Prognosis Of Amyotrophic Lateral Sclerosis Research Articles

Could the motor unit number index be an early prognostic biomarker for amyotrophic lateral sclerosis?

ObjectiveTo evaluate the associations between motor unit number index (MUNIX) and disease progression and prognosis in amyotrophic lateral sclerosis (ALS) in a large-scale longitudinal study. MethodsMUNIX was performed at the patient's first visit, at 3, 6, and 12 months in 4 muscles. MUNIX data from the patients were compared with those from 38 age-matched healthy controls. Clinical data included the revised ALS functional rating scale (ALSFRS-R), the forced vital capacity (FVC), and the survival of the patients. ResultsEighty-two patients were included at baseline, 62 were evaluated at three months, 48 at six months, and 33 at twelve months. MUNIX score was lower in ALS patients compared to controls. At baseline, MUNIX was correlated with ALSFRS-R and FVC. Motor unit size index (MUSIX) was correlated with patient survival. Longitudinal analyses showed that MUNIX decline was greater than ALSFRS-R decline at each evaluation. A baseline MUNIX score greater than 378 predicted survival over the 12-month period with a sensitivity of 82% and a specificity of 56%. ConclusionsThis longitudinal study suggests that MUNIX could be an early quantitative marker of disease progression and prognosis in ALS. SignificanceMUNIX might be considered as potential indicator for monitoring disease progression.

Peripheral immunity relate to disease progression and prognosis in amyotrophic lateral sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Abnormalities in the peripheral immune system in ALS have been paid attention; however, the results of changes in peripheral immune parameters were inconsistent. Methods: A total of 1109 ALS patients were enrolled in the study. All patients received clinical evaluation and peripheral immune parameters measurement. The outcomes were analyzed by correlation analysis, multiple linear regression and cox survival analysis. Results: We found that ALS patients had significantly higher percentage of CD4+ T cells (39.3 vs. 37.1%, p < 0.001) and CD4+/CD8+ ratio (1.88 vs. 1.72, p = 0.011), significantly lower IgG (11.73 vs.12.82, p < 0.001) and IgA (2130.70 vs. 2284.8, p = 0.013) compared with the health controls. In the multivariate linear model, we found that each increase of 1.262, 0.278, and 4.44E-4 in ALSFRS-R scores were significantly associated with each increment of lymphocyte count, IgG, and IgA, respectively. However, each decrease of 0.341, 0.068, and 0.682 in ALSFRS-R score was associated with each increment in neutrophils, CD4+ T cells, and CD4+/CD8+ ratio, respectively. Cox survival regression analysis showed that the death risk of ALS patients was related to the levels of C3 (HR 0.592, 95% CI 0.361–0.973). Conclusion: We found that there were differences in peripheral immune parameters of ALS patients with the severity of the disease, especially neutrophil, lymphocyte, CD4+ T, and IgG; C3 is an independent predictor of survival in ALS patients. More studies are needed to elucidate the mechanisms associated with altered immune parameters in ALS.

Clinical characteristic and prognosis of amyotrophic lateral sclerosis in a cohort of Thai patients

Background &amp; Objective: Clinical course and prognosis in amyotrophic lateral sclerosis (ALS) patients were highly variable. The information in the Thai population is still lacking. This study aimed to determine the clinical association with disease progression and prognostic factors in ALS in Thailand. Methods: This prospective cohort study evaluated 62 patients who has a diagnosis of ALS and followed up at Neurological Institute of Thailand between January 2014 and December 2018. These patients were classified into an alive group and a deceased group. The demographics, clinical characteristics, disease-related severity, and prognosis were analyzed. Results: Of the included patients, there were 40 male and 22 female, the median age at onset was 53.2 years. The median diagnosis time was 13.1 months and median follow-up duration was 18.5 months; 72.6% of patients presented with spinal onset ALS, and 27.4% with bulbar-onset. There were 20 deaths during follow-up, and the median survival time in the deceased cases was 14 months. Worse prognosis factors were bulbar symptoms at onset and low amyotrophic lateral sclerosis functional rating scale (ALSFRS) at diagnosis. Conclusion: The factors associated with lower survival in ALS patients were bulbar symptoms at onset and low ALSFRS at diagnosis.

The impact of upper motor neuron involvement on clinical features, disease progression and prognosis in amyotrophic lateral sclerosis.

ObjectivesIn amyotrophic lateral sclerosis (ALS) both upper (UMNs) and lower motor neurons (LMNs) are involved in the process of neurodegeneration, accounting for the great disease heterogeneity. We evaluated the associations of the burden of UMN impairment, assessed through the Penn Upper Motor Neuron Score (PUMNS), with demographic and clinical features of ALS patients to define the independent role of UMN involvement in generating disease heterogeneity, predicting disease progression and prognosis.MethodsWe collected the following clinical parameters on a cohort of 875 ALS patients: age and site of onset, survival, MRC scale, lower motor neuron score (LMNS), PUMNS, ALSFRS-R, change in ALSFRS-R over time (DFS), MITOS and King’s staging systems (KSS). Transcranial magnetic stimulation was performed on a subgroup of patients and central motor conduction time (CMCT) and cortical silent period (CSP) were calculated.ResultsWe observed that patients with an earlier age at onset and bulbar onset had higher PUMNS values. Higher values were also associated to lower ALSFRS-R and to higher DFS scores, as well as to higher MITOS and KSS, indicating that a greater UMN burden correlates with disease severity. Conversely, we did not appreciate any association between UMN involvement and survival or markers of LMN impairment. Moreover, PUMNS values showed a positive association with CMCT and a negative one with CSP values.InterpretationOur results suggest that the burden of UMN pathology, assessed through PUMNS, has an important independent role in defining clinical characteristics, functional disability, disease progression and prognosis in ALS patients. We also support the role of TMS in defining severity of UMN involvement.

Association Between Fat Depletion and Prognosis of Amyotrophic Lateral Sclerosis: CT-Based Body Composition Analysis.

The purpose of this study was to present the results of our investigation of the prognostic value of adipopenia and sarcopenia in patients with amyotrophic lateral sclerosis (ALS). Consecutive patients with ALS with abdominal computed tomography (CT) were retrospectively identified at a single tertiary hospital between January 2010 and July 2021. Deep learning-based volumetric CT body composition analysis software was used to obtain abdominal waist fat volume, fat attenuation, and skeletal muscle area at the L3 level, then normalized to the fat volume index (FVI) and skeletal muscle index (SMI). Adipopenia and sarcopenia were defined as the sex-specific lowest quartile and SMI reference values, respectively. The associations of CT-derived body composition parameters with clinical variables, such as body mass index (BMI) and creatinine, were evaluated by Pearson correlation analyses, and associations with survival were assessed using the multivariable Cox regression analysis. Eighty subjects (40 men, 65.5 ± 9.4 years of age) were investigated (median interval between disease onset and CT examination = 25 months). The mean BMI at the CT examination was 20.3 ± 4.3 kg/m2 . The BMI showed a positive correlation with both FVI (R = 0.70, p < 0.001) and SMI (R = 0.63, p < 0.001), and the serum creatinine level was associated with SMI (R = 0.68, p < 0.001). After adjusting for sex, age, King's stage, BMI, creatinine, progression rate, and sarcopenia, adipopenia was associated with shorter survival (hazard ratio [HR] = 5.94, 95% confidence interval [CI] = 1.01, 35.0, p = 0.049). In a subgroup analysis for subjects with nutritional failure (stage 4a), the HR of adipopenia was 15.1 (95% CI = 2.45, 93.4, p = 0.003). Deep learning-based CT-derived adipopenia in patients with ALS is an independent poor prognostic factor for survival. ANN NEUROL 2023;94:1116-1125.

Neutrophils Are Associated with Higher Risk of Incident Amyotrophic Lateral Sclerosis in a BMI- and Age-Dependent Manner.

Peripheral immune markers have been associated with the progression and prognosis of amyotrophic lateral sclerosis (ALS). However, whether dysregulation of peripheral immunity is a risk factor for ALS or a consequence of motor neuron degeneration has not yet been clarified. We aimed to identify longitudinal associations between prediagnostic peripheral immunity and the risk of incident ALS. A total of 345,000 individuals from the UK Biobank between 2006 and 2010 were included at the baseline. The counts of peripheral immune markers (neutrophils, lymphocytes, monocytes, platelets, and CRP) and its derived metrics (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], lymphocyte-to-monocyte ratio [LMR], and systemic immune-inflammation index [SII]) were analyzed in relation to the following incident ALS by Cox proportional hazard models. Subgroup and interaction analyses were performed to explore the covariates of these relationships further. After adjusting for all covariates, the multivariate analysis showed that high neutrophil counts and their derived metrics (NLR and SII) were associated with an increased risk of ALS incidence (per SD increment hazard ratio [HR] = 1.15, 95% confidence interval [CI] = 1.02-1.29 for neutrophils; HR = 1.15, 95% CI = 1.03-1.28 for NLR; and HR = 1.17, 95% CI = 1.05-1.30 for SII). Subgroup and interaction analyses revealed that body mass index (BMI) and age had specific effects on this association. In participants with BMI ≥ 25 or age < 65 years, higher neutrophil counts, and their metrics increased the risk of incident ALS; however, in participants with BMI < 25 or age ≥ 65 years, neutrophils had no effect on incident ALS. Our study provides evidence that increased neutrophil levels and neutrophil-derived metrics (NLR and SII) are associated with an increased risk of developing ALS. ANN NEUROL 2023;94:942-954.

Prognostic Value of Regular Nutritional Treatment in Patients With Amyotrophic Lateral Sclerosis.

Malnutrition adversely affects the prognosis of amyotrophic lateral sclerosis (ALS). The aim of this study was to evaluate the effect of regular nutrition treatment and follow-up in clinical nutrition outpatient clinic (CNOC) on survival in ALS patients. The study included 55 ALS patients who were admitted and followed up in CNOC. Malnutrition was diagnosed using ESPEN criteria and nutrition treatment was planned according to needs of each patient. Nutritional status was followed up by body mass index (BMI), bioelectrical impedence analysis, and serum albumin. During the follow-up, survivors and nonsurvivors were compared according to their nutrition treatment success and changes in the anthropometric and laboratory measurements. Body weight, BMI, and fat free mass were decreased during the follow-up in both survivors and nonsurvivors (P<0.01). The decrease in the serum albumin and BMI were significantly higher in nonsurvivors (P<0.01). Mortality rate was lower in those with higher adherence to nutrition treatment (P<0.01) and patients with lower adherence to nutrition treatment showed more significant decrease in serum albumin levels (P<0.01). A personalized nutrition treatment combined with increased nutritional adherence in CNOC can decrease mortality in ALS patients.

Serum neurofilament light chain cut-off definition for clinical diagnosis and prognosis of amyotrophic lateral sclerosis.

The neurofilament light chain (NfL) assay is gradually becoming an essential diagnostic tool for the diagnosis of many neurological diseases including amyotrophic lateral sclerosis (ALS). Different methods for the determination of this biomarker in serum have been developed in recent years. We measured blood NfL in 429 patients referred to the tertiary ALS center of Montpellier, France using two different ultrasensitive methods (Ella™ and Simoa™) and we compared the clinical performances of these two approaches. We also converted NfL values into age and body mass index-adjusted Z-scores to assess cut-off values of this biomarker in this clinical context. We show comparable diagnostic and prognostic performance of Ella™ and Simoa™ technologies in ALS, with specificities and sensitivities exceeding 80% for both. We propose cut-off values for serum NfL in this clinical context, thus enabling the routine clinical use of this biomarker. The use of NfL in routine clinical practice will help predict survival and improve diagnostic accuracy by distinguishing ALS from other neurological diseases and motor neuron disease mimics.

Biofluid Biomarkers in the Prognosis of Amyotrophic Lateral Sclerosis: Recent Developments and Therapeutic Applications.

Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the degeneration of motor neurons for which effective therapies are lacking. One of the most explored areas of research in ALS is the discovery and validation of biomarkers that can be applied to clinical practice and incorporated into the development of innovative therapies. The study of biomarkers requires an adequate theoretical and operational framework, highlighting the "fit-for-purpose" concept and distinguishing different types of biomarkers based on common terminology. In this review, we aim to discuss the current status of fluid-based prognostic and predictive biomarkers in ALS, with particular emphasis on those that are the most promising ones for clinical trial design and routine clinical practice. Neurofilaments in cerebrospinal fluid and blood are the main prognostic and pharmacodynamic biomarkers. Furthermore, several candidates exist covering various pathological aspects of the disease, such as immune, metabolic and muscle damage markers. Urine has been studied less often and should be explored for its possible advantages. New advances in the knowledge of cryptic exons introduce the possibility of discovering new biomarkers. Collaborative efforts, prospective studies and standardized procedures are needed to validate candidate biomarkers. A combined biomarkers panel can provide a more detailed disease status.

Association of blood lipids with onset and prognosis of amyotrophic lateral sclerosis: results from the ALS Swabia registry

BackgroundTo date, the role of blood lipid levels and their association with the onset and prognosis of ALS is controversial. We explored these associations in a large, population-based case–control study.MethodsBetween October 2010 and June 2014, 336 ALS patients (mean age 65.7 ± 10.7; 57.7% male) and 487 sex- and age-matched controls from the same geographic region were recruited within the ALS registry in Southwest Germany. Triglycerides and cholesterol (high-density lipoprotein (HDL), low-density lipoprotein (LDL), total) were measured. The ALS cohort was followed up for vital status. Conditional logistic regression models were applied to calculate odds ratio (OR) for risk of ALS associated with serum lipid concentrations. In ALS patients only, survival models were used to appraise the prognostic value.ResultsHigh concentration of total cholesterol (OR 1.60, 95% confidence interval (CI) 1.03–2.49, top vs. bottom quartile), but not HDL, LDL, LDL–HDL ratio, or triglycerides, was positively associated with the risk of ALS. During the median follow-up time of 88.9 months, 291 deaths occurred among 336 ALS patients. In the adjusted survival analysis, higher HDL (HR 1.72, 95% CI 1.19–2.50) and LDL cholesterol levels (HR 1.58, 95% CI 1.11–2.26) were associated with higher mortality in ALS patients. In contrast, higher triglyceride levels were associated with lower mortality (HR 0.68, 95% CI 0.48–0.96).ConclusionThe results highlight the importance to distinguish cholesterol from triglycerides when considering the prognostic role of lipid metabolism in ALS. It further strengthens the rationale for a triglyceride-rich diet, while the negative impact of cholesterol must be further explored.

TH-233. Association between adipopenia and the prognosis of amyotrophic lateral sclerosis: CT-based deep learning approaches

TH-233. Association between adipopenia and the prognosis of amyotrophic lateral sclerosis: CT-based deep learning approaches

Association between vascular risk factors and cognitive impairment in amyotrophic lateral sclerosis: a case-control study

Objective The disease-modifying effects of type 2 diabetes mellitus (T2DM), and hyperlipidemia on the risk and prognosis of amyotrophic lateral sclerosis (ALS) have gained significant attention. We aim to evaluate the association between common vascular risk factors and cognitive impairment in patients with ALS. Methods Patients with ALS were consecutively recruited between June 2012 and November 2019 from a tertiary referral center for ALS at the West China Hospital. Vascular risk factors (hypertension, T2DM, hyperlipidemia, overweight, and smoking) were confirmed based on clinical data. Cognitive function was evaluated by the Chinese version of Addenbrooke’s Cognitive Examination-revised. With careful confounder adjustment, multivariable logistic regression analysis was performed separately and accumulatively to determine the association between cognitive impairment and vascular risk factors in ALS. Results Of 870 patients, 266 (30.6%) had cognitive impairment. No cognitive burden from vascular risk factors was found in patients with ALS. On the contrary, we first observed that T2DM (odds ratio [OR], 0.50; 95% confidence interval [CI], 0.25–0.98; p = 0.04) and hyperlipidemia (OR, 0.50; 95% CI, 0.26–0.97; p = 0.04) showed protective effects against cognitive decline in ALS, adjusted for age, sex, educational level, site of onset, Revised-ALS Functional Rating Scale score, predominant upper motor neuron phenotype, family history of ALS, and the remaining vascular risk factors. Sensitivity analyses of sex did not substantially reverse the risk estimates. Conclusions T2DM and hyperlipidemia decrease the risk of cognitive impairment in patients with ALS. The fitness hypothesis in ALS has been tested and expanded in our work.

Relationship between Dietary Total Antioxidant Capacity and the Prognosis of Amyotrophic Lateral Sclerosis.

Antioxidant intake has been suggested to be associated with the prognosis of amyotrophic lateral sclerosis (ALS). This study aimed to investigate whether dietary total antioxidant capacity (DTAC) and that of major food groups are related to disease progression rate (ΔFS) and survival time in ALS patients. A total of 301 participants diagnosed with sporadic ALS according to the revised El Escorial criteria were recruited from March 2011 and followed up to the event occurrence, or the end of October 2021. Events included percutaneous endoscopic gastrostomy, tracheostomy, and death. DTAC was estimated using task automation and an algorithm based on 24 h dietary recall. ΔFS was negatively correlated with the vegetable and legume DTAC, and event-free survival was different among the tertiles of vegetables and legumes DTAC. Consistently, the risk of events was negatively associated with DTAC from vegetables and legumes. These results suggest that the intake of antioxidants, especially those derived from vegetables and legumes, has a beneficial effect on delaying disease progression and prolonging survival in patients with ALS. Further studies with large prospective cohorts and clinical trials are needed to determine whether the consumption of foods with high DTAC improves the prognosis of ALS.

Repeated neurofilament light chain measurements did not capture Riluzole therapeutic effect in amyotrophic lateral sclerosis patients.

BackgroundLittle is known about the influence of Riluzole on serum neurofilament light chain (sNfL) levels, a biomarker of prognosis in amyotrophic lateral sclerosis (ALS), and variations with time of sNfL concentrations are controversial.MethodsSera from ALS patients (n = 141) and controls (n = 33) were collected at inclusion (sNfL1) and second visit (sNfL2, mean delay 10.4 ± 8.7 months). sNfL levels, determined by single‐molecule array, were compared between ALS and controls at both time points. sNfL concentration changes were compared between patients with Riluzole (w/Ril) at inclusion in the study and those who were treated by Riluzole following inclusion (w/o Ril). The factors influencing sNfL concentrations and changes were studied using linear regression and multivariate analysis.ResultssNfL levels were higher in ALS patients than in controls at the two time points (p < 0.00001). In ALS patients, sNfL concentrations were higher in females for both sNfL1 (p = 0.014) and sNfL2 (p < 0.001). In the whole ALS group, sNfL levels were higher at sNfL2 than at sNfL1 (p < 0.001). sNfL1 and sNfL2 concentrations were similar between the two ALS subgroups (w/ and w/o Ril). ALS functional rating scale‐revised rate of decline and gender were the two main factors significantly influencing both sNfL1 and sNfL2 levels (p < 0.01). However, only gender was shown to significantly influence sNfL changes with time (p = 0.003).ConclusionsIn this study, sNfL levels increased with time in ALS patients and there was no difference between subjects already treated by Riluzole and those treated after sNfL1. Further studies with larger population samples and different sampling intervals are warranted to better determine the real potential of sNfL measurement as a tool to monitor treatment response in ALS.

Creatine kinase and prognosis in amyotrophic lateral sclerosis: a literature review and multi-centre cohort analysis

BackgroundAmyotrophic lateral sclerosis (ALS) is a prognostically heterogeneous neurodegenerative disease. Blood creatine kinase (CK) level has been inconsistently reported as a prognostic biomarker and raised levels in some ALS patients have been presumed to reflect muscle wasting, which is also variable.MethodsMEDLINE was systematically searched for papers related to CK in ALS and the relevant studies were reviewed. Using data from 222 ALS patients in a multi-centre, prospective, longitudinal cohort, survival analyses using Kaplan–Meier and Cox proportional hazards models were undertaken in relation to CK and other prognostic factors.ResultsTwenty-five studies investigating CK in ALS were identified, of which 10 specifically studied the link between CK and survival. Five studies observed no association, four found that higher CK levels were associated with longer survival and one, the opposite. In our cohort (n = 222), 39% of patients had a CK level above the laboratory reference range. Levels were higher in males compared to females (p < 0.001), in patients with limb versus bulbar onset of symptoms (p < 0.001) and in patients with higher lower motor neuron burden (p < 0.001). There was no significant trend in longitudinal CK values. Although a higher standardised log (CK) at first visit was associated with longer survival in univariate analysis (hazard ratio 0.75, p = 0.003), there was no significant association after adjusting for other prognostic covariates.ConclusionWhile raised CK levels in ALS do reflect lower motor neuron denervation to a large extent, they are not independently associated with survival when measured in the symptomatic phase of the disease.

Machine Learning Solutions Applied to Amyotrophic Lateral Sclerosis Prognosis: A Review

The prognosis of Amyotrophic Lateral Sclerosis (ALS), a complex and rare disease, represents a challenging and essential task to better comprehend its progression and improve patients' quality of life. The use of Machine Learning (ML) techniques in healthcare has produced valuable contributions to the prognosis field. This article presents a systematic and critical review of primary studies that used ML applied to the ALS prognosis, searching for databases, relevant predictor biomarkers, the ML algorithms and techniques, and their outcomes. We focused on studies that analyzed biomarkers commonly present in the ALS disease clinical practice, such as demographic, clinical, laboratory, and imaging data. Hence, we investigate studies to provide an overview of solutions that can be applied to develop decision support systems and be used by a higher number of ALS clinical settings. The studies were retrieved from PubMed, Science Direct, IEEEXplore, and Web of Science databases. After completing the searching and screening process, 10 articles were selected to be analyzed and summarized. The studies evaluated and used different ML algorithms, techniques, datasets, sample sizes, biomarkers, and performance metrics. Based on the results, three distinct types of prediction were identified: Disease Progression, Survival Time, and Need for Support. The biomarkers identified as relevant in more than one study were the ALSFRS/ALSFRS-R, disease duration, Forced Vital Capacity, Body Mass Index, age at onset, and Creatinine. In general, the studies presented promissory results that can be applied in developing decision support systems. Besides, we discussed the open challenges, the limitations identified, and future research opportunities.

Clinical characteristics and prognosis of amyotrophic lateral sclerosis with autoimmune diseases.

IntroductionThe occurrence of autoimmune diseases (AIDs) in amyotrophic lateral sclerosis (ALS) patients is widely reported, but little is known about the associated clinical phenotype. This study aims to evaluate the clinical features and prognosis of ALS patients with AID.MethodsThis retrospective study was based on the ALS Registry dataset of Peking Union Medical College Hospital from 2013 to 2020. Clinical features and inflammatory biomarkers at registration were compared between ALS patients with coexisting AIDs and those without (controls). The medical records of immunotherapy were also collected. The Kaplan–Meier method and Cox proportional hazard model were used to study the survival of ALS patients.ResultsThere are 26 (1.6%) ALS patients with AIDs in our database. The ALS patients with AIDs had older ages at onset and poorer respiratory function than controls (p<0.05). After propensity score matching by sex, onset age, and disease duration, the difference in respiratory function remained significant between groups. We found no differences in overall survival between ALS patients with and without AIDs before and after matching (p = 0.836; p = 0.395). Older age at onset, rapid disease progression, and lower erythrocyte sedimentation rate (ESR) were associated with shorter survival (p<0.05). Among ALS patients with AIDs, 8 (30.8%) had a history of immunotherapy and showed slightly prolonged survival compared with those without immunotherapy, but the results did not reach statistical significance (p = 0.355).ConclusionsPatients with coexisting ALS and AIDs had older onset age and poorer respiratory function but similar overall survival than those with pure ALS.

Integrated evaluation of a panel of neurochemical biomarkers to optimize diagnosis and prognosis in amyotrophic lateral sclerosis.

Background and purposeThis study was undertaken to determine the diagnostic and prognostic value of a panel of serum biomarkers and to correlate their concentrations with several clinical parameters in a large cohort of patients with amyotrophic lateral sclerosis (ALS).MethodsOne hundred forty‐three consecutive patients with ALS and a control cohort consisting of 70 patients with other neurodegenerative disorders (DEG), 70 patients with ALS mimic disorders (ALSmd), and 45 healthy controls (HC) were included. Serum neurofilament light chain (NfL), ubiquitin carboxyl‐terminal hydrolase isozyme L1 (UCHL1), glial fibrillary acidic protein (GFAP), and total tau protein levels were measured using ultrasensitive single molecule array.ResultsNfL correlated with disease progression rate (p < 0.001) and with the measures of upper motor neuron burden (p < 0.001). NfL was higher in the ALS patients with classic and pyramidal phenotype. GFAP was raised in ALS with cognitive–behavioral impairment compared with ALS with normal cognition. NfL displayed the best diagnostic performance in discriminating ALS from HC (area under the curve [AUC] = 0.990), DEG (AUC = 0.946), and ALSmd (AUC = 0.850). UCHL1 performed well in distinguishing ALS from HC (AUC = 0.761), whereas it was not helpful in differentiating ALS from DEG and ALSmd. In multivariate analysis, NfL (p < 0.001) and UCHL1 (p = 0.038) were independent prognostic factors. Survival analysis combining NfL and UCHL1 effectively stratified patients with lower NfL levels (p < 0.001).ConclusionsNfL is a useful biomarker for the diagnosis of ALS and the strongest predictor of survival. UCHL1 is an independent prognostic factor helpful in stratifying survival in patients with low NfL levels, likely to have slowly progressive disease. GFAP reflects extramotor involvement, namely cognitive impairment or frontotemporal dementia.

Correlation between leukocyte phenotypes and prognosis of amyotrophic lateral sclerosis.

The prognostic role of immune cells in amyotrophic lateral sclerosis (ALS) remains undetermined. Therefore, we conducted a longitudinal cohort study including 288 ALS patients with up to 5-year follow-up during 2015-2020 recruited at the only tertiary referral center for ALS in Stockholm, Sweden, and measured the levels of differential leukocytes and lymphocyte subpopulations. The primary outcome was risk of death after diagnosis of ALS and the secondary outcomes included functional status and disease progression rate. Cox model was used to evaluate the associations between leukocytes and risk of death. Generalized estimating equation model was used to assess the correlation between leukocytes and functional status and disease progression rate. We found that leukocytes, neutrophils, and monocytes increased gradually over time since diagnosis and were negatively correlated with functional status, but not associated with risk of death or disease progression rate. For lymphocyte subpopulations, NK cells (HR= 0.61, 95% CI = [0.42-0.88] per SD increase) and Th2-diffrentiated CD4+ central memory T cells (HR= 0.64, 95% CI = [0.48-0.85] per SD increase) were negatively associated with risk of death, while CD4+ effector memory cells re-expressing CD45RA (EMRA) T cells (HR= 1.39, 95% CI = [1.01-1.92] per SD increase) and CD8+ T cells (HR= 1.38, 95% CI = [1.03-1.86] per SD increase) were positively associated with risk of death. None of the lymphocyte subpopulations was correlated with functional status or disease progression rate. Our findings suggest a dual role of immune cells in ALS prognosis, where neutrophils and monocytes primarily reflect functional status whereas NK cells and different T lymphocyte populations act as prognostic markers for survival.

Serum asymmetric dimethylarginine level correlates with the progression and prognosis of amyotrophic lateral sclerosis.

Background and purpose:The aim was to investigate the association between serum asymmetric dimethylarginine (ADMA) levels and the progression and prognosis of amyotrophic lateral sclerosis (ALS), and to compare cerebrospinal fluid (CSF) and serum ADMA levels with other biomarkers of ALS.MethodsSerum ADMA levels of sporadic ALS patients (n = 68), disease control patients (n = 54) and healthy controls (n = 20) were measured using liquid chromatography tandem mass spectrometry. Correlations of the ADMA level and other markers (nitric oxide and neurofilament light chain levels) were analyzed. Changes in the ALS Functional Rating Scale Revised (ALSFRS‐R) score from the onset of disease (ALSFRS‐R pre‐slope) was used to assess disease progression. Survival was evaluated using the Cox proportional hazards model and Kaplan–Meier analysis.ResultsThe serum ADMA level was substantially higher in patients with ALS than in healthy controls and disease controls. Serum ADMA level correlated with CSF ADMA level (r = 0.591, p < 0.0001) and was independently associated with the ALSFRS‐R pre‐slope (r = 0.505, p < 0.0001). Patients with higher serum ADMA levels had less favorable prognoses. CSF ADMA level significantly correlated with CSF neurofilament light chain level (r = 0.456, p = 0.0002) but not with nitric oxide level (r = 0.194, p = 0.219).ConclusionSerum ADMA level is an independent biomarker of ALS disease progression and prognosis and reflects the degree of motor neuron degeneration.