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Background: With increasing recognition of the value of incorporating prognostic markers into amyotrophic lateral sclerosis (ALS) trial design and analysis plans, there is a pressing need to understand which among the prevailing clinical and biochemical markers have real value, and how they can be optimally used., Methods: A subset of patients with ALS recruited through the multi-center Phenotype-Genotype-Biomarker study (clinicaltrials.gov: NCT02327845) was identified as "trial-like" based on meeting common trial eligibility criteria. Clinical phenotyping was performed by evaluators trained in relevant assessments. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH), urinary p75 ECD , plasma microRNA-181, and an array of biochemical and clinical measures were evaluated for their prognostic value. Associations with functional progression were estimated by random-slopes mixed models of ALS functional rating scale-revised (ALSFRS-R) score. Associations with survival were estimated by log-rank test and Cox proportional hazards regression. Potential sample size savings from adjusting for given biomarkers in a hypothetical trial were estimated., Findings: Baseline serum NfL is a powerful prognostic biomarker, predicting survival and ALSFRS-R rate of decline. Serum NfL <40 pg/mL and >100 pg/mL correspond to future ALSFRS-R slopes of ∼0.5 and ∼1.5 points/month, respectively. Serum NfL also adds value to the best available clinical predictors, encapsulated by the European Network to Cure ALS (ENCALS) predictor score. In models of functional decline, the addition of NfL yields ∼25% sample size saving above those achieved by inclusion of either clinical predictors or ENCALS score alone. The prognostic value of serum pNfH, urinary p75 ECD , and plasma miR-181ab is more limited., Interpretation: Among the multitude of biomarkers considered, only blood NfL adds value to the ENCALS prediction model and should be incorporated into analysis plans for all ongoing and future ALS trials. Defined thresholds of NfL might also be used in trial design, for enrichment or stratified randomisation, to improve trial efficiency., Funding: NIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242)., Competing Interests: Declaration of interests MB reports grants from the NIH (U01NS107027, U54NS092091) and the ALS Association (16-TACL-242) in support of this work. He is also an unpaid member of the Board of Trustees for the ALS Association. He has served as a consultant to Alector, Alexion, Annexon, Arrowhead, Biogen, Cartesian, Denali, Eli Lilly, Horizon, Immunovant, Novartis, Roche, Sanofi, Takeda, UCB, and UniQure. EAM reports grants from the NIH (U01NS107027, U54NS092091). He also serves as a consultant to Annexon, Biogen, Bial Biotech, Cortexyme, Chase Therapeutics, Enterin, nQ Medical, Partner Therapeutics, Stoparkinson Healthcare, and UCB. He has served on DSMBs for NeuroSense Therapeutics, Novartis, and Sanofi. AM reports grants from the NIH (U01NS107027). He has also provided consulting services to Roche, Pfizer, and Accure Therapeutics. MLR reports support from grants from the NIH (U01NS107027, U54NS092091) and FightMND. EH has nothing to declare. VL has nothing to declare. DR has nothing to declare. SS has nothing to declare. IM has nothing to declare. YC has nothing to declare. VG currently is an employee of Biohaven Pharmaceutical Inc. JS receives research funding from the NIH < MDA, FSHD Society, Friends of FSH Research, and FSHD Canada. He also serves as a consultant or on scientific advisory boards for Avidity, Fulcrum, Dyne, Armatus, Epic Bio, Roche, Lupin, and Entrada. JH has nothing to declare. RR reports grants from the NIH (U54NS092091) in support of this work. She is also an unpaid member of the Medical Advisory Board of the Association for Frontotemporal Dementias (AFTD) and a paid member of the Scientific Advisory Board of the Kissick Family Foundation FTD Grant Program. CAM reports funding from the ALS Association and the NIH (U54NS092091). LP reports support from the Mayo Clinic Foundation and grants from the National Institute on Aging (5P30AG0062677, U19AG063911) the National Institute of Neurological Disorders and Stroke (U54NS123743, R35NS097273, P01NS084974) and Target ALS Foundation. CM reports grants from the NIH (AG066597, AG076411, AG066152, AG072979, NS109260, NS092091), Department of Defense, and support from the Penn Institute on Aging, Decrane Family PPA Fund, and Newhouse Fund.2. JW reports funding from the NIH (U01NS107027, U54NS092091) and the ALS Association (16-TACL-242) in support of this work. The CReATe Consortium (U54NS092091) is part of the NIH Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), NCATS. This Consortium is funded through a collaboration between NCATS and the NINDS. This work was also supported by a Clinical Trial Readiness grant (U01NS107027) from NINDS and by a grant from the ALS Association to support the CReATe Biorepository (grant ID 16-TACL-242)., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective : The identification of effective therapeutics for ALS necessitates valid and responsive outcome measures to track disease progression and therapeutic gain in clinical trial settings. The Amyotrophic Lateral Sclerosis-Health Index (ALS-HI) is a multifaceted, disease-specific patient-reported outcome measure (PRO) designed to measure ALS symptomatic disease burden in adults with ALS. Methods: Through a national cross-sectional study of individuals with ALS, we identified the most important symptoms in ALS. These symptoms were incorporated into the ALS-HI, a measure that quantifies the multifaceted disease burden in ALS. We performed factor analysis, qualitative patient interviews, test-retest reliability assessment, and known groups analysis to evaluate and validate the ALS-HI. Results: The cross-sectional study included 497 participants with ALS who identified the most important symptoms to include in the ALS-HI. Fifteen participants beta tested the ALS-HI and found it to be clear, easy to use, and relevant. Twenty-one participants engaged in a test-retest reliability study, which indicated the reliability of the instrument (intraclass correlation coefficient = 0.952 for full instrument). The final ALS-HI and its subscales demonstrated a high internal consistency (Cronbach's α = 0.981 for full instrument) and an ability to differentiate between groups with dissimilar disease severity. Conclusions: This research supports use of the ALS-HI as a valid, sensitive, reliable, and relevant PRO to assess the multifactorial disease burden faced by adults with ALS. The ALS-HI has potential as a mechanism to track disease progression and treatment efficacy during therapeutic trials.

Objective : Amyotrophic lateral sclerosis (ALS) is a multi-system disorder characterized primarily by motor neuron degeneration, but may be accompanied by cognitive dysfunction. Statistically appropriate criteria for establishing cognitive impairment (CI) in ALS are lacking. We evaluate quantile regression (QR), that accounts for age and education, relative to a traditional two standard deviation (SD) cutoff for defining CI. Methods : QR of cross-sectional data from a multi-center North American Control (NAC) cohort of 269 healthy adults was used to model the 5 th percentile of cognitive scores on the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). The QR approach was compared to traditional two SD cutoff approach using the same NAC cohort (2SD-NAC) and to existing UK-based normative data derived using the 2SD approach (2SD-UK) to assess the impact of cohort selection and statistical model in identifying CI in 182 ALS patients. Results : QR-NAC models revealed that age and education impact cognitive performance on the ECAS. Based on QR-NAC normative cutoffs, the frequency of CI in the 182 PENN ALS patients was 15.9% for ALS specific, 12.6% for ALS nonspecific, and 15.4% for ECAS total. This frequency of CI is substantially more conservative in comparison to the 2SD-UK (20.3%-34.6%) and modestly more conservative to the 2SD-NAC (14.3%-16.5%) approaches for estimating CI. Conclusions : The choice of normative cohort has a substantial impact and choice of statistical method a modest impact on defining CI in ALS. This report establishes normative ECAS thresholds to identify whether ALS patients in the North American population have CI.

Amyotrophic lateral sclerosis, when viewed as a biological entity rather than a clinical syndrome, probably evolves along a continuum, with the initial clinically silent phase eventually evolving into clinically manifest amyotrophic lateral sclerosis. Since motor neuron degeneration is incremental and cumulative over time, it stands to reason that the clinical syndrome of amyotrophic lateral sclerosis is probably preceded by a prodromal state characterized by minor motor abnormalities that are initially insufficient to permit a diagnosis of amyotrophic lateral sclerosis. This prodromal period, however, is usually missed, given the invariably long delays between symptom onset and diagnostic evaluation. The Pre-Symptomatic Familial ALS Study, a cohort study of pre-symptomatic gene mutation carriers, offers a unique opportunity to observe what is typically unseen. Here we describe the clinical characterization of 20 pre-symptomatic mutation carriers (in SOD1, FUS and C9orf72) whose phenoconversion to clinically manifest disease has been prospectively studied. In so doing, we observed a prodromal phase of mild motor impairment in 11 of 20 phenoconverters. Among the n = 12 SOD1 A4V mutation carriers, phenoconversion was characterized by abrupt onset of weakness, with a short (1-3.5 months) prodromal period observable in a small minority (n = 3); the observable prodrome invariably involved the lower motor neuron axis. By contrast, in all n = 3 SOD1 I113T mutation carriers, diffuse lower motor neuron and upper motor neuron signs evolved insidiously during a prodromal period that extended over a period of many years; prodromal manifestations eventually coalesced into a clinical syndrome that is recognizable as amyotrophic lateral sclerosis. Similarly, in all n = 3 C9orf72 hexanucleotide repeat expansion mutation carriers, focal or multifocal manifestations of disease evolved gradually over a prodromal period of 1-2 years. Clinically manifest ALS also emerged following a prodromal period of mild motor impairment, lasting >4 years and ∼9 months, respectively, in n = 2 with other gene mutations (SOD1 L106V and FUS c.521del6). On the basis of this empirical evidence, we conclude that mild motor impairment is an observable state that precedes clinically manifest disease in three of the most common genetic forms of amyotrophic lateral sclerosis (SOD1, FUS, C9orf72), and perhaps in all genetic amyotrophic lateral sclerosis; we also propose that this might be true of non-genetic amyotrophic lateral sclerosis. As a diagnostic label, mild motor impairment provides the language to describe the indeterminate (and sometimes intermediate) transition between the unaffected state and clinically manifest amyotrophic lateral sclerosis. Recognizing mild motor impairment as a distinct clinical entity should generate fresh urgency for developing biomarkers reflecting the earliest events in the degenerative cascade, with potential to reduce the diagnostic delay and to permit earlier therapeutic intervention., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer's disease based on inferred underlying histopathology. Parkinson's disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM sleep behaviour disorder. Huntington's disease benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. Spinal muscular atrophy clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in frontotemporal dementia illustrate the differential role of biomarkers based on genotype. Similar advances in amyotrophic lateral sclerosis would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic amyotrophic lateral sclerosis relies on a clear conceptual framework for defining the earliest stages of disease. Clinically manifest amyotrophic lateral sclerosis may emerge abruptly, especially among those who harbour genetic mutations associated with rapidly progressive amyotrophic lateral sclerosis. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioural impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioural impairment before progression to amyotrophic lateral sclerosis. Biomarkers are critically important to studying pre-symptomatic amyotrophic lateral sclerosis and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counselling, informed consent, communication of results and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counselling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building on what we have learned-more broadly from other pre-symptomatic neurodegenerative diseases and specifically from amyotrophic lateral sclerosis gene mutation carriers-we present a road map to early intervention, and perhaps even disease prevention, for all forms of amyotrophic lateral sclerosis., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

The electronic health record (EHR) is designed principally to support the provision and documentation of clinical care, as well as billing and insurance claims. Broad implementation of the EHR, however, also yields an opportunity to use EHR data for other purposes, including research and quality improvement. Indeed, effective use of clinical data for research purposes has been a long-standing goal of physicians who provide care for patients with ALS, but the quality and completeness of clinical data, as well as the burden of double data entry into the EHR and into a research database, have been persistent barriers. These factors provided motivation for the development of the ALS Toolkit, a set of interactive digital forms within the EHR that enable easy, consistent, and structured capture of information relevant to ALS patient care (as well as research and quality improvement) during clinical encounters. Routine use of the ALS Toolkit within the context of the CReATe Consortium's institutional review board-approved Clinical Procedures to Support Research in ALS (CAPTURE-ALS) study protocol, permits aggregation of structured ALS patient data, with the goals of empowering research and driving quality improvement. Widespread use of the ALS Toolkit through the CAPTURE-ALS protocol will help to ensure that ALS clinics become a driving force for collecting and aggregating clinical data in a way that reflects the true diversity of the populations affected by this disease, rather than the restricted subset of patients that currently participate in dedicated research studies., (© 2021 Wiley Periodicals LLC.)

Amyotrophic lateral sclerosis (ALS) is a multi-system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients; however, factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-learning technique, we observed that single nucleotide polymorphisms collectively associate with baseline cognitive performance in a large ALS patient cohort (N = 327) from the multicenter Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium. We demonstrate that a polygenic risk score derived using sCCA relates to longitudinal cognitive decline in the same cohort and also to in vivo cortical thinning in the orbital frontal cortex, anterior cingulate cortex, lateral temporal cortex, premotor cortex, and hippocampus (N = 90) as well as post-mortem motor cortical neuronal loss (N = 87) in independent ALS cohorts from the University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Our findings suggest that common genetic polymorphisms may exert a polygenic contribution to the risk of cortical disease vulnerability and cognitive dysfunction in ALS., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

Objective: To identify preferred neurofilament assays and clinically validate serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) as prognostic and potential pharmacodynamic biomarkers relevant to amyotrophic lateral sclerosis (ALS) therapy development., Methods: In this prospective, multicenter, longitudinal observational study of patients with ALS (n = 229), primary lateral sclerosis (n = 20), and progressive muscular atrophy (n = 11), biological specimens were collected, processed, and stored according to strict standard operating procedures (SOPs). Neurofilament assays were performed in a blinded manner by independent contract research organizations., Results: For serum NfL and pNfH measured using the Simoa assay, there were no missing data (i.e., technical replicates below the lower limit of detection were not encountered). For the Iron Horse and Euroimmun pNfH assays, such missingness was encountered in ∼4% and ∼10% of serum samples, respectively. Mean coefficients of variation for NfL in serum and CSF were both ∼3%. Mean coefficients of variation for pNfH in serum and CSF were ∼4%-5% and ∼2%-3%, respectively, in all assays. Baseline serum NfL concentration, but not pNfH, predicted the future Revised ALS Functional Rating Scale (ALSFRS-R) slope and survival. Incorporation of baseline serum NfL into mixed effects models of ALSFRS-R slopes yields an estimated sample size saving of ∼8%. Depending on the method used to estimate effect size, use of serum NfL (and perhaps pNfH) as pharmacodynamic biomarkers, instead of the ALSFRS-R slope, yields significantly larger sample size savings., Conclusions: Serum NfL may be considered a clinically validated prognostic biomarker for ALS. Serum NfL (and perhaps pNfH), quantified using the Simoa assay, has potential utility as a pharmacodynamic biomarker of treatment effect., (© 2020 American Academy of Neurology.)