European Journal of Neurology

BackgroundNon-invasive mechanical ventilation (NIMV) improves Amyotrophic Lateral Sclerosis (ALS) quality of life and survival. However, data about its effect on disease progression are still lacking. ObjectiveTo test whether NIMV use changed the rate of functional decline among ALS patients. MethodsIn this retrospective observational study, we included 465 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 when adjusting for covariates. Functional decline was based on the non-respiratory items of the ALS Functional Rating Score - Revised (ALSFRS-R). ResultsA slower progression of functional decline followed NIMV initiation (mean improvement 0.13, 95%CI 0.11 to 0.16, p<0.001) regardless of sex, age at diagnosis, and disease duration prior to NIMV initiation. Indeed, the disease stage at NIMV initiation (early or advanced) did not influence the results. Respiratory support exerts its slowing effect mainly on the progression of spinal motor function. ConclusionsWe proved that NIMV influences the rate of motor progression in ALS. This result was not a consequence of the ALSFRS-R floor effect. The functional decline slowed after starting NIMV independently of the site of disease onset. Our results reinforce the importance of not delaying NIMV initiation in all ALS patients. NIMV-induced slowing of disease progression should also be accounted for when evaluating clinical trial outcomes.

Amyotrophic Lateral Sclerosis (ALS) is a terminal condition with accelerated loss of motor neurons (MN), resulting in the progressive paralysis of affected patients. ALS is either sporadic (90%) or genetically transmitted (10%) and affects cortical (pyramidal) and spinal cord (lower) MN, axons, and respective muscle endplates. ALS research has focused on MN survival, and current FDA-approved therapies provide only small patient survival benefits. This study reports the intravenous (IV) delivery of serial infusions of allogenic Schwann cell-derived extracellular vesicles (SCEV). The recipient had transient clinical stabilization during treatment but deteriorated rapidly during a pause in the infusions. There were no SCEV infusion-related adverse events observed. Allogeneic SCEV appeared safe for IV delivery in this case and may have therapeutic potential.

IntroductionSerum cardiac troponin T (cTnT) levels are elevated in the majority of amyotrophic lateral sclerosis (ALS) patients and increase over time. Neurofilament light chain (NfL) is an established therapy response biomarker in ALS as superoxide dismutase 1 (SOD1)-ALS patients treated with the antisense oligonucleotide tofersen show a decrease in NfL. In this study we assess the course of cTnT levels in SOD1-ALS at baseline and during tofersen treatment. MethodsSerum cTnT was analyzed at baseline and during tofersen treatment in 23 SOD1-ALS patients at two specialized ALS centers in Germany and compared to a control cohort of 74 ALS patients without SOD1-mutations and not treated with tofersen. ResultscTnT levels increased in the control ALS-cohort over time (p<0.0001) but not in the tofersen group (p=0.36). CK, and CK-MB levels did not show relevant changes over time. The median monthly increase of cTnT was 0.045 points (IQR 0.02-0.08) in the control ALS cohort and 0.01 points (IQR -0.01-0.03) in the tofersen group (p=0.0013). The fold change in cTnT levels of the tofersen-treated cohort (median 1.2; IQR 0.77-1.59) was significantly less and even showed a reduction in some patients compared to the control group (median 1.89; IQR 1.35-2.75) (p=0.0003). DiscussionIn this study, we find a response signal of cTnT to tofersen treatment, which supports the value of cTnT as an independent biomarker in ALS. These results contribute to the notion that cTnT may provide additional value as a progression and treatment response biomarker in ALS complementary to NfL and warrant further investigations. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/25322198v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@1c4870aorg.highwire.dtl.DTLVardef@17ddef4org.highwire.dtl.DTLVardef@b86903org.highwire.dtl.DTLVardef@f67176_HPS_FORMAT_FIGEXP M_FIG C_FIG

IntroductionMany individuals with sickle cell disease (SCD) die before age 60, despite early detection via neonatal screening and implementation of treatments such as vaccines and antibiotic prophylaxis and the increasing availability of disease modifying therapies. This study evaluated the causes and independent predictors of mortality in a SCD population in Brazil. MethodsThis analysis was performed within the multicenter Recipient Epidemiology and Donor Evaluation (REDS)-III SCD cohort which was established at 6 participating centers in Brazil from 2013-2018. Participants were randomly selected as eligible and recruited at routine visits. Medical records were reviewed to abstract clinical and laboratory data. Mortality and cause of death were confirmed by local chart review as well as linkage to the Brazilian death certificate database. Key variables were compared between deceased and alive participants using Chi2 test for categorical variables and Mann-Whitney test for continuous variables. Stepwise logistic regression then a Cox regression multivariable model was performed to identify independent predictors for mortality within the adult participants. ResultsThere were 2,793 participants in the cohort (1,558, 55.8%, <18 years) and 159 (5.7%) were confirmed to be deceased by the end of follow up: 142 adults (>18 years) and 17 children. The median life expectancy was 65.7. Within adults, infection was the main identifiable cause of death (33.3%), followed by pulmonary causes (25.2%) and neurologic causes (14.5%). Five (3.1%) patients had an unknown cause of death. Independent predictors of mortality were age [Hazard Ratio (HR) 1.03; 95% CI 1.01-1.04; p<.01], iron overload (HR 1.68; 95% CI1.09-2.60; p<.02] and previous hospital admission (HR 1.68; 95% CI 1.10-2.56; p<.02). DiscussionMortality in Brazilian SCD individuals is shifting from children to adults, with increased rates of death in the third and fourth decades of life. Individuals with SCD are dying 10 years before the general population in Brazil. The main causes of death in our cohort were infections, acute chest syndrome and stroke, highlighting the need for prompt recognition and treatment of these complications. Screening and treatment for iron overload and closer monitoring and consideration of disease modifying therapies for patients with frequent hospital admissions are important as both were identified as independent predictors of mortality.

ObjectiveTo describe the safety and efficacy of risdiplam in non-sitter adult patients with 5q spinal muscular atrophy (SMA). MethodsType 2 SMA adult patients, who were not eligible for nusinersen, were offered risdiplam through the expanded access program. Patients were followed up with a battery of scales and clinical measures. ResultsSix non-sitter patients (17 - 46 years old) were treated with risdiplam. One patient reported mild adverse events (dyspepsia and headache). After one year of treatment, all patients showed clinically meaningful improvements in at least one scale and none of them showed any clinically meaningful deterioration. Two patients showed a clinically significant increase in the body mass index and other two in the revised upper limb module. Moreover, clinically meaningful improvements were found in motor (axial and upper limbs), bulbar (speech and swallowing) and respiratory (coughing) domains of functional scales, in five patients. Four subjects achieved at least one of the goals set with the goal attainment scale (GAS). DiscussionThis series suggests the safety and efficacy of risdiplam in non-sitter adult SMA patients. In these patients, functional scales and GAS are more appropriate than motor scales to detect changes, because they include axial, bulbar and respiratory domains.

BackgroundAmyotrophic lateral sclerosis (ALS) is an old onset devastating neurodegenerative disorder. Young-onset ALS cases especially sporadic ones who are between 25 and 45 years are rarely affected by the disease. Despite the identification of numerous candidate genes associated with ALS, the aetiology of the disease remains elusive due to extreme genetic and phenotypic variability. The advent of affordable whole exome sequencing has opened new avenues for unraveling the diseases pathophysiology better. Methods and ResultsOur aim was to determine the genetic basis of an Indian-origin, young onset sporadic ALS patient with very rapid deterioration of the disease course without any cognitive decline who was screened for mutations in major ALS candidate genes by Whole exome sequencing. Variants detected were reconfirmed by Sanger Sequencing. The clinicopathological features were investigated and two heterozygous missense variants harboring each in ANXA11, in one of the four conserved C terminal domains (R452W) and another in the SIGMAR1 (R208W) were thus identified respectively. Both of these variants were predicted to be damaging by pathogenicity prediction tools and various In silico methods. ConclusionsOur study revealed two potentially pathogenic variants in two ALS candidate genes. The genetic makeup of ALS patients from India has been the subject of a few prior studies, but none of them examined ANXA11 and SIGMAR1 genes so far. These results establish the framework for additional research into the pathogenic processes behind these variations that result in sporadic ALS disease and further our understanding of the genetic makeup of Indian ALS patients.

Amyotrophic Lateral Sclerosis is the most common motor neuron disease. It is incurable and, at the time of this study, only two treatments with a limited therapeutical effect are available: riluzole and edavarone (not in Europe). These treatments have been shown to delay the progression of the disease by a maximum of 10%. We recently showed that glycolic acid (GA) and D-lactate (DL) are able to revert some of the phenotypes observed in iPSC-derived neurons from FUS- and SOD-1-ALS patients in vitro. Here we show that the administration of GA and DL is able to delay the progression of the disease in SOD1-G93A mice and protect spinal motor neurons against neuronal death. Interestingly, GA and DL were also able to attenuate the lethality in the TBPH silencing strain (iTBPHpkk(108354)) in Drosophila, showing a conserved role between species. Based on these results, we performed two experimental treatments in ALS patients carrying a disease-causing mutation in FUS and SOD-1 respectively. As GA and DL have been shown to be toxic (kidney stones, altered hepatic metabolism) and even lethal above certain doses in humans, we developed and used a specific formulation containing L-alanine to avoid these side effects. Our results show that, together with L-alanine as supportive treatment, GA and DL were well tolerated by the patients. Although promising, well designed and placebo-controlled clinical trials need to be performed in order to confirm the good tolerability and the therapeutic effects in ALS patients.

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by reduced expression of the survival motor neuron (SMN) protein. In addition to affecting motor neuron survival, SMN deficiency impacts multisystem physiology and neurotransmission. Dopaminergic dysfunction has been reported in mouse models of SMA, leading to postural and locomotor impairments that improve upon treatment with L-DOPA and benserazide. However, whether altered dopamine metabolism contributes to clinical symptoms in SMA patients remains unclear. To investigate this issue, we conducted a real-world observational study involving pediatric patients with SMA1, SMA2, and SMA3. We performed a longitudinal measurement of the main dopamine-related catabolites - 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) - in cerebrospinal fluid (CSF) samples collected at baseline and after five intrathecal doses of Nusinersen, an SMN-enhancing therapy. No significant differences were observed in CSF DOPAC and HVA levels across SMA types or following treatment, and no association emerged with SMN2 copy number. In contrast, lower baseline DOPAC levels were detected in SMA1 patients requiring gastrostomy and tracheostomy, and were associated with reduced improvement on the CHOP-INTEND scale. These findings suggest that reduced central dopaminergic turnover reflects disease progression in SMA1 and is associated with more severe clinical impairment and limited functional recovery.

1.1BackgroundNusinersen has substantially increased survival and improved disease progression in Spinal Muscular Atrophy (SMA) patients. However, treatment response is heterogeneous, with some patients gaining the ability to sit and walk whilst others display less obvious changes. MethodFrom the SMA Reach UK and the Italian Telethon Network, 124 non-sitter SMA patients treated with nusinersen under 4 years were included and randomly allocated to training and testing (80/20%). Tree and regression-based machine learning for survival outcomes were compared, and oblique random forests were selected, with a testing C-Index of 0.74. The features were selected from items of the CHOP-INTEND and HINE-2 motor function assessments, respiratory and swallowing status using mutual information. FindingsSixty-two patients (50%) achieved sitting, at a median age of 2.4 years. The predicted median time-to-sitting in those requiring tube feeding at treatment initiation was 4-months later than those without, and this was the most influential factor. Specific motor function features, including the ability to kick in supine, were strongly associated with a higher likelihood of sitting. InterpretationThis work provides a framework for predicting nusinersen-response and represents the first stage in personalised counselling on treatment plans for SMA. FundingSupport for SMA Reach is provided by Biogen, Roche and Novartis, and historically NIHR BRC, SMA Trust, the MRC Translational Research Centre and MD UK. Support for the Italian network is provided by Famiglie SMA, Telethon (GSP 13002), and ASAMSI. 1.2 Research Into ContextO_ST_ABSEvidence before this studyC_ST_ABSA literature search on PubMed up to January 1st 2025 with the term "("Spinal Muscular Atrophy" OR "SMA") AND ("Nusinersen" OR "Spinraza" OR "ISIS-SMNRx" OR "ISIS 396443") AND ("predict*")" across all fields was performed. Achievement of sitting after nusinersen treatment in SMA 1 has been linked to the age of treatment, symptom onset and general motor function severity (CHOP-INTEND and HINE-2 score), but no multivariable analysis or prediction of outcomes after treatment was found. Added value of this studyOur study identifies key patient features that are linked to nusinersen treatment response in non-sitter SMA 1 patients. This work provides a higher level of granularity beyond previous univariate models, yielding a framework for predicting personalised patient sitting. Crucially, we highlight that bulbar impairment as a proxy for disease severity is very influential in predicting a patients likelihood of sitting, along with specific motor function abilities at baseline. Implications of all the available evidenceDespite considerable evidence of efficacy, this work provides insights into the homogenous gross motor function response observed in SMA patients treated with nusinersen, which has been under researched. The results of this study provide individualised predictions of the likelihood of patients outcomes after treatment with nusinersen. Crucially, this work can inform clinicians in their discussions on treatment-response with parents and carers of babies with SMA.

ObjectiveTo determine if the co-presence of genetic polymorphisms related to ALS has additive effects on the course of the disease in a population-based cohort of Italian patients. MethodsThe study population includes 1245 ALS patients identified through the Piemonte Register for ALS, diagnosed between 2007 and 2016 and not carrying SOD1, TARDBP and FUS mutations. Controls were 766 age, sex, and geographically matched Italian subjects. We considered UNC13A (rs12608932), CAMTA1 (rs2412208), SLC112A (rs407135) and ZNF512B (ZNF512B) polymorphisms, as well as ATXN2 polyQ intermediate repeats and C9ORF72 GGGGCC intronic expansion. ResultsThe variants in C9orf72 (p=0.016), ATXN2 (p<0.001) and UNC13A (p<0.001) were significantly related to survival in univariate analysis, while the other considered variants did not influence ALS outcome. However, in the Cox multivariable analysis, also CAMTA1 emerged to be independently related to survival. When assessing the interaction by pairs of genes, we found that the presence of both detrimental alleles/expansion was correlated with significantly shorter survival compared to subjects non-carrying both detrimental alleles/expansions. Each association of pairs of detrimental alleles was characterized by specific clinical phenotypes. Conclusionswe demonstrated that gene polymorphisms acting as genetic modifiers of ALS survival can act on their own or in unison. Overall, 54% of patients carried at least one detrimental common polymorphism or repeat expansion, highlighting the clinical impact of our findings. In addition, the identification of the synergic effects of modifier genes represents an essential clue for explaining ALS clinical heterogeneity and should be considered in designing and interpreting clinical trials. Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSBesides the disease-causing genes, several other genes have been reported to act as modifiers of ALS phenotype, especially patients survival. However, the interactions of these genes at clinical level have never been explored. What this study addsWe demonstrated that gene polymorphisms and expansions acting as genetic modifiers of ALS survival can act on their own or in unison. Overall, 54% of patients carried at least one detrimental allele at common polymorphism or repeat expansion, highlighting the clinical impact of our findings. How this study might affect research, practice, or policThe identification of the synergic effects of modifier genes represents an essential clue for explaining ALS clinical heterogeneity, will have deep effects on clinical trial design and interpretation and support the inclusion of these polymorphisms in ALS genetic panels.

Background and AimsElderly patients, especially octogenarians, are underrepresented in recently published studies, that showed a benefit of endovascular stroke treatment (EST) for patients with acute basilar artery occlusion (BAO). We aimed to compare the clinical outcome of octogenarians with BAO and EST compared to younger patients and to identify independent outcome predictors. MethodsThis is a retrospective, single-center analysis of patients treated for BAO with EST from 01/2013 until 06/2021 in a tertiary stroke center. Octogenarians ([&ge;] 80 years) were compared to younger patients. Study endpoint was the clinical outcome as per modified Rankin Scale (mRS) 90d after stroke onset. The study groups were compared in univariate analysis and a multivariable logistic regression analysis was performed to define independent predictors for clinical outcome. ResultsIn this study cohort, 74/191 (38.7 %) octogenarians had a higher pre-stroke mRS (Median, IQR: 2, 1 - 3 octogenarians vs. 0, 0 - 1 younger patients, p < 0.001) and a comparable NIHSS before EST (Median, IQR: 21, 8 - 34 vs. 22, 10 - 38 younger, p = 0.712). They showed a comparable mRS 90d after stroke onset (Median, IQR: 5, 2 - 6 younger vs. 5, 3 - 6 octogenarians, p = 0.194), but less often a good clinical outcome (mRS 0-2: n = 27, 23% younger vs. n = 9, 11.7% octogenarians, p = 0.004). The rate of bad clinical outcome was comparable (mRS 5-6, n = 63, 46.7% younger vs. 39, 50.6 % octogenarians, p = 0.194). Baseline NIHSS was a stable independent predictor for clinical outcome in both study groups (e.g. for bad clinical outcome: in octogenarians OR 1.04, CI 100 - 10.85, p = 0.0019, in younger OR 1.061, CI 1.027-1.098, p = 0.005) ConclusionOctogenarians with acute BAO eligible for EST are less likely to be functionally independent at 90 days after stroke onset, but the rate of death or severe handicap is comparable to younger patients. The admission NIHSS predicts clinical outcome in both age groups.

BackgroundDefinitive diagnosis of amyotrophic lateral sclerosis (ALS) is only possible through a postmortem examination. Extracellular vesicles (EVs) have emerged as promising minimally invasive biomarkers for ALS, but studies vary widely in methodology and reproducibility. We conducted a systematic review and meta-analysis to evaluate the diagnostic potential of EV-associated proteins and RNAs in ALS. MethodsFollowing PRISMA guidelines, we searched PubMed and EMBASE from inception to October 15, 2025. Thirty-nine studies met inclusion criteria. Random-effects models were used for continuous outcomes, and diagnostic accuracy was assessed using hierarchical summary ROC and bivariate random-effects models. Publication bias was evaluated using Begg, Egger, and funnel plots. ResultsEV-associated TDP-43 was the most frequently studied protein. Meta-analysis of five studies showed a moderate but non-significant increase in ALS vs. controls (SMD = 1.30) with high heterogeneity (I{superscript 2} = 97.8%). Sixteen studies assessing EV-RNA biomarkers showed minimal overlap and limited independent replication. Diagnostic accuracy meta-analysis across 11 studies yielded moderate performance (AUC = 0.839). No publication bias was found across both meta-analyses. ConclusionsEV biomarkers for ALS show biological promise but are limited by methodological variability and insufficient replication. Standardized protocols, transparent data sharing, and independent validation are needed.

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options. Masitinib, a tyrosine kinase inhibitor targeting microglial and mast cell activity in ALS pathogenesis, offers potential neuroprotection. This study presents a post-hoc analysis of long-term survivors treated with masitinib at 4.5 mg/kg/day in study AB10015, comparing observed survival to predicted and historical benchmarks. Methods: Study AB10015 was a randomized, double-blind, placebo-controlled trial assessing masitinib with riluzole in ALS patients. Overall survival (OS) was measured from symptom onset to death, encompassing the double-blind period and post-study follow-up, including an optional open-label program. The ENCALS model predicted survival of long-term survivors ([&ge;]5 years). A delay in the need for mechanical assistance, such as permanent ventilation, gastrostomy, tracheostomy, or wheelchair dependence, was used as a surrogate measure for quality of life (QoL). Results: Among 130 patients receiving masitinib 4.5 mg/kg/day, the 5-year survival rate from onset was 42.3%, increasing to 50.0% in patients with an ALSFRS-R progression rate from disease onset of <1.1 points/month (AB10015 primary efficacy population), and 52.9% in a subgroup of patients without complete loss of functionality at baseline. Half of the long-term survivors had satisfactory QoL, defined as no mechanical assistance. The median OS for long-term survivors (n=55) was 121 months versus the ENCALS-predicted 42 months, yielding a 79-month residual median survival gain. Long-term survivors were prevalent across ALS baseline prognostic factors, including slow or moderate disease progression rate ({Delta}FS), severe or moderate functional severity, bulbar or spinal site of onset, respiratory function, and age. Long-term survival was less likely in patients with complete loss of function at baseline or fast progressing disease ({Delta}FS [&ge;]1.1 points/month) at baseline. Conclusions: Masitinib treatment in ALS patients showed substantial survival benefit. Long-term survivors were largely independent of ALS prognostic factors, suggesting a subpopulation driven by microglial/mast cell activity. A recently identified biomarker detecting masitinib effect on pro-inflammatory microglia may help identify responsive patients.

ObjectiveTo evaluate the diagnostic performance of serum neurofilament light chain (sNfL) and cardiac troponin T (cTnT) as biomarkers for amyotrophic lateral sclerosis (ALS) and to determine whether their combination improves diagnostic accuracy. MethodsWe retrospectively analyzed 293 ALS patients, 47 neurodegenerative disease controls and 24 healthy controls. An independent validation cohort of 501 ALS patients was additionally analyzed to confirm reproducibility of the results. Receiver operating characteristic (ROC) curve analysis was performed for sNfL, cTnT and their combination, and the area under the curve (AUC) was compared across groups. An ALS-specific cTnT cut-off of 8.35 ng/L was determined using the Youden index and applied in subgroup analyses, in which biomarker-negative ALS patients (normal sNfL and cTnT) were compared to biomarker-positive patients regarding disease duration and progression rate. ResultssNfL alone showed excellent performance in discriminating ALS patients from healthy controls (AUC = 0.951), but only moderate performance in discriminating neurodegenerative disease controls (AUC = 0.789). Combining sNfL and cTnT improved diagnostic accuracy for ALS over neurodegenerative disease controls, with a combined AUC of 0.866. Similar AUCs were observed in the validation cohort. Biomarker-negative ALS patients had a longer disease duration (73.0 vs. 18.0 months, p=0.0003) and a lower progression rate (0.19 vs. 0.70 points per months, p<0.0001) than biomarker-positive patients. InterpretationWhile sNfL alone performs well in distinguishing ALS from healthy controls, cTnT provides additional value in distinguishing ALS from disease controls. The combination of sNfL and cTnT improves diagnostic accuracy and may help identify clinically distinct ALS subgroups.

BackgroundThe glucagon-like-peptide-1 (GLP-1) hormone exerts metabolic effects leading to delayed gastric emptying, decreased appetite, and lower blood glucose levels. GLP-1 receptor activators (GLP-1RACT) are increasingly used to treat diabetes mellitus (DM) and obesity. However, their impact on the progression of amyotrophic lateral sclerosis (ALS) is unknown. ObjectiveWe examined the relationship between GLP-1RACT treatment and disease progression among people with ALS and DM. MethodsAn electronic health record search was conducted to identify consecutive patients seen at a single institution from July/2020 to February/2024 with ALS and DM diagnostic codes. All charts were reviewed for demographics, disease history, medication use, and tracheostomy/survival. Patients who did not meet Awaji ALS diagnostic criteria, lacked a documented history of DM, or had insufficient records were excluded. Those who were treated with GLP-1 receptor agonists or dipeptidyl peptidase-4 inhibitors were grouped with GLP-1RACT. The others were grouped with No-GLP-1RACT. Tracheostomy-free survival was compared between the GLP-1RACT and No-GLP-1RACT groups using Kaplan-Meier survival curves and Cox-proportional hazard models adjusted for age, sex, bulbar onset, body mass index (BMI) at diagnosis, and riluzole use. ResultsAmong the 1,310 ALS patients screened, 85 had confirmed ALS and DM diagnosis, 36 (42%) of whom were treated with GLP-1RACT. Sixty (71%) of the cohort died during follow-up. Diagnostic delay was shorter in GLP-1RACT compared to the No-GLP-1RACT group (371 vs 561 days, p=0.01). Other baseline characteristics were not significantly different between groups. Tracheostomy-free survival from symptom onset was significantly shorter in the GLP-1RACT group (median survival 31 vs 45 months, p=0.007). After adjusting for covariates, the GLP-1RACT group was associated with increased mortality compared to the No-GLP-1RACT group (hazard ratio 3.1, 95% confidence interval [1.6, 6.0], p<0.001). ConclusionsTreatment with GLP-1RACT is associated with shorter tracheostomy-free survival in people with ALS and comorbid DM.

Neurodegenerative diseases often feature a prolonged presymptomatic phase during which pathological processes evolve before overt clinical manifestation. In Amyotrophic lateral sclerosis (ALS), defining this prodromal period is critical for identifying early disease features and the optimal window for intervention, yet it remains poorly characterised. In this cross-sectional study, we compared 475 ALS patients with 285 controls recruiting across 20 ALS expert centres in Germany and Switzerland. Participants completed a structured digital questionnaire capturing prodromal complaints, healthcare utilisation, comorbidities, lifestyle factors, and weight changes during the 10 years preceding ALS symptom onset. ALS patients reported substantially higher burden of prodromal complaints than controls (OR=7.50, 95% CI 4.27-13.17; P < 0.001; Padj < 0.001), particularly neuro-motor, sensory, and pain-related symptoms. Prior to symptom onset, ALS patients more frequently consulted neurologists (OR=1.26, CI 1.10-1.44; P < 0.001; Padj = 0.007). Speech therapy consultations were significantly more common among female patients (OR = 2.35, CI 1.05-5.28; P = 0.038) and those with bulbar-onset ALS (OR = 8.67, CI 3.80-19.77; P < 0.001). Prodromal musculoskeletal dysfunction was more frequently reported by ALS patients and exhibited sex- and site-specific patterns. Herniated discs were reported more often by male ALS patients (OR=2.21, CI 1.04-4.68; P = 0.038) and by those with spinal-onset disease (OR=2.32, CI 1.38-3.93; P = 0.002). ALS patients more often completed lower secondary education (OR=1.93, CI 1.24-3.01; P = 0.004; Padj = 0.020) and were more likely to have worked in physically demanding occupations (OR=2.21, CI 1.42-3.43; P < 0.001; Padj = 0.003). Lifestyle factors differed significantly, with higher prior consumption of caffeine (OR=7.21, CI 3.27-15.89; P < 0.001; Padj < 0.001), alcohol (OR=2.25, CI 1.47-3.43; P < 0.001; Padj = 0.002), and cigarettes (OR=1.64, CI 1.20-2.24; P = 0.002) among ALS patients (Padj = 0.011). Weight trajectories differed by sex (P = 0.009), with male ALS patients showing significant loss already during the pre-onset phase (P < 0.001). These findings demonstrate that ALS is preceded by a distinct prodromal phase characterised by mild motor impairment, altered healthcare engagement, and sex- and site-specific patterns in comorbidities, lifestyle, and metabolic change. Characterising these early features of ALS may facilitate earlier diagnosis and enable timely enrolment in clinical trials.

IntroductionInternationally about 3% of people [&ge;]65 years live in Long Term Care (LTC). We examined the characteristics and outcomes of people admitted from LTC with stroke nationally and how this changed over the COVID19 pandemic. MethodsData from Irish National Audit of Stroke 2019-2023 were analysed by source of admission. An age, sex and subtype matched control group was derived from patients admitted from home. Pre-stroke and discharge modified Rankin Disability Scores (mRS) were analysed. ResultsOf 25451 admissions, 891 (3.5%) came from LTC and 22393 (88.0%) from home, 864 (4.6%) of 18805 [&ge;]65 years came from LTC. Patients median ages were higher from LTC (84 vs. 74 years) and there were more women (58.4% vs 42.6% (p<0.001, Chi Sq)). Ischaemic strokes (IS) constituted 750 (84.2%) of LTC and 19106 (85.3%) of home admissions (p=0.34). LTC admissions declined significantly during the pandemic 2019 3.74%, 2020: 3.07%, 2021: 3.19, 2022: (3.58%) and 2023: (3.98%) (p=0.045 Chi Sq). A lower proportion of LTC admissions than controls were independent pre-stroke (mRS<3) (17.1% vs. 73.5%) (Figure 1). Mortality was significantly higher for LTC residents (21.2% vs 17.3%, p=0.03). LTC patients were admitted less frequently to stroke units (60.4% vs 70.7%, p<0.001) but were equally likely to be thrombolysed (LTC: 8.9%, Home: 9.6% p=0.74). Admission from nursing home was not independently associated with discharge mRS on linear regression. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/25326324v1_fig1.gif" ALT="Figure 1"> View larger version (11K): org.highwire.dtl.DTLVardef@19a61adorg.highwire.dtl.DTLVardef@82b92borg.highwire.dtl.DTLVardef@4aba6aorg.highwire.dtl.DTLVardef@14a519_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1.C_FLOATNO Changes in proportion of admissions (p=0.045 Chi Sq) and inpatient mortality (p=0.09 Chi Sq) of patients admitted from LTC with stroke over the period of the COVID19 pandemic C_FIG Conclusion.Strokes from LTC had worse outcomes than controls and were less likely to receive organized care. The proportion of strokes from LTC declined during the pandemic.

The end-stage of amyotrophic lateral sclerosis [ALS] is presumed to be a complete Locked-In Syndrome [cLIS], assuming an internally preserved consciousness that would not be accessible anymore from the outside. However, whether consciousness persists at this stage of ALS remains to be demonstrated. Shifting the perspective from cLIS (presupposed consciousness) to Cognitive Motor Dissociation (to-be-demonstrated consciousness), we attempted to demonstrate consciousness and communication with two cLIS-ALS patients using a multimodal awareness assessment battery. It involved complete neurophysiological assessments, passive and active auditory oddball paradigm (Subject-Own-Name/P300), an auditory-based Brain-Computer-Interface [BCI] and activation-task imaging using functional MRI or [15O]H2O PET. Wakefulness (long-term EEG), brain morphology (CT or MRI scans) and resting brain metabolism ([18F]fluoro-deoxy-glucose PET) were used to describe the underlying cLIS brain function. While Patient 1 could initially follow simple commands, he failed twice to control the BCI. At follow-up, he showed no more evidence of command following and his oddball (Own Name - P300) cognitive responses has disappeared. At his unique evaluation, Patient 2 was neither able to follow simple commands nor to control the BCI. Both patients had altered wakefulness, brain atrophy, and a global cortico-sub-cortical hypometabolism pattern compatible with a disorder of consciousness, regarded as an extreme form of an ALS-associated fronto-temporal dementia. While it is not possible to firmly demonstrate the absence of awareness, each independent measure concurred with suggesting that a "degenerative disorder of consciousness" rather than a cLIS might be the final stage of ALS. In future cases, this dramatic cognitive decline should be anticipated before communication disappears to enable precise advance directives regarding end-of-life issues in case complete - and neurophysiologically confirmed - unresponsiveness occurs. Altogether, the neuroimaging features distinguishing the mechanisms in this rare condition is a significant milestone to understand end-stage ALS. The present clinical study calls for further exploration of this terminal stage to determine the prevalence of this profile in whom communication seems hopeless.

BackgroundSpinocerebellar ataxia type 3 (SCA3) is one of the most common dominantly inherited ataxia worldwide. Despite research advances, no approved disease-modifying treatment exists, and management focuses on symptom alleviation and functional capacity maximization. Symptomatic treatment guidelines are scarce, leaving decisions to physicians discretion. The lack of studies on SCA3 symptom management hinders therapy standardization. This study investigated medication usage patterns among SCA3 mutation carriers and controls recruited by the multicentric European Spinocerebellar Ataxia Type-3/Machado-Joseph Disease Initiative (ESMI). MethodsWe collected medication data from ESMI cohort participants (n=474), comparing SCA3 mutation carriers (n=344) at different disease stages with controls (n=130). We analysed medication usage based on age and ataxia severity groups as well as research centre locations using the ATC code system for classification. ResultsThere were significant differences in medication usage between mutation carriers and controls. SCA3 subjects took more vitamins, mineral supplements, and muscle relaxants, and medications targeting the nervous system. Psychoanaleptics and vitamins were introduced earlier in the disease course, with 29.2% and 25.0% of mildly ataxic individuals using such subclasses medications, respectively. Most medications, however, were only initiated during the mid-to-late stages of the disease, coinciding with the onset of most neurological symptoms. There were substantial disparities in medication usage across study centres. No significant impact on disease progression was observed for the medication subclasses more frequently used by SCA3 patients. ConclusionsThis is the first study to explore medication usage patterns in SCA3 mutation carriers. Our study provides a comprehensive overview of the medications administered in SCA3 and underscore the importance of collaborative efforts toward achieving standardized clinical practices in the management of this disease.

Background and objectivesThe most common autosomal-dominantly inherited spinocerebellar ataxias (SCA), SCA1, SCA2, SCA3 and SCA6, account for more than half of all SCA families. Disease course is characterized by progressive ataxia and additional neurological signs. Each of these SCAs is caused by a CAG repeat expansion, leading to an expanded polyglutamine stretch in the resulting type-specific protein. To comparatively investigate determinants of disease progression, we analyzed demographic and genetic data and three-year clinical time courses of neurological symptoms. The aim was to provide tailored marker candidates and prediction models to support type-specific clinical monitoring and trial design. MethodsTo analyze relationships among the different neurological symptoms, we examined co-occurrence patterns of deterioration events. Predicting disease progression was treated as a survival analysis problem. ResultsThe data set contained 1538 subjects from five different longitudinal cohorts and 3802 visits. The pattern of neurological symptoms that showed progression varied with the SCA type. Mining of the progression data revealed the Scale for the Assessment and Rating of Ataxia (SARA) sum score to be the most representative descriptor of disease progression, reflecting progression of the majority of the other included symptoms. We trained models for predicting the progression of each neurological symptom for each SCA type from genetic features, age and symptoms at the baseline visit. The most universal predictors included the SARA sum score, gait and the CAG repeat length of the expanded allele. Finally, deterioration in disease staging was studied in detail: For the milestones of deterioration, (i) the need to use walking aids and (ii) the requirement to use a wheelchair, we discovered common as well as diverging predictive markers. For clinical interpretability, a decision tree was built to indicate the probability of progression within 3 years in dependence of the top predictive features. DiscussionData-driven approaches are potent tools to identify the main contributing features of progression prediction. Progression events for the disease stage were predictable from the baseline neurological status. Remarkably, a limited number of features had predictive importance, and only few were shared among all four SCA types, including gait and the SARA sum score, confirming the need for type-specific models.