Examining short interval intracortical inhibition with different transcranial magnetic stimulation-induced current directions in ALS.

Objective: To establish if induced current direction across the motor cortex alters the sensitivity of transcranial magnetic stimulation (TMS)-evoked short-interval intracortical inhibition (SICI) as an ALS biomarker. Methods: Threshold tracking-TMS was undertaken in 35 people with ALS and 39 controls. Using a coil orientation which induces posterior-anterior (PA)-directed current across the motor cortex, SICI (1 ms and 3 ms interstimulus intervals) and intracortical facilitation (ICF, 10 ms interstimulus interval) were recorded. SICI3ms was also recorded using a coil orientation which induces anterior-posterior (AP)-directed current across the motor cortex. Results: At group level, SICI3ms-PA (AUROC = 0.7), SICI3ms-AP (AUROC = 0.8) and SICI1ms (AUROC = 0.66) were substantially lower in those with ALS, although there was considerable interindividual heterogeneity. Averaging across interstimulus intervals (ISIs) marginally improved SICIPA sensitivity (AUROC = 0.76). Averaging SICI values across ISIs and orientations into a single SICI measure did not substantially improve sensitivity (AUROC = 0.81) compared to SICI3ms-AP alone. SICI3ms-AP and SICI3ms-PA did not significantly correlate (rho = 0.19, p = 0.313), while SICI1ms-PA and SICI3ms-PA did (rho = 0.37, p = 0.006). Further, those with ALS with the lowest SICI3ms-PA were not those with the lowest SICI3ms-AP. ICF was similar between groups (AUROC = 0.50). Conclusions: SICIPA and SICIAP are uncorrelated measures of motor cortical inhibitory functions which are useful as distinct, unequally affected, measures of disinhibition in ALS. Significance: Examining both SICIPA and SICIAP may facilitate more comprehensive characterisation of motor cortical disinhibition in ALS.

Incidence of amyotrophic lateral sclerosis in Chile.

OBJECTIVE: This study aimed to estimate amyotrophic lateral sclerosis (ALS) incidence and survival rates in the Metropolitan region of Chile. METHODS: We conducted a cohort study of ALS cases in the Metropolitan Region from 2016 to 2019. A total of 219 ALS patients were recruited from Corporación ELA-Chile registry, in collaboration with neurologists from Sociedad de Neurología, Psiquiatría y Neurocirugía de Chile. We calculated incidence rates by sex and age and determined median survival from onset and diagnosis. Survival analysis used the Kaplan-Meier statistic, estimating hazard ratios for age, sex, time from symptom onset and from diagnosis using a Weibull regression model. All analyses were done using R 4.1.0. RESULTS: Overall, ALS diagnosis incidence was 0.97 cases per 100,000 inhabitants, peaking in the 70-79 age group and declining thereafter. The male-to-female ratio was 1.23. The median time to death from diagnosis was 2.3 years (95% confidence interval [CI]: 1.9-2.5), and from the first symptom, it was 3.1 years (95% CI: 2.8-3.5). CONCLUSIONS: This is the first population-based study reporting ALS incidence and survival rates in Chile's Metropolitan region. Incidence resembled other Latin American studies. Median survival from diagnosis and from the first symptom were in line with previous findings. Our results corroborated lower ALS rates in Latin America, consistent with prior research.

Electroencephalographic ß-band oscillations in the sensorimotor network reflect motor symptom severity in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Resting-state electroencephalography (EEG) holds promise for assessing brain networks in amyotrophic lateral sclerosis (ALS). We investigated whether neural ß-band oscillations in the sensorimotor network could serve as an objective quantitative measure of progressive motor impairment and functional disability in ALS patients. METHODS: Resting-state EEG was recorded in 18 people with ALS and 38 age- and gender-matched healthy controls. We estimated source-localized ß-band spectral power in the sensorimotor cortex. Clinical evaluation included lower (LMN) and upper motor neuron scores, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score, fine motor function (FMF) subscore, and progression rate. Correlations between clinical scores and ß-band power were analysed and corrected using a false discovery rate of q = 0.05. RESULTS: ß-Band power was significantly lower in people with ALS than controls (p = 0.004), and correlated with LMN score (R = -0.65, p = 0.013), FMF subscore (R = -0.53, p = 0.036), and FMF progression rate (R = 0.52, p = 0.036). CONCLUSIONS: ß-Band spectral power in the sensorimotor cortex reflects clinically evaluated motor impairment in ALS. This technology merits further investigation as a biomarker of progressive functional disability.

LAENALS: epidemiological and clinical features of amyotrophic lateral sclerosis in Latin America.

OBJECTIVE: The Latin American Epidemiologic study of ALS (LAENALS) aims to gather data on ALS epidemiology, phenotype, and risk factors in Cuba, Chile, and Uruguay, to understand the impact of genetic and environmental factors on ALS. METHODS: A harmonized data collection protocol was generated, and a Latin-American Spanish language Register was constructed. Patient data were collected in Uruguay in 2018, in Chile from 2017 to 2019, and in Cuba between 2017 and 2018. Statistical analysis was performed using SPSS 25.0.0 software. Crude cumulative incidence, standardized incidence, and prevalence were calculated in the population aged 15 years and older. RESULTS: During 2017-2019, 90 people with ALS from Uruguay (55.6% men), 219 from Chile (54.6% men), and 49 from Cuba (55.1% men) were included. The cumulative crude incidence in 2018 was 1.73/100,000 persons in Uruguay, 1.08 in Chile and 0.195 in Cuba. Crude prevalence in 2018 was 2.19 per 100,000 persons in Uruguay, 1.39 in Chile and 0.55 in Cuba. Mean age at onset was 61.8 ± 11.96 SD years in Uruguay, 61.9 ± 10.4 SD years in Chile, and 60.21 ± 12.45 SD years in Cuba (p = 0.75). Median survival from onset was 32.43 months (21.93 - 42.36) in Uruguay, 24 months (13.5 - 33.5) in Chile, and 29 months (15 - 42.5) in Cuba (p = 0.006). CONCLUSIONS: These preliminary data from LAENALS confirm the lower incidence and prevalence of ALS in counties with admixed populations. The LAENALS database is now open to other Latin American countries for harmonized prospective data collection.

Functional network dynamics revealed by EEG microstates reflect cognitive decline in amyotrophic lateral sclerosis.

Recent electroencephalography (EEG) studies have shown that patterns of brain activity can be used to differentiate amyotrophic lateral sclerosis (ALS) and control groups. These differences can be interrogated by examining EEG microstates, which are distinct, reoccurring topographies of the scalp's electrical potentials. Quantifying the temporal properties of the four canonical microstates can elucidate how the dynamics of functional brain networks are altered in neurological conditions. Here we have analysed the properties of microstates to detect and quantify signal-based abnormality in ALS. High-density resting-state EEG data from 129 people with ALS and 78 HC were recorded longitudinally over a 24-month period. EEG topographies were extracted at instances of peak global field power to identify four microstate classes (labelled A-D) using K-means clustering. Each EEG topography was retrospectively associated with a microstate class based on global map dissimilarity. Changes in microstate properties over the course of the disease were assessed in people with ALS and compared with changes in clinical scores. The topographies of microstate classes remained consistent across participants and conditions. Differences were observed in coverage, occurrence, duration, and transition probabilities between ALS and control groups. The duration of microstate class B and coverage of microstate class C correlated with lower limb functional decline. The transition probabilities A to D, C to B and C to B also correlated with cognitive decline (total ECAS) in those with cognitive and behavioural impairments. Microstate characteristics also significantly changed over the course of the disease. Examining the temporal dependencies in the sequences of microstates revealed that the symmetry and stationarity of transition matrices were increased in people with late-stage ALS. These alterations in the properties of EEG microstates in ALS may reflect abnormalities within the sensory network and higher-order networks. Microstate properties could also prospectively predict symptom progression in those with cognitive impairments.

C9orf72 Repeat Expansion Discordance in 6 Multigenerational Kindreds.

Background and Objectives: A hexanucleotide repeat expansion in the noncoding region of the C9orf72 gene is the most common genetically identifiable cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in populations of European ancestry. Pedigrees associated with this expansion exhibit phenotypic heterogeneity and incomplete disease penetrance, the basis of which is poorly understood. Relatives of those carrying the C9orf72 repeat expansion exhibit a characteristic cognitive endophenotype independent of carrier status. To examine whether additional shared genetic or environmental risks within kindreds could compel this observation, we have conducted a detailed cross-sectional study of the inheritance within multigenerational Irish kindreds carrying the C9orf72 repeat expansion. Methods: One hundred thirty-one familial ALS pedigrees, 59 of which carried the C9orf72 repeat expansion (45.0% [95% CI 36.7-53.5]), were identified through the Irish population-based ALS register. C9orf72 genotyping was performed using repeat-primed PCR with amplicon fragment length analysis. Pedigrees were further investigated using SNP, targeted sequencing data, whole-exome sequencing, and whole-genome sequencing. Results: We identified 21 kindreds where at least 1 family member with ALS carried the C9orf72 repeat expansion and from whom DNA was available from multiple affected family members. Of these, 6 kindreds (28.6% [95% CI 11.8-48.3]) exhibited discordant segregation. The C9orf72 haplotype was studied in 2 families and was found to segregate with the C9orf72-positive affected relative but not the C9orf72-negative affected relative. No other ALS pathogenic variants were identified within these discordant kindreds. Discussion: Family members of kindreds associated with the C9orf72 repeat expansion may carry an increased risk of developing ALS independent of their observed carrier status. This has implications for assessment and counseling of asymptomatic individuals regarding their genetic risk.

IMPACT-ALS: summary of results from a European survey of people living with ALS.

OBJECTIVE: The IMPACT-ALS survey collected the experiences of people living with ALS (plwALS) across nine European countries. We aimed to better understand the functional burden of ALS to ensure the experiences of plwALS inform the development of person-centered therapies. METHODS: The content was informed by the US IMPACT-ALS survey, with adjustments relevant to the European population. Questionnaires consisted of four modules, each of which was pilot tested in advance of distribution. Data were captured using the Qualtrics software and were analyzed in SPSS. RESULTS: 857 respondents completed the survey, with a participation rate ranging from 0.2% to 6.3% across the nine participating countries. The majority were male and aged 55-74 years old. In the previous 2 weeks, symptoms experienced included weakness (81%), fatigue (61%), speech impairment (38%), pain (27%), and depression and other mood changes (23%). Eighty-two percent of respondents reported fears, of which the most common were leaving family too soon (68%) and death from respiratory failure (50%). Lifestyle changes since diagnosis were reported by 89% of respondents, with less time spent doing most daily activities but more time on the internet (81%), reading (56%) and communicating with family and friends (55%). Stopping progression of ALS was the most desired impact for a new therapy for 68% respondents. CONCLUSIONS: The European IMPACT-ALS survey has generated insights into the complex experiences of plwALS. The data provide unique patient perspectives on common symptoms, fears, functional limitations, lifestyle changes, and wishes for future therapies that will enhance patient-centric care in ALS.

Epidemiologic Trends of Amyotrophic Lateral Sclerosis in Ireland, 1996-2021.

BACKGROUND AND OBJECTIVES: The objective of this study was to examine changes to the incidence, prevalence, age at onset, and survival of patients diagnosed with amyotrophic lateral sclerosis (ALS) in the Republic of Ireland over 25 years. METHODS: Incident and prevalent cases of ALS were estimated using the Irish population-based ALS Register, which has been in continuous operation since 1994. Incident cases were age standardized using the direct method and applied to 3 standard populations (Irish, European, and American). Survival was determined using Kaplan-Meier curves and Cox regression models. Non-normally distributed groups were compared using the Kruskal-Wallis test with a Bonferroni correction. RESULTS: A total of 2,771 patients with ALS were identified in the Republic of Ireland over 25 years. Incidence per 100,000 was determined for the population older than 15 years. Crude incidence increased from 2.64 to 5.46 per 100,000. Standardized incidence increased from 2.64 to 3.1 per 100,000. Prevalence increased from 5.83 to 8.10 per 100,000. The median age at onset increased from 64 to 67 years. The peak age of incidence increased from those between 70 and 74 years to those between 75 and 79 years. Overall, women had a consistently later median age at onset of 67 years compared with men at 65 years (p < 0.001). No significant difference in survival was noted between those captured across 3 different epochs (1996-2003, 2004-2012, 2013-2021). Older age at onset (hazard ratio [HR] 1.03, CI 1.02-1.04, p < 0.001) was a negative predictive factor of survival in multivariate Cox regression analysis. Riluzole use (HR 0.67, CI 0.50-0.90, p = 0.033) and diagnostic delay (HR 0.98, CI 0.98-0.99, p < 0.001) were positive predictive factors. DISCUSSION: Within the Republic of Ireland, the age-standardized overall incidence, peak incidence, prevalence, and age at onset of ALS have all increased over 25 years. Despite the widespread use of noninvasive ventilation, aggressive secretion management, and changes in ALS care, the mean survival within the Irish population has not changed.

Cognitive and neuropsychiatric endophenotypes in amyotrophic lateral sclerosis.

First- and second-degree relatives of people with amyotrophic lateral sclerosis report higher rates of neuropsychiatric disorders, indicating that risk genes may be pleiotropic, causing multiple phenotypes within kindreds. Such phenotypes may constitute a disease endophenotype that associates with disease liability. We have directly investigated cognitive functioning and neuropsychiatric traits among relatives of people with amyotrophic lateral sclerosis to identify potential endophenotypes of the disease. In a family-based, cross-sectional study design, first- and second-degree relatives of people with amyotrophic lateral sclerosis (n = 149) were compared to controls (n = 60) using an in-depth neuropsychological and neuropsychiatric assessment. Subgroup analyses examined the effect of family history and C9orf72 repeat expansion status (n = 16 positive carriers). Relatives of people with amyotrophic lateral sclerosis had lower scores on executive functioning, language and memory tasks compared to controls, with large effect sizes observed on object naming (d = 0.91, P = 0.00001) and phonemic verbal fluency (d = 0.81, P = 0.0003). Relatives also had higher autism quotient attention to detail traits (d = -0.52, P = 0.005), lower conscientiousness (d = 0.57, P = 0.003) and lower openness to experience personality traits (d = 0.54, P = 0.01) than controls. These effects were typically larger in relatives of people with familial, rather than sporadic, amyotrophic lateral sclerosis and were present in both gene carrier and non-carrier relatives of probands with a C9orf72 repeat expansion. Poorer phonemic fluency and object naming, along with autism and personality traits, are more frequent in relatives of people with amyotrophic lateral sclerosis. Among kindreds carrying the C9orf72 repeat expansion, these traits were identified in relatives regardless of their carrier status, suggesting the presence of a disease-associated endophenotype that is not exclusively mediated by the C9orf72 expansion.

Cortico-muscular coherence in primary lateral sclerosis reveals abnormal cortical engagement during motor function beyond primary motor areas.

Primary lateral sclerosis (PLS) is a slowly progressing disorder, which is characterized primarily by the degeneration of upper motor neurons (UMNs) in the primary motor area (M1). It is not yet clear how the function of sensorimotor networks beyond M1 are affected by PLS. The aim of this study was to use cortico-muscular coherence (CMC) to characterize the oscillatory drives between cortical regions and muscles during a motor task in PLS and to examine the relationship between CMC and the level of clinical impairment. We recorded EEG and EMG from hand muscles in 16 participants with PLS and 18 controls during a pincer-grip task. In PLS, higher CMC was observed over contralateral-M1 (α- and γ-band) and ipsilateral-M1 (ß-band) compared with controls. Significant correlations between clinically assessed UMN scores and CMC measures showed that higher clinical impairment was associated with lower CMC over contralateral-M1/frontal areas, higher CMC over parietal area, and both higher and lower CMC (in different bands) over ipsilateral-M1. The results suggest an atypical engagement of both contralateral and ipsilateral M1 during motor activity in PLS, indicating the presence of pathogenic and/or adaptive/compensatory alterations in neural activity. The findings demonstrate the potential of CMC for identifying dysfunction within the sensorimotor networks in PLS.

PRECISION ALS-an integrated pan European patient data platform for ALS.

Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative condition. Despite significant advances in pre-clinical models that enhance understanding of disease pathobiology, translation of candidate drugs to effective human therapies has been disappointing. There is increasing recognition of the need for a precision medicine approach toward drug development, as many failures in translation can be attributed in part to disease heterogeneity in humans. PRECISION-ALS is an academic industry collaboration between clinicians, Computer Scientists, Information engineers, technologists, data scientists and industry partners that will address the key clinical, computational, data science and technology associated research questions to generate a sustainable precision medicine based approach toward new drug development. Using extant and prospectively collected population based clinical data across nine European sites, PRECISION-ALS provides a General Data Protection Regulation (GDPR) compliant framework that seamlessly collects, processes and analyses research-quality multimodal and multi-sourced clinical, patient and caregiver journey, digitally acquired data through remote monitoring, imaging, neuro-electric-signaling, genomic and biomarker datasets using machine learning and artificial intelligence. PRECISION-ALS represents a first-in-kind modular transferable pan-European ICT framework for ALS that can be easily adapted to other regions that face similar precision medicine related challenges in multimodal data collection and analysis.

Care, burden and self-described positive aspects of caring in amyotrophic lateral sclerosis: an exploratory, longitudinal, mixed-methods study.

OBJECTIVES: To explore factors associated with care burden and the self-described positive aspects of caring for a person living with amyotrophic lateral sclerosis (ALS) over time. DESIGN: Exploratory longitudinal mixed-methods study. SETTING: A national multidisciplinary tertiary clinic in Dublin, Ireland. PARTICIPANTS: Participants were informal caregivers of people living with ALS (plwALS) attending the national ALS/motor neuron disease Clinic Dublin. This study focuses on informal caregivers who completed five consecutive interviews (n = 17) as part of a larger multisite study, over the course of 2.5 years. Participants were over the age of 18. Formal paid caregivers were not included. OUTCOME MEASURES: Data were collected on demographic and well-being measures and an open-ended question asked about positive aspects of caregiving. Relevant statistical analysis was carried out on quantitative data and qualitative data were analysed thematically. RESULTS: The caregivers in this study were predominantly female and spouse/partners of the plwALS. Hours of care provided and self-assessed burden increased substantially over time, psychological distress reached clinical significance and quality of life remained relatively stable. Positive aspects identified were thematised as meaning in life and personal satisfaction and varied in relative frequency across phases of the caregiving trajectory. CONCLUSIONS: The co-occurrence of negative and positive factors influences the experiences of informal caregivers in ALS. It is important to explore and acknowledge positive aspects, how they develop and are sustained in order to inform supportive services. The cyclical adaptation identified in this study provides evidence for time sensitive targeted supports.

Urine concentrations of selected trace metals in a cohort of Irish adults.

Human biomonitoring studies are of increasing importance in regulatory toxicology; however, there is a paucity of human biomonitoring data for the Irish population. In this study, we provide new data for urinary biomarker concentrations of aluminium, arsenic, cadmium, chromium, copper, mercury, manganese, lead and selenium. One hundred urine samples, collected between 2011 and 2014 from healthy participants of the EuroMOTOR project, were randomly selected. Metal concentrations were measured via ICPMS. Descriptive statistics for each of the metals stratified by gender were performed. There were 58 male and 42 female participants and metals were detectable for all samples. Geometric mean urinary concentrations for each metal in males were as follows: aluminium 8.5 µg/L, arsenic 8.1 µg/L, cadmium 0.3 µg/L, chromium 0.5 µg/L, copper 5.1 µg/L, mercury 0.4 µg/L, manganese 0.3 µg/L, lead 1.3 µg/L and selenium 10.8 µg/L; and in females: aluminium 8.5 µg/L, arsenic 10.2 µg/L, cadmium 0.4 µg/L, chromium 0.6 µg/L, copper 5.6 µg/L, mercury 0.3 µg/L, manganese 0.2 µg/L, lead 1.6 µg/L and selenium 13.7 µg/L. We observed higher geometric mean concentrations in women for arsenic, cadmium, chromium, copper, lead and selenium, with equal geometric mean concentrations for aluminium and manganese, leaving only mercury with lower geometric mean concentrations in women. Aluminium, cadmium, chromium, lead and urinary concentrations of metals were slightly elevated compared to European data, while for arsenic, copper, manganese and selenium, Irish levels were lower. Our findings highlight that there are differences in urinary metal concentrations between European populations.

Burden and benefit-A mixed methods study of informal Amyotrophic Lateral Sclerosis caregivers in Ireland and the Netherlands.

OBJECTIVES: Amyotrophic Lateral Sclerosis (ALS) is a systemic and terminal disorder of the central nervous system which causes paralysis of limbs, respiratory and bulbar muscles, impacting on physical, communication, cognitive and behavioural functioning. Informal caregivers play a key role in the care of people with ALS. This study aimed to explore experiences of burden along with any beneficial aspects of caregiving in ALS. An understanding of both burden and benefit is important to support the informal caregiver and the person with ALS. METHODS/DESIGN: This exploratory mixed methods study characterizes two groups of informal caregivers in Ireland (n = 76) and the Netherlands (n = 58). In a semi-structured interview, quantitative data were collected in the form of standardized measures assessing psychological distress, quality of life and burden. Qualitative data were collected from an open ended question, in which caregivers identified positive aspects in their caregiving experience. These data types were purposefully mixed in the analysis and interpretation stages, to provide a greater depth of evidence through diverse research lenses. RESULTS: The caregiver cohorts were predominantly female (69%) and spouse/partners (84%) of the person with ALS. Greater levels of self-assessed burden were found among the caregivers in the Netherlands (p < 0.05), and higher levels of quality of life among the cohort from Ireland (p < 0.05). Themes generated through qualitative analysis identified caregiver satisfaction, ability to meet the patient's needs and the (re) evaluation of meaning and existential aspects of life as positive aspects of caregiving. Existential factors were identified frequently by the caregivers in Ireland, and personal satisfaction and meeting their care recipient's needs by caregivers in the Netherlands. Three percent of all respondents reported there was nothing positive about caregiving. CONCLUSIONS: Based on our findings, we suggest that both burden and the presence of positive factors should be evaluated and monitored. The possibility of concurrent positive and challenging experiences should be considered in the design and delivery of supportive interventions for informal caregivers.

A Clinical Decision Support System for the Prediction of Quality of Life in ALS.

Amyotrophic Lateral Sclerosis (ALS), also known as Motor Neuron Disease (MND), is a rare and fatal neurodegenerative disease. As ALS is currently incurable, the aim of the treatment is mainly to alleviate symptoms and improve quality of life (QoL). We designed a prototype Clinical Decision Support System (CDSS) to alert clinicians when a person with ALS is experiencing low QoL in order to inform and personalise the support they receive. Explainability is important for the success of a CDSS and its acceptance by healthcare professionals. The aim of this work isto announce our prototype (C-ALS), supported by a first short evaluation of its explainability. Given the lack of similar studies and systems, this work is a valid proof-of-concept that will lead to future work. We developed a CDSS that was evaluated by members of the team of healthcare professionals that provide care to people with ALS in the ALS/MND Multidisciplinary Clinic in Dublin, Ireland. We conducted a user study where participants were asked to review the CDSS and complete a short survey with a focus on explainability. Healthcare professionals demonstrated some uncertainty in understanding the system's output. Based on their feedback, we altered the explanation provided in the updated version of our CDSS. C-ALS provides local explanations of its predictions in a post-hoc manner, using SHAP (SHapley Additive exPlanations). The CDSS predicts the risk of low QoL in the form of a probability, a bar plot shows the feature importance for the specific prediction, along with some verbal guidelines on how to interpret the results. Additionally, we provide the option of a global explanation of the system's function in the form of a bar plot showing the average importance of each feature. C-ALS is available online for academic use.

The Latin American Epidemiology Network for ALS (Laenals).

Background: There is evolving evidence of non-uniform distribution of ALS worldwide, with apparently lower incident and prevalent rates outside populations of European origin. However, the phenotype, survival and environmental risk in populations of mixed ancestral origin have not been well established. Large scale population based studies of incidence, prevalence, phenotype and risk factors in admixed populations are necessary to determine the true demography of ALS, and to test the hypothesis of differential risk and phenotype in populations of mixed ancestry. Methods: The Latin American Epidemiological Network of ALS (LAENALS) has been established to perform a comparative analysis of ALS epidemiology between three different Latin American populations (Cuba, Uruguay and Chile), and to test the hypothesis that the demographics, phenotype and outcome of ALS are influenced by ancestral origin, and that environmental and occupational risk factors differ across different ethnicities due to subtle differences in gene- environmental interactions. Recognition and interrogation of these differences is an important step toward novel therapeutic approaches and personalized medicine for all ALS both in the US, and worldwide. Discussion: This work will enable direct and detailed comparative studies between different ancestral populations with varying degrees of admixture, with facility for comparison with a large European reference dataset for ALS, and will provide a unique and rich dataset of admixed populations for later comparative genomic studies.

Resting-state EEG reveals four subphenotypes of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a devastating disease characterized primarily by motor system degeneration, with clinical evidence of cognitive and behavioural change in up to 50% of cases. Amyotrophic lateral sclerosis is both clinically and biologically heterogeneous. Subgrouping is currently undertaken using clinical parameters, such as site of symptom onset (bulbar or spinal), burden of disease (based on the modified El Escorial Research Criteria) and genomics in those with familial disease. However, with the exception of genomics, these subcategories do not take into account underlying disease pathobiology, and are not fully predictive of disease course or prognosis. Recently, we have shown that resting-state EEG can reliably and quantitatively capture abnormal patterns of motor and cognitive network disruption in amyotrophic lateral sclerosis. These network disruptions have been identified across multiple frequency bands, and using measures of neural activity (spectral power) and connectivity (comodulation of activity by amplitude envelope correlation and synchrony by imaginary coherence) on source-localized brain oscillations from high-density EEG. Using data-driven methods (similarity network fusion and spectral clustering), we have now undertaken a clustering analysis to identify disease subphenotypes and to determine whether different patterns of disruption are predictive of disease outcome. We show that amyotrophic lateral sclerosis patients (n = 95) can be subgrouped into four phenotypes with distinct neurophysiological profiles. These clusters are characterized by varying degrees of disruption in the somatomotor (α-band synchrony), frontotemporal (ß-band neural activity and γl-band synchrony) and frontoparietal (γl-band comodulation) networks, which reliably correlate with distinct clinical profiles and different disease trajectories. Using an in-depth stability analysis, we show that these clusters are statistically reproducible and robust, remain stable after reassessment using a follow-up EEG session, and continue to predict the clinical trajectory and disease outcome. Our data demonstrate that novel phenotyping using neuroelectric signal analysis can distinguish disease subtypes based exclusively on different patterns of network disturbances. These patterns may reflect underlying disease neurobiology. The identification of amyotrophic lateral sclerosis subtypes based on profiles of differential impairment in neuronal networks has clear potential in future stratification for clinical trials. Advanced network profiling in amyotrophic lateral sclerosis can also underpin new therapeutic strategies that are based on principles of neurobiology and designed to modulate network disruption.

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.

Patterns of Language Impairment in Early Amyotrophic Lateral Sclerosis.

OBJECTIVE: To investigate the incidence and nature of language change and its relationship to executive dysfunction in a population-based incident amyotrophic lateral sclerosis (ALS) sample, with the hypothesis that patterns of frontotemporal involvement in early ALS extend beyond areas of executive control to regions associated with language processing. METHODS: One hundred seventeen population-based incident ALS cases without dementia and 100 controls matched by age, sex, and education were included in the study. A detailed assessment of language processing including lexical processing, word spelling, word reading, word naming, semantic processing, and syntactic/grammatical processing was undertaken. Executive domains of phonemic verbal fluency, working memory, problem-solving, cognitive flexibility, and social cognition were also evaluated. RESULTS: Language processing was impaired in this incident cohort of individuals with ALS, with deficits in the domains of word naming, orthographic processing, and syntactic/grammatical processing. Conversely, phonological lexical processing and semantic processing were spared. Although executive dysfunction accounted in part for impairments in grammatical and orthographic lexical processing, word spelling, reading, and naming, primary language deficits were also present. CONCLUSIONS: Language impairment is characteristic of ALS at early stages of the disease and can develop independently of executive dysfunction, reflecting selective patterns of frontotemporal involvement at disease onset. Language change is therefore an important component of the frontotemporal syndrome associated with ALS.