Amyotrophic Lateral Sclerosis Cohort Research Articles

Irish Amyotrophic Lateral Sclerosis Incidence: Age, Period, and Cohort Effects Using a Partial Least Squares Regression Model.

To investigate the underlying reasons for variability in the incidence rate of amyotrophic lateral sclerosis (ALS) within the Irish population between the years 1996 and 2021. The Irish ALS register was used to calculate the incidence and to subsequently extract age at diagnosis (age), year of diagnosis (period), and date of birth (cohort) for all incident patients within the study period (n = 2,771). An age-period-cohort (APC) model using partial least squares regression was constructed to examine each component separately and their respective contribution to the incidence while minimizing the well-known identifiability problem of APC effects. A dummy regression model consisting of 5 periods, 19 cohorts, and 16 age groups was used to examine nonlinear relationships within the data over time. The CIs for each of these were estimated using the jackknife method. The nonlinear model achieved R2 of 99.43% with 2-component extraction. Age variation was evident with those in the ages 65-79 years contributing significantly to the incidence (βmax = 0.0746, SE = 0.000410, CI 0.00665-0.00826). However, those aged 25-60 years contributed significantly less (βmin = -0.00393, SE = 0.000291, CI -0.00454 to -0.00340). Each successive period showed an increase in the regression model coefficient suggesting an increasing incidence over time, independent of the other factors examined-an increase of β from -0.00489 (SE = 0.000264, CI -0.00541 to -0.00437) to 0.00973 (SE = 0.000418, CI 0.0105-0.00891). A cohort effect was demonstrated showing that the contribution of those born between 1927 and 1951 contributed to a significantly greater degree than the other birth cohorts (βmax = 0.00577, SE = 0.000432, CI 0.00493-0.00662). Using the Irish population-based ALS Register, robust age, period, and cohort effects can be identified. The age effect may be accounted for by demographic shifts within the population. Changes in disease categorization, competing risks of death, and improved surveillance may account for period effects. The cohort effect may reflect lifestyle and environmental factors associated with the challenging economic circumstances in Ireland between 1927 and 1951. Age-period-cohort studies can help to account for changes in disease incidence and prevalence, providing additional insights into likely demographic and environmental factors that influence population-based disease risk.

Abnormal brain functional network dynamics in amyotrophic lateral sclerosis patients with depression.

Since depression is common in amyotrophic lateral sclerosis (ALS) patients, we aimed to explore the specific brain functional network dynamics in ALS patients with depression (ALS-D) compared with healthy controls (HCs) and ALS patients without depressive symptoms (ALS-ND). According to the DSM-V, 32 ALS-D patients were selected from a large and newly diagnosed ALS cohort. Then, 32 demographic- and cognitive-matched ALS-ND patients were also selected, and 64 HCs were recruited. These participants underwent resting-state fMRI scans, and functional connectivity state analysis and dynamic graph theory were applied to evaluate brain functional network dynamics. Moreover, the Hamilton Depression Rating Scale (HDRS) was used to quantify depressive symptoms in the ALS-D patients. Four distinct states were identified in the ALS-D patients and controls. Compared with that in HCs, the fraction rate (FR) in state 2 was significantly decreased in ALS-D patients, and the FR in state 4 was significantly increased in ALS-D patients. Compared with that of HCs, the dwell time in state 4 was significantly increased in the ALS-D patients. Moreover, compared with that in the ALS-D patients, the FR in state 3 was significantly decreased in the ALS-ND patients. Among the ALS-D patients, there was the suggestion of a positive association between HDRS scores and dwell time of state 4, but this association did not reach statistical significance (r = 0.354; p = 0.055). Depression is an important feature of ALS patients, and we found a special pattern of brain functional network dynamics in ALS-D patients. Our findings may play an important role in understanding the mechanism underlying depression in ALS patients and help develop therapeutic interventions for depressed ALS patients.

LINC complex alterations are a key feature of sporadic and familial ALS/FTD

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that primarily affects motor neurons, leading to progressive muscle weakness and loss of voluntary muscle control. While the exact cause of ALS is not fully understood, emerging research suggests that dysfunction of the nuclear envelope (NE) may contribute to disease pathogenesis and progression. The NE plays a role in ALS through several mechanisms, including nuclear pore defects, nucleocytoplasmic transport impairment, accumulation of mislocalized proteins, and nuclear morphology abnormalities. The LINC complex is the second biggest multi-protein complex in the NE and consists of the SUN1/2 proteins spanning the inner nuclear membrane and Nesprin proteins embedded in the outer membrane. The LINC complex, by interacting with both the nuclear lamina and the cytoskeleton, transmits mechanical forces to the nucleus regulating its morphology and functional homeostasis. In this study we show extensive alterations to the LINC complex in motor and cortical iPSC-derived neurons and spinal cord organoids carrying the ALS causative mutation in the C9ORF72 gene (C9). Importantly, we show that such alterations are present in vivo in a cohort of sporadic ALS and C9-ALS postmortem spinal cord and motor cortex specimens. We also found that LINC complex disruption strongly correlated with nuclear morphological alterations occurring in ALS neurons, independently of TDP43 mislocalization. Altogether, our data establish morphological and functional alterations to the LINC complex as important events in ALS pathogenic cascade, making this pathway a possible target for both biomarker and therapy development.

Detection of pTDP-43 via routine muscle biopsy: A promising diagnostic biomarker for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, pathologically characterized by TDP-43 aggregates. Recent evidence has been indicated that phosphorylated TDP-43 (pTDP-43) is present not only in motor neurons but also in muscle tissues. However, it is unclear whether testing pTDP-43 aggregation in muscle tissue would assist in the diagnosis of ALS. We propose three key questions: (i) Is aggregation of pTDP-43 detectable in routine biopsied muscles? (ii) Can detection of pTDP-43 aggregation discriminate between ALS and non-ALS patients? (iii) Can pTDP-43 aggregation be observed in the early stages of ALS? We conducted a diagnostic study comprising 2 groups: an ALS group in which 18 cases underwent muscle biopsy screened from a registered ALS cohort consisting of 802 patients and a non-ALS control group, in which we randomly selected 54 muscle samples from a biospecimen bank of 684 patients. Among the 18 ALS patients, 3 patients carried pathological GGGGCC repeats in the C9ORF72 gene, 2 patients carried SOD1 mutations, and 7 patients were at an early stage with only one body region clinically affected. The pTDP-43 accumulation could be detected in routine biopsied muscles, including biceps brachii, deltoid, tibialis anterior, and quadriceps. Abnormal aggregation of pTDP-43 was present in 94.4% of ALS patients (17/18) compared to 29.6% of non-ALS controls (16/54; p < 0.001). The pTDP-43 aggregates were mainly close to the sarcolemma. Using a semi-quantified pTDP-43 aggregates score, we applied a cut-off value of 3 as a diagnostic biomarker, resulting in a sensitivity of 94.4% and a specificity of 83.3%. Moreover, we observed that accumulation of pTDP-43 occurred in muscle tissues prior to clinical symptoms and electromyographic lesions. Our study provides proof-of-concept for the detection of pTDP-43 accumulation via routine muscle biopsy which may serve as a novel biomarker for diagnosis of ALS.

Assessing pulmonary function in ALS using electrical impedance tomography

Objective: We sought to determine whether thoracic electrical impedance tomography (EIT) could characterize pulmonary function in amyotrophic lateral sclerosis (ALS) patients, including those with facial weakness. Thoracic EIT is a noninvasive, technology in which a multi-electrode belt is placed across the chest, producing real-time impedance imaging of the chest during breathing. Methods: We enrolled 32 ALS patients and 32 age- and sex-matched healthy controls (HCs) without underlying lung disease. All participants had EIT measurements performed simultaneously with standard pulmonary function tests (PFTs), including slow and forced vital capacity (SVC and FVC) in upright and supine positions and maximal inspiratory and expiratory pressures (MIPs and MEPs, respectively). Intraclass correlation coefficients (ICCs) were calculated to assess the immediate reproducibility of EIT measurements and Pearson’s correlations were used to explore the relationships between EIT and PFT values. Results: Data from 30 ALS patients and 27 HCs were analyzed. Immediate upright SVC reproducibility was very high (ICC 0.98). Correlations were generally strongest between EIT and spirometry measures, with R values ranging from 0.64 to 0.82 (p < 0.001) in the ALS cohort. There were less robust correlations between EIT values and both MIPs and MEPs in the ALS patients, with R values ranging from 0.33 to 0.44. There was no significant difference for patients with and without facial weakness. There were no reported adverse events. Conclusion: EIT-based pulmonary measures hold the promise of providing an alternative approach for lung function assessment in ALS patients. Based on these early results, further development and study of this technology are warranted.

Venous thromboembolism risk in amyotrophic lateral sclerosis: a hospital record-linkage study

BackgroundVenous thromboembolism (VTE) can occur in amyotrophic lateral sclerosis (ALS) and pulmonary embolism causes death in a minority of cases. The benefits of preventing VTE must be weighed against the...

A Potential Role of Interleukin-5 in the Pathogenesis and Progression of Amyotrophic Lateral Sclerosis: A New Molecular Perspective.

Cumulative data suggest that neuroinflammation plays a prominent role in amyotrophic lateral sclerosis (ALS) pathogenesis. The purpose of this work was to assess if patients with ALS present a specific peripheral cytokine profile and if it correlates with neurological disability assessed by ALSFRS-R, the rate of disease progression, and the pattern of disease progression (horizontal spreading [HSP] versus vertical spreading [VSP]). We determined the levels of 15 cytokines in the blood of 59 patients with ALS and 40 controls. We identified a positive correlation between levels of pro-inflammatory cytokines (interleukin [IL]-17F, IL-33, IL-31) and the age of ALS patients, as well as a positive correlation between IL-12p/70 and survival from ALS onset and ALS diagnosis. Additionally, there was a positive correlation between the ALSFRS-R score in the upper limb and respiratory domain and IL-5 levels. In our ALS cohort, the spreading pattern was 42% horizontal and 58% vertical, with patients with VSP showing a faster rate of ALS progression. Furthermore, we identified a negative correlation between IL-5 levels and the rate of disease progression, as well as a positive correlation between IL-5 and HSP of ALS. To the best of our knowledge, this is the first study reporting a "protective" role of IL-5 in ALS.

Estimated Familial Amyotrophic Lateral Sclerosis Proportion: A Literature Review and Meta-analysis.

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder. Familial (fALS) cases are usually reported to constitute 5%-10% of all ALS cases; however, no recent literature review or meta-analysis of this proportion (referred to throughout as "proportion fALS") has been conducted. Our objective was to estimate the proportion fALS by geographic region and to assess the effect of study characteristics on the estimates. A comprehensive literature review was performed to identify all original studies reporting the number of fALS cases in an ALS cohort. The results were stratified by geographic region, study design (case series or population-based), and decade of study publication. Subgroup analyses were conducted according to family history criteria used to define fALS. We report pooled estimates of the proportion fALS from random-effects meta-analyses when >2 studies are available and I2 is < 90%; weighted averages and ranges are otherwise presented. The overall pooled proportion fALS based on a total 165 studies was 8% (0%, 71%). The proportion fALS was 9% (0%, 71%) among 107 case series and 5% (4%, 6%) among 58 population-based studies. Among population-based studies, proportion fALS by geographic region was 6% (5%, 7%; N = 37) for Europe, 5% (3%, 7%; N = 5) for Latin America, and 5% (4%, 7%; N = 12) for North America. Criteria used to define fALS were reported by 21 population-based studies (36%), and proportion fALS was 5% (4%, 5%; N = 9) for first-degree relative, 7% (4%, 11%; N = 4) for first or second-degree relative, and 11% (N = 1) for more distant ALS family history. Population-based studies published in the 2000s or earlier generated a lower pooled proportion fALS than studies published in the 2010s or later. The results suggest that variability in the reported proportion fALS in the literature may be, in part, due to the differences in geography, study design, fALS definition, and decade of case ascertainment. Few studies outside of European ancestral populations were available. The proportion fALS was marginally higher among case series compared with population-based studies, likely because of referral bias. Criteria used to define fALS were largely unreported. Consensus criteria for fALS and additional population-based studies in non-European ancestral populations are needed.

Prognostic value of motor and extramotor involvement in ALS

Objective Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder resulting in upper and lower motor neuron loss. ALS often has a focal onset of weakness, which subsequently spreads to other body regions. Survival is limited to two to five years after disease onset, often due to respiratory failure. Cognitive impairment is present in approximately 30% to 50% of patients and in 10%–15% of patients, the clinical criteria of frontotemporal dementia (FTD) are met. Methods In this retrospective single-center ALS cohort study, we examined the occurrence of cognitive and behavioral impairment in relation to motor impairment at disease presentation and studied its impact on survival. Results The degree of lower motor neuron involvement was associated with a worse survival, but there was no effect for upper motor neuron involvement. Patients who were cognitively normal had a significantly better survival compared to patients with cognitive or behavioral impairment and to patients with comorbid FTD. There was no significant difference regarding survival between patients with FTD and patients with cognitive or behavioral impairment. Conclusions The extent of motor and extramotor involvement in patients with ALS at disease presentation holds complementary prognostic information.

Genetic overlap between ALS and other neurodegenerative or neuromuscular disorders

Objective In Norway, 89% of patients with Amyotrophic lateral sclerosis (ALS) lacks a genetic diagnose. ALS genes and genes that cause other neuromuscular or neurodegenerative disorders extensively overlap. This population-based study examined whether patients with ALS have a family history of neurological disorders and explored the occurrence of rare genetic variants associated with other neurodegenerative or neuromuscular disorders. Methods During a two-year period, blood samples and clinical data from patients with ALS were collected from all 17 neurological departments in Norway. Our genetic analysis involved exome sequencing and bioinformatics filtering of 510 genes associated with neurodegenerative and neuromuscular disorders. The variants were interpreted using genotype-phenotype correlations and bioinformatics tools. Results A total of 279 patients from a Norwegian population-based ALS cohort participated in this study. Thirty-one percent of the patients had first- or second-degree relatives with other neurodegenerative disorders, most commonly dementia and Parkinson’s disease. The genetic analysis identified 20 possible pathogenic variants, in ATL3, AFG3L2, ATP7A, BICD2, HARS1, KIF1A, LRRK2, MSTO1, NEK1, NEFH, and SORL1, in 25 patients. NEK1 risk variants were present in 2.5% of this ALS cohort. Only four of the 25 patients reported relatives with other neurodegenerative or neuromuscular disorders. Conclusion Gene variants known to cause other neurodegenerative or neuromuscular disorders, most frequently in NEK1, were identified in 9% of the patients with ALS. Most of these patients had no family history of other neurodegenerative or neuromuscular disorders. Our findings indicated that AFG3L2, ATP7A, BICD2, KIF1A, and MSTO1 should be further explored as potential ALS-causing genes.

The Beaumont behavioral intervention in a Chinese amyotrophic lateral sclerosis cohort

Objective The prevalence of behavior impairment (27.38%) in the Chinese amyotrophic lateral sclerosis (ALS) cohort is lower. We hypothesize that the screening scales used among studies might not be appropriate to diagnose behavioral disorders in ALS patients. So, we urgently need to find a behavior scale with a high detection rate designed specifically for ALS. This study aims to verify the Chinese translation of the Beaumont Behavioral Inventory (BBI) as an effective assessment in a Chinese ALS cohort. Methods Ninety-eighty ALS patients and ninety-three healthy controls were included in this cross-sectional study. All participants took emotional state, overall cognitive, sleep quality and gastroenteric function, and behavioral evaluation. Results The BBI scores showed a strong association with the amyotrophic lateral sclerosis-Frontotemporal Dementia-Questionnaire (ALS-FTD-Q) (rs = 0.71, p < 0.001) as well as a moderate correlation with the Frontal Behavioral Inventory (FBI) (rs = 0.55, p < 0.001). High internal consistency was demonstrated in patients using BBI-after items (Cronbach’s a = 0.89). When tested against clinical diagnoses, the optimal cutoff of total BBI score was identified at 5.5 (AUC = 0.95; SE = 0.02; 95% CI [0.91, 0.99]), the BBI reached optimal sensitivity and specificity values (91.5% and 87.2%). The BBI turned out to be more precise than the FBI (AUC = 0.76; SE = 0.05; 95% CI [0.66, 0.86]) and the ALS-FTD-Q (AUC = 0.84; SE = 0.04; 95% CI [0.77, 0.92]). Conclusion The Chinese version of BBI is a quicker and more efficient instrument for assessing behavioral impairment in the ALS population in China.

Environmental risk scores of persistent organic pollutants associate with higher ALS risk and shorter survival in a new Michigan case/control cohort

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal, progressive neurogenerative disease caused by combined genetic susceptibilities and environmental exposures. Identifying and validating these exposures are of paramount importance to modify disease...

Classifying flow cytometry data using Bayesian analysis helps to distinguish ALS patients from healthy controls.

Given its wide availability and cost-effectiveness, multidimensional flow cytometry (mFC) became a core method in the field of immunology allowing for the analysis of a broad range of individual cells providing insights into cell subset composition, cellular behavior, and cell-to-cell interactions. Formerly, the analysis of mFC data solely relied on manual gating strategies. With the advent of novel computational approaches, (semi-)automated gating strategies and analysis tools complemented manual approaches. Using Bayesian network analysis, we developed a mathematical model for the dependencies of different obtained mFC markers. The algorithm creates a Bayesian network that is a HC tree when including raw, ungated mFC data of a randomly selected healthy control cohort (HC). The HC tree is used to classify whether the observed marker distribution (either patients with amyotrophic lateral sclerosis (ALS) or HC) is predicted. The relative number of cells where the probability q is equal to zero is calculated reflecting the similarity in the marker distribution between a randomly chosen mFC file (ALS or HC) and the HC tree. Including peripheral blood mFC data from 68 ALS and 35 HC, the algorithm could correctly identify 64/68 ALS cases. Tuning of parameters revealed that the combination of 7 markers, 200 bins, and 20 patients achieved the highest AUC on a significance level of p < 0.0001. The markers CD4 and CD38 showed the highest zero probability. We successfully validated our approach by including a second, independent ALS and HC cohort (55 ALS and 30 HC). In this case, all ALS were correctly identified and side scatter and CD20 yielded the highest zero probability. Finally, both datasets were analyzed by the commercially available algorithm 'Citrus', which indicated superior ability of Bayesian network analysis when including raw, ungated mFC data. Bayesian network analysis might present a novel approach for classifying mFC data, which does not rely on reduction techniques, thus, allowing to retain information on the entire dataset. Future studies will have to assess the performance when discriminating clinically relevant differential diagnoses to evaluate the complementary diagnostic benefit of Bayesian network analysis to the clinical routine workup.

The role of peripheral immunity in ALS: a population-based study.

Systemic inflammation has been proposed as a relevant mechanism in amyotrophic lateral sclerosis (ALS). Still, comprehensive data on ALS patients' innate and adaptive immune responses and their effect on the clinical phenotype are lacking. Here, we investigate systemic immunity in a population-based ALS cohort using readily available hematological indexes. We collected clinical data and the complete blood count (CBC) at diagnosis in ALS patients from the Piemonte and Valle d'Aosta Register for ALS (PARALS) from 2007 to 2019. Leukocytes populations, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic-immune-inflammation index (SII), and lymphocyte-to-monocyte ratio (LMR) were derived from CBC. All variables were analyzed for association with clinical features in the entire cohort and then in sex- and age-based subgroups. Neutrophils (P = 0.001) and markers of increased innate immunity (NLR, P = 0.008 and SII, P = 0.006) were associated with a faster disease progression. Similarly, elevated innate immunity correlated with worse pulmonary function and shorter survival. The prognosis in women also correlated with low lymphocytes (P = 0.045) and a decreased LMR (P = 0.013). ALS patients with cognitive impairment exhibited lower monocytes (P = 0.0415). The dysregulation of the systemic immune system plays a multifaceted role in ALS. More specifically, an elevated innate immune response is associated with faster progression and reduced survival. Conversely, ALS patients with cognitive impairment showed a reduction in monocyte count. Additionally, immune response varied according to sex and age, thus suggesting that involved immune pathways are patient specific. Further studies will help translate those findings into clinical practice or targeted treatments.

Distinct neuroinflammatory signatures exist across genetic and sporadic amyotrophic lateral sclerosis cohorts.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. ALS is on a pathogenetic disease spectrum with frontotemporal dementia, referred to as ALS-frontotemporal spectrum disorder (ALS-FTSD). For mutations associated with ALS-FTSD, such as the C9orf72 hexanucleotide repeat expansion, the molecular factors associated with heterogeneity along this spectrum require further characterization. Here, using a targeted NanoString molecular barcoding approach, we interrogate neuroinflammatory dysregulation and heterogeneity at the level of gene expression in post-mortem motor cortex tissue from a cohort of clinically heterogeneous C9-ALS-FTSD cases. We identified 20 dysregulated genes in C9-ALS-FTSD, with enrichment of microglial and inflammatory response gene sets. Two genes with significant correlations to available clinical metrics were selected for validation: FKBP5, a correlate of cognitive function, and brain-derived neurotrophic factor (BDNF), a correlate of disease duration. FKBP5 and its signalling partner, NF-κB, appeared to have a cell type-specific staining distribution, with activated (i.e. nuclear) NF-κB immunoreactivity in C9-ALS-FTSD. Expression of BDNF, a correlate of disease duration, was confirmed to be higher in individuals with long compared to short disease duration using BaseScope™ in situ hybridization. Our analyses also revealed two distinct neuroinflammatory panel signatures (NPS), NPS1 and NPS2, delineated by the direction of expression of proinflammatory, axonal transport and synaptic signalling pathways. We compared NPS between C9-ALS-FTSD cases and those from sporadic ALS and SOD1-ALS cohorts and identified NPS1 and NPS2 across all cohorts. Moreover, a subset of NPS was also able to separate publicly available RNA sequencing data from independent C9-ALS and sporadic ALS cohorts into two inflammatory subgroups. Importantly, NPS subgroups did not clearly segregate with available demographic, genetic, clinical or pathological features, highlighting the value of molecular stratification in clinical trials for inflammatory subgroup identification. Our findings thus underscore the importance of tailoring therapeutic approaches based on distinct molecular signatures that exist between and within ALS-FTSD cohorts.

Role of the immune system in amyotrophic lateral sclerosis. Analysis of the natural killer cells and other circulating lymphocytes in a cohort of ALS patients

AimsNeuroinflammation might be involved in the degeneration and progression of Amyotrophic Lateral Sclerosis (ALS). Here, we studied the role of the circulating lymphocytes in ALS, in particular the NK cells. We focused on the relationship between blood lymphocytes, ALS clinical subtype and disease severity.Subjects and MethodsBlood samples were collected from 92 patients with sporadic ALS, 21 patients with Primary Lateral Sclerosis (PLS) and 37 patients affected by primary progressive multiple sclerosis (PPMS) with inactive plaques. Blood was taken from ALS and controls at the time of diagnosis/referral. Circulating lymphocytes were analyzed by flow cytometry with specific antibodies. Values were expressed as absolute number (n°/µl) of viable lymphocytes subpopulations in ALS were compared with controls. Multivariable analysis was made using site of onset, gender changes in ALSFRS-R and disease progression rate (calculated as ΔFS score).ResultsAge at onset was 65y (58–71) in ALS (spinal 67.4%; bulbar, 32.6%), 57y (48–78) in PLS and 56y (44–68) PPMS. Absolute blood levels of the lymphocytes in the different cohorts were within normal range. Furthermore, while levels of lymphocytes T and B were not different between disease groups, NK cells were increased in the ALS cohort (ALS = 236 [158–360] vs. Controls = 174[113–240], p < 0.001). In ALS, blood levels of NK cells were not related with the main clinical-demographic variables, including the rate of disease progression. Multivariable analysis suggested that male gender and bulbar onset were independently associated with a risk of high blood NK cells levels.ConclusionsWe show that blood NK cells are selectively increased in ALS, though their level appear unaffected in patients with an estimated rapidly progressing disease. Being of a male gender and with a bulbar onset seems to confer higher susceptibility to have increased NK lymphocytes levels at diagnosis/referral. Our experiments provides a further clear-cut evidence of the role of the NK lymphocytes as a significant player in ALS pathogenesis.

Serum chloride as a respiratory failure marker in amyotrophic lateral sclerosis.

Respiratory failure is the most common cause of death in patients with amyotrophic lateral sclerosis (ALS) and occurs with great variability among patients according to different phenotypic features. Early predictors of respiratory failure in ALS are important to start non-invasive ventilation (NIV). Venous serum chloride values correlate with carbonate (HCO3-) blood levels and reflect metabolic compensation of respiratory acidosis. Despite its wide availability and low cost, few data on serum chloride as a prognostic marker exist in ALS literature. In the present study, we evaluated serum chloride values at diagnosis as prognostic biomarkers for overall survival and NIV adaptation in a retrospective center-based cohort of ALS patients. We collected all ALS patients with serum chloride assessment at diagnosis, identified through the Piemonte and Valle d'Aosta Register for ALS, evaluating the correlations among serum chloride, clinical features, and other serum biomarkers. Thereafter, time-to-event analysis was modeled to predict overall survival and NIV start. We found a significant correlation between serum chloride and inflammatory status markers, serum sodium, forced vital capacity (FVC), ALS functional rating scale-revised (ALSFRS-R) item 10 and 11, age at diagnosis, and weight loss. Time-to-event analysis confirmed both in univariate analysis and after multiple confounders' adjustment that serum chloride value at diagnosis significantly influenced survival and time to NIV start. According to our analysis, based on a large ALS cohort, we found that serum chloride analyzed at diagnosis is a low-cost marker of impending respiratory decompensation. In our opinion, it should be added among the serum prognostic biomarkers that are able to stratify patients into different prognostic categories even when performed in the early phases of the disease.

Genetic and Phenotypic Spectrum of Amyotrophic Lateral Sclerosis Patients with CCNF Variants from a Large Chinese Cohort

Cyclin F (CCNF) variants have been found to be associated with amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). However, the genetic and clinical characteristics of ALS patients who carry CCNF variants are largely unknown. Genetic analysis was performed for 1587 Chinese ALS patients, and missense variants were predicted by software analyses. Additionally, we searched PubMed, Embase, and Web of Science for relevant literature and conducted a meta-analysis of the frequency of variants. In our ALS cohort, we identified 29 nonsynonymous variants in 41 ALS patients. Among these ALS patients, 18 (1.1%) were carriers of 15 rare missense variants that were considered probably pathogenic variants, and 11 of 15 variants were novel. Seven relevant studies were identified, and a total of 43 CCNF variants in 59 ALS patients with a frequency of 0.8% were reported. The ratio of males to females in our cohort (10/8) was similar to that in Caucasian populations (4/7) and significantly higher than that in Asian populations (10/1). The proportion of bulbar onset in Caucasian CCNF carriers was similar to our cohort (25.0 vs. 27.8%); however, bulbar onset had never been reported in previous Asian studies (0/11). FTD was not found in CCNF carriers in previous Asian studies and our cohort, but it has been reported in a FALS cohort (1/75) of Caucasian individuals. There were some differences in the clinical characteristics among different ethnic ALS populations. More basic scientific studies are needed to elucidate the pathogenic mechanisms and genotype-phenotype associations of CCNF variants.

Weight Loss and Disease Progression in Amyotrophic Lateral Sclerosis and Primary Lateral Sclerosis (P2-8.009)

<h3>Objective:</h3> We studied the association of changes in body mass index (BMI) with disease progression among amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) Multicenter Cohort Study of Oxidative Stress (COSMOS) study participants, prospectively followed up to 24 months. <h3>Background:</h3> Weight loss is a poor prognostic factor in ALS. However, less is known about weight change in PLS. <h3>Design/Methods:</h3> Participants had a confirmed diagnosis of ALS or PLS and completed baseline and at least one follow-up visit. The rate of BMI change (ΔBMI) and total revised ALS functional rating scale change (ΔALSFRS-r) were calculated between baseline and the first follow-up. Correlation between ΔBMI and ΔALSFRS-r were assessed using Pearson correlation among ALS and PLS participants separately. The demographics and proportion of participants with swallowing dysfunction at baseline and significant weight loss were compared between ALS and PLS groups using chi-square test. Cox proportional hazard models examined the association between significant weight loss (ΔBMI&lt;−1kg/m2/year) and survival in ALS, adjusted for other prognostic factors. <h3>Results:</h3> 279 ALS and 37 PLS participants were included. Mean age of ALS and PLS were both 60 years and 61% male. At baseline, swallowing dysfunction was more frequent in the PLS (78% vs 48%, p&lt;0.001) while significant weight loss was more frequent in the ALS (53% vs 19%, p&lt;0.001). ΔBMI and ΔALSFRS-r correlated significantly in ALS (r=0.3, p&lt;0.0001) but not in PLS (r= −0.21, p=0.2). Significant weight loss was associated with increased risk of death (hazard ratio 2.08, p&lt;0.0001) in ALS after adjusting for age, disease-duration, bulbar-onset, diagnostic-certainty, riluzole-intake, forced vital capacity, baseline BMI, baseline ALSFRS-r and ΔALSFRS-r. <h3>Conclusions:</h3> In ALS, significant weight loss is a strong independent prognostic factor for survival and rate of BMI change correlates with faster functional decline. In contrast, significant weight loss is infrequent in PLS despite a high prevalence of swallowing dysfunction. <b>Disclosure:</b> Dr. Lee has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Lee has received personal compensation in the range of $0-$499 for serving as a Consultant for Amylyx. Dr. Lee has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Regeneron. The institution of Dr. Lee has received research support from Myasthenia Gravis Foundation of America. The institution of Dr. Lee has received research support from CReATe consortium/American Brain Foundation. Dr. Mitsumoto has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly. Pam Factor-Litvak has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for ICF. Pam Factor-Litvak has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Frontiers Publishing. The institution of Pam Factor-Litvak has received research support from NIH. Prof. Nieves has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Bone Health and Osteoporosis Foundation. The institution of Prof. Nieves has received research support from Radius Pharmaceuticals. Prof. Nieves has received personal compensation in the range of $0-$499 for serving as a DSMB member with NIH.

At-Home Telespirometry (AHT) In Amyotrophic Lateral Sclerosis (ALS) Implementation Science: Different Patient Rates of Erect Forced Vital Capacity (eFVC) 3 percent predicted (%p) Drops per Month in Two ALS Populations with Different Baseline Rates of Non-Invasive Ventilation (NIV) Utilization (P8-8.009)

At-Home Telespirometry (AHT) In Amyotrophic Lateral Sclerosis (ALS) Implementation Science: Different Patient Rates of Erect Forced Vital Capacity (eFVC) 3 percent predicted (%p) Drops per Month in Two ALS Populations with Different Baseline Rates of Non-Invasive Ventilation (NIV) Utilization (P8-8.009)