Theme 01 - EPIDEMIOLOGY AND INFORMATICS

Background: Amyotrophic lateral sclerosis (ALS) is an incurable and rapidly neurodegenerative disease that affects 1/350 individuals. The cause of ALS is unknown but the majority of cases are thought to result from a complex gene-environment interaction. Two sample Mendelian randomisation (MR) enables causal inference between environmental exposures, such as serum metabolite concentrations, and disease risk. Objective: To use MR to perform an unbiased screen of 974 serum metabolite concentrations, to search for candidates which modify the risk of ALS. Methods: We obtained summary statistics from genomewide association study (GWAS) of serum concentrations of 974 metabolites which were population matched with a GWAS study of ALS. For each metabolite we performed two sample MR using a liberal instrument (p< 5e-06). Causal effect on ALS was evaluated by using an inverse variance weighted model. We removed tests with too few (<6) or too many (>15) instruments as this is likely to lead to false positive results due to instrument pleiotropy. Results: After filtering p-value statistics were not significantly inflated (kGC 1⁄41.1). After Bonferroni multiple testing correction three metabolites were significantly related to ALS risk: Estrone-3-sulfate (p1⁄4 6.58e-05, beta1⁄4 0.03, se 1⁄40.008) and bradykinin (p1⁄4 8.07e-05, beta1⁄4 0.05, se 1⁄40.01) were protective which is consistent with literature describing a male preponderance of ALS and the protective effect of medications known to increase serum bradykinin. Serum isoleucine was positively associated with ALS risk (p1⁄4 1.29e-04, beta 1⁄40.05, se 1⁄40.01). For each of these three metabolites MR results remained significant using robust measures and the association was confirmed in a distinct ALS GWAS, moreover there was no evidence of genetic pleiotropy or instrument heterogeneity. Isoleucine is metabolised via methylmalonylCoA mutase (MCM) in a reaction that consumes vitamin B12. Vitamin B12 insufficiency has been previously associated with ALS risk and our MR analysis revealed that serum vitamin B12 is protective against ALS (p1⁄4 0.005, beta1⁄4 0.17, se 1⁄40.06). Multivariate MR revealed that the toxic effect of isoleucine is dependent on vitamin B12 (p> 0.05 after correcting for serum vitamin B12). Leucine is a structural isomer of isoleucine but it is not metabolised via MCM; interestingly our MR analysis revealed no relationship between serum leucine and ALS risk. Discussion: It is notable that a clinical trial of administration of branch chain amino acids, including isoleucine, was previously terminated because of excessive deterioration in the treatment group; this would be consistent with our conclusion that isoleucine exacerbates neuronal damage in ALS via depletion of vitamin B12. We suggest screening ALS patients for high serum isoleucine levels and supplementation with vitamin B12.

Background: Amyotrophic lateral sclerosis (ALS) is an incurable and rapidly neurodegenerative disease that affects 1/350 individuals. The cause of ALS is unknown but the majority of cases are thought to result from a complex gene-environment interaction. Two sample Mendelian randomisation (MR) enables causal inference between environmental exposures, such as serum metabolite concentrations, and disease risk. Objective: To use MR to perform an unbiased screen of 974 serum metabolite concentrations, to search for candidates which modify the risk of ALS. Methods: We obtained summary statistics from genomewide association study (GWAS) of serum concentrations of 974 metabolites which were population matched with a GWAS study of ALS. For each metabolite we performed two sample MR using a liberal instrument (p < 5e-06). Causal effect on ALS was evaluated by using an inverse variance weighted model. We removed tests with too few (<6) or too many (>15) instruments as this is likely to lead to false positive results due to instrument pleiotropy. Results: After filtering p-value statistics were not significantly inflated (kGC ¼1.1). After Bonferroni multiple testing correction three metabolites were significantly related to ALS risk: Estrone-3-sulfate (p ¼ 6.58e-05, beta ¼ À0.03, se ¼0.008) and bradykinin (p ¼ 8.07e-05, beta ¼ À0.05, se ¼0.01) were protective which is consistent with literature describing a male preponderance of ALS and the protective effect of medications known to increase serum bradykinin. Serum isoleucine was positively associated with ALS risk (p ¼ 1.29e-04, beta ¼0.05, se ¼0.01). For each of these three metabolites MR results remained significant using robust measures and the association was confirmed in a distinct ALS GWAS, moreover there was no evidence of genetic pleiotropy or instrument heterogeneity. Isoleucine is metabolised via methylmalonyl-CoA mutase (MCM) in a reaction that consumes vitamin B12.
Vitamin B12 insufficiency has been previously associated with ALS risk and our MR analysis revealed that serum vitamin B12 is protective against ALS (p ¼ 0.005, beta ¼ À0.17, se ¼0.06). Multivariate MR revealed that the toxic effect of isoleucine is dependent on vitamin B12 (p > 0.05 after correcting for serum vitamin B12). Leucine is a structural isomer of isoleucine but it is not metabolised via MCM; interestingly our MR analysis revealed no relationship between serum leucine and ALS risk. Discussion: It is notable that a clinical trial of administration of branch chain amino acids, including isoleucine, was previously terminated because of excessive deterioration in the treatment group; this would be consistent with our conclusion that isoleucine exacerbates neuronal damage in ALS via depletion of vitamin B12. We suggest screening ALS patients for high serum isoleucine levels and supplementation with vitamin B12.
j.cooper-knock@sheffield.ac.uk EPI-02 Verification audit of amyotrophic lateral sclerosis (ALS) cases identified by community neurologists according to revised El Escorial Criteria (rEEC) in Center for Disease Control and Prevention-Agency for Toxic Substance Disease Registry (CDC-ATSDR) state and metropolitan area ALS surveillance projects [revised El Escorial criteria (rEEC)/Awaji Shima criteria (ASC)] have lower false-positive diagnostic rates [1.3-9.4%]. The proposed ICD-11 ALS/MND diagnostic designations comprise ALS/MND phenotypes with/without laboratory abnormalities of unknown significance and ALS -Plus phenotypes structured according to rEEC. The international ALS/MND community endorsed the need to field test among community neurologists the strength and weaknesses of these criteria across the broad spectrum of ALS/MND phenotypes including ALS -Plus syndromes and atypical ALS presentations with laboratory abnormalities of unknown significance as well as ALS Mimics.
Objective: Analyze application of the rEEC in the Center for Disease Control and Prevention Agency for Toxic Substance Disease Registry [CDC -ATSDR] state and metropolitan regional time-limited epidemiological studies by community neurologists with an audit of clinical records supporting the diagnostic designation of ALS attending to the proportion of clinically definite ALS that is a necessary designation for disease trajectory prediction algorithms. Methods: Because of the non-traditional methodology used by the National ALS Registry to identify persons with ALS, CDC -ATSDR initiated surveillance projects in three states and eight metropolitan areas with large minority populations requiring two reporting forms [ALS Case Reporting Form (CRF) and ALS Medical Records Verification Form (MRVF)] to obtain data elements for diagnosis and audit. Results: Data was obtained on the largest number of clinically reviewed ALS patients in the USA. During the 2009-2011 study epoch there were a total of 7062 case reports with 5883 unique ALS patients (3620states; 2263metropolitan areas) seen by 554 neurologists in a cohort of available 4842 neurologists. MRVF were obtained from 846 (87.5%) of 967 (13.7%) requested for audit. In these audited subjects, 80% received rEEC clinically definite, probable, or possible diagnostic designation and only 15 (1.8%) were determined to not be ALS. Survival trajectory post 2011 is ongoing and will be reported to establish the relationship between rEEC diagnostic designation by community neurologists and survival post diagnosis in the USA. Conclusions: CDC -ATSDR time-limited epidemiological studies involving 554 community neurologists employing rEEC documented by CRF and verified by MRVF completed a limited data set audit identifying a false-positive diagnosis rate of 1.8% within the 1.3-9.4% false-positive rate range identified in previous smaller time-limited epidemiological studies. This result indicates that appropriate application of the rEEC by community neurologists can provide data elements supporting the accurate diagnosis of ALS phenotypes. Further effort is required to ensure that these appropriate data elements are incorporated into the information in administrative datasets such as outpatient/hospital claims data and death certificates.

M. Dourado and R. Gurgel de Oliveira
Hospital Universit ario Onofre Lopes/Universidade Federal do Rio Grande do Norte, Natal, Brazil Background: In a previous study, a mathematical modeling approach, adapted from cancer research, demonstrated a linear relationship between the natural log incidence and log age, indicating that sporadic ALS was a multistep process (1)(2)(3). Objective: To establish whether ALS is a multistep process in northeastern Brazil Methods: We used collected data of 142 ALS patients in the period from 2005 to 2018 in Rio Grande do Norte, state in northeastern Brazil, to calculate yearly incidence of ALS. For each year we computed the incidence of ALS per 100,000 inhabitants for ages of disease's onset ranging from 30 to 79 years for male and female patients separately and for the whole group of patients. In each case, we fitted a linear model of the log of age-specific incidence against the log of age with least squares regression for ALS population.
Results: The linear model is a good fit for all cases analysed with adjusted r-squared statistics of 0.85, 0.90 and 0.93 for the female, male and total populations, respectively. The slopes of the curves with 95% confidence interval are 3.75 (1.29, 6.21) for the female, 3.20 (1.56, 4.84) for male and 3.34 (1.86, 4.82) for the total population. Discussion: The linear relationship between log age and log incidence is consistent with a multistage model of disease. The slopes estimated suggest that most likely five steps were required for the development of ALS in the female population and 4 steps in the male population in northeastern Brazil. These findings are consistent with those of other studies and, although the most probable number of steps is lower in this study than in others (1-3), the wide confidence intervals in our study prevent any stronger conclusions regarding a real distinction between the population in this analysis and those of other studies. Identification of the steps of this process would be an important advance for understanding the pathogenesis of ALS and could lead to novel therapeutic strategies.
medourado03@gmail.com EPI-04 The relation of exposure to ambient air toxics and ALS using the EPA National Air Toxics Assessment Database: a casecontrol study of ALS involving the National ALS Registry Background: ALS has a largely unknown etiology and few risk factors have been identified, with gene-environment interaction suspected. Past studies have utilized ambient air and air toxic databases to define environmental risks of neurodevelopmental/neurodegenerative disorders including autism, Alzheimer's disease, and Parkinson's disease although less is known about ALS. We examined associations between air toxics exposure and ALS, hypothesizing that ALS cases were more likely than controls to have lived in areas with higher ambient air concentrations of neurotoxicants.
Methods: This population-based, case-control study included 267 ALS cases identified through the Centers for Disease Control and Prevention (CDC)/Agency for Toxic Substances and Disease Registry (ATSDR) National ALS Registry and 267 birthyear, gender and county-matched controls. United States (US) Environmental Protection Agency (EPA) National Scale Air Toxics Assessment (NATA) modeled, census-tract level data on 34 ambient air neurotoxicants (concentration lg/m3) were assigned to the residential address of each study subject. The individual air neurotoxicants were grouped structurally by class of compound into metals, chlorinated solvents, aromatic solvents, pesticides, or other hazardous air pollutants (HAPs). Quartile scores of 1-4 were used to define the exposure levels of each compound based on the distribution among controls. Group scores were calculated as the sum of the individual compound scores within the group. The total score summed all 34 compound scores together. Wilcoxon signed-rank test was conducted to consider the differences in scores between matched cases and controls. Results: Average age (±SD) at ALS diagnosis of the cases was 61.4 ± 9.9 years. Male constituted 62.6% of cases and controls. A descriptive comparison of exposure scores for the individual compounds and groups between cases and controls was performed. Mean (±SD) exposure scores for matched cases and controls (N ¼ 267 pairs) by neurotoxicant compound group revealed for: Metals: 17.7 ± 5.8 and 17.5 ± 5.7 for cases and controls, respectively (p ¼ 0.50); Aromatic Solvents: 15.2 ± 5.7 and 15.0 ± 6.0 (p ¼ 0.65); Chlorinated Solvents: 27.9 ± 7.4 and 27.4 ± 7.6 (p ¼ 0.09), Pesticides: 15.2 ± 3.9 and 15.0 ± 3.9 (p ¼ 0.11); and the Total Score: 85.8 ± 22.5 and 84.7 ± 22.8 (p ¼ 0.17). Among the other HAPs, cyanide showed a significant case-control difference (2.6 ± 1.2 and 2.5 ± 1.1, respectively) (p ¼ 0.004). Summary: Preliminary analysis shows there is consistently higher exposure in cases compared to controls for all four groups of neurotoxicants, HAPs compounds, and overall exposure. These initial findings support our hypothesis; however, caution in the interpretation of these findings should be considered, as the differences between cases and controls are small and are not consistently statistically significant. Additionally, multivariate analyses with adjustment for other covariates such as smoking, education, military, and occupational history need to be conducted. More in-depth analyses and further studies are needed to examine the potential relation between ambient air toxicant exposure and ALS. Methods: A web application, updated with each patient's clinical visit, was developed following consultation with relevant disciplines involved in the management of patients attending the South Australian MND clinic based at Flinders Medical Centre, which is responsible for the care of about 90% of the patients with MND in the state. An initial consultative phase was undertaken with the clinicians involved in the multidisciplinary clinic including representatives from the Department of Neurology, Respiratory/Sleep medicine, Gastroenterology, Speech Pathology, and Dietetics, to identify the most useful clinical information to include on the application. The application was devised which separates the patient's data into three main categories, namely General, Respiratory and Swallowing. The information included in each category is as follows: General category: Patient's weight, Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R score), Forced Vital Capacity (FVC) predicted, King's staging, use of BiPAP, presence of a feeding tube; Respiratory category: FVC predicted, Sniff Nasal Inspiratory Pressure (SNIP), Maximum Inspiratory Pressure (MIP), Maximum Expiratory Pressure (MEP), BiPAP; Swallowing category: Weight, Eating Assessment Tool (EAT-10), Dysphagia Severity Scale rating, Iowa Oral Performance Instrument (IOPI). Each new data entry registered is pegged to a new date to assist in trend analysis. Conclusion: This web application is an online platform that facilitates the management of MND patients, particularly in critical timing for interventions such as NIV or gastrostomy insertion. As a centralized database system, it improves communication across a multidisciplinary clinic within the various disciplines involved. If found to be clinically useful, other clinics may wish to consider it as an option to better patient monitoring and management. Background: Amyotrophic lateral sclerosis (ALS) is a group of neurodegenerative diseases. ALS patients are often accompanied by clinical features of other neurological diseases, such as extrapyramidal symptoms, cerebellar symptoms, abnormal eye movements, sensory disorders, autonomic nervous dysfunction, and including (or not including) cognitive dysfunction, etc. This phenomenon is collectively known as ALS-Plus syndrome. We aimed to analyze the clinical and genetic characteristics of ALS-plus patients in southern China. Methods: The clinical data of 976 patients with ALS were retrospectively analyzed. According to the clinical data, the ALS patients were classified in detail by ALS-plus syndrome, and rare damage variants (RDVs) were analyzed in the ALS patients who completed the whole exome sequencing. Results: 1. No cognitive impairment was included in the non-motor symptoms study. Among the 976 ALS patients, 168 cases were ALS-Plus, of which 68 cases were classified sensory impairment group, 46 cases were classified extrapyramidal group, 27 cases were classified multi-system involvement group, 21 cases were classified ataxia group, 6 cases were classified eye movement disorder group. Seven hundred and thirteen ALS patients who completed genetic testing found that the occurrence of RDVs between the ALS-plus group and the non-ALS-plus group was statistically significant. ALS patients with RDVs are about twice as likely to be non-ALS-Plus than ALS-Plus. There was no significant difference in the survival time between the ALS-plus group and the non-ALS-plus group. 2. Cognitive impairment was included in non-motor symptoms. Cognitive function tests were completed in 498 ALS patients. There were 57.23% ALS system-affected patients who accompany non-motor symptoms including extrapyramidal symptoms, cerebellar symptoms, abnormal eye movements, sensory disorders, autonomic nervous dysfunction, and cognitive dysfunction and 42.77% pure ALS patients. There was a statistical difference in the years of education between the two groups. Three hundred and sixty-six ALS patients who completed genetic testing found that no significant difference in the occurrence of RDVs between the two groups. There was no statistical difference in survival time between the two groups. Conclusion: ALS-plus is not rare among ALS patients in southern China, and sensory disorders are the most common. The clinical symptoms of ALS-plus patients were severe, but there was no significant effect on survival or prognosis. There may be differences in genetic mechanism between patients with ALS-Plus and pure ALS.

lp2019@csu.edu.cn
Background: This is the first study to provide incidence and prevalence data for MND in South Australia and is an important initial step in outlining the impact this disease has upon the state. The Global Burden of Disease (GBD) project recently estimated the MND all-age global prevalence to be 4.5 (95% CI ¼4.1-5.0) per 100,000 persons and the all-age incidence 0.78 (95% CI ¼0.71-0.86) per 100,000 person-years (1). Whether the prevalence and incidence of MND within South Australia using registry data is in keeping with these global estimates has not previously been studied. Objective: To describe the prevalence and annual incidence rates of MND in South Australia between 2017 and 2019 using local registry data. Methods: A retrospective cohort study that calculated the point prevalence of MND (including primary lateral sclerosis) on 31 December of 2017, 2018 and 2019 utilising data from the Australasian Motor Neurone Disease Registry (AMNDR). The annual incidence rates between 2017 and 2019 were calculated using the estimated all-age population and the adult population !20 years reported in the 2016 census data for South Australia. Descriptive analysis of the patients was also performed to compare the South Australian cohort internationally. Through post code analysis we were also able to analyse regional prevalence differences within the state. Results: A total of 256 MND patients were identified during the study period, of whom 114 were alive on 31 December 2019. Based on the 2016 population of 1,676,653 persons, the estimated prevalence was 6.79 per 100,000 persons. There were 65, 48 and 55 incident cases of MND for 2017, 2018 and 2019, respectively. The crude incidence rate for the all-age South Australian population was 3.34 per 100,000 person-years (95% CI, 2.85-3.88). The estimated annual incidence rates based on the 2016 adult population !20 yo were 4.98 (3.84-6.35), 3.68 (2.71-4.88) and 4.21 (3.17-5.49) per 100,000 person-years respectively. These results indicate the prevalence and incidence of MND in South Australia are high in comparison to global estimates. Discussion: The prevalence and incidence of MND in South Australia were considerably higher than global estimates. This may reflect higher rates of the disease or higher rates of case ascertainment compared to the GBD project. Background: Motor Neuron Diseases (MND) have a large clinical spectrum, the most common is amyotrophic lateral sclerosis (ALS) that has a significant clinical heterogeneity, but our knowledge about its clinical features over a large period is poor. Objective: To describe a Portuguese large cohort of MND patients and study transitional patterns in clinical and demographic characteristics. Methods: Data from patients who visit our unit (categorized and followed by the same specialist) from 1994 to 2020 were analysed to determine phenotype features, including age, gender, presentation, baseline functional impairment and interventions. Patients were divided into three groups according to the time of the first visit to our unit, 1994-2003, 2004-2011 and 2012-2021. Results: Of the 1542 entries in our database, 1279 (83%) were classified as ALS (63.3% of which with spinal-onset and 28.7% with bulbar-onset), 202 (13%) as progressive muscular atrophy (PMA), 48 (2.5%) as primary lateral sclerosis (PLS) and 13 (<1%) as monomelic amyotrophy (MMA). Regarding ALS patients, the male-to-female relative risk was 1.37:1 for spinalonset and 0.65:1 for bulbar-onset. The mean onset age was 59.9 years for spinal-onset ALS, and 66.2 for bulbar-onset. Both these differences were statistically significant (p < 0.001). PMA patients had a mean age of onset of 64 years and the probability of having the disease was 2.9 times higher in males. In terms of trends in demographics, only for PMA a significant increase in age onset was found in female patients (p ¼ 0.001), however there were no differences in gender distribution. Methods: The QResearch database in England was interrogated from 1998 to 2019 for incident cases of MND in adults of Bangladeshi, Indian, Pakistani and all non-Indian subcontinent ethnicities. Crude and age adjusted rates were calculated for each of the three Indian subcontinent ethnicities separately and combined, and for adults of non-Indian subcontinent ethnicities. Incidence rate ratios were calculated, quantifying crude and age adjusted MND incidence rates in adults of Bangladeshi, Indian, Pakistani and all Indian subcontinent ethnicities relative to the non-Indian subcontinent ethnicity adult MND incidence rate for England. Results: MND Incident cases were found in 19 Bangladeshi, 69 Indian, 32 Pakistani and 6317 non-Indian subcontinent ethnicity adults over the study period. Ethnicity was recorded for 3563 (55.4%) of the MND cases. Crude incidence of MND was 2.4 (95%CI 1.6-3.8)/100,000 adult years in Bangladeshi, 3.5 (2.7-4.4)/100,000 in Indian, 2.8 (2.0-3.9)/100,000 in Pakistani, 3.1 (2.6-3.6)/100,000 in all Indian subcontinent ethnicity and 5.8 (5.7-6.0)/100,000 adult years in adults of non-Indian subcontinent ethnicity in England. Crude incidence rate ratios were 0.42 (0.25-0.65, p < 0.0001) for Bangladeshi, 0.59 (0.46-0.75, p < 0.0001) for Indian, 0.47 (0.32-0.67, p < 0.0001) for Pakistani and 0.52 (0.43-0.63, p < 0.0001) for Indian subcontinent adults relative to adults of non-Indian subcontinent ethnicity in England. Age adjusted incidence of MND was 4.5 (2.2-6.7)/ 100,000 adult years in Bangladeshi, 5.5 (4.1-6.9)/100,000 in Indian, 4.4 (2.8-6.0)/100,000 in Pakistani, 5.2 (4.1-6.2)/100,000 in Indian subcontinent and 5.8 (5.6-5.9)/100,000 adult years in adults of non-Indian subcontinent ethnicity in England Background: Amyotrophic lateral sclerosis (ALS) is a mostly sporadic neurodegenerative disease. The role of environmental factors has been extensively investigated but associations remain controversial. Considering that a substantial proportion of adult life is spent at work, identifying occupations and work-related exposures is considered an effective way to detect factors that increase ALS risk. This process may be further facilitated in population isolates due to environmental and genetic homogeneity. The archipelago of Malta, a sovereign microstate in the south of Europe, is home to a geographically and culturally isolated population. Objective: Our study investigated occupations and occupational exposures potentially associated with ALS risk in the isolated island population of Malta, using a case-control study design. Methods: Patients with ALS and randomly identified matched controls (1:1) were recruited throughout a four-year window, from 2017 through 2020. Data on educational level, residence, main occupation, smoking, and alcohol history were collected. Results: We found that compared to controls (44.4%), a higher percentage (73.7%) of ALS patients reported a bluecollar job as their main occupation (OR 2.04, 95% CI 1.2-3.72; p ¼ 0.0072). Through regression analysis, craft and related trades occupations such as carpentry and construction (ISCO-08 major group 7), were found to be positively associated with ALS, with patients in this occupational category found to be more prone to develop bulbar-onset ALS (p ¼ 0.0297). Overall, patients with ALS reported a significantly higher exposure to work-related strenuous physical activity (OR 2.35, 95% CI 1.53-3.59; p ¼ 0.0002). Discussion and conclusions: Our findings suggest that manual workers particularly those working in the carpentry and construction industries have an increased ALS risk, possibly due to a history of intense or sustained physical activity.
ruben.cauchi@um.edu.mt EPI-11 Amyotrophic lateral sclerosis mortality in Latin America: a population based meta-analysis  (1). Furthermore, significant differences in ALS risk have been described between ethnic groups in the region (2,3). We conducted a meta-analysis using general population data aiming to describe ALS mortality rates in Latin America. We explored the relationship between mortality rates and the proportion of Caucasian population. Methods: National mortality registers from Latin American countries were searched to identify ALS deaths according to the International Classification of Diseases (ICD 9th: code 335.2 and ICD 10th: code G12.2). The crude and standardized mortality rates were calculated. A random-effect meta-analysis was conducted to estimate pooled mortality. Linear regression assessed the relationship between mortality rate and proportion of Caucasian population. Results: Overall, 28 548 ALS deaths and 819 million personyears of follow-up (PYFU) were considered from 10 Latin American countries: Argentina, Brazil, Chile, Colombia, Costa Rica, Cuba, Ecuador, Guatemala, Mexico and Uruguay. Standardized mortality varied among countries. The highest mortality rates were observed in Uruguay and Costa Rica at 1.3 and 1.2 per 100,000 PYFU, respectively. Pooled crude mortality rate was 0.38 (95%CI: 0.27-0.52) and pooled standardized mortality was 0.61 (95%CI: 0.49-0.77) per 100,000 PYFU. Heterogeneity was highly significant (I2: 99.9%, p ¼ 0.000). A strong positive correlation was reported between ALS mortality rates and the proportion of Caucasians (R: 0.83; p ¼ 0.003). Conclusion: This meta-analysis confirms a lower ALS occurrence in Latin America compared to Europe and North America. It also supports an epidemiological association between ethnic populations and ALS. Further studies are needed to investigate the role of ancestral origin on ALS. Background: Age is a major risk factor for all neurodegenerative disorders, and familial ALS cases have been associated with a marked deviation from normal brain ageing years before symptom onset. More common neurodegenerative diseases such as Alzheimer's and Parkinson's disease exhibit increased progression of changes seen in multiple hallmarks of ageing. This raises the question of whether ALS arises as an entirely distinct process or reflects an exaggeration of certain aspects of natural ageing of the motor system. This is critical to any long-term aspiration of presymptomatic screening of large populations for the earliest changes associated with presymptomatic ALS pathology. Methods: UK Biobank (UKB) is a unique resource following half a million people who were enrolled aged 40-70. Almost 50,000 participants have already undergone multimodal structural and functional MRI brain scans. By studying such a large population, we aimed to understand more specifically how brain motor system components vary across ages. Nonhealthy participants (defined by the UKB derived disease variable) and those with missing modalities were excluded, resulting in 40,481 individual data sets. We analysed structural, diffusion and resting-state connectivity imaging-derived phenotypes (IDPs) relating to the motor cortex and the main white matter tracts that have been implicated in ALS. The UKB data set allows for the modelling of a comprehensive set of imaging confounds. These fall into five primary families: subject-specific, scanner/acquisition protocol/processing parameters, head motion, table position and temporal drift confounds. After unconfounding the IDPs, linear mixed-effect modelling was used to test for associations between the IDPs and basic characteristics of age, sex and handedness. Bonferroni correction was used to control for multiple comparisons. Results: We demonstrated the linear nature and significance of the effects of age on a range of structural and functional motor system components. Despite the strong significance of the associations between many of the IDPs and age, between-subject IDP variation remained high even after deconfounding. Discussion and conclusions: Distinctly varying rates of change in motor system IDPs may suggest some selective vulnerability of structural motor system components with increasing age. We aim to improve upon the resulting low Rsquared values by broadening the number of confounds and including non-linear and interaction confounds. We will then be able to extend the analysis to look for any effect of ALSimplicated lifestyle factors also recorded in UKB e.g. premorbid physical activity and lipid profiles, in relation to motor system ageing. matthew.gabel@ndcn.ox.ac.uk Background: The current lack of treatment for ALS is largely attributed to the fact that the etiology of most patients is still unknown. High-quality data are clearly needed in better understanding the etiopathogenesis of ALS. Objectives: To create a better understanding of the disease mechanisms by studying how biomarkers, lifestyle, and environmental factors are related to the risk or prognosis of ALS. Methods: ALSrisc is a case-control study that started 2015. All incident cases newly diagnosed at the ALS Center Karolinska, with either ALS, primary lateral sclerosis, progressive spinal muscular atrophy or other MND, are recruited from Stockholm, Sweden. Through clinical follow-up and cross-linkage to the Swedish National MND Quality Registry, which includes >99% of all newly diagnosed patients with MND in Stockholm (1), ALSrisc follows patients from diagnosis until death. Two groups of controls are recruited, namely sibling (shared genetic and early-life environmental factors), and spouse (shared adult-life environmental factors). ALSrisc collects clinical data, questionnaire data and biological samples. From cases, clinical data are extracted from medical journals and the MND Quality Registry, including site of onset, disease progression, spreading pattern, treatment, and routine clinical testing. Patients also undergo additional clinical testing, including MRI-and FDG-PET imaging and cardiac studies.
Information on environmental factors (e.g. housing, employment, military, physical activity), family medical history, and dietary habits, is collected from both cases and controls using questionnaires. Data on cognitive abilities and mental health from cases are recorded on 6-month intervals. Participants also provide biological samples (cerebrospinal fluid, blood, serum, plasma, saliva, feces, hair, and nails) creating a large biobank of paired samples. For cases, we collect samples at the time of diagnosis and then annually. Results: Data collection in ALSrisc is ongoing. Between 2015 and June 2021 a total of 316 cases (ALS: n ¼ 285) and 191 controls (spouses: n ¼ 122, siblings: n ¼ 69) were recruited. The main reasons for non-participation are being too sick (54.8%) and unwillingness (29%). 51.6% (n ¼ 163) of the cases are male and 32.3% (n ¼ 102) had a bulbar onset. The average age at diagnosis is 65.9 years and the average diagnostic delay is 1.4 years. The characteristics of the ALSrisc cases are generally comparable to those of all ALS patients diagnosed in Stockholm during the same period according to the MND Quality Registry. During the follow-up 57.9% of the cases died (n ¼ 183). Conclusion: ALSrisc cases are representative for all patients newly diagnosed with ALS in Stockholm. ALSrisc has created a large biobank and data collection of over 300 ALS patients and two control groups with shared genetic and environmental background. These resources are currently being used in a diverse set of ALS research projects. Background: Despite extensive investigation, the full etiopathogenesis of ALS is still to elucidate. Besides being a MND mimic, thyroid disease has been proposed in the past to be linked to ALS origin. Few reports with small samples did not identify an association between the two conditions, and it has been suggested that thyroid dysfunction is less prevalent in ALS (1). Objectives: To investigate the prevalence thyroid disease in ALS patients. Methods: We performed a case-control study to investigate the prevalence of thyroid dysfunction (hyperthyroidism and hypothyroidism) of prospectively enrolled ALS patients followed in our centre, between 2015 and 2020. We compared them with consecutive patients, also prospectively enrolled, with other neurological mimicking disorders not related to thyroid dysfunction, observed within the same time frame. Positive thyroid disease was defined by previous chronic drug treatment established by an endocrinologist. We used odds-ratio (OR) with a 95% confidence interval (CI) to compare groups. Results: We included 579 ALS patients and 415 age-gender matched disease controls. Hypothyroidism was more prevalent than hyperthyroidism in both ALS (5.0% versus 0.34%) and controls (8.67% versus 1.20%). Women had around nineand five-fold odd of having hypothyroidism than men in the ALS (OR ¼9.38, 95% CI 3.22-27.31) and control (OR ¼4.54, 95% CI 2.02-10.22) groups, respectively. Hypothyroidism (OR ¼0.56, 95% CI 0.34, 0.921), hyperthyroidism (OR ¼0.28, 95% CI 0.06-1.47) and overall thyroid disease (OR ¼0.54, 95% CI 0.33-0.89) were less prevalent in ALS patients than controls. Discussion: As expected, hypothyroidism was much more prevalent than hyperthyroidism and had a female predominance. Thyroid disease was less prevalent in ALS patients. The prevalence of hypothyroidism in our ALS population was similar to the one described for the Portuguese population (4.9%) (2), while it was higher in the control group. This is most likely due to the significative prevalence of autoimmune diseases in the control group, such as bulbar myasthenia gravis or myositis. In conclusion, this study indicates that thyroid disease is not a risk factor for ALS.

csantosilva2@gmail.com
Introduction: Telehealth in the routine care of people with motor neuron disease (MND) is becoming increasingly common. The Sheffield MND multidisciplinary team (MDT) has implemented a remote patient-monitoring system, Telehealth in MND (TiM), into its clinical service. Patients are asked to complete fortnightly, health-related questionnaires (e.g. ALS-FRS-R, SNAQ, PHQ-9, GAD-7, breathing and weight). TiM has enabled the collection of longitudinal natural history data at frequent intervals, representing a far broader range of patients than those enrolled in clinical trials. Analysis of the data could provide a more accurate picture of the natural history of ALS, as well as enable an evaluation of the clinical needs of patients and the effectiveness of the service provided.
Methods: This is a descriptive analysis of all the data collected through TiM, with the aim of describing the population; measuring the course of MND progression, including ALS-FRS-R slope; and identifying associations between clinical outcomes. Results: 59 patients currently use TiM, 39 male, 20 female, with a mean age of 67 years (standard deviation (SD) ¼ 13 years) and they have completed a total of 4138 questionnaires between May 2020 and June 2021. Patients have a wide range of ALS-FRS-R scores (mean 29.63, SD 9.21), with the ALS-FRS-R slope of À0.68 points/month (SD 0.80) across the first 6 months (n ¼ 31). The slope was higher (À0.83 points/month, SD 1.11) in the first 3 months and lower (À0.54 points/month, SD 0.90) from 3 to 6 months. The prevalence of anxiety and depressive symptoms was relatively low (mean GAD-7 and PHQ-9 scores of 2.15 and 4.19 respectively) but 20% of patients reported moderate symptoms of anxiety (GAD-7 score !10) and 32% reported moderate symptoms of depression (PHQ score !10) at least once. In multiple regression analyses examining the impact of the other questionnaires on PHQ-9 scores, ALS-FRS-R scores could predict PHQ-9 scores prior to the development of respiratory impairment (p < 0.001). Conclusion: TiM has the potential to collect whole-population natural history data, which could be used to better understand the disease as well as provide control data for clinical trials. TiM also highlights unmet needs in our population. Symptoms of anxiety and depression were commonly experienced and may be at least partly related to severity of disability.
jpsutherland1@sheffield.ac.uk These patients presented with UMN-predominant and classic phenotype more commonly than intermediate progressors [RRR: 44.7 (CI: 12.74-156) and 3.48 (CI: 1.86-6.5), respectively), besides having a long diagnostic latency and low progression rate at baseline. Hypercholesterolemia and hypertension remained in the multinomial logistic regression model as explanatory variables of slow progressors membership. Importantly, baseline ALSFRS-r scores, BMI and forced vital capacity could not predict group membership. Time to reach each disease stage was significantly longer in this subgroup of patients, especially when looking at King's stage 3 [p-value