RESUMEN
BACKGROUND: Social cognition (SC) deficits are included in the amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTDS) revised diagnostic criteria. However, the impact of SC assessment on cognitive classification and the cognitive-behavioural correlates of SC remain unclear. This cross-sectional study aimed to assess the impact of SC assessment on ALS-FTDS categorisation and explore the relationship of SC with executive functions (EF) and behaviour changes in a cohort of ALS patients. METHODS: 121 patients and 56 healthy controls from the Turin ALS Centre underwent cognitive/behavioural testing, including the SC subdomains of facial emotion recognition, and cognitive and affective theory of mind (ToM). RESULTS: Patients performed significantly worse than controls in all SC explored domains, and 45% of patients exhibited a deficit in at least one SC test, dissociated from the presence of EF deficits. In 13% of cases, the SC deficit was isolated and subclinical. SC assessment contributed to the attribution of cognitive impairment in 10% of patients. Through a statistical clustering approach, we found that ToM only partially overlaps with EF while behaviour changes are associated with emotional disorders (anxiety and depression). CONCLUSIONS: SC is overall independent of EF in ALS, with ToM only partially associated with specific EF measures, and behaviour changes associated with emotional disorders. The influence of SC on cognitive categorisation and the frequent identification of a subclinical SC impairment have implications in a clinical setting, considering the substantial impact of cognitive impairment on disease burden and therapeutic choices.
Asunto(s)
Esclerosis Amiotrófica Lateral , Función Ejecutiva , Cognición Social , Teoría de la Mente , Humanos , Esclerosis Amiotrófica Lateral/psicología , Esclerosis Amiotrófica Lateral/complicaciones , Esclerosis Amiotrófica Lateral/fisiopatología , Masculino , Femenino , Persona de Mediana Edad , Estudios Transversales , Teoría de la Mente/fisiología , Anciano , Pruebas Neuropsicológicas , Disfunción Cognitiva/psicología , Disfunción Cognitiva/diagnóstico , Estudios de Casos y ControlesRESUMEN
Introduction: Serum heat shock protein (HSP) concentrations have been reported as potential biomarkers for amyotrophic lateral sclerosis (ALS). Here, we investigate the role of serum HSP70, HSP90, and DNAJC7 as biomarkers for ALS. Methods: Serum samples were collected from ALS patients and volunteer controls from three different clinical cohorts (in Germany, Ireland, and Italy). Serum HSP concentrations were determined using enzyme-linked immunosorbent assay. Descriptive statistics, generalized logistic regression, and Cox proportional hazards models were used to model associations between log serum HSP concentrations and ALS risk. Results: In total, 251 ALS patients and 184 healthy volunteers were included. Logistic regression models failed to find associations between ALS risk and log serum concentration of HSP70 (OR 0.43, 95% CI: 0.10-1.78, p = 0.242), HSP90 (OR 0.95, 95% CI: 0.39-2.37, p = 0.904), or DNAJC7 (OR 1.55, 95% CI: 0.90-2.68, p = 0.118). Survival of ALS patients was not associated with log serum concentration of HSP HSP70 (HR1.06, 95% CI: 0.36-3.14, p = 0.916), HSP90 (HR 1.17, 95% CI: 0.67-2.02, p = 0.584), or DNAJC7 (HR 0.83, 95% CI: 0.57-1.21, p = 0.337). Discussion: We did not replicate previous findings that serum HSP70 and HSP90 concentrations were associated with risk of ALS. DNAJC7 was not associated with ALS risk, and there were no obvious longitudinal patterns in log serum concentrations of HSP70, HSP90, or DNAJC7. In addition, serum HSP concentrations were not associated with ALS survival.
RESUMEN
OBJECTIVE: To systematically assess decline in respiratory measures in amyotrophic lateral sclerosis (ALS) and to examine the impact of sex, disease onset type and baseline morbidity on progression. METHODS: The REVEALS study (Registry of Endpoints and Validated Experiences in ALS) was conducted between April 2018 and February 2021 in six European ALS centers. Slow and forced vital capacity (S/FVC), sniff nasal inspiratory pressure (SNIP), peak cough flow, amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R), and respiratory morbidity were collected. Data were analyzed using a Bayesian multiple outcomes random effects model. RESULTS: Two hundred and eighty participants had a median of three assessments (IQR 2.0, 5.0) over a median of 8 months (IQR 2.3, 14.1). There were 974 data collection timepoints. Differences in respiratory measures and rates of decline between disease-onset and sex subgroups were identified. Females had lower scores in all respiratory measures and females with bulbar onset ALS had faster decline compared with other sub-groups. These differences were not detected by the ALSFRS-r respiratory subscale. Dyspnea, orthopnea, and a higher King's stage at baseline were associated with lower respiratory scores throughout follow-up, while having a regular productive cough at baseline was associated with lower peak cough flow scores. CONCLUSION: Respiratory function declines more quickly in females with ALS compared with males when measured by FVC, SVC, SNIP, or PCF, but not the ALSFRS-R respiratory sub-score. Higher baseline King's staging and the presence of clinical respiratory symptoms at baseline were associated with worse respiratory function. The ALSFRS-R respiratory sub-score is poorly correlated with objective respiratory measurements.
RESUMEN
OBJECTIVE: To analyze disease-modifying effects of percutaneous endoscopic gastrostomy (PEG) insertion for supporting nutrition, noninvasive ventilation (NIV), and tracheostomy-assisted ('invasive') ventilation (TIV) in amyotrophic lateral sclerosis (ALS). METHODS: We retrospectively analyzed survival in a large population-based incident cohort that was prospectively followed up in our center. Analysis considered several known ALS-related prognostic variables. RESULTS: In this population, PEG and NIV in multivariable analysis significantly correlated to survival as computed by disease onset to death/tracheostomy. NIV was associated with better survival while PEG was associated with reduced survival. Other independent prognostic factors were age at ALS onset, diagnostic delay, and flail arm/leg and pure upper motor neuron (PUMN) phenotypes. The length of survival after TIV was significantly associated with age at ALS onset (inverse correlation) whereas other variables did not. The length of survival after TIV correlated to age at ALS onset in such a way that each additional year of age at ALS onset decreased survival by about 0.7 months. Patients who underwent both TIV and NIV did not experience a better survival than those who underwent TIV alone. CONCLUSION: The lack of effect of enteral nutrition on ALS survival probably reflected the timing of PEG insertion in patients with more severe disease. By contrast, patients who used mechanical ventilation had an increased overall survival compared with non-ventilated ones. The study also provided new information showing that the combined use of NIV and TIV did not may prolong ALS survival as compared to TIV alone.
Asunto(s)
Esclerosis Amiotrófica Lateral , Gastrostomía , Respiración Artificial , Humanos , Esclerosis Amiotrófica Lateral/mortalidad , Esclerosis Amiotrófica Lateral/terapia , Gastrostomía/métodos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Respiración Artificial/estadística & datos numéricos , Estudios de Cohortes , Estudios Retrospectivos , Nutrición Enteral/métodos , Nutrición Enteral/estadística & datos numéricos , Adulto , Ventilación no Invasiva/métodos , Análisis de SupervivenciaRESUMEN
BACKGROUND AND PURPOSE: The use of multiple tests, including spirometry, arterial blood gas (ABG) analysis and overnight oximetry (OvOx), is highly recommended to monitor the respiratory function of patients with motor neuron disease (MND). In this study, we propose a composite score to simplify the respiratory management of MND patients and better stratify their prognosis. MATERIALS AND METHODS: We screened the clinical charts of 471 non-ventilated MND patients referred to the Neuro-rehabilitation Unit of the San Raffaele Scientific Institute of Milan (January 2001-December 2019), collecting spirometric, ABG and OvOx parameters. To evaluate the prognostic role of each measurement, univariate Cox regression for death/tracheostomy was performed, and the variables associated with survival were selected to design a scoring system. Univariate and multivariate Cox regression analyses were then carried out to evaluate the prognostic role of the score. Finally, results were replicated in an independent cohort from the Turin ALS Center. RESULTS: The study population included 450 patients. Six measurements were found to be significantly associated with survival and were selected to design a scoring system (maximum score = 8 points). Kaplan-Meier analysis showed significant stratification of survival and time to non-invasive mechanical ventilation adaptation according to score values, and multivariate analysis confirmed the independent effect of the respiratory score on survival of each cohort. CONCLUSION: Forced vital capacity, ABG and OvOx parameters provide complementary information for the respiratory management and prognosis of MND patients and the combination of these parameters into a single score might help neurologists predict prognosis and guide decisions on the timing of the implementation of different diagnostic or therapeutic approaches.
Asunto(s)
Análisis de los Gases de la Sangre , Enfermedad de la Neurona Motora , Oximetría , Espirometría , Humanos , Femenino , Masculino , Persona de Mediana Edad , Anciano , Análisis de los Gases de la Sangre/métodos , Oximetría/métodos , Enfermedad de la Neurona Motora/sangre , Enfermedad de la Neurona Motora/fisiopatología , Enfermedad de la Neurona Motora/diagnóstico , Pronóstico , Estudios Retrospectivos , AdultoRESUMEN
Amyotrophic lateral sclerosis (ALS) is a heterogeneous progressive neurodegenerative disorder with available treatments such as riluzole and edaravone extending survival by an average of 3-6 months. The lack of highly effective, widely available therapies reflects the complexity of ALS. Omics technologies, including genomics, transcriptomic and proteomics have contributed to the identification of biological pathways dysregulated and targeted by therapeutic strategies in preclinical and clinical trials. Integrating clinical, environmental and neuroimaging information with omics data and applying a systems biology approach can further improve our understanding of the disease with the potential to stratify patients and provide more personalised medicine. This chapter will review the omics technologies that contribute to a systems biology approach and how these components have assisted in identifying therapeutic targets. Current strategies, including the use of genetic screening and biosampling in clinical trials, as well as the future application of additional technological advances, will also be discussed.
Asunto(s)
Esclerosis Amiotrófica Lateral , Genómica , Biología de Sistemas , Humanos , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/terapia , Biología de Sistemas/métodos , Genómica/métodos , Proteómica/métodos , AnimalesRESUMEN
BACKGROUND: Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis. METHODS: ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed. FINDINGS: Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI -0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]). INTERPRETATION: Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated. FUNDING: Orphazyme.
Asunto(s)
Esclerosis Amiotrófica Lateral , Fármacos Neuroprotectores , Humanos , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Masculino , Femenino , Método Doble Ciego , Persona de Mediana Edad , Anciano , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/efectos adversos , Resultado del Tratamiento , Adulto , Hidroxilaminas/uso terapéutico , Hidroxilaminas/efectos adversos , Hidroxilaminas/farmacología , Oxadiazoles/uso terapéutico , Oxadiazoles/efectos adversosRESUMEN
OBJECTIVE: While the cognitive-behavioral characteristics of amyotrophic lateral sclerosis (ALS) patients carrying C9orf72 pathological repeat expansion have been extensively studied, our understanding of those carrying SOD1 variants is mostly based on case reports. The aim of this paper is to extensively explore the cognitive-behavioral characteristics of a cohort of ALS patients carrying pathogenetic variants of SOD1 gene, comparing them to patients without pathogenetic variants of 46 ALS-related genes (wild-type [WT]-ALS) and healthy controls. METHODS: All ALS patients seen at the Turin ALS expert center in the 2009-2021 period who underwent both cognitive/behavioral and extensive genetic testing were eligible to be included in the study. Only patients with SOD1 pathogenetic variants (n = 28) (SOD1-ALS) and WT-ALS (n = 829) were enrolled in the study. A series of 129 controls was also included. RESULTS: Among the 28 SOD1-ALS patients, 16 (57.1%) had normal cognitive function, 5 (17.9%) isolated cognitive impairment (ALSci) (17.9%), 6 (21.4%) isolated behavioral impairment (ALSbi), 1 (3.6%) cognitive and behavioral impairment (ALScbi), and no one ALS-FTD. SOD1-ALS performed worse than controls in all explored domains, in particular Social Cognition and Language domains. SOD1-ALS patients had similar scores in all tests compared to WT-ALS, except the Story-based Empathy Task (SET), where they performed worse. INTERPRETATION: Cognitive-behavioral impairment is much more common in SOD1 patients than previously assumed. SOD1-ALS are characterized by a more frequent impairment of Social Cognition and, less markedly, of Language domains. These findings have relevant implication both in the clinical and in the research setting, also considering recently approved treatment for SOD1-ALS. ANN NEUROL 2024;96:150-158.
Asunto(s)
Esclerosis Amiotrófica Lateral , Disfunción Cognitiva , Superóxido Dismutasa-1 , Humanos , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/psicología , Esclerosis Amiotrófica Lateral/complicaciones , Masculino , Femenino , Superóxido Dismutasa-1/genética , Anciano , Persona de Mediana Edad , Disfunción Cognitiva/genética , Disfunción Cognitiva/psicología , AdultoRESUMEN
OBJECTIVE: To investigate sex-related differences in amyotrophic lateral sclerosis (ALS) prognosis and their contributing factors. METHODS: Our primary cohort was the Piemonte and Aosta Register for ALS (PARALS); the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) and the Answer ALS databases were used for validation. Survival analyses were conducted accounting for age and onset site. The roles of forced vital capacity and weight decline were explored through a causal mediation analysis. Survival and disease progression rates were also evaluated after propensity score matching. RESULTS: The PARALS cohort included 1,890 individuals (44.8% women). Men showed shorter survival when stratified by onset site (spinal onset HR 1.20, 95% CI 1.00-1.44, p = 0.0439; bulbar onset HR 1.36, 95% CI 1.09-1.70, p = 0.006917), although women had a steeper functional decline (+0.10 ALSFRS-R points/month, 95% CI 0.07-0.15, p < 0.00001) regardless of onset site. Instead, men showed worse respiratory decline (-4.2 forced vital capacity%/month, 95% CI -6.3 to -2.2, p < 0.0001) and faster weight loss (-0.15 kg/month, 95% CI -0.25 to -0.05, p = 0.0030). Causal mediation analysis showed that respiratory function and weight loss were pivotal in sex-related survival differences. Analysis of patients from PRO-ACT (n = 1,394, 40.9% women) and Answer ALS (n = 849, 37.2% women) confirmed these trends. INTERPRETATION: The shorter survival in men is linked to worse respiratory function and weight loss rather than a faster disease progression. These findings emphasize the importance of considering sex-specific factors in understanding ALS pathophysiology and designing tailored therapeutic strategies. ANN NEUROL 2024;96:159-169.
Asunto(s)
Esclerosis Amiotrófica Lateral , Progresión de la Enfermedad , Caracteres Sexuales , Humanos , Esclerosis Amiotrófica Lateral/mortalidad , Esclerosis Amiotrófica Lateral/fisiopatología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Capacidad Vital/fisiología , Estudios de Cohortes , Sistema de Registros , Factores Sexuales , Pronóstico , Análisis de Supervivencia , AdultoRESUMEN
BACKGROUND AND PURPOSE: Thalamic alterations have been reported as a major feature in presymptomatic and symptomatic patients carrying the C9orf72 mutation across the frontotemporal dementia-amyotrophic lateral sclerosis (ALS) spectrum. Specifically, the pulvinar, a high-order thalamic nucleus and timekeeper for large-scale cortical networks, has been hypothesized to be involved in C9orf72-related neurodegenerative diseases. We investigated whether pulvinar volume can be useful for differential diagnosis in ALS C9orf72 mutation carriers and noncarriers and how underlying functional connectivity changes affect this region. METHODS: We studied 19 ALS C9orf72 mutation carriers (ALSC9+) accurately matched with wild-type ALS (ALSC9-) and ALS mimic (ALSmimic) patients using structural and resting-state functional magnetic resonance imaging data. Pulvinar volume was computed using automatic segmentation. Seed-to-voxel functional connectivity analyses were performed using seeds from a pulvinar functional parcellation. RESULTS: Pulvinar structural integrity had high discriminative values for ALSC9+ patients compared to ALSmimic (area under the curve [AUC] = 0.86) and ALSC9- (AUC = 0.77) patients, yielding a volume cutpoint of approximately 0.23%. Compared to ALSmimic, ALSC9- showed increased anterior, inferior, and lateral pulvinar connections with bilateral occipital-temporal-parietal regions, whereas ALSC9+ showed no differences. ALSC9+ patients when compared to ALSC9- patients showed reduced pulvinar-occipital connectivity for anterior and inferior pulvinar seeds. CONCLUSIONS: Pulvinar volume could be a differential biomarker closely related to the C9orf72 mutation. A pulvinar-cortical circuit dysfunction might play a critical role in disease progression and development, in both the genetic phenotype and ALS wild-type patients.
Asunto(s)
Esclerosis Amiotrófica Lateral , Proteína C9orf72 , Imagen por Resonancia Magnética , Mutación , Pulvinar , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/diagnóstico por imagen , Esclerosis Amiotrófica Lateral/fisiopatología , Esclerosis Amiotrófica Lateral/patología , Proteína C9orf72/genética , Demencia Frontotemporal/genética , Demencia Frontotemporal/fisiopatología , Demencia Frontotemporal/diagnóstico por imagen , Demencia Frontotemporal/patología , Heterocigoto , Pulvinar/diagnóstico por imagen , Pulvinar/fisiopatología , Pulvinar/patologíaRESUMEN
BACKGROUND: This update of the guideline on the management of amyotrophic lateral sclerosis (ALS) was commissioned by the European Academy of Neurology (EAN) and prepared in collaboration with the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD) and the support of the European Network for the Cure ALS (ENCALS) and the European Organization for Professionals and Patients with ALS (EUpALS). METHODS: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the effectiveness of interventions for ALS. Two systematic reviewers from Cochrane Response supported the guideline panel. The working group identified a total of 26 research questions, performed systematic reviews, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available. RESULTS: A guideline mapping effort revealed only one other ALS guideline that used GRADE methodology (a National Institute for Health and Care Excellence [NICE] guideline). The available evidence was scarce for many research questions. Of the 26 research questions evaluated, the NICE recommendations could be adapted for 8 questions. Other recommendations required updates of existing systematic reviews or de novo reviews. Recommendations were made on currently available disease-modifying treatments, multidisciplinary care, nutritional and respiratory support, communication aids, psychological support, treatments for common ALS symptoms (e.g., muscle cramps, spasticity, pseudobulbar affect, thick mucus, sialorrhea, pain), and end-of-life management. CONCLUSIONS: This update of the guideline using GRADE methodology provides a framework for the management of ALS. The treatment landscape is changing rapidly, and further updates will be prepared when additional evidence becomes available.
Asunto(s)
Esclerosis Amiotrófica Lateral , Esclerosis Amiotrófica Lateral/terapia , Humanos , Europa (Continente) , Neurología/normas , Neurología/métodos , Enfermedades Neuromusculares/terapiaAsunto(s)
Neuropatía Hereditaria Motora y Sensorial , Enfermedad de la Neurona Motora , Humanos , Neuropatía Hereditaria Motora y Sensorial/genética , Neuropatía Hereditaria Motora y Sensorial/diagnóstico , Enfermedad de la Neurona Motora/genética , Enfermedad de la Neurona Motora/diagnóstico , Italia , Masculino , Femenino , Adulto , Persona de Mediana Edad , LinajeRESUMEN
The Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) was developed more than 25 years ago as an instrument to monitor functional change over time in patients with ALS. It has since been revised and extended to meet the needs of high data quality in ALS trials (ALSFRS-R), however a full re-validation of the scale was not completed. Despite this, the scale has remained a primary outcome measure in clinical trials. We convened a group of clinical trialists to discuss and explore opportunities to improve the scale and propose alternative measures. In this meeting report, we present a call to action on the use of the ALSFRS-Revised scale in clinical trials, focusing on the need for (1) harmonization of the ALSFRS-R administration globally, (2) alignment on a set of recommendations for clinical trial design and statistical analysis plans (SAPs), and (3) use of additional outcome measures.
Asunto(s)
Esclerosis Amiotrófica Lateral , Humanos , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Progresión de la EnfermedadRESUMEN
Respiratory failure assessment is among the most debatable research topics in amyotrophic lateral sclerosis (ALS) clinical research due to the wide heterogeneity of its presentation. Among the different pulmonary function tests (PFTs), maximal voluntary ventilation (MVV) has shown potential utility as a diagnostic and monitoring marker, able to capture early respiratory modification in neuromuscular disorders. In the present study, we explored calculated MVV (cMVV) as a prognostic biomarker in a center-based, retrospective ALS population belonging to the Piemonte and Valle d'Aosta registry for ALS (PARALS). A Spearman's correlation analysis with clinical data and PFTs showed a good correlation of cMVV with forced vital capacity (FVC) and a moderate correlation with some other features such as bulbar involvement, ALSFRS-R total score, blood oxygen (pO2), carbonate (HCO3-), and base excess (BE), measured with arterial blood gas analysis. Both the Cox proportional hazard models for survival and the time to non-invasive ventilation (NIV) measurement highlighted that cMVV at diagnosis (considering cMVV(40) ≥ 80) is able to stratify patients across different risk levels for death/tracheostomy and NIV indication, especially considering patients with FVC% ≥ 80. In conclusion, cMVV is a useful marker of early respiratory failure in ALS, and is easily derivable from standard PFTs, especially in asymptomatic ALS patients with normal FVC measures.
RESUMEN
OBJECTIVES: This study assessed the feasibility of using the Milano-Torino staging (MiToS) system for conducting economic evaluation to measure health outcomes in amyotrophic lateral sclerosis (ALS). METHODS: A Markov model was developed using the MiToS system and evaluated with a hypothetical treatment versus standard of care. Health utilities and transition probabilities were derived from the literature. Four-time horizons (1, 5, 10, and 20 years) were examined. Treatment effects of 20-35% relative risk reduction (RRR) of progressing to the next MiToS stage were assessed. Three patient distribution scenarios were tested: (1) all patients began in stage 0; (2) patient distribution based on real-world TONiC study; (3) distribution based on the PRO-ACT database. Health outcomes (quality-adjusted life-years [QALYs], life-years [LYs]) were reported with a 3% discount rate. RESULTS: A time horizon of 10 years fully captured treatment benefits: incremental QALYs were 0.28-0.60, 0.21-0.45, and 0.26-0.55 for scenarios 1-3, respectively; incremental LYs were 0.56-1.17, 0.46-0.97, and 0.53-1.11, respectively. CONCLUSION: MiToS-based staging can be used for conducting economic analyses in ALS. Estimated incremental QALY and LY gains were meaningful within the context of ALS, for hypothetical treatments with RRR of 20-35%.
Asunto(s)
Esclerosis Amiotrófica Lateral , Humanos , Esclerosis Amiotrófica Lateral/terapia , Análisis Costo-Beneficio , Estudios de Factibilidad , Membranas Asociadas a Mitocondrias , Progresión de la Enfermedad , Años de Vida Ajustados por Calidad de VidaRESUMEN
OBJECTIVE: The resting-state functional connectome has not been extensively investigated in amyotrophic lateral sclerosis (ALS) spectrum disease, in particular in relationship with patients' genetic status. METHODS: Here we studied the network-to-network connectivity of 19 ALS patients carrying the C9orf72 hexanucleotide repeat expansion (C9orf72+), 19 ALS patients not affected by C9orf72 mutation (C9orf72-), and 19 ALS-mimic patients (ALSm) well-matched for demographic and clinical variables. RESULTS: When compared with ALSm, we observed greater connectivity of the default mode and frontoparietal networks with the visual network for C9orf72+ patients (P = 0.001). Moreover, the whole-connectome showed greater node degree (P < 0.001), while sensorimotor cortices resulted isolated in C9orf72+. INTERPRETATION: Our results suggest a crucial involvement of extra-motor functions in ALS spectrum disease. In particular, alterations of the visual cortex may have a pathogenic role in C9orf72-related ALS. The prominent feature of these patients would be increased visual system connectivity with the networks responsible of the functional balance between internal and external attention.
Asunto(s)
Esclerosis Amiotrófica Lateral , Conectoma , Humanos , Imagen por Resonancia Magnética , Esclerosis Amiotrófica Lateral/diagnóstico por imagen , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Proteína C9orf72/genética , Expansión de las Repeticiones de ADN/genética , Proteínas/genética , MutaciónRESUMEN
OBJECTIVE: Noninvasive mechanical ventilation (NIMV) improves amyotrophic lateral sclerosis (ALS) quality of life and survival. However, data about its effect on disease progression are still lacking. Here, we test whether NIMV use changed the rate of functional decline among ALS patients. METHODS: In this retrospective observational study, we included 448 ALS patients followed up at the ALS Center in Turin, Italy, who underwent NIMV during the disease course. The primary outcome was the change in functional decline after NIMV initiation adjusting for covariates. Functional decline was based on the nonrespiratory items of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R). RESULTS: NIMV initiation resulted in a slower functional decline (mean improvement = 0.16 points per month, 95% confidence interval = 0.12-0.19, p < 0.001), with consistent effects observed across various demographic factors, including sex, age at diagnosis, and disease duration before NIMV initiation. This finding was replicated using the PRO-ACT (Pooled Resource Open-Access ALS Clinical Trials) dataset. The favorable impact of NIMV on ALSFRS-R progression was evident independently of disease stages. Notably, NIMV benefits were not dose-dependent but were particularly prominent for nighttime respiratory support. INTERPRETATION: NIMV significantly influences the rate of motor progression in ALS, and this effect is not determined by the nonlinearity of ALSFRS-R trajectory. The functional decline slowed following NIMV initiation, independently of the site of disease onset or disease severity at the time of NIMV initiation. Our findings underscore the importance of timely NIMV initiation for all ALS patients and highlight the need to consider NIMV-induced slowing of disease progression when evaluating clinical trial outcomes. ANN NEUROL 2024;95:817-822.
Asunto(s)
Esclerosis Amiotrófica Lateral , Humanos , Esclerosis Amiotrófica Lateral/diagnóstico , Respiración Artificial , Progresión de la Enfermedad , Calidad de Vida , Neuronas MotorasRESUMEN
BACKGROUND AND OBJECTIVES: TARDBP patients are considered particularly prone to cognitive involvement, but no systematic studies of cognitive impairment in TARDBP patients are available. The aim of this article was to depict in depth the cognitive-behavioral characteristics of a cohort of patients with amyotrophic lateral sclerosis (ALS) carrying TARDBP pathogenetic variants followed by an ALS referral center. METHODS: We enrolled all patients with ALS seen at the Turin ALS expert center in the 2009-2021 period who underwent extensive genetic testing and a neuropsychological battery encompassing executive function, verbal memory, language, visual memory, visuoconstructive abilities, attention/working memory, psychomotor speed, nonverbal intelligence, cognitive flexibility, social cognition, and behavior. Tests were compared with the Mann-Whitney U test on age-corrected, sex-corrected, and education-corrected scores. Cognition was classified as normal (ALS-CN); isolated cognitive impairment (ALSci), that is, evidence of executive and/or language dysfunction; isolated behavioral impairment (ALSbi), that is, identification of apathy; cognitive and behavioral impairment (ALScbi), that is, evidence meeting the criteria for both ALSci and ALSbi; and frontotemporal dementia (ALS-FTD). RESULTS: This study includes 33 patients with TARDBP pathogenetic variants (TARDBP-ALS) (median age 61 years [interquartile range (IQR) 53-67], 8 female [24.2%]) and 928 patients with ALS not carrying the pathogenic variant (WT-ALS) (median age 67 years [IQR 59-74], 386 female [41.6%]). TARDBP-ALS cases were also compared with 129 matched controls (median age 66 years [IQR 57.5-71.5], 55 female [42.6%]). TARDBP-ALS and WT-ALS patients were cognitively classified as ALS-CN (54% vs 58.8%, respectively), ALSci (21.2% vs 18.3%), ALSci (9.1% vs 9.5%), ALScbi (6.1% vs 6.0%), and ALS-FTD (9.1 vs 6.7%), with no significant difference (p = 0.623). Compared with controls, TARDBP-ALS had a worse performance in executive functions, visual memory, visuoconstructive abilities, verbal fluency, and the apathy behavioral component of FrSBe. The scores of performed tests, including all Edinburgh Cognitive and Behavioral ALS Screen subdomains, were similar in TARDBP-ALS and WT-ALS. DISCUSSION: TARDBP-ALS patients were significantly more impaired than controls in most examined domains but do not show any specific pattern of cognitive impairment compared with WT-ALS. Our findings are relevant both clinically, considering the effect of cognitive impairment on patients' decision-making and caregivers' burden, and in designing clinical trials for the treatment of patients carrying TARDBP pathogenetic variants.
Asunto(s)
Esclerosis Amiotrófica Lateral , Apatía , Demencia Frontotemporal , Anciano , Femenino , Humanos , Persona de Mediana Edad , Cognición , Memoria a Corto Plazo , MasculinoRESUMEN
BACKGROUND: Uric acid (UA) has emerged as a factor that can modify cognitive function both in the general population and in people with neurodegenerative disorders. Since very few data are available concerning amyotrophic lateral sclerosis (ALS), we explored the correlation of UA levels and cognitive impairment in a large cohort of ALS patients. METHODS: We enrolled ALS patients consecutively seen at the Turin ALS expert center in the 2007-2018 period who underwent both cognitive/behavioral and UA evaluation at diagnosis. Patients were classified in 5 categories: normal cognition (ALS-CN), isolated cognitive impairment (ALSci), isolated behavioural impairment (ALSbi), cognitive and behavioural impairment (ALScbi), frontotemporal dementia (ALS-FTD). For this study, ALSci, ALSbi and ALScbi were merged as ALS with intermediate cognitive impairment (ALS-INT). RESULTS: Out of the 841 ALS patients, 422 had ALS-CN, 271 ALS-INT and 148 ALS-FTD. The mean values of UA were significantly different among the cognitive subgroups of patients, with the lowest values in the ALS-FTD (ALS-CN, 288.5 ± 78.0 (µmol/L; ALS-INT, 289.7 ± 75.5 µmol/L; ALS-FTD, 271.8 ± 74.9 µmol/L; p = 0.046). The frequency of ALS-FTD was significantly higher in the 1st tertile of UA. Lower UA levels were independently associated with FTD (OR 1.32, 95% c.i. 1.01-1.43; p = 0.038) in binary logistic regression. CONCLUSIONS: We found that in ALS lower UA serum levels are correlated with reduced frequency of co-morbid FTD. Patients with intermediate cognitive impairment showed UA levels similar to ALS-CN but higher than ALS-FTD, implying that higher UA levels can prevent or delay cognitive function deterioration.