Gastrostomy placement in patients with amyotrophic lateral sclerosis: assessment of risk factors for post-procedural respiratory failure.

OBJECTIVE: Radiologically inserted gastrostomy placement may be performed in patients with dysphagia secondary to amyotrophic lateral sclerosis (ALS). This study assessed technical outcomes and complications related to gastrostomy placement in patients with ALS. METHODS: A retrospective review of patients with ALS who underwent gastrostomy placement between 2021 and 2023 was performed. Patient demographics, medical history, ALS disease manifestations, survival, and post-procedural complications were obtained from the electronic medical record. Technical outcomes related to gastrostomy placement were obtained from operative notes and review of procedural imaging. RESULTS: A total of 100 patients were included in the study. The mean duration of ALS diagnosis at time of gastrostomy placement was 1.3 +/-1.2 years. The mean slow vital capacity at time of gastrostomy placement was 54.0 +/-20.2% (range 10-155%). Technical success was 100%, with 91 placed using fluoroscopic guidance and 9 placed with computed tomography guidance. Eighty-three percent of gastrostomies were performed as outpatient procedures, while 17/100 patients were admitted following the procedure for monitoring. Post-procedural adverse events were noted in 21/100 patients (15 mild and 6 moderate or greater). Three patients developed respiratory failure after gastrostomy tube placement and died within 1-week post-procedure. Lower pre-procedural slow vital capacity was associated with higher risk of post-procedural respiratory failure (p = 0.0003*). CONCLUSIONS: Gastrostomy placement in patients with ALS has a high technical success rate and may be performed safely in the outpatient setting in appropriate patients. Patients with low slow vital capacity related to ALS should be admitted post-procedurally for airway monitoring and support.

A novel digital tool for detection and monitoring of amyotrophic lateral sclerosis motor impairment and progression via keystroke dynamics.

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative condition leading to progressive muscle weakness, atrophy, and ultimately death. Traditional ALS clinical evaluations often depend on subjective metrics, making accurate disease detection and monitoring disease trajectory challenging. To address these limitations, we developed the nQiALS toolkit, a machine learning-powered system that leverages smartphone typing dynamics to detect and track motor impairment in people with ALS. The study included 63 ALS patients and 30 age- and sex-matched healthy controls. We introduce the three core components of this toolkit: the nQiALS-Detection, which differentiated ALS from healthy typing patterns with an AUC of 0.89; the nQiALS-Progression, which separated slow and fast progression at specific thresholds with AUCs ranging between 0.65 and 0.8; and the nQiALS-Fine Motor, which identified subtle progression in fine motor dysfunction, suggesting earlier prediction than the state-of-the-art assessment. Together, these tools represent an innovative approach to ALS assessment, offering a complementary, objective metric to traditional clinical methods and which may reshape our understanding and monitoring of ALS progression.

Allogeneic B cell immunomodulatory therapy in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease. Immune system dysregulation plays an essential role in ALS onset and progression. Our preclinical studies have shown that the administration of exogenous allogeneic B cells improves outcomes in murine models of skin and brain injury through a process termed pligodraxis, in which B cells adopt an immunoregulatory and neuroprotective phenotype in an injured environment. Here, we investigated the effects of B-cell therapy in the SOD1G93A mouse preclinical model of ALS and in a person living with ALS. Purified splenic mature naïve B cells from haploidentical donor mice were administered intravenously in SOD1G93A mice for a total of 10 weekly doses. For the clinical study in a person with advanced ALS, IgA gammopathy of unclear significance, and B lymphopenia, CD19+ B cells were positively selected from a healthy haploidentical donor and infused intravenously twice, at a 60-day interval. Repeated intravenous B-cell administration was safe and significantly delayed disease onset, extended survival, reduced cellular apoptosis, and decreased astrogliosis in SOD1G93A mice. Repeated B-cell infusion in a person with ALS was safe and did not appear to generate a clinically evident inflammatory response. An improvement of 5 points on the ALSFRS-R scale was observed after the first infusion. Levels of inflammatory markers showed persistent reduction post-infusion. This represents a first demonstration of the efficacy of haploidentical B-cell infusion in the SOD1G93A mouse and the safety and feasibility of using purified haploidentical B lymphocytes as a cell-based therapeutic strategy for a person with ALS.

Listener effort quantifies clinically meaningful progression of dysarthria in people living with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative motor neuron disease that causes progressive muscle weakness. Progressive bulbar dysfunction causes dysarthria and thus social isolation, reducing quality of life. The Everything ALS Speech Study obtained longitudinal clinical information and speech recordings from 292 participants. In a subset of 120 participants, we measured speaking rate (SR) and listener effort (LE), a measure of dysarthria severity rated by speech pathologists from recordings. LE intra- and inter-rater reliability was very high (ICC 0.88 to 0.92). LE correlated with other measures of dysarthria at baseline. LE changed over time in participants with ALS (slope 0.77 pts/month; p<0.001) but not controls (slope 0.005 pts/month; p=0.807). The slope of LE progression was similar in all participants with ALS who had bulbar dysfunction at baseline, regardless of ALS site of onset. LE could be a remotely collected clinically meaningful clinical outcome assessment for ALS clinical trials.

Multicenter expanded access program for access to investigational products for amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Expanded access (EA) is a Food and Drug Administration-regulated pathway to provide access to investigational products (IPs) to individuals with serious diseases who are ineligible for clinical trials. The aim of this report is to share the design and operations of a multicenter, multidrug EA program for amyotrophic lateral sclerosis (ALS) across nine US centers. METHODS: A central coordination center was established to design and conduct the program. Templated documents and processes were developed to streamline study design, regulatory submissions, and clinical operations across protocols. The program included three protocols and provided access to IPs that were being tested in respective regimens of the HEALEY ALS Platform Trial (verdiperstat, CNM-Au8, and pridopidine). Clinical and safety data were collected in all EA protocols (EAPs). The program cohorts comprised participants who were not eligible for the platform trial, including participants at advanced stages of disease progression and with long disease duration. RESULTS: A total of 85 participants were screened across the 3 EAPs from July 2021 to September 2022. The screen failure rate was 3.5%. Enrollment for the regimens of the platform trial was completed as planned and results informed the duration of the corresponding EAP. The verdiperstat EAP was concluded in December 2022. Mean duration of participation in the verdiperstat EAP was 5.8 ± 4.1 months. The CNM-Au8 and pridopidine EAPs are ongoing. DISCUSSION: Multicenter EAPs conducted in parallel to randomized clinical trials for ALS can successfully enroll participants who do not qualify for clinical trials.

The relationship of rate and pause features to the communicative participation of people living with ALS.

INTRODUCTION/AIMS: Many people living with amyotrophic lateral sclerosis (PALS) report restrictions in their day-to-day communication (communicative participation). However, little is known about which speech features contribute to these restrictions. This study evaluated the effects of common speech symptoms in PALS (reduced overall speaking rate, slowed articulation rate, and increased pausing) on communicative participation restrictions. METHODS: Participants completed surveys (the Communicative Participation Item Bank-short form; the self-entry version of the ALS Functional Rating Scale-Revised) and recorded themselves reading the Bamboo Passage aloud using a smartphone app. Rate and pause measures were extracted from the recordings. The association of various demographic, clinical, self-reported, and acoustic speech features with communicative participation was evaluated with bivariate correlations. The contribution of salient rate and pause measures to communicative participation was assessed using multiple linear regression. RESULTS: Fifty seven people living with ALS participated in the study (mean age = 61.1 years). Acoustic and self-report measures of speech and bulbar function were moderately to highly associated with communicative participation (Spearman rho coefficients ranged from rs = 0.48 to rs = 0.77). A regression model including participant age, sex, articulation rate, and percent pause time accounted for 57% of the variance of communicative participation ratings. DISCUSSION: Even though PALS with slowed articulation rate and increased pausing may convey their message clearly, these speech features predict communicative participation restrictions. The identification of quantitative speech features, such as articulation rate and percent pause time, is critical to facilitating early and targeted intervention and for monitoring bulbar decline in ALS.

Tracking amyotrophic lateral sclerosis disease progression using passively collected smartphone sensor data.

BACKGROUND: Passively collected smartphone sensor data provide an opportunity to study physical activity and mobility unobtrusively over long periods of time and may enable disease monitoring in people with amyotrophic lateral sclerosis (PALS). METHODS: We enrolled 63 PALS who used Beiwe mobile application that collected their smartphone accelerometer and GPS data and administered the self-entry ALS Functional Rating Scale-Revised (ALSFRS-RSE) survey. We identified individual steps from accelerometer data and used the Activity Index to summarize activity at the minute level. Walking, Activity Index, and GPS outcomes were then aggregated into day-level measures. We used linear mixed effect models (LMMs) to estimate baseline and monthly change for ALSFRS-RSE scores (total score, subscores Q1-3, Q4-6, Q7-9, Q10-12) and smartphone sensor data measures, as well as the associations between them. FINDINGS: The analytic sample (N = 45) was 64.4% male with a mean age of 60.1 years. The mean observation period was 292.3 days. The ALSFRS-RSE total score baseline mean was 35.8 and had a monthly rate of decline of -0.48 (p-value <0.001). We observed statistically significant change over time and association with ALSFRS-RSE total score for four smartphone sensor data-derived measures: walking cadence from top 1 min and log-transformed step count, step count from top 1 min, and Activity Index from top 1 min. INTERPRETATION: Smartphone sensors can unobtrusively track physical changes in PALS, potentially aiding disease monitoring and future research.

Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes.

INTRODUCTION/AIMS: Biomarkers have shown promise in amyotrophic lateral sclerosis (ALS) research, but the quest for reliable biomarkers remains active. This study evaluates the effect of debamestrocel on cerebrospinal fluid (CSF) biomarkers, an exploratory endpoint. METHODS: A total of 196 participants randomly received debamestrocel or placebo. Seven CSF samples were to be collected from all participants. Forty-five biomarkers were analyzed in the overall study and by two subgroups characterized by the ALS Functional Rating Scale-Revised (ALSFRS-R). A prespecified model was employed to predict clinical outcomes leveraging biomarkers and disease characteristics. Causal inference was used to analyze relationships between neurofilament light chain (NfL) and ALSFRS-R. RESULTS: We observed significant changes with debamestrocel in 64% of the biomarkers studied, spanning pathways implicated in ALS pathology (63% neuroinflammation, 50% neurodegeneration, and 89% neuroprotection). Biomarker changes with debamestrocel show biological activity in trial participants, including those with advanced ALS. CSF biomarkers were predictive of clinical outcomes in debamestrocel-treated participants (baseline NfL, baseline latency-associated peptide/transforming growth factor beta1 [LAP/TGFß1], change galectin-1, all p < .01), with baseline NfL and LAP/TGFß1 remaining (p < .05) when disease characteristics (p < .005) were incorporated. Change from baseline to the last measurement showed debamestrocel-driven reductions in NfL were associated with less decline in ALSFRS-R. Debamestrocel significantly reduced NfL from baseline compared with placebo (11% vs. 1.6%, p = .037). DISCUSSION: Following debamestrocel treatment, many biomarkers showed increases (anti-inflammatory/neuroprotective) or decreases (inflammatory/neurodegenerative) suggesting a possible treatment effect. Neuroinflammatory and neuroprotective biomarkers were predictive of clinical response, suggesting a potential multimodal mechanism of action. These results offer preliminary insights that need to be confirmed.

Longitudinal comparison of the self-administered ALSFRS-RSE and ALSFRS-R as functional outcome measures in ALS.

OBJECTIVE: Test the feasibility, adherence rates and optimal frequency of digital, remote assessments using the ALSFRS-RSE via a customized smartphone-based app. METHODS: This fully remote, longitudinal study was conducted over a 24-week period, with virtual visits every 3 months and weekly digital assessments. 19 ALS participants completed digital assessments via smartphone, including a digital version of the ALSFRS-RSE and mood survey. Interclass correlation coefficients (ICC) and Bland-Altman plots were used to assess agreement between staff-administered and self-reported ALSFRS-R pairs. Longitudinal change was evaluated using ANCOVA models and linear mixed models, including impact of mood and time of day. Impact of frequency of administration of the ALSFRS-RSE on precision of the estimate slope was tested using a mixed effects model. RESULTS: In our ALS cohort, digital assessments were well-accepted and adherence was robust, with completion rates of 86%. There was excellent agreement between the digital self-entry and staff-administered scores computing multiple ICCs (ICC range = 0.925-0.961), with scores on the ALSFRS-RSE slightly higher (1.304 points). Digital assessments were associated with increased precision of the slope, resulting in higher standardized response mean estimates for higher frequencies, though benefit appeared to diminish at biweekly and weekly frequency. Effects of participant mood and time of day on total ALSFRS-RSE score were evaluated but were minimal and not statistically significant. CONCLUSION: Remote collection of digital patient-reported outcomes of functional status such as the ALSFRS-RSE yield more accurate estimates of change over time and provide a broader understanding of the lived experience of people with ALS.

Upper limb movements as digital biomarkers in people with ALS.

BACKGROUND: Objective evaluation of people with amyotrophic lateral sclerosis (PALS) in free-living settings is challenging. The introduction of portable digital devices, such as wearables and smartphones, may improve quantifying disease progression and hasten therapeutic development. However, there is a need for tools to characterize upper limb movements in neurologic disease and disability. METHODS: Twenty PALS wore a wearable accelerometer, ActiGraph Insight Watch, on their wrist for six months. They also used Beiwe, a smartphone application that collected self-entry ALS Functional Rating Scale-Revised (ALSFRS-RSE) survey responses every 1-4 weeks. We developed several measures that quantify count and duration of upper limb movements: flexion, extension, supination, and pronation. New measures were compared against ALSFRS-RSE total score (Q1-12), and individual responses to specific questions related to handwriting (Q4), cutting food (Q5), dressing and performing hygiene (Q6), and turning in bed and adjusting bed clothes (Q7). Additional analysis considered adjusting for total activity counts (TAC). FINDINGS: At baseline, PALS with higher Q1-12 performed more upper limb movements, and these movements were faster compared to individuals with more advanced disease. Most upper limb movement metrics had statistically significant change over time, indicating declining function either by decreasing count metrics or by increasing duration metric. All count and duration metrics were significantly associated with Q1-12, flexion and extension counts were significantly associated with Q6 and Q7, supination and pronation counts were also associated with Q4. All duration metrics were associated with Q6 and Q7. All duration metrics retained their statistical significance after adjusting for TAC. INTERPRETATION: Wearable accelerometer data can be used to generate digital biomarkers on upper limb movements and facilitate patient monitoring in free-living environments. The presented method offers interpretable monitoring of patients' functioning and versatile tracking of disease progression in the limb of interest. FUNDING: Mitsubishi-Tanabe Pharma Holdings America, Inc.

Identification of gene fusions associated with amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Genetics is an important risk factor for amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting motor neurons. Recent findings demonstrate that in addition to specific genetic mutations, structural variants caused by genetic instability can also play a causative role in ALS. Genomic instability can lead to deletions, duplications, insertions, inversions, and translocations in the genome, and these changes can sometimes lead to fusion of distinct genes into a single transcript. Gene fusion events have been studied extensively in cancer; however, they have not been thoroughly investigated in ALS. The aim of this study was to determine whether gene fusions are present in ALS. METHODS: Gene fusions were identified using STAR Fusion v1.10.0 software in bulk RNA-Seq data from human postmortem samples from publicly available data sets from Target ALS and the New York Genome Center ALS Consortium. RESULTS: We report the presence of gene fusion events in several brain regions as well as in spinal cord samples in ALS. Although most gene fusions were intra-chromosomal events between neighboring genes and present in both ALS and control samples, there was a significantly greater number of unique gene fusions in ALS compared to controls. Lastly, we identified specific gene fusions with a significant burden in ALS, that were absent from both control samples and known cancer gene fusion databases. DISCUSSION: Collectively, our findings reveal an enrichment of gene fusions in ALS and suggest that these events may be an additional genetic cause linked to ALS pathogenesis.

A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS-FTD.

Although loss of TAR DNA-binding protein 43 kDa (TDP-43) splicing repression is well documented in postmortem tissues of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), whether this abnormality occurs during early-stage disease remains unresolved. Cryptic exon inclusion reflects loss of function of TDP-43, and thus detection of proteins containing cryptic exon-encoded neoepitopes in cerebrospinal fluid (CSF) or blood could reveal the earliest stages of TDP-43 dysregulation in patients. Here we use a newly characterized monoclonal antibody specific to a TDP-43-dependent cryptic epitope (encoded by the cryptic exon found in HDGFL2) to show that loss of TDP-43 splicing repression occurs in ALS-FTD, including in presymptomatic C9orf72 mutation carriers. Cryptic hepatoma-derived growth factor-like protein 2 (HDGFL2) accumulates in CSF at significantly higher levels in familial ALS-FTD and sporadic ALS compared with controls and is elevated earlier than neurofilament light and phosphorylated neurofilament heavy chain protein levels in familial disease. Cryptic HDGFL2 can also be detected in blood of individuals with ALS-FTD, including in presymptomatic C9orf72 mutation carriers, and accumulates at levels highly correlated with those in CSF. Our findings indicate that loss of TDP-43 cryptic splicing repression occurs early in disease progression, even presymptomatically, and that detection of the HDGFL2 cryptic neoepitope serves as a potential diagnostic biomarker for ALS, which should facilitate patient recruitment and measurement of target engagement in clinical trials.

Identifying amyotrophic lateral sclerosis through interactions with an internet search engine.

INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS), a motor neuron disease, remains a clinical diagnosis with an average time from onset of symptoms to diagnosis of about 1 year. Herein we examine the possibility that interactions with an internet search engine can identify people with ALS. METHODS: We identified 285 anonymous Bing users whose queries indicated that they had been diagnosed with ALS and matched them to: (1) 3276 control users; and (2) 1814 users whose searches indicated they had ALS disease mimics. We tested whether the ALS group could be distinguished from controls and disease mimics based on search engine query data. Finally, we conducted a prospective validation from participants who provided access to their Bing search data. RESULTS: The model distinguished between the ALS group and controls with an area under the curve (AUC) of 0.81. Model scores for the ALS group differed from the disease mimics group (rank sum test, p < .05 with Bonferroni correction). Mild cognitive impairment could not be distinguished from ALS (p > .05). In the prospective analysis, the model reached an AUC of 0.74. DISCUSSION: Our results suggest that interactions with search engines should be further studied to understand the potential to act as a tool to assist in screening for ALS and to reduce diagnostic delay.

Targeting amyotrophic lateral sclerosis by neutralizing seeding-competent TDP-43 in CSF.

In amyotrophic lateral sclerosis, a disease driven by abnormal transactive response DNA-binding protein of 43 kDa aggregation, CSF may contain pathological species of transactive response DNA-binding protein of 43 kDa contributing to the propagation of pathology and neuronal toxicity. These species, released in part by degenerating neurons, would act as a template for the aggregation of physiological protein contributing to the spread of pathology in the brain and spinal cord. In this study, a robust seed amplification assay was established to assess the presence of seeding-competent transactive response DNA-binding protein of 43 kDa species in CSF of apparently sporadic amyotrophic lateral sclerosis patients. These samples resulted in a significant acceleration of substrate aggregation differentiating the kinetics from healthy controls. In parallel, a second assay was developed to determine the level of target engagement that would be necessary to neutralize such species in human CSF by a therapeutic monoclonal antibody targeting transactive response DNA-binding protein of 43 kDa. For this, evaluation of the pharmacokinetic/pharmacodynamic effect for the monoclonal antibody, ACI-5891.9, in vivo and in vitro confirmed that a CSF concentration of ≍1100 ng/mL would be sufficient for sustained target saturation. Using this concentration in the seed amplification assay, ACI-5891.9 was able to neutralize the transactive response DNA-binding protein of 43 kDa pathogenic seeds derived from amyotrophic lateral sclerosis patient CSF. This translational work adds to the evidence of transmission of transactive response DNA-binding protein of 43 kDa pathology via CSF that could contribute to the non-contiguous pattern of clinical manifestations observed in amyotrophic lateral sclerosis and demonstrates the ability of a therapeutic monoclonal antibody to neutralize the toxic, extracellular seeding-competent transactive response DNA-binding protein of 43 kDa species in the CSF of apparently sporadic amyotrophic lateral sclerosis patients.

Efficacy and Safety of Ravulizumab, a Complement C5 Inhibitor, in Adults With Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial.

Importance: Additional therapies for amyotrophic lateral sclerosis (ALS) are urgently needed. Immune-mediated complement activation may be involved in ALS pathogenesis as evidenced by the upregulation of terminal components; thus, complement inhibition could potentially slow progression. Objective: To evaluate the safety and efficacy of the terminal complement C5 inhibitor ravulizumab in adults with ALS. Design, Setting, and Participants: This double-blind, placebo-controlled, parallel-group, multinational, randomized, phase 3 clinical trial was conducted from March 30, 2020, to October 17, 2021, in 81 ALS specialty centers across 17 countries. A preplanned, unmasked, nonbinding interim futility analysis was conducted when 33% of participants had completed week 26, wherein a conditional power of less than 10% would halt the trial. A total of 478 individuals were screened, and 96 were excluded. Inclusion criteria were weight of 40 kg or more, fulfillment of the El Escorial diagnostic criteria, and a minimal prestudy Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) progression score of -0.3 points per month. Interventions: Study treatment consisted of placebo or a weight-based dose of intravenous ravulizumab every 8 weeks until week 42. Participants could continue standard-of-care treatment. Main Outcomes and Measures: The primary end point was change from baseline in ALSFRS-R score at week 50 based on the Combined Assessment of Function and Survival (CAFS). Results: A total of 382 participants were randomly assigned 2:1 to receive ravulizumab (n = 255; mean [SD] age, 58.6 [10.6] years; 94 female [36.9%] and 161 male [63.1%]) or placebo (n = 127; mean [SD] age, 58.0 [11.0] years; 58 female [45.7%] and 69 male [54.3%]). The interim analysis showed that the observed mean change from baseline in ALSFRS-R at week 50 was -14.67 points (SE, 0.89 points; 95% CI, -16.42 to -12.91 points) for ravulizumab and -13.33 points (SE, 1.22 points; 95% CI, -15.72 to -10.93 points) for placebo, with no significant difference between the groups (mean [SE] difference, -1.34 [1.46] points; 95% CI, -4.21 to 1.53 points). Based on these data, the trial was terminated for futility. The primary analysis at week 50 showed no significant difference in CAFS between groups (mean [SE], 5.5 [10.8] points; 95% CI, -15.7 to 26.6 points; P = .61). Overall incidence rates for treatment-emergent adverse events were similar for ravulizumab (204 participants [80.0%]) and placebo (108 participants [85.0%]). Conclusions and Relevance: This trial rapidly showed that terminal complement C5 inhibition with ravulizumab did not slow functional decline in participants with ALS and that the safety profiles of ravulizumab and placebo were similar. Highly effective, novel treatments are critically needed to slow functional decline and extend survival in patients with ALS. Trial Registration: ClinicalTrials.gov Identifier: NCT04248465.

Comparing Amyotrophic lateral sclerosis (ALS) patient characteristics from the National ALS Registry and the Massachusetts ALS Registry, data through 2015.

OBJECTIVE: To compare, for completeness, ALS patients identified in the National ALS Registry (National Registry) from MA to those in the Massachusetts ALS Registry (MA Registry) through 2015. METHODS: Sensitivity analyses were conducted to determine the completeness among patients reported in both registries. Patients were matched on first and last name, month and year of birth, sex, as well as Soundex name matching. Demographics for matching and nonmatching ALS patients were also examined using bivariate analyses and logistic regression. RESULTS: There were 1,042 ALS patients in the MA Registry, and 642 patients matched (61.6%) in the National Registry. Sensitivity analyses found the National Registry had a sensitivity of 87.7% and specificity of 60%. For these matched patients, 522 (81.2%) came from Medicare. Of the 400 patients in the MA Registry not matched to the National Registry, 11.1% were nonwhite, compared to 6.0% in the matched group) (p = 0.0091) and 59.2% were diagnosed before age 60, compared to 28.6% in the matched group (p < 0.0001). Multivariate logistic regression analysis showed being an ALS case (p < 0.0001) and having an ALS diagnosis at age 60 or later (p < 0.0001) were associated with being more likely to match between the two registries. CONCLUSIONS: These findings show that ALS's non-notifiable condition status at the national level continues to pose a challenge in identifying all ALS patients. This analysis also showed missing cases at the state level even with a reporting statute. Additional strategies are needed for better patient-ascertainment to quantify all ALS patients in the U.S.

Resilient together-ALS: leveraging the NDD transdiagnostic framework to develop an early dyadic intervention for people with amyotrophic lateral sclerosis and their informal care-partners.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive weakness and eventual death, usually within 3-5 years. An ALS diagnosis is associated with substantial emotional distress for both the affected person and their family care-partners which impairs the ability to engage in important conversations about long term care planning, negatively impacts ALS symptoms for the patient, and quality of life for both patient and care-partner. Here we 1) discuss published works identified by the authors about psychosocial interventions for the ALS population, 2) identify a lack of early, dyadic interventions to support psychosocial needs of people with ALS and care-partners; 3) describe the Neurodegenerative Diseases (NDD) framework for early dyadic intervention development and 4) propose an adaptation of an evidence-based early dyadic psychosocial intervention, Recovering Together, for the unique needs of people with ALS and their care-partners (Resilient Together-ALS; RT-ALS) using the NDD framework. Future work will use stakeholder feedback to optimize the intervention for subsequent efficacy testing.

Design and Statistical Innovations in a Platform Trial for Amyotrophic Lateral Sclerosis.

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 Platform Trial, the complex statistical objectives are met using a Bayesian shared parameter analysis of function and survival. This analysis serves to provide a common integrated estimate of treatment benefit, overall slowing in disease progression, as measured by function and survival while accounting for potential differences in the shared control group using Bayesian hierarchical modeling. Clinical trial simulation is used to provide a better understanding of this novel analysis method and complex design. ANN NEUROL 2023;94:547-560.