Stephen A Goutman

IntroductionEnvironmental exposures strongly influence ALS risk and identification is needed to reduce ALS burden. Participation in hobbies and exercise may alter ALS risk and phenotype, warranting an assessment to understand their contribution to the ALS exposome.MethodsParticipants with ALS and healthy controls were recruited from University of Michigan and self-completed a survey to ascertain hobbies, exercise, and avocational exposures. Exposure variables were associated with ALS risk, survival, onset segment, and onset age.ResultsALS (n = 400) and control (n = 287) participants self-reported avocational activities. Cases were slightly older (median age 63.0 vs. 61.1 years, p = 0.019) and had a lower educational attainment (p < 0.001) compared to controls; otherwise, demographics were well balanced. Risks associating with ALS after multiple comparison correction included golfing (odds ratio (OR …

Background: Environmental exposures impact amyotrophic lateral sclerosis (ALS) risk and progression, a fatal and progressive neurodegenerative disease. Better characterization of these exposures is needed to decrease disease burden. Objective: To identify exposures in the residential setting that associate with ALS risk, survival, and onset segment. Methods: ALS and control participants recruited from University of Michigan completed a survey that ascertained exposure risks in the residential setting. ALS risk was assessed using logistic regression models followed by latent profile analysis to consider exposure profiles. A case-only analysis considered the contribution of the residential exposure variables via a Cox proportional hazards model for survival outcomes and multinomial logistic regression for onset segment, a polytomous outcome. Results: This study included 367 ALS and 255 control participants …

BackgroundNovel intrathecal treatments for amyotrophic lateral sclerosis (ALS) may require delivery using lumbar puncture (LP). Implanted drug-delivery devices (IDDDs) could be an alternative but little is known about patients’ preferences for intrathecal drug-delivery methods.ObjectiveWe aimed to elicit preferences of patients with ALS for routine LP and IDDD use.MethodsA discrete choice experiment (DCE) and a threshold technique (TT) exercise were conducted online among patients with ALS in the US and Europe. In the DCE, patients made trade-offs between administration attributes. Attributes were identified from qualitative interviews. The TT elicited maximum acceptable risks (MARs) of complications from device implantation surgery. DCE data were analyzed using mixed logit to quantify relative attribute importance (RAI) as the maximum contribution of each attribute to a preference, and to estimate MARs …

INTRODUCTION Anti‐amyloid therapies are at the forefront of efforts to treat Alzheimer's disease (AD). Identifying amyloid risk factors may aid screening and intervention strategies. While veterans face increased exposure to risk factors, whether they face a greater neuropathologic amyloid burden is not well understood. METHODS Male decedents donating to two Alzheimer's Disease Research Center (ADRC) brain banks from 1986 to 2018 with categorized neuritic plaque density and neurofibrillary tangles (n = 597) were included. Using generalized ordered logistic regression we modeled each outcome's association with military history adjusting for age and death year. RESULTS Having served in the military (60% of sample) is associated with post mortem neuritic amyloid plaque (for each comparison of higher to lower C scores OR = 1.26; 95% confidence interval [CI] = 1.06–1.49) and tau pathology (B score …

Amyotrophic lateral sclerosis (ALS) is a complex, fatal neurodegenerative disease. Disease pathophysiology is incompletely understood but evidence suggests gut dysbiosis occurs in ALS, linked to impaired gastrointestinal integrity, immune system dysregulation and altered metabolism. Gut microbiome and plasma metabolome have been separately investigated in ALS, but little is known about gut microbe-plasma metabolite correlations, which could identify robust disease biomarkers and potentially shed mechanistic insight. Here, gut microbiome changes were longitudinally profiled in ALS and correlated to plasma metabolome. Gut microbial structure at the phylum level differed in ALS versus control participants, with differential abundance of several distinct genera. Unsupervised clustering of microbe and metabolite levels identified modules, which differed significantly in ALS versus control participants …

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal, progressive neurogenerative disease caused by combined genetic susceptibilities and environmental exposures. Identifying and validating these exposures are of paramount importance to modify disease risk. We previously reported that persistent organic pollutants (POPs) associate with ALS risk and survival and aimed to replicate these findings in a new cohort.MethodParticipants with and without ALS recruited in Michigan provided plasma samples for POPs analysis by isotope dilution with triple quadrupole mass spectrometry. ORs for risk models and hazard ratios for survival models were calculated for individual POPs. POP mixtures were represented by environmental risk scores (ERS), a summation of total exposures, to evaluate the association with risk (ERSrisk) and survival (ERSsurvival).ResultsSamples from 164 ALS and 105 control participants …

Background The pathogenesis of amyotrophic lateral sclerosis (ALS) involves both genetic and environmental factors. This study investigates associations between metal measures in plasma and urine, ALS risk and survival, and exposure sources. Methods Participants with and without ALS from Michigan provided plasma and urine samples for metal measurement via inductively coupled plasma mass spectrometry. Odds and hazard ratios for each metal were computed using risk and survival models. Environmental risk scores (ERS) were created to evaluate the association between exposure mixtures and ALS risk and survival and exposure source. ALS (ALS-PGS) and metal (metal-PGS) polygenic risk scores were constructed from an independent genome-wide association study and relevant literature-selected SNPs. Results Plasma and urine samples from 454 ALS and 294 control participants were analyzed. Elevated levels of individual metals, including copper, selenium, and zinc, significantly associated with ALS risk and survival. ERS representing metal mixtures strongly associated with ALS risk (plasma, OR=2.95, CI=2.38-3.62, p<0.001; urine, OR=3.10, CI=2.43-3.97, p<0.001) and poorer ALS survival (plasma, HR=1.42, CI=1.24-1.63, p<0.001; urine, HR=1.52, CI=1.31-1.76, p<0.001). Addition of the ALS-PGS or metal-PGS did not alter the significance of metals with ALS risk and survival. Occupations with high potential of metal exposure associated with elevated ERS. Additionally, occupational and non-occupational metal exposures associated with measured plasma and urine metals. Conclusion Metals in plasma and urine …

Neurodegenerative diseases are increasing in prevalence and place a significant burden on society. The causes are multifactorial and complex, and increasing evidence suggests a dynamic interplay between genes and the environment, emphasizing the importance of identifying and understanding the role of lifelong exposures, known as the exposome, on the nervous system. This review provides an overview of recent advances toward defining neurodegenerative disease exposomes, focusing on Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. We present the current state of the field based on emerging data, elaborate on key themes and potential mechanisms, and conclude with limitations and future directions. ANN NEUROL 2024

Introduction/Aims Body mass index (BMI) is linked to amyotrophic lateral sclerosis (ALS) risk and prognosis, but additional research is needed. The aim of this study was to identify whether and when historical changes in BMI occurred in ALS participants, how these longer term trajectories associated with survival, and whether metabolomic profiles provided insight into potential mechanisms. Methods ALS and control participants self‐reported body height and weight 10 (reference) and 5 years earlier, and at study entry (diagnosis for ALS participants). Generalized estimating equations evaluated differences in BMI trajectories between cases and controls. ALS survival was evaluated by BMI trajectory group using accelerated failure time models. BMI trajectories and survival associations were explored using published metabolomic profiling and correlation networks. Results Ten‐year BMI trends differed between …

Objective To report multiple cause of death (MCOD) occurrence among patients in the United States with amyotrophic lateral sclerosis (ALS). Methods Using death certificate data for all ALS deaths from 50 U.S. states and the District of Columbia, 2011–2014, we tabulated MCOD, used association rules mining (ARM) to determine if MCOD occurred together, and calculated standardized mortality odds ratios (SMOR) for select causes, comparing ALS with other U.S. decedents. Results Among 24,328 death certificates, there were 25,704 MCOD, excluding ALS. ALS was listed as the sole cause of death in n = 11,263 (46%). The most frequent causes of death co‐occurring with ALS were respiratory failure (n = 6503; 25.3%), cardiovascular disease (n = 6077; 12.6%), pneumonia (n = 1345; 5.2%), and pneumonitis (n = 856; 3.3%). The SMORs among ALS decedents compared with non‐ALS decedents for falls and …

Objective Advances in amyotrophic lateral sclerosis (ALS) gene discovery, ongoing gene therapy trials, and patient demand have driven increased use of ALS genetic testing. Despite this progress, the offer of genetic testing to persons with ALS is not yet “standard of care.” Our primary goal is to develop clinical ALS genetic counseling and testing guidelines to improve and standardize genetic counseling and testing practice among neurologists, genetic counselors or any provider caring for persons with ALS. Methods Core clinical questions were identified and a rapid review performed according to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA‐P) 2015 method. Guideline recommendations were drafted and the strength of evidence for each recommendation was assessed by combining two systems: the Grading of Recommendations, Assessment, Development and Evaluation …

Amyotrophic lateral sclerosis (ALS) is often considered a relatively rare disease, but risk estimates suggest that the lifetime risk of ALS is 1: 263 for males and 1: 417 for females by age 85. 1 Therapeutic efforts to date have failed to meaningfully slow disease progression or prolong survival. This may, at least in part, reflect that treatment is typically initiated late in the disease process, when damage may already be too advanced to reverse. Indeed, some evidence suggests that earlier treatment may yield better outcomes. 2 3 These observations prompt a reassessment of potential approaches for treating ALS, with a shift towards a proactive strategy for preventing ALS. 4 Achieving the ambitious goal of preventing ALS requires a large body of knowledge, including an understanding of the causes and risk factors for ALS. It also requires identifying a window of opportunity to study those at risk for disease, methods for …

Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neuron degeneration with typical survival of only 2–5 years from diagnosis. The causes of ALS are multifactorial: known genetic mutations account for only around 70% of cases of familial ALS and 15% of sporadic cases, and heritability estimates range from 8% to 61%, indicating additional causes beyond genetics. Consequently, interest has grown in environmental contributions to ALS risk and progression. The gene–time–environment hypothesis posits that ALS onset occurs through an interaction of genes with environmental exposures during ageing. An alternative hypothesis, the multistep model of ALS, suggests that several hits, at least some of which could be environmental, are required to trigger disease onset, even in the presence of highly penetrant ALS-associated mutations. Studies have sought to characterize the ALS exposome — the …

ObjectiveTo identify associations between occupational settings and self-reported occupational exposures on amyotrophic lateral sclerosis (ALS) survival and phenotypes.MethodsAll patients seen in the University of Michigan Pranger ALS Clinic were invited to complete an exposure assessment querying past occupations and exposures. Standard occupational classification (SOC) codes for each job and the severity of various exposure types were derived. Cox proportional hazards models associated all-cause mortality with occupational settings and the self-reported exposures after adjusting for sex, diagnosis age, revised El Escorial criteria, onset segment, revised ALS Functional Rating Scale (ALSFRS-R), and time from symptom onset to diagnosis. Multinomial logistic regression models with three categories, adjusted for age, assessed the association between occupational settings and exposures to onset …

Platform trials allow efficient evaluation of multiple interventions for a specific disease. The HEALEY ALS Platform Trial is testing multiple investigational products in parallel and sequentially in persons with amyotrophic lateral sclerosis (ALS) with the goal of rapidly identifying novel treatments to slow disease progression. Platform trials have considerable operational and statistical efficiencies compared with typical randomized controlled trials due to their use of shared infrastructure and shared control data. We describe the statistical approaches required to achieve the objectives of a platform trial in the context of ALS. This includes following regulatory guidance for the disease area of interest and accounting for potential differences in outcomes of participants within the shared control (potentially due to differences in time of randomization, mode of administration, and eligibility criteria). Within the HEALEY ALS …

ObjectiveTo evaluate the impact of 1) updating the existing algorithm to improve case-finding sensitivity and 2) reclassifying the Registry’s diagnostic status nomenclature into four new categories (“confirmed ALS,” “likely ALS,” “undetermined ALS,” or “not ALS”) versus the current three (“definite ALS,” “possible ALS,” or “not ALS”) to be more inclusive and descriptive of cases and individuals.MethodsA retrospective analysis of Registry data from 2011–2017 was conducted to follow “possible ALS” individuals over time to determine what qualifier caused them to convert, if at all and when, to Registry-eligible cases (i.e. “confirmed ALS” or “likely ALS”).ResultsIn 2011, 720 individuals were classified by the Registry algorithm as having “possible ALS”. By 2017, 42% of these had converted to Registry-eligible ALS cases. Approximately 14% of those who were identified solely based on an ALS prescription drug never …

Introduction/Aims. Primary lateral sclerosis (PLS) is exceedingly rare and has been an enigmatic disease. Recent progress has drastically changed this perception, with early biomarkers being investigated and potential medications for PLS emerging at the preclinical stage. The aim of this paper is to describe a study of PLS natural history and discuss the limitations and proposed solutions to the study of a rare and slowly progressive disease. Methods. The PLS Natural History Study is a 30-site, 24-month, prospective study that is supported by multiple funding sources. The study aims to enroll 50 early PLS (disease duration ≤4 years) and 50 definite PLS (disease duration 4 to 15 years) participants using modified PLS Diagnostic Criteria. Smartphone-based assessments including semi-quantitative and quantitative measures and patient-reported outcomes are utilized. In-person quantitative measures are also …

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Its complex pathogenesis and phenotypic heterogeneity hinder therapeutic development and early diagnosis. Altered RNA metabolism is a recurrent pathophysiologic theme, including distinct microRNA (miRNA) profiles in ALS tissues. We profiled miRNAs in accessible biosamples, including skin fibroblasts and whole blood and compared them in age- and sex-matched healthy controls versus ALS participants with and without repeat expansions to chromosome 9 open reading frame 72 (C9orf72; C9-ALS and nonC9-ALS), the most frequent ALS mutation. We identified unique and shared profiles of differential miRNA (DmiRNA) levels in each C9-ALS and nonC9-ALS tissues versus controls. Fibroblast DmiRNAs were validated by quantitative real-time PCR and their target mRNAs by 5-bromouridine and 5-bromouridine-chase …

Background and ObjectivesMost patients with amyotrophic lateral sclerosis (ALS) lack a monogenic mutation. This study evaluates ALS cumulative genetic risk in an independent Michigan and Spanish replication cohort using polygenic scores.MethodsParticipant samples from University of Michigan were genotyped and assayed for the chromosome 9 open reading frame 72 hexanucleotide expansion. Final cohort size was 219 ALS and 223 healthy controls after genotyping and participant filtering. Polygenic scores excluding the C9 region were generated using an independent ALS genome-wide association study (20,806 cases, 59,804 controls). Adjusted logistic regression and receiver operating characteristic curves evaluated the association and classification between polygenic scores and ALS status, respectively. Population attributable fractions and pathway analyses were conducted. An independent …

MethodsWe followed 56 ALS subjects measuring both immune markers and ALS functional rating scale-revised (ALSFRS-R) scores at monthly intervals. Immune cell levels, natural killer (NK) cell subpopulations levels, and NK cell surface marker expression was assessed using flow cytometry, and changes in immune levels were assessed in control and ALS subjects over time. First, a linear mixed effect model was used to correlate changes in ALSFRS-R. Next, these metrics were associated with disease in a larger cohort of 241 participants using LASSO-Cox and the associations were stratified by age and sex. Finally, random forest was used to create prediction models of disease based on multiple immune metrics.ResultsWe found that immune changes preceded changes in ALSFRS-R and that the use of multiple immune metrics enhanced short-term prediction of changes in disease score compared to clinical …