Impact of SARS-CoV-2 infection and COVID-19 pandemic on the morbidity and mortality of amyotrophic lateral sclerosis patients in Valencia, Spain.

BACKGROUND AND PURPOSE: The purpose was to describe the risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hospitalization for coronavirus disease 2019 (COVID-19) and related death and to assess the impact of the pandemic in the survival of amyotrophic lateral sclerosis (ALS) patients. METHODS: The risk of SARS-CoV-2 infection, hospitalization for COVID-19 and related death was assessed in ALS patients alive between March 2020 and July 2022. To evaluate its impact in the overall survival of ALS patients, the survival of patients who died before and during the pandemic was compared. RESULTS: Amongst 263 ALS patients alive during the pandemic, 62 got infected during the study period (infection rate 14.34 per 100 person-years). Most infections (68%) occurred during the sixth wave (November 2021 to January 2022) and most patients (67%) were vaccinated at the time of infection. The hospitalization rate due to COVID-19 was 4.16 per 100 person-years. The multivariable model confirmed non-invasive ventilation (NIV) use prior to infection as a risk factor for hospitalization (odds ratio [OR] = 7.96, p = 0.003) and COVID-19 vaccination as a protective factor (OR = 0.093, p = 0.025) independent of age, sex and gastrostomy. Within 30 days after infection, 7% of non-ventilated patients started NIV and five patients (8.06%) died, of whom four were previously ventilated. The median survival of ALS patients was similar before and during the pandemic and no effect was found in the Cox regression model (hazard ratio 1.02, p = 0.89). CONCLUSIONS: This study shows a high risk of severe COVID-19 amongst ALS patients requiring NIV. Nevertheless, the pandemic showed no impact in the overall survival of ALS patients, probably due to a high vaccination rate and an adequate access to healthcare resources.

Spinal Muscular Atrophy Update in Best Practices: Recommendations for Diagnosis Considerations.

Background and Objectives: Spinal muscular atrophy (SMA) is an autosomal recessive progressive neurodegenerative primary motor neuron disorder caused by biallelic variants of the survival motor neuron 1 (SMN1) gene. The most recent SMA best practice recommendations were published in 2018 shortly after the approval of the first SMN-enhancing treatment. The availability of disease-modifying therapies for 5q SMA and implementation of SMA newborn screening (NBS) has led to urgency to update the SMA best practice recommendations for diagnosis and to reevaluate the current classification of SMA. In addition, the availability of disease-modifying therapies has opened the door to explore improved diagnosis of adult-onset SMA. Methods: A systematic literature review was conducted on SMA NBS. An SMA working group of American and European health care providers developed recommendations through a modified Delphi technique with serial surveys and virtual meeting feedback on SMA diagnosis to fill information gaps for topics with limited evidence. A community working group of an individual with SMA and caregivers provided insight and perspective on SMA diagnosis and support through a virtual meeting to guide recommendations. Results: The health care provider working group achieved consensus that SMA NBS is essential to include in the updated best practice for SMA diagnosis (100%). Recommendations for the following are described: characterizing NBS-identified infants before treatment; minimum recommendations for starting or offering SMA NBS in a state or country; recommendations for activities and services to be provided by an SMA specialty care center accepting SMA NBS referrals; and recommendations for partnership with individuals with SMA and caregivers to support NBS-identified infants and their caregivers. Limited data are available to advance efficient diagnosis of adult-onset SMA. Discussion: Updating best practice recommendations for SMA diagnosis to include SMA NBS implementation is essential to advancing care for individuals with SMA. In addition to testing, processes for the efficient management of positive newborn screen with access to knowledgeable and skilled health care providers and access to treatment options is critical to successful early diagnosis. Additional evidence is required to improve adult-onset SMA diagnosis.

Design and Validation of a Clinical Outcome Measure for Adolescents and Adult Patients with Spinal Muscular Atrophy: SMA Life Study Protocol.

INTRODUCTION: The objective of this study is to develop a clinical tool for the evaluation and follow-up of adolescent and adult patients with 5q spinal muscular atrophy (SMA) and to design its validation. METHODS: This prospective, non-interventional study will be carried out at five centres in Spain and will include patients aged 16 years or older with a confirmed diagnosis of 5q SMA (biallelic mutation of the survival motor neuron 1 [SMN1] gene). A panel of experts made up of neurologists, physiatrists and Spanish patients' association (FundAME), participated in the design of the clinical tool. Physicians will administer the tool at three time points (baseline, 12 months and 24 months). Additionally, data from other questionnaires and scales will be collected. Once recruitment is achieved, an interim statistical analysis will be performed to assess its psychometric properties by applying Rasch analysis and classical statistical tests. RESULTS: The tool will consist of up to 53 items to assess functional status from a clinical perspective in seven key dimensions (bulbar, respiratory, axial, lower, upper, fatigability and other symptoms), which will be collected together with objective clinical measures (body mass index, forced vital capacity, pinch strength and 6-minute walk test). CONCLUSIONS: The validation of this tool will facilitate the clinical evaluation of adult and adolescent patients with SMA and the quantification of their response to new treatments in both clinical practice and research.

Life-Saving Treatments for Spinal Muscular Atrophy: Global Access and Availability.

Background and Objectives: Spinal muscular atrophy (SMA) is a neurodegenerative disorder manifesting with progressive muscle weakness and atrophy. SMA type 1 used to be fatal within the first 2 years of life, but is now treatable with therapies targeting splicing modification and gene replacement. Nusinersen, risdiplam, and onasemnogene abeparvovec-xioi improve survival, motor strength, endurance, and ability to thrive, allowing many patients to potentially attain a normal life; all have been recently approved by major regulatory agencies. Although these therapies have revolutionized the world of SMA, they are associated with a high economic burden, and access to these therapies is limited in some countries. The primary objective of this study was to compare the availability and implementation of treatment of SMA from different regions of the world. Methods: In this qualitative study, we surveyed health care providers from 21 countries regarding their experiences caring for patients with SMA. The main outcome measures were provider survey responses on newborn screening, drug availability/access, barriers to treatment, and related questions. Results: Twenty-four providers from 21 countries with decades of experience (mean 26 years) in treating patients with SMA responded to the survey. Nusinersen was the most available therapy for SMA. Our survey showed that while genetic testing is usually available, newborn screening is still unavailable in many countries. The provider-reported treatment cost also varied between countries, and economic burden was a major barrier in treating patients with SMA. Discussion: Overall, this survey highlights the global inequality in managing patients with SMA. The spread of newborn screening is essential in ensuring improved access to care for patients with SMA. With the advancement of neurotherapeutics, more genetic diseases will soon be treatable, and addressing the global inequality in clinical care will require novel approaches to mitigate such inequality in the future.

Validation of a Set of Instruments to Assess Patient- and Caregiver-Oriented Measurements in Spinal Muscular Atrophy: Results of the SMA-TOOL Study.

INTRODUCTION: Outcome measures traditionally used in spinal muscular atrophy (SMA) clinical trials are inadequate to assess the full range of disease severity. The aim of this study was to assess the psychometric properties of a set of existing questionnaires and new items, gathering information on the impact of SMA from the patient and caregiver perspectives. METHODS: This was a multicenter, prospective, noninterventional study including patients with a confirmed diagnosis of 5q-autosomal-recessive SMA aged 8 years and above, or their parents (if aged between 2 and 8 years). The set of outcome measurements included the SMA Independence Scale (SMAIS) patient and caregiver versions, the Neuro-QoL Fatigue Computer Adaptive Test (CAT), the Neuro-QoL Pain Short Form-Pediatric Pain, the PROMIS adult Pain Interference CAT, and new items developed by Fundación Atrofia Muscular España: perceived fatigability, breathing and voice, sleep and rest, and vulnerability. Reliability, construct validity, discriminant validity, and sensitivity to change (4 months from baseline) were measured. RESULTS: A total of 113 patients were included (59.3% 2-17 years old, 59.3% male, and 50.4% with SMA type II). Patients required moderate assistance [mean patient and caregiver SMAIS (SD) scores were 31.1 (12.8) and 7.6 (11.1), respectively]. Perceived fatigability was the most impacted domain, followed by vulnerability. Cronbach's alpha coefficient for perceived fatigability, breathing and voice, and vulnerability total scores were 0.92, 0.88, and 0.85, respectively. The exploratory factor analysis identified the main factors considered in the design, except in the sleep and rest domain. All questionnaires were able to discriminate between the Clinical Global Impression-Severity scores and SMA types. Sensitivity to change was only found for the SMAIS caregiver version and vulnerability items. CONCLUSIONS: This set of outcome measures showed adequate reliability, construct validity, and discriminant validity and may constitute a valuable option to measure symptom severity in patients with SMA.

Characterizing SOD1 mutations in Spain. The impact of genotype, age, and sex in the natural history of the disease.

INTRODUCTION: The aim of this study is to describe the frequency and distribution of SOD1 mutations in Spain, and to explore those factors contributing to their phenotype and prognosis. METHODS: Seventeen centres shared data on amyotrophic lateral sclerosis (ALS) patients carrying pathogenic or likely pathogenic SOD1 variants. Multivariable models were used to explore prognostic modifiers. RESULTS: In 144 patients (from 88 families), 29 mutations (26 missense, 2 deletion/insertion and 1 frameshift) were found in all 5 exons of SOD1, including 7 novel mutations. 2.6% of ALS patients (including 17.7% familial and 1.3% sporadic) were estimated to carry SOD1 mutations. Its frequency varied considerably between regions, due to founder events. The most frequent mutation was p.Gly38Arg (n = 58), followed by p.Glu22Gly (n = 11), p.Asn140His (n = 10), and the novel p.Leu120Val (n = 10). Most mutations were characterized by a protracted course, and some of them by atypical phenotypes. Older age of onset was independently associated with faster disease progression (exp(Estimate) = 1.03 [0.01, 0.05], p = 0.001) and poorer survival (HR = 1.05 [1.01, 1.08], p = 0.007), regardless of the underlying mutation. Female sex was independently associated to faster disease progression (exp(Estimate) = 2.1 [1.23, 3.65], p = 0.012) in patients carrying the p.Gly38Arg mutation, resulting in shorter survival compared with male carriers (236 vs 301 months). CONCLUSIONS: These data may help to evaluate the efficacy of SOD1 targeted treatments, and to expand the number of patients that might benefit from these treatments.

Validation of motor and functional scales for the evaluation of adult patients with 5q spinal muscular atrophy.

BACKGROUND AND PURPOSE: Mos scales currently used to evaluate spinal muscular atrophy (SMA) patients have only been validated in children. The aim of this study was to assess the construct validity and responsiveness of several outcome measures in adult SMA patients. METHODS: Patients older than 15 years and followed up in five referral centres for at least 6 months, between October 2015 and August 2020, with a motor function scale score (Hammersmith Functional Motor Scale Expanded [HFMSE], Revised Upper Limb module [RULM]) were included. Bedside functional scales (Egen Klassification [EK2], Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) were also collected when available. Spearman's rho correlations (rs) and Bangdiwala's concordance test (B) were used to evaluate the scales' construct validity. Monthly slopes of change were used to calculate their responsiveness of the scales. RESULTS: The study included 79 SMA patients, followed up for a mean of 16 months. All scales showed strong correlations with each other (rs > 0.70). A floor effect in motor function scales was found in the weakest patients (HFMSE < 5 and RULM < 10), and a ceiling effect was found in stronger patients (HFMSE > 60 and RULM > 35). The ALSFRS-R (B = 0.72) showed a strong ability to discriminate between walkers, sitters and non-sitters, and the HFMSE (B = 0.86) between walkers and sitters. The responsiveness was low overall, although in treated patients a moderate responsiveness was found for the ALSFRS-R and HFMSE in walkers (0.69 and 0.61, respectively) and for EK2 in sitters (0.65) and non-sitters (0.60). CONCLUSIONS: This study shows the validity and limitations of the scales most frequently used to assess adult SMA patients. Overall, bedside functional scales showed some advantages over motor scales, although all showed limited responsiveness.

Nusinersen in adult patients with 5q spinal muscular atrophy: A multicenter observational cohorts' study.

BACKGROUND AND PURPOSE: The aim was to assess the safety and efficacy of nusinersen in adult 5q spinal muscular atrophy (SMA) patients. METHODS: Patients older than 15 years and followed for at least 6 months with one motor scale (Hammersmith Functional Motor Scale Expanded, HFMSE; Revised Upper Limb Module, RULM) in five referral centers were included. The clinical and patients' global impression of change (CGI-C and PGI-C) were recorded in treated patients at the last visit. Functional scales (Egen Klassification, EK2; Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, ALSFRS-R) and the percentage predicted forced vital capacity were collected when available. RESULTS: Seventy-nine SMA patients (39 treated with nusinersen) were included. Compared with untreated patients, treated patients showed a significant improvement of 2 points (±0.46) in RULM (p < 0.001) after 6 months. After a mean follow-up of 16 months, nusinersen treatment was associated with a significant improvement in HFMSE (odds ratio [OR] 1.15, p = 0.006), the 6-min walk test (OR = 1.07, p < 0.001) and the EK2 (OR = 0.81, p = 0.001). Compared with untreated patients, more treated patients experienced clinically meaningful improvements in all scales, but these differences were statistically significant only for RULM (p = 0.033), ALSFRS-R (p = 0.005) and EK2 (p < 0.001). According to the CGI-C and PGI-C, 64.1% and 61.5% of treated patients improved with treatment. Being a non-sitter was associated with less response to treatment, whilst a longer time of treatment was associated with better response. Most treated patients (77%) presented at least one adverse event, mostly mild. CONCLUSIONS: Nusinersen treatment is associated with some improvements in adult SMA patients. Most severely affected patients with complex spines are probably those with the most unfavorable risk-benefit ratio.

A novel TRMT5 mutation causes a complex inherited neuropathy syndrome: The role of nerve pathology in defining a demyelinating neuropathy.

AIMS: We aim to present data obtained from three patients belonging to three unrelated families with an infantile onset demyelinating neuropathy associated to somatic and neurodevelopmental delay and to describe the underlying genetic changes. METHODS: We performed whole-exome sequencing on genomic DNA from the patients and their parents and reviewed the clinical, muscle and nerve data, the serial neurophysiological studies, brain and muscle MRIs, as well as the respiratory chain complex activity in the muscle of the three index patients. Computer modelling was used to characterise the new missense variant detected. RESULTS: All three patients had a short stature, delayed motor milestone acquisition, intellectual disability and cerebellar abnormalities associated with a severe demyelinating neuropathy, with distinct morphological features. Despite the proliferation of giant mitochondria, the mitochondrial respiratory chain complex activity in skeletal muscle was normal, except in one patient in whom there was a mild decrease in complex I enzyme activity. All three patients carried the same two compound heterozygous variants of the TRMT5 (tRNA Methyltransferase 5) gene, one known pathogenic frameshift mutation [c.312_315del (p.Ile105Serfs*4)] and a second rare missense change [c.665 T > C (p.Ile222Thr)]. TRMT5 is a nuclear-encoded protein involved in the post-transcriptional maturation of mitochondrial tRNA. Computer modelling of the human TRMT5 protein structure suggests that the rare p.Ile222Thr mutation could affect the stability of tRNA binding. CONCLUSIONS: Our study expands the phenotype of mitochondrial disorders caused by TRTM5 mutations and defines a new form of recessive demyelinating peripheral neuropathy.

Role of the nigrosome 1 absence as a biomarker in amyotrophic lateral sclerosis.

INTRODUCTION: The absence of nigrosome 1 on brain MRI and the hyperechogenicity of substantia nigra (SNh) by transcranial sonography are two useful biomarkers in the diagnosis of parkinsonisms. We aimed to evaluate the absence of nigrosome 1 in amyotrophic lateral sclerosis (ALS) and to address its meaning. METHODS: 136 ALS patients were recruited, including 16 progressive muscular atrophy (PMA) and 22 primary lateral sclerosis (PLS) patients. The SNh area was measured planimetrically by standard protocols. The nigrosome 1 status was qualitatively assessed by two blind evaluators in susceptibility weight images of 3T MRI. Demographic and clinical data were collected and the C9ORF72 expansion was tested in all patients. RESULTS: Nigrosome 1 was absent in 30% of ALS patients (36% of PLS, 29% of classical ALS and 19% of PMA patients). There was no relationship between radiological and clinical laterality, nor between nigrosome 1 and SNh area. Male sex (OR = 3.63 [1.51, 9.38], p = 0.005) and a higher upper motor neuron (UMN) score (OR = 1.10 [1.02, 1.2], p = 0.022) were independently associated to nigrosome 1 absence, which also was an independent marker of poor survival (HR = 1.79 [1.3, 2.8], p = 0.013). CONCLUSION: In ALS patients, the absence of nigrosome 1 is associated with male sex, UMN impairment and shorter survival. This suggests that constitutional factors and the degree of pyramidal involvement are related to the substantia nigra involvement in ALS. Thus, nigrosome 1 could be a marker of a multisystem degeneration, which in turn associates to poor prognosis.

Clinical and genetic characteristics of 21 Spanish patients with biallelic pathogenic SPG7 mutations.

Spastic paraplegia type 7 (SPG7) is one of the most common hereditary spastic paraplegias. SPG7 mutations most often lead to spastic paraparesis (HSP) and/or hereditary cerebellar ataxia (HCA), frequently with mixed phenotypes. We sought to clinically and genetically characterize a Spanish cohort of SPG7 patients. Patients were recruited from our HCA and HSP cohorts. We identified twenty-one patients with biallelic pathogenic SPG7 mutations. Mean age at onset was 37.4 years (SD ± 14.3). The most frequent phenotype was spastic ataxia (57%), followed by pure spastic paraplegia (19%) and complex phenotypes (19%). Isolated patients presented with focal or multifocal dystonia, subclinical myopathy or ophthalmoplegia. p.Ala510Val was the most frequent pathogenic variant encountered. Compound heterozygous for p.Ala510Val displayed younger onset (p < 0.05) and more complex phenotypes (p < 0.05) than p.Ala510Val homozygotes. Two novel variants were found: p.Lys559Argfs*33 and p.Ala312Glu. In conclusion, spastic ataxia is the most common phenotype found in Spanish patients. Nonetheless, SPG7 analysis should also be considered in patients with less frequent clinical findings such as dystonia or ophthalmoplegia especially when these symptoms are associated with mild spastic ataxia.

Facial Onset Sensory and Motor Neuronopathy: New Cases, Cognitive Changes, and Pathophysiology.

PURPOSE OF REVIEW: To improve our clinical understanding of facial onset sensory and motor neuronopathy (FOSMN). RECENT FINDINGS: We identified 29 new cases and 71 literature cases, resulting in a cohort of 100 patients with FOSMN. During follow-up, cognitive and behavioral changes became apparent in 8 patients, suggesting that changes within the spectrum of frontotemporal dementia (FTD) are a part of the natural history of FOSMN. Another new finding was chorea, seen in 6 cases. Despite reports of autoantibodies, there is no consistent evidence to suggest an autoimmune pathogenesis. Four of 6 autopsies had TAR DNA-binding protein (TDP) 43 pathology. Seven cases had genetic mutations associated with neurodegenerative diseases. SUMMARY: FOSMN is a rare disease with a highly characteristic onset and pattern of disease progression involving initial sensory disturbances, followed by bulbar weakness with a cranial to caudal spread of pathology. Although not conclusive, the balance of evidence suggests that FOSMN is most likely to be a TDP-43 proteinopathy within the amyotrophic lateral sclerosis-FTD spectrum.

Estimation of the prevalence and incidence of motor neuron diseases in two Spanish regions: Catalonia and Valencia.

According to the degree of upper and lower motor neuron degeneration, motor neuron diseases (MND) can be categorized into amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS) or progressive muscular atrophy (PMA). Although several studies have addressed the prevalence and incidence of ALS, there is a high heterogeneity in their results. Besides this, neither concept has been previously studied in PLS or PMA. Thus, the objective of this study was to estimate the prevalence and incidence of MND, (distinguishing ALS, PLS and PMA), in the Spanish regions of Catalonia and Valencia in the period 2011-2019. Two population-based Spanish cohorts were used, one from Catalonia and the other from Valencia. Given that the samples that comprised both cohorts were not random, i.e., leading to a selection bias, we used a two-part model in which both the individual and contextual observed and unobserved confounding variables are controlled for, along with the spatial and temporal dependence. The prevalence of MND was estimated to be between 3.990 and 6.334 per 100,000 inhabitants (ALS between 3.248 and 5.120; PMA between 0.065 and 0.634; and PLS between 0.046 and 1.896), and the incidence between 1.682 and 2.165 per 100,000 person-years for MND (ALS between 1.351 and 1.754; PMA between 0.225 and 0.628; and PLS between 0.409-0.544). Results were similar in the two regions and did not differ from those previously reported for ALS, suggesting that the proposed method is robust and that neither region presents differential risk or protective factors.

Improving Care and Empowering Adults Living with SMA: A Call to Action in the New Treatment Era.

While Spinal Muscular Atrophy (SMA) has historically been managed with supportive measures, the emergence of innovative medicines has given those living with SMA hope for improved quality of life and has revolutionized care. Despite these advances, the use of therapies and changes in disease management strategies have focused on pediatric populations, leaving adults living with SMA, and those transitioning into adulthood, relatively neglected. Through a multi-faceted approach that gathered unbiased perspectives from clinical experts, validated insights from individuals with lived experiences, and substantiated findings with evidence from the literature, we have exposed unmet needs that are hindering the field and, ultimately, impacting care and quality of life for adults living with SMA. Here, we set new aspirations and calls to action to inspire continued research in this field, stimulate dialogue across the SMA community and inform policies that deliver effective management and care throughout an adult's journey living with SMA.

Design of a Non-Interventional Study to Validate a Set of Patient- and Caregiver-Oriented Measurements to Assess Health Outcomes in Spinal Muscular Atrophy (SMA-TOOL Study).

INTRODUCTION: There is a need to optimize the current clinical outcome measures in spinal muscular atrophy (SMA) incorporating patients' and caregivers' perspectives. The aim of this study is to evaluate the psychometric properties (validity, reliability and sensitivity to change) of a set of existing questionnaires and newly created items grouped in a "toolbox" to assess the impact of SMA on the physical, psychological and activities of daily living domains of the patient's life. METHODS: This non-interventional, prospective study will be conducted at 12 neuromuscular clinics specialized in the management of patients with SMA in Spain. An expert panel of pediatric and adult neurologists, rehabilitation physicians, and a patient representative participated in the study design and selected key disease dimensions to explore and their respective measurements: mobility-independence, fatigue and endurance, pain, fatigability, breathing and voice, sleep and rest, and vulnerability. Patients aged 2 years or older with a confirmed diagnosis of 5q-autosomal recessive SMA (genetic confirmation of homozygous deletion or heterozygosity predictive of loss of function of the SMN1 gene) will be recruited. PLANNED OUTCOMES: The development of robust outcome measures in collaboration with the patient community is essential to determine what is meaningful to patients and their caregivers. This study will provide us with a comprehensive set of tools to better capture the course of the disease and the response to treatments.

A study of the phenotypic variability and disease progression in Laing myopathy through the evaluation of muscle imaging.

BACKGROUND: Laing myopathy is characterized by broad clinical and pathological variability. They are limited in number and protocol of study. We aimed to delineate muscle imaging profiles and validate imaging analysis as an outcome measure. METHODS: This was a cross-sectional and longitudinal cohort study. Data from clinical, functional and semi-quantitative muscle imaging (60 magnetic resonance imaging [MRI] and six computed tomography scans) were studied. Hierarchical analysis, graphic heatmap representation and correlation between imaging and clinical data using Bayesian statistics were carried out. RESULTS: The study cohort comprised 42 patients from 13 families harbouring five MYH7 mutations. The cohort had a wide range of ages, age at onset, disease duration, and myopathy extension and Gardner-Medwin and Walton (GMW) functional scores. Intramuscular fat was evident in all but two asymptomatic/pauci-symptomatic patients. Anterior leg compartment muscles were the only affected muscles in 12% of the patients. Widespread extension to the thigh, hip, paravertebral and calf muscles and, less frequently, the scapulohumeral muscles was commonly observed, depicting distinct patterns and rates of progression. Foot muscles were involved in 40% of patients, evolving in parallel to other regions with absence of a disto-proximal gradient. Whole cumulative imaging score, ranging from 0 to 2.9 out of 4, was associated with disease duration and with myopathy extension and GMW scales. Follow-up MRI studies in 24 patients showed significant score progression at a variable rate. CONCLUSIONS: We confirmed that the anterior leg compartment is systematically affected in Laing myopathy and may represent the only manifestation of this disorder. However, widespread muscle involvement in preferential but variable and not distance-dependent patterns was frequently observed. Imaging score analysis is useful to categorize patients and to follow disease progression over time.

Moral reasoning and moral conflict in patients of the amyotrophic lateral sclerosis - Frontotemporal dementia spectrum.

The aim of this study was to investigate the moral reasoning and moral conflict in patients of the amyotrophic lateral sclerosis - frontotemporal dementia (ALSFTD) spectrum. Ten ALS patients without cognitive impairment, 10 ALS patients with cognitive or behavioral impairment, 10 ALSFTD patients and 23 controls were examined with neuropsychological and behavioral tests as well as with a set of eight well -designed moral dilemmas. The responses to the moral dilemmas were used as proxies to evaluate interpersonal moral reasoning. Reactivity to change, reaction time and arousal were used as markers of moral conflict. ALSFTD patients showed more "utilitarian" responses and less moral conflict than control participants. ALS patients without dementia showed a trend toward slower reaction time, which could be largely attributed to physical disability. No significant changes in arousal were found in ALS patients compared with control participants. Behavioral changes (apathy and dysexecutive symptoms) were partly responsible for the changes found in patients of the ALSFTD spectrum. Our results suggest that most ALS patients without dementia, but not those with concomitant dementia, would be able to deal with the conflict of complex moral decisions, such as end-of-life decisions, at least in mild to moderate stages of the disease.