-sustaining measures (LSMs) (percutaneous endoscopic gastrostomy, non-invasive, and invasive ventilation). To analyze the data, we employed statistical methods, including Mann-Whitney U, Kruskal-Wallis, chi-square tests, Spearman's rank correlation, and multiple regression analysis. RESULTS: One third of the neurologists initiated the discussion about ESs with PALS. Half were ready to have this conversation upon patient's request. Age, gender, religiousness, and nationality were closely associated with this approach. One in 9 neurologists received a request to terminate an LSM, whereas 1 in 10 to implement an ES. German neurologists and palliative care trainees acquired both demands more commonly. Neurologists quoted a low quality of life, decreased mood, and being a burden to the family/closest ones as primary reasons for a wish to hasten death among PALS. Although the majority expressed a willingness to terminate an LSM at a request of the patient, most opposed the legalization of euthanasia. Younger and less religious individuals were more likely to favor accepting euthanasia. CONCLUSION: Neurologists vary significantly in their approaches to terminal care. Complex relationships exist among personal indices, shared beliefs, and current practices.

Quality of life and depression in patients with amyotrophic lateral sclerosis - does the country of origin matter?

BACKGROUND: Given the inevitable relentless progressing nature of amyotrophic lateral sclerosis (ALS), it is essential to identify factors influencing patients' wellbeing. The study aimed to prospectively assess factors influencing the quality of life (QoL) and depression in ALS patients compared to healthy controls (HCs) from Poland, Germany and Sweden and their relationship to socio-demographic and clinical factors. METHODS: 314 ALS patients (120 from Poland, 140 from Germany, 54 from Sweden) and 311 age-, sex- and education-level-matched HCs underwent standardized interviews for quality of life, depression, functional status and pain. RESULTS: Patients from all three countries showed similar levels of functional impairment (ALSFRS-R). Overall, ALS patients assessed their quality of life as lower compared to HCs (p < 0.001 for the anamnestic comparative self-assessment (ACSA), p = 0.002 for the Schedule for the evaluation of the subjective quality of life - SEIQoL- direct weighting (SEIQoL-DW). Also, the German and Swedish patients, but not the Polish, reported higher depression levels than the corresponding HCs (p < 0.001). Analysis of ALS groups revealed that functional impairment was related to a lower quality of life (ACSA) and higher depression levels among German ALS patients. Longer time since diagnosis predicted lower depression and (in male subjects) higher quality of life. CONCLUSIONS: ALS patients assess their quality of life and mood lower than healthy individuals within the studied countries. The relationships between clinical and demographic factors are moderated by country of provenance, which bears implications for the design and interpretation of scientific and clinical studies, which should reflect the complexity and heterogeneity of mechanisms determining QoL.

Association of the practice of contact sports with the development of amyotrophic lateral sclerosis.

Objectives: High-intensity physical activity and sports prone to repetitive injuries of the cervical spine and head (when associated with vigorous practice) have been suggested as possible risk factors for amyotrophic lateral sclerosis (ALS). Our objective was to evaluate the relationship between the practice of contact sports (boxing, hockey, football, rugby) and ALS. Methods: The study included 2247 individuals, 1326 patients and 921 controls from several European countries. Analysis of the effect of contact sports on ALS was conducted in male participants only, as very few women practiced contact sports. Logistic regression models were used with the response variable as the presence or absence of ALS, with α = 0.05 significance level. Results: A relationship between the practice of contact sports and ALS was found, with those practicing contact sports having 76% higher odds of an ALS diagnosis (OR = 1.76, p = 0.001). In addition, univariate analyses for age (higher risk for older people, p < 0.001), smoking status (higher risk for ex-smokers, p = 0.022) and tobacco exposure (higher risk for more exposure, p = 0.038) also indicated that these variables are risk factors for ALS. In multivariate models, in addition to age, the interaction term between practice of contact sports and tobacco exposure was still significant (p = 0.03). Conclusions: This is one of the largest studies on the role of contact sport in ALS development. Our results support the existence of a relationship between the practice of sports with repetitive trauma at the level of the cervical spine and head, and ALS. This risk appears to be enhanced by tobacco exposure.

Determining impairment in the Swedish, Polish and German ECAS: the importance of adjusting for age and education.

Objective: Age and years of education are strong predictors of cognitive performance in several versions of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) and cutoffs for the Swedish and Polish versions are not established yet. Here we evaluated the performance of healthy subjects on the national versions of the Swedish and Polish ECAS and compared cognitive performance on three European translations of the ECAS. Methods: The ECAS performances of healthy subjects from Sweden (n = 111), Poland (n = 124) and Germany (n = 86) were compared. Based on the test results on the national versions of ECAS, age- and education-adjusted cutoffs were compared for the German, Swedish and Polish versions, respectively. Results: Age and years of education correlated with performance in the ECAS. Swedish subjects under the age of 60 years and Swedish subjects with low education level scored significantly higher in memory than the respective German and Polish subgroups. German and Polish subjects over 60 years of age performed significantly better in language than the respective Swedish subgroup. The Polish cohort in total had lower executive scores compared to the Swedish cohort, and lower than the German subjects in the higher education subgroup. Conclusions: The results highlight the importance of establishing age- and education-adjusted ECAS cutoffs not only in general, but also for seemingly similar populations of different origins. The results should be taken into account when comparing cognition data across patient populations including in drug trials where an ECAS test result is being used as an inclusion criterium or outcome measure.

Religiosity in patients with amyotrophic lateral sclerosis, a cross-country comparison.

PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive motor impairment leading to early death. Religiousness is one of the factors potentially alleviating the psychological burden of patients. However, its role might vary according to cultural context. Our study aimed to analyze religiosity, and its clinical, psychological and socio-demographic correlates in ALS patients and controls, comparing two European countries with different cultural backgrounds. METHODS: 268 Polish and German ALS patients, including 18 with locked-in syndrome (LIS) and 198 healthy controls (HC) were interviewed about religiousness, quality of life (Qol), depression, functional status and pain. A follow-up was conducted on 71 patients. RESULTS: Polish subjects had a significantly higher level of public, private and general religiosity than the German sample. Importantly, we found no difference in total and public religiousness between ALS patients and HC within either population. Only the private religiousness was significantly higher in German patients compared to controls. In the same sample, private religiousness correlated with functional impairment due to disease progression. In ALS groups and LIS patients, religiousness did not correlate with any disease-associated factors: disease duration, pain, Qol or depression. Follow-up comparisons in the ALS group revealed worsening functional status, increased depression and no significant change in religiosity. CONCLUSIONS: Religiosity was linked to the cultural background rather than ALS. Generally, it did not correlate with clinical, psychological and socio-demographic parameters and was stable throughout disease progression. The only exception was the relationship between the functional decline and private religiosity among German patients.

The quality of life and depression in primary caregivers of patients with amyotrophic lateral sclerosis is affected by patient-related and culture-specific conditions.

Objective: To analyze the quality of life (QoL) and frequency of depression in primary caregivers of patients with amyotrophic lateral sclerosis (ALS) in two neighboring European countries. Methods: a cross-sectional study performed in 164 dyads of ALS patients and caregivers followed at clinical ALS centers in Poland and Germany between 2015 and 2018. The quality of life (Anamnestic Comparative Self-Assessment - ACSA, Quality of Life in Life-Threatening Illness - Family Carer Version - QOLLTI-F) and depression (ALS-Depression-Inventory 12-Items - ADI-12) of the caregivers was assessed and correlated with caregivers- and patient-related factors. Patient's clinical status was assessed by ALS Functional Rating Scale - revised and the Behavioral Score of the Edinburgh Cognitive and Behavioral ALS Screen. Results: the caregivers reported a positive QoL associated with functional and behavioral status of the patient, disease duration and caregivers's depression The most impaired domains of the QoL differed depending on the country of provenance, cultural background and/or social support of the caregivers. Depression was present in 1/3 of the caregivers and was significantly more frequent in the Polish group. It positively correlated with female gender, disease duration, sleep disturbances and functional decline. Both QoL and mood were significantly lower in the caregivers more burdened with the functional care of the patients. Conclusions: the wellbeing of caregivers of ALS patients is affected by patient-related and culture-specific conditions. Understanding the needs and background of psychological adaptation of the caregivers from various countries may translate into better QoL and local patient care.

Attitudes of caregivers towards prolonging and shortening life in advanced stages of amyotrophic lateral sclerosis.

INTRODUCTION: Inevitable disease progression in amyotrophic lateral sclerosis (ALS) forces patients and their caregivers (CGs) to reflect on end-of-life treatment. The CGs are often heavily burdened with their role of surrogate decision-makers. The aim of the study was to analyze attitudes of CGs and presumable attitudes of ALS patients from the CGs' perspective towards palliative care in advanced disease stages. MATERIAL AND METHODS: One hundred and sixty four CGs from Germany and Poland were interviewed regarding their own preferences and patients' ideational attitudes towards life-prolonging (invasive and non-invasive ventilation, tube feeding) and life-shortening methods (termination of measures, active measures if permitted by law). The data were correlated with patient- and CG-related factors: demographic and clinical data, care commitment, depression and quality of life (QoL). RESULTS: The CGs were mostly female spouses of ALS patients, with secondary/higher education. Nearly 70% (81% in Poland, 57% in Germany; p = 0.0001) reported positive attitudes towards life-prolonging methods, which positively correlated with religiousness and negatively with patients' age. Approximately 40% of CGs (25% and 51% respectively; p = 0.001) reported positive attitudes towards life-shortening methods. It positively correlated with time since diagnosis and negatively with the CG's QoL, religiosity and religious/spiritual faith as factors that significantly influenced end-of-life decisions. There was a strongly positive correlation between CGs' positive attitudes towards life-shortening methods and presumed positive patients' attitudes assessed by their CGs ( p < 0.000001). CONCLUSIONS: Although attitudes towards treatment differed between countries, the CGs of ALS patients were generally positive towards life-prolonging treatment. A greater acceptance of life-shortening methods in the case of longer disease duration and poorer QoL may indicate worse coping with disease progression and weaker adaptation mechanisms in CGs compared to those previously reported in ALS patients. A close resemblance of the CGs' answers to probable patients' attitudes reported by the CGs indicates that many GCs might actually express their own culturally shaped attitudes towards end-of-life methods. In light of earlier-reported discrepancies between presumed opinions of the CGs and of patients themselves, a greater focus should be placed on thorough discussions on future treatment options with ALS patients in the presence of their CGs, to stay in line with the patient's authentic will.

Well-being on supportive techniques in amyotrophic lateral sclerosis: from neurologists' perspective.

OBJECTIVE: To investigate intercultural neurologists' perception of well-being in patients with amyotrophic lateral sclerosis (ALS) using gastrostomy (PEG), non-invasive, and/or invasive ventilation (NIV/IV) and to analyse the determinants and impact on the management of the above medical interventions (MIs). METHODS: The study was based on anonymous questionnaires addressing the clinical approach and personal attitude towards the use of PEG, NIV and IV in ALS patients completed by 465 neurologists: 228 from Germany and 237 from Poland. RESULTS: The German and Polish neurologists estimated the quality of life in ALS patients using PEG and NIV as neutral, whilst low in individuals using IV. A regression model revealed an independent influence of palliative care training (PCT) and age on that attitude in the German group. Higher values of estimated patients' depressiveness on PEG, NIV and IV were found amongst the Polish neurologists. Marital status, experience in ALS and being a parent independently influenced the perception of patients' depressiveness in the German, whilst marital status, age and PCT were factors in the Polish group. Amongst German neurologists, a higher perception of patients' depressiveness in individuals using PEG, NIV and IV was linked to the later timing of the MIs discussion. In the Polish group, it was a lower estimation of QoL in patients using PEG. CONCLUSION: Neurologists' perception of ALS patients' well-being on MIs reflects their demographic status, professional experience and potentially their cultural background. This perception plays an important role in the timing of MIs discussion, possibly influencing the decision-making process.

Role of DTI-MRI parameters in diagnosis of ALS: useful biomarkers for daily practice? Tertiary centre experience and literature review.

INTRODUCTION: Despite the rapid development of neuroimaging techniques, the diagnosis of amyotrophic lateral sclerosis (ALS) remains a significant challenge. Magnetic resonance imaging (MRI) is important for ruling out ALS mimickers, while Diffusion Tensor Imaging (DTI) is a useful tool for the identification of cortical tract damage. The aim of this study was to identify the optimal set of DTI parameters to support the diagnosis of ALS that could be applied to everyday MRI and be used as a disease biomarker in daily practice. MATERIAL AND METHODS: Forty-seven ALS patients and 55 age- and gender-matched healthy individuals underwent MRI using a 1.5-Tesla scanner including a DTI sequence with 30 spatial directions and a b-value 0/1,000 s/mm2. Two independent researchers measured the DTI parameters: fractional anisotropy (FA), TRACE and apparent diffusion coefficient (ADC) using freehand regions of interest (ROIs) placed along both corticospinal tracts (CSTs), starting at the level of the internal capsule and ending at the medulla. RESULTS: Statistical significance was only achieved for fractional anisotropy (FA) (ALS vs controls, p < 0.001). The highest sensitivity was found in the brainstem (cerebral peduncles, pons and pyramids) where it ranged from 72.3% to 80.9%, whereas the highest specificity was observed at the level of the internal capsule (94.6%). The combined highest sensitivity and specificity was obtained in the pons (72.3% and 72.7%, respectively). Classifier based positive predictive values for Youden index cut-off scores varied between 60.7% and 69.4%. CONCLUSIONS: Fractional anisotropy (FA) measured at the level of the brainstem was shown to be the single most relevant parameter in differentiating patients with ALS from healthy subjects. This has the potential to become an ALS-specific biomarker for patient identification in daily practice.

Analysis of routine blood parameters in patients with amyotrophic lateral sclerosis and evaluation of a possible correlation with disease progression-a multicenter study.

Objective: Amyotrophic lateral sclerosis (ALS) pathogenesis is still unclear, its course is considerably variable, and prognosis is hard to determine. Despite much research, there is still a lack of easily accessible markers predicting prognosis. We investigated routine blood parameters in ALS patients regarding correlations with disease severity, progression rate, and survival. Additionally, we analyzed disease and patients' characteristics relating to baseline blood parameter levels. Methods: We analyzed creatine kinase (CK), albumin (ALB), creatinine (CREA), total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and triglycerides (TG) levels around time of diagnosis in 1,084 ALS patients. We carried out linear regression analyses including disease and patients' characteristics with each blood parameter to detect correlations with them. Linear regression models were performed for ALSFRS-R at study entry, its retrospectively defined rate of decay and prospectively collected progression rate. Different survival analysis methods were used to examine associations between blood parameters and survival. Results: We found higher CK (p-value 0.001), ALB (p-value <0.001), CREA (p-value <0.001), and HDL levels (p-value 0.044) at time of diagnosis being associated with better functional status according to ALSFRS-R scores at study entry. Additionally, higher CREA levels were associated with lower risk of death (p-value 0.003). Conclusions: Our results indicate potential of CK, ALB, CREA, and HDL as disease severity or progression markers, and may also provide clues to ALS pathogenesis. However, these values are highly dependent on other variables, and further careful, longitudinal analyses will be necessary to prove the relevance of our findings.

TREM2 Gene Compound Heterozygosity in Neurodegenerative Disorders.

BACKGROUND: Homozygous variants of the TREM2 and TYROBP genes have been shown to be causative for multiple bone cysts and neurodegeneration leading to progressive dementia (NHD, Nasu-Hakola disease). OBJECTIVE: To determine if biallelic variants of these genes and/or oligogenic inheritance could be responsible for a wider spectrum of neurodegenerative conditions. METHODS: We analyzed 52 genes associated with neurodegenerative disorders using targeted next generation sequencing in a selected group of 29 patients (n = 14 Alzheimer's disease, n = 8 frontotemporal dementia, n = 7 amyotrophic lateral sclerosis) carrying diverse already determined rare variants in exon 2 of TREM2. Molecular modeling was used to get an insight into the potential effects of the mutation. RESULTS: We identified a novel mutation c.401_406delinsTCTAT; p.(Asp134Valfs*55) in exon 3 of TREM2 in an Alzheimer's disease patient also carrying the p.Arg62His TREM2 variant. Molecular modeling revealed that the identified mutation prevents anchoring of the TREM2 protein in the membrane, leaving the core of the Ig-like domain intact. CONCLUSION: Our results expand the spectrum of neurodegenerative diseases, where the carriers of biallelic mutations in TREM2 have been described for Alzheimer's disease, and highlight the impact of variant burden in other genes on phenotypic heterogeneity.

Physical activity in patients with amyotrophic lateral sclerosis: Prevalence, patients' perspectives and relation to the motor performance.

BACKGROUND: There are no recommendations for physical activity in amyotrophic lateral sclerosis (ALS) patients. OBJECTIVE: (i) To describe the prevalence and pattern of physical activity (PA) in ALS patients; (ii) to explore patients' attitude towards PA; and (iii) to investigate the relationship between PA at home environment and the rate of functional decline. METHODS: 96 ALS patients were followed for 6 months at 3-month intervals and assessed by site of disease onset, disease duration, diagnosis delay, functional status, muscle strength, fatigue and prevalence of PA. RESULTS: Over 70% of patients performed regular exercise and reported a positive effect of PA on functional status and mood. Regularly exercising individuals showed a higher ALSFRS-R bulbar score (11.0 vs 9.0, p = 0.011) and a lower decline of respiratory sub-score of ALSFRS-R compared to non-regularly exercising patients (0 vs 1.0, p = 0.026). Bulbar onset was a negative prognostic factor for regular exercise (odds ratio [OR]: 5.2, p = 0.004). CONCLUSION: The majority of ALS patients perform regular PA and find it positively influence their motor performance and mood. Bulbar disease onset, but not functional status, is a negative prognostic factor for regular exercise in ALS patients. Regular mild PA may result in a slower deterioration of functional status, especially the respiratory function.

Clinical trials in pediatric ALS: a TRICALS feasibility study.

Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA).Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe.Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS.Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS.Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.

SOD1 mutations associated with amyotrophic lateral sclerosis analysis of variant severity.

Mutations in superoxide dismutase 1 gene (SOD1) are linked to amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder predominantly affecting upper and lower motor neurons. The clinical phenotype of ALS shows inter- and intrafamilial heterogeneity. The aim of the study was to analyze the relations between individual SOD1 mutations and the clinical presentation using in silico methods to assess the SOD1 mutations severity. We identified SOD1 causative variants in a group of 915 prospectively tested consecutive Polish ALS patients from a neuromuscular clinical center, performed molecular modeling of mutated SOD1 proteins and in silico analysis of mutation impact on clinical phenotype and survival analysis of associations between mutations and hazard of clinical end-points. Fifteen SOD1 mutations were identified in 21.1% familial and 2.3% sporadic ALS cases. Their effects on SOD1 protein structure and functioning inferred from molecular modeling and in silico analyses correlate well with the clinical data. Molecular modeling results support the hypothesis that folding intermediates rather than mature SOD1 protein give rise to the source of cytotoxic conformations in ALS. Significant associations between type of mutation and clinical end-points were found.

Caregivers' divergent perspectives on patients' well-being and attitudes towards hastened death in Germany, Poland and Sweden.

Background: During the course of amyotrophic lateral sclerosis (ALS), patients and their families are faced with existential decisions concerning life-prolonging and -shortening measures. Correct anticipation of patient's well-being and preferences is a prerequisite for patient-centered surrogate decision making. Methods: In Germany (N = 84), Poland (N = 77) and Sweden (N = 73) patient-caregiver dyads were interviewed. Standardized questionnaires on well-being (ADI-12 for depressiveness; ACSA for global quality of life) and wish for hastened death (SAHD) were used in ALS patients. Additionally, caregivers were asked to fill out the same questionnaires by anticipating patients' perspective (surrogate perspective). Results: Caregivers significantly underestimated patients' well-being in Germany and Poland. For Swedish caregivers, there were just as many who underestimated and overestimated well-being. The same was true for wish for hastened death in all three countries. For Swedish and Polish patients, caregivers' estimation of well-being was not even associated with patients' responses and the same was true for estimation of wish for hastened death in all three countries. Older caregivers and those with the most frequent encounter with the patient were the closest in their rating of well-being and wish for hastened death to the patients' actual state, while caregivers with chronic disease him/herself were more likely to underestimate patient's well-being. Discussion: Despite distinct cultural differences, there was a clear discrepancy between patients' and caregivers' perspective on patients' well-being and preferences towards life in all three countries. This possible bias in caregivers' judgment needs to be taken into account in surrogate decision making.

Trends in the diagnostic delay and pathway for amyotrophic lateral sclerosis patients across different countries.

Background: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with a median survival of 2-5 years. An early diagnosis is essential for providing ALS patients the finest management possible. Studies from different countries report a similar median diagnostic delay of around 12 months, which is still far from desirable. We analyzed the diagnostic pathway in different countries in order to identify the major challenges. Methods: We studied a cohort of 1,405 ALS patients from five different centers, in four different countries (Turkey, Germany, Poland, and Portugal), which collaborated in a common database. Demographic, disease and sociocultural factors were collected. Time from first symptom onset to first medical evaluation and to diagnosis, the specialist assessment and investigations requested were analyzed. Factors contributing to diagnostic delay were evaluated by multivariate linear regression. Results: The median diagnostic delay from first symptom onset was 11 months and was similar between centers. Major differences were seen in the time from symptom onset to first medical evaluation. An earlier first medical evaluation was associated with a longer time to diagnosis, highlighting that ALS diagnosis is not straightforward in the early stages of the disease. The odds for ALS diagnosis were superior when evaluated by a neurologist and increased over time. Electromyography was decisive in establishing the diagnosis. Conclusions: We suggest that a specific diagnostic test for ALS-a specific biomarker-will be needed to achieve early diagnosis. Early referral to a neurologist and to electromyography is important for early ALS diagnosis.

Delayed Diagnosis and Diagnostic Pathway of ALS Patients in Portugal: Where Can We Improve?

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with unsatisfactory treatment options. Best management and recruitment into clinical trials requires early diagnosis. However, diagnosis is often delayed. Analysis of the diagnostic pathway and identification of the causes of diagnostic delay are imperative. Methods: We studied a cohort of 580 ALS patients followed up in our ALS clinic in Lisbon. Demographic, disease, and sociocultural factors were collected. Time from first symptom onset to diagnosis, the specialist's assessment, and investigations requested were analyzed. Predictors of diagnostic delay were evaluated by multivariate linear regression, adjusting for potential confounders. Results: The median diagnostic delay from first symptom onset was 10 months. Spinal-onset, slower disease progression, cognitive symptoms at onset, and lower income were associated with increased diagnostic delay. Most patients were first assessed by general practitioners. Patients who were first evaluated by a neurologist were more likely to be correctly diagnosed, decreasing time to diagnosis. Electromyography was decisive in establishing the diagnosis. Conclusions: Late referral from non-neurologists to a neurologist is a potentially modifiable factor contributing to significant diagnostic delay. Educational interventions targeted to non-neurologists physicians, in order to increase awareness of ALS and, consequently, promote early referral to a neurologist at a tertiary center, will be important in reducing diagnostic delay.

Motor neuron disease beginning with frontotemporal dementia: clinical features and progression.

Objective: To study disease characteristics, progression and outcome in a group of motor neuron disease (MND) patients beginning with frontotemporal dementia (FTD) by comparing them with patients with the typical motor-onset. Methods: 849 patients recruited from tertiary centers were studied according to FTD-onset and motor-onset. We studied clinical data, functional decline and survival. Results: Twenty six patients (3.1%) had FTD-onset of whom seven (26.9%) had coincident motor dysfunction. In those with isolated FTD-onset, motor symptoms developed after a median of 12 months (IQR: 4-18). FTD-onset patients were older at presentation; the bulbar-region was more frequently first affected than in the motor-onset group; there was a predominant upper motor neuron (UMN) phenotype; fasciculations were less common than in motor onset disease but facial and upper limb apraxia was more frequent; as well as ALS and FTD familial history. No differences were observed for gender, frequency of C9orf72 hexanucleotide repeat expansion, family history of Alzheimer's and Parkinson's diseases, median delay from motor symptoms to diagnosis, median ALSFRS-R rate of change, handedness, emotional lability, depression, weight loss, resting tremor, bradykinesia, sensory changes or neuropathy. Clinical and demographic features were similar between FTD-onset patients developing bulbar MND and bulbar-onset ALS patients. Once bulbar symptoms manifested functional progression and survival were similar to those of bulbar-onset ALS patients. Conclusions: MND patients with FTD-onset have a distinctive phenotype characterized by predominant UMN presentation and rapid progression to bulbar involvement. The main factor impacting functional decline and survival is the onset of bulbar dysfunction.