Christian Lunetta

Introduction/Aims: Study of clinical milestones, particularly intermediate events like loss of ambulation, in large amyotrophic lateral sclerosis (ALS) cohorts is limited. Here, we leverage the ALS Natural History Consortium dataset to evaluate the time‐to‐event for several outcomes and prognostic factors that predict risk. Methods: Longitudinal data from 1950 participants were used in time‐to‐event analyses based on time from diagnosis. Outcomes were gastrostomy, loss of ambulation, loss of useful speech, non‐invasive ventilation (NIV) usage, and death equivalent (death or mechanical ventilation). Median times‐to‐event were calculated along with Kaplan–Meier curves. Cox proportional hazards models for each outcome estimated (through adjusted hazard ratios [HR]) the impact of several prognostic factors, including sex, region of onset, age at diagnosis, and the initial rate of change (delta‐FRS) in ALS Functional Rating Scale‐Revised (ALSFRS‐R) scores. Results: Estimated median times‐to‐event for clinical outcomes ranged from 1.44 to 6.21 years, with a median time to death equivalent of 2.12 years. A higher delta‐FRS was the greatest risk factor for all outcomes (HRs between 2.01 and 3.05). Limb onset decreased risk of loss of speech, NIV use, gastrostomy, and death equivalent (HRs 0.41–0.78). Older age at diagnosis increased risk of gastrostomy, NIV use, and death equivalent (HRs 1.08–1.27). Discussion: These findings further inform expectations of time to various outcomes, especially rarely investigated intermediate events, and their risk factors. The importance of progression rate supports other recent findings, highlighting delta‐FRS as a key prognostic factor with potential utility in clinical trial designs.

Background: In January 2024, the Italian Ministry of Health introduced the Rehabilitation Hospital Discharge Form (Scheda di Dimissione Ospedaliera: SDO-R), integrating functional outcome measures—Barthel Index (BI), Modified Rankin Scale (mRS), and Rehabilitation Complexity Scale– Extended (RCS-E)—with ICD-9-CM diagnosis and procedure codes to better capture rehabilitation complexity and resource use. However, no RCS-E or BI cut-offs for reimbursement have been established. Objective: To describe SDO-R data from an Intensive Rehabilitation Service (IRS) and assess whether RCS-E groupings better reflect patient complexity and functional outcomes than MDC- based diagnostic categories. Methods: Retrospective analysis of 983 consecutive admissions (January 2024–June 2025) at ICS Maugeri, Genoa. Patients with neurological (MDC 1) or orthopaedic (MDC 8) conditions were classified into three RCS-E groups: 8 (low), 9–10 (intermediate), and ≥11 (high). Statistical analyses (Kruskal–Wallis, Wilcoxon post-hoc, Chi-square) compared groups for BI, complexity markers, and therapy involvement. Results: Higher RCS-E scores were associated with lower BI scores (p-value <0.0001), greater multidisciplinary involvement (p < 0.01), and increased clinical complexity, regardless of MDC. ICD-9-CM codes did not adequately capture resource-intensive procedures such as robotic rehabilitation. Conclusions: RCS-E categories, that we identified, reflect patient complexity and resource use more effectively than MDC-based tariffs and may better inform reimbursement models. Revision of ICD-9-CM coding is needed to ensure accurate representation of resources in IRS admissions.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of upper and lower motor neurons, leading to muscle weakness, atrophy, dysarthria, ...

Tofersen is a gene-targeted therapy for superoxide dismutase 1 (SOD1)-associated amyotrophic lateral sclerosis (ALS), but neurofilament light chain (NfL) may not fully capture the biological response to treatment. We performed a multicentre retrospective longitudinal study including 24 patients with SOD1-ALS treated with intrathecal tofersen at four Italian referral centres between 2022 and 2025. Cerebrospinal fluid (CSF) and serum biomarkers were assessed at baseline, month 3, month 6, and last available administration using single-molecule array assays to quantify NfL, glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCHL–1), and total Tau. NfL decreased after treatment initiation in both CSF and serum, providing the clearest pharmacodynamic signal. In contrast, CSF GFAP increased progressively over follow-up, while CSF total Tau and UCHL–1 rose mainly at later timepoints; serum GFAP, total Tau, and UCHL–1 also showed increases during follow-up. ALS Functional Rating Scale–Revised trajectories were broadly stable, whereas disease progression rate was lower at last follow-up than at baseline. Greater reductions in CSF NfL were observed in pathogenic versus uncertain SOD1 variants, and early serum NfL and UCHL–1 changes were associated with longer-term changes in disease progression. These findings suggest that longitudinal multi-analyte profiling may refine biological response stratification beyond NfL alone in tofersen-treated SOD1-ALS.

Tofersen is a gene-targeted therapy for superoxide dismutase 1 (SOD1)-associated amyotrophic lateral sclerosis (ALS), but neurofilament light chain (NfL) may not fully capture the biological response to treatment. We performed a multicentre retrospective longitudinal study including 24 patients with SOD1-ALS treated with intrathecal tofersen at four Italian referral centres between 2022 and 2025. Cerebrospinal fluid (CSF) and serum biomarkers were assessed at baseline, month 3, month 6, and last available administration using single-molecule array assays to quantify NfL, glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCHL-1), and total tau. NfL decreased after treatment initiation in both CSF and serum, providing the clearest pharmacodynamic signal. In contrast, CSF GFAP increased progressively over follow-up, while CSF total tau and UCHL-1 rose mainly at later timepoints; serum GFAP, total tau, and UCHL-1 also showed increases during follow-up. ALS Functional Rating Scale-Revised trajectories were broadly stable, whereas disease progression rate was lower at last follow-up than at baseline. Greater reductions in CSF NfL were observed in pathogenic versus uncertain SOD1 variants, and early serum NfL and UCHL-1 changes were associated with longer-term changes in disease progression. These findings suggest that longitudinal multi-analyte profiling may refine biological response stratification beyond NfL alone in tofersen-treated SOD1-ALS.

Background: Dysphagia is common in amyotrophic lateral sclerosis (ALS), contributing to malnutrition and accelerated disease progression. Although early nutritional intervention is recommended, the optimal timing for percutaneous endoscopic gastrostomy (PEG) placement remains uncertain. This study aimed to develop and validate simple prediction models, accessible via an online calculator, to identify ALS patients likely to require PEG within 6 months. Methods: We conducted a retrospective cohort study including ALS patients followed at three Italian reference centres between February 2018 and October 2023. Predictors of PEG placement within 6 months were identified using univariate and multivariable binary logistic regression models. Prediction models were developed following Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines and underwent both internal and external validation. Results: In the development cohort (n=263; median age 63.8 years), 138 patients (52.5%) underwent PEG within 6 months. Three models were developed: the Anamnestic Prediction Model, based on age, onset site and non-invasive ventilation (NIV), showed fair predictive performance. The Anamnestic and Functional Prediction Model, incorporating age, bulbar subscore of Amyotrophic Lateral Sclerosis Functional Rating Scale—revised (ALSFRS-r) and forced vital capacity (%), demonstrated strong predictive performance (Brier score: 0.1230), excellent discrimination (concordance index (c-index) 0.91) and good calibration (Hosmer-Lemeshow p=0.59). The Anamnestic and Nutritional Prediction Model, including age, onset site, NIV, body mass index and weight loss, showed good predictive performance (Brier score: 0.1719), discrimination (c-index 0.81) and calibration (Hosmer-Lemeshow p=0.48). These findings were confirmed in an external validation cohort of 116 ALS patients. Conclusions: The prediction models provide accurate, easily implementable tools to predict PEG need within 6 months, enabling timely nutritional interventions that may improve outcomes and care quality in ALS.

Objective: Despite its clinical heterogeneity, amyotrophic lateral sclerosis is unified by early and prominent alterations in cortical excitability, increasingly recognized as contributors to disease progression. This study assessed whether the ratio between motor evoked potential (MEP) amplitude, reflecting upper motor neuron integrity, and compound muscle action potential (CMAP) amplitude, indexing lower motor neuron function, could provide an accessible marker of corticospinal excitability to stratify patients by phenotype, stage, and survival. Methods: In this multicenter retrospective study, 743 amyotrophic lateral sclerosis patients from 16 tertiary centers in Italy were analyzed. The MEP:CMAP ratio, recorded from upper limb muscles, was categorized as hyperexcitable, normal, or hypoexcitable. Phenotypes included progressive muscular atrophy (or lower motor neuron), flail arm/leg, classic, bulbar, patient with predominant upper motor neuron signs (or pyramidal), and primary lateral sclerosis. Disease stage was assessed using King's staging. Survival was analyzed using Kaplan–Meier curves and Cox regression models. Results: The MEP:CMAP ratio differed significantly across phenotypes ( p < 0.0001), with hyperexcitability predominating in lower motor neuron, flail, classic, and bulbar forms, and hypoexcitability in pyramidal and primary lateral sclerosis. Hypoexcitability increased in advanced King's stages ( p < 0.0001). Hyperexcitable patients had shorter survival ( p = 0.004), including when tested within 1 year of onset ( p = 0.006). Cox regression identified the MEP:CMAP ratio as an independent survival predictor (HR 1.84, 95% CI 1.12–3.03, p = 0.016). Interpretation: This real‐world study supports the clinical value of the MEP:CMAP ratio as a scalable biomarker of cortical excitability in amyotrophic lateral sclerosis, with prognostic relevance across phenotypes and disease stages. ANN NEUROL 2025;98:801–813

Background: Rehabilitation after stroke often employs Robots and Allied Digital Technologies (RADTs). However, evidence of their effectiveness remains inconclusive due to study heterogeneity and limited sample sizes. Methods: This is a protocol of a pragmatic multicentre, multimodal, randomised, controlled, parallel-group (1:1) interventional study with blinded assessors aimed at assessing the effectiveness and sustainability of RADT-mediated rehabilitation compared to traditional rehabilitation. The trial will recruit 596 adult subacute post-stroke patients. Participants will be randomised into either the experimental group (using RADTs and two therapists supervising four to six patients) or the control group (individual traditional rehabilitation). Patients in both groups will undergo a comprehensive rehabilitation treatment, targeting (a) upper limb sensorimotor abilities; (b) lower limb sensorimotor abilities and gait; (c) balance; and (d) cognitive abilities. Patients will undergo 25 sessions, each lasting 45 min, with a frequency of 5 (inpatients) or 3 (outpatients) times a week. The primary endpoint is the non-inferiority of RADTs in the recovery of the activities of daily living (ADL) using the modified Barthel Index. If non-inferiority is established, the study will evaluate the superiority. Secondary endpoints will analyse the improvements in the aforementioned domains, as well as changes in neural plasticity and biochemical aspects. Upper limb dexterity and gait recovery rates during treatment will be monitored. The study will also evaluate ADL and quality of life during a six-month follow-up period. Acceptability and usability of integrated RADTs-based rehabilitation for patients, families, and healthcare providers, along with economic and organisational sustainability for patients, payers, and society, will also be assessed. Conclusions: This study aims to establish stronger evidence on the effectiveness of RADTs in post-stroke patients. Trial registration number: NCT06547827.

Introduction/Aims: Hypermetabolism and weight loss are established negative prognostic factors in amyotrophic lateral sclerosis (ALS). However, the role of individualized body composition parameters in predicting ALS progression has been underexplored. This study aimed to investigate the correlation between nutritional parameters, neurofilament light chain (NfL) levels, and disease progression in ALS patients.Methods: The Global Leadership Initiative on Malnutrition criteria were used to define malnutrition in this study. Nutritional status was assessed using body mass index and bioelectrical impedance analysis. The rate of disease progression was defined by the change in the Revised ALS Functional Rating Scale score (ΔFRS). NfL was quantified using single molecule array technology. Spearman's analyses were used to assess correlations.Results: Sixty of 110 ALS patients were classified as malnourished. There was a strong positive correlation between NfL and ΔFRS (r = 0.71), and a moderate negative correlation with disease duration (r = −0.55). The correlations between NfL and body composition parameters were statistically significant, although weak. NfL levels were significantly higher in fast progressors (p < 0.0001 compared to slow progressors) and in malnourished patients (p = 0.0001). Of the 34 fast progressor patients, 28 (82%) exhibited some degree of malnutrition.Discussion: Our findings indicate that poor nutritional status, particularly reduced skeletal muscle mass—both independently and in combination with fat mass loss—is associated with elevated NfL levels and faster ALS progression. NfL, combined with nutritional parameters, could serve as a valuable biomarker for disease severity. Further research is warranted to clarify the role of skeletal muscle abnormalities in ALS progression.

Parkinson’s disease (PD) and multiple sclerosis (MS) are two chronic neurological diseases (CNDs) that have a high demand for early and continuous rehabilitation. However, accessing professional care remains a challenge, making it a key priority to identify sustainable solutions for ensuring early rehabilitation availability. Objective: The FIT4TeleNEURO pragmatic trial proposes to investigate, in real-life care settings, the superiority in terms of the effectiveness of early rehabilitation intervention with harmonized, mix-model telerehabilitation (TR) protocols (TR single approach, task-oriented—TRsA; TR combined approach, task-oriented and impairment-oriented—TRcA) compared to conventional management (control treatment, CeT) in people with PD and MS. Design, and Methods: This multicenter, randomized, three-treatment arm pragmatic trial will involve 300 patients with CNDs (PD, N = 150; MS, N = 150). Each participant will be randomized (1:1:1) to the experimental groups (20 sessions of TRsA or TRcA according to a mix-model—3 asynchronous + 1 synchronous session/week) or the control group (20 sessions of CeT). Primary and secondary outcome measures will be obtained at the baseline (T0), post-intervention (T1, 5 weeks after baseline), and follow-up (T2, 3 months after the end of the treatment). A multidimensional evaluation (cognitive, motor, and quality of life domains) will be conducted at each time point of assessment (T0; T1; T2). The primary outcome measures will be the assessment of change (T0 vs. T1 vs. T2) in static and dynamic balance, measured using the Mini-Balance Evaluation Systems Test. Usability and acceptability assessment will be also investigated. Expected Results: Implementing TR protocols will enable a more targeted and efficient response to the growing demand for rehabilitation in the early stages of CNDs. Both the TRsA and TRcA approaches are expected to be more effective than CeT, with the combined approach likely providing greater benefits in secondary outcome measures. Finally, the acceptability of the asynchronous modality could open the door to scalable solutions, such as digital therapeutics.