Amyotrophic Lateral Sclerosis Functional Rating Scale Score Research Articles

Tongue pressure is a strong predictor of recommendation for gastrostomy in amyotrophic lateral sclerosis.

Objective and practical biomarkers to determine the need for gastrostomy in patients with amyotrophic lateral sclerosis (ALS) are lacking. Tongue pressure (TP) is a promising biomarker because it is associated with bulbar dysfunction. The aims of this study were to evaluate the association of TP with the need for gastrostomy, and to determine its optimal cut-off value. This prospective observational study included participants with ALS taking nutrition orally. TP was evaluated using the Iowa Oral Performance Instrument. Need for gastrostomy as determined by a multidisciplinary team during a 12-month follow up period was recorded. Associations between TP and need for gastrostomy placement were performed. ROC curve analysis determined the optimal cut-off value of TP to predict gastrostomy. Of 208 screened participants, 119 were included. Gastrostomy was indicated in 45% (53), in a 12-month follow up period. TP of ≤20 kPA was a strong predictor of gastrostomy indication (OR 11.8, CI 95% [4.61, 34.7], p < .001). The association persisted even after adjustment for weight loss, pneumonia, prolonged feeding duration, Revised ALS Functional Rating Scale score, and American Speech-Language-Hearing Association scale score (OR 4.51, CI 95% [1.50, 14.9], p = .009). By receiver operating characteristic curve analysis, 20 kPA represented the optimal cut-off value (sensitivity 0.75, specificity 0.89). TP is a strong independent predictor of gastrostomy indication in the subsequent 12 months in patients with ALS, with good sensitivity and specificity at a cutoff value of ≤20 kPA, suggesting that it may be a promising biomarker in clinical practice.

Volume loss in the left anterior-superior subunit of the hypothalamus in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) causes motor neuron loss and progressive paralysis. While traditionally viewed as motor neuron disease (MND), ALS also affects non-motor regions, such as the hypothalamus. This study aimed to quantify the hypothalamic subregion volumes in patients with ALS versus healthy controls (HCs) and examine their associations with demographic and clinical features. Forty-eight participants (24 ALS patients and 24 HCs) underwent structural MRI. A deep convolutional neural network was used for the automated segmentation of the hypothalamic subunits, including the anterior-superior (a-sHyp), anterior-inferior (a-iHyp), superior tuberal (supTub), inferior tuberal (infTub), and posterior (posHyp). The neural network was validated using FreeSurfer v7.4.1, with individual head size variations normalized using total intracranial volume (TIV) normalization. Statistical analyses were performed for comparisons using independent sample t-tests. Correlations were calculated using Pearson's and Spearman's tests (p < 0.05). The standard mean difference (SMD) was used to compare the mean differences between parametric variables. The volume of the left a-sHyp hypothalamic subunit was significantly lower in ALS patients than in HCs (p = 0.023, SMD = -0.681). No significant correlation was found between the volume of the hypothalamic subunits, body mass index (BMI), and ALSFRS-R in patients with ALS. However, right a-sHyp (r = 0.420, p = 0.041) was correlated with disease duration, whereas right supTub (r = -0.471, p = 0.020) and left postHyp (r = -0.406, p = 0.049) were negatively correlated with age. There was no significant difference in the volume of hypothalamic subunits between males and females, and no significant difference was found between patients with revised ALS Functional Rating Scale (ALSFRS-R) scores ≤41 and >41 and those with a disease duration of 9 months or less. The main finding suggests atrophy of the left a-sHyp hypothalamic subunit in patients with ALS, which is supported by previous research as an extra-motor neuroimaging finding for ALS.

P.052 Utility of amyotrophic lateral sclerosis functional rating scale (ALSFRS) bulbar subscores for predicting need for gastrostomy tube

Background: We evaluated the utility of the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) in predicting risk of gastrostomy tube (G-tube) insertion in patients with ALS. Methods: We conducted a retrospective study using the Pooled Resource Open-Access ALS Clinical Trials Database. People with ALS, at least two ALSFRS scores, and baseline swallowing subscore &gt;1 were included. G-tube outcome was defined as reaching a swallowing subscore ≤1. Predictors were ALSFRS bulbar subscores (swallowing, speech, salivation). Survival analyses estimated median time to outcome and cumulative probability of outcome within 91 days. Individuals were censored at last ALSFRS score. Results: We included 6,943 participants. Median [95% CI] time to G-tube insertion was 245 [228, 285], 562 [547, 621], and 1,268 [980, 1,926] for baseline swallowing subscores of 2, 3, and 4, respectively. Probability of G-tube insertion was associated with baseline swallowing, speech, and salivation subscores (log-rank test p &lt; 0.0001). For patients who transitioned to a swallowing subscore of 2 or 3, 18.1% [95% CI 16.1, 20.3] and 1.9% [95% CI 1.3, 2.7] required G-tube insertion within 91 days of score transition. Conclusions: ALSFRS bulbar subscores may identify patients at risk of G-tube insertion. Probability of G-tube insertion within 91 days is low if swallowing subscore ≥3.

Describing and characterising variability in ALS disease progression

Background, Objectives Decrease in the revised ALS Functional Rating Scale (ALSFRS-R) score is currently the most widely used measure of disease progression. However, it does not sufficiently encompass the heterogeneity of ALS. We describe a measure of variability in ALSFRS-R scores and demonstrate its utility in disease characterization. Methods We used 5030 ALS clinical trial patients from the Pooled Resource Open-Access ALS Clinical Trials database to calculate variability in disease progression employing a novel measure and correlated variability with disease span. We characterized the more and less variable populations and designed a machine learning model that used clinical, laboratory and demographic data to predict class of variability. The model was validated with a holdout clinical trial dataset of 84 ALS patients (NCT00818389). Results Greater variability in disease progression was indicative of longer disease span on the patient-level. The machine learning model was able to predict class of variability with accuracy of 60.1–72.7% across different time periods and yielded a set of predictors based on clinical, laboratory and demographic data. A reduced set of 16 predictors and the holdout dataset yielded similar accuracy. Discussion This measure of variability is a significant determinant of disease span for fast-progressing patients. The predictors identified may shed light on pathophysiology of variability, with greater variability in fast-progressing patients possibly indicative of greater compensatory reinnervation and longer disease span. Increasing variability alongside decreasing rate of disease progression could be a future aim of trials for faster-progressing patients.

The necessity to improve disaster preparedness among patients with amyotrophic lateral sclerosis and their families

Disaster preparation is an important issue for patients with amyotrophic lateral sclerosis (ALS). However, to the best of our knowledge, no studies have investigated disaster preparedness among patients with ALS. In this study, we aimed to investigate disaster preparation in patients with ALS and their caregivers, including their families, in Japan. We conducted a nationwide webinar in September 2022 titled “ALS Café” and distributed a self-report questionnaire to participants with questions about awareness of disaster preparedness, social countermeasures, stockpiles, and electricity demand. Forty-eight patients with ALS (27 male; average age 60.0 ± 9.3 years) and 23 caregivers (8 male; 55.7 ± 9.9 years) responded. The median revised ALS Functional Rating Scale score was 30.5, and 25% of the patients with ALS were on a ventilator. More than 70% of the respondents answered that they were not prepared for disasters, increasing to 89% in patients not using ventilators. In the event of their phones being down, 86% of the respondents had no plans for alternative means of communication. <30% of the respondents, including ventilator users, had secured human resources for transportation. Twenty-five percent of the respondents did not stockpile food and beverages, and 12% of the ventilator users had no government-recommended ventilator preparation equipment. Thus, although patients with ALS and their families with ventilators have a high awareness of disaster preparedness, their awareness remains insufficient. Furthermore, patients with ALS and their families without ventilators have a low awareness of disaster preparedness. Therefore, better education regarding disaster preparedness is necessary for these groups.

Dextromethorphan/quinidine for the treatment of bulbar impairment in amyotrophic lateral sclerosis.

No efficacious treatments exist to improve or prolong bulbar functions of speech and swallowing in persons with amyotrophic lateral sclerosis (pALS). This study evaluated the short-term impact of dextromethorphan/quinidine (DMQ) treatment on speech and swallowing function in pALS. This was a cohort trial conducted between August 2019 to August 2021 in pALS with a confirmed diagnosis of probable-definite ALS (El-Escorial Criteria-revisited) and bulbar impairment (ALS Functional Rating Scale score ≤ 10 and speaking rate ≤ 140 words per minute) who were DMQ naïve. Efficacy of DMQ was assessed via pre-post change in the ALS Functional Rating Scale-Revised bulbar subscale and validated speech and swallowing outcomes. Paired t-tests, Fisher's exact, and χ2 tests were conducted with alpha at 0.05. Twenty-eight pALS enrolled, and 24 participants completed the 28-day trial of DMQ. A significant increase in ALSFRS-R bulbar subscale score pre- (7.47 ± 1.98) to post- (8.39 ± 1.79) treatment was observed (mean difference: 0.92, 95% CI: 0.46-1.36, p < 0.001). Functional swallowing outcomes improved, with a reduction in unsafe (75% vs. 44%, p = 0.003) and inefficient swallowing (67% vs. 58%, p = 0.002); the relative speech event duration in a standard reading passage increased, indicating a greater duration of uninterrupted speech (mean difference: 0.33 s, 95% CI: 0.02-0.65, p = 0.035). No differences in diadochokinetic rate or speech intelligibility were observed (p > 0.05). Results of this study provide preliminary evidence that DMQ pharmacologic intervention may have the potential to improve or maintain bulbar function in pALS.

Dynamic analysis of muscles and the internal structure of the peripheral nerve as biomarkers of amyotrophic lateral sclerosis: A pilot study with ultrasound imaging

IntroductionThe aim of this study was to determine the behaviour of ultrasound biomarkers of fascicle density and muscle strength in patients with amyotrophic lateral sclerosis (ALS). MethodsWe conducted an observational, cross-sectional pilot study of 14 patients with ALS (28.6% women) and 14 controls. Bilateral cross-sectional ultrasound scans were performed in the abductor pollicis brevis (APB) and tibialis anterior (TA) muscles, with recording of muscle thickness (MT) at rest and in contraction, and the difference in thickness. In the median, sciatic, and common peroneal nerves, we analysed the cross-sectional area (CSA), number of fascicles (NF) and fascicle density (FD). Analyses were nested by laterality. ResultsIntra- and interrater agreement regarding NF was very good, with a minimum detectable error of < 0.7%. In patients with ALS, MT was lower in the APB both at rest (P = .003; g-Hedges = 1.03) and in contraction (P = .017; g-Hedges = 0.78) and in TA at rest (P = .002; g-Hedges = 0.15) and in contraction (P = .001; g-Hedges = 0.46), with lower thickening capacity. In the nerves, patients displayed lower CSA, with lower NF and higher FD. Significant correlations were found between MT of the ABP and Medical Research Council (MRC) scores for muscle strength (r = 0.34; r2 = 12%; P = .011) and with revised ALS Functional Rating Scale scores (r = 0.44; r2 = 19%; P < .001). The difference in TA thickening correlated with MRC scores (r = 0.30; r2 = 15%; P = .003) and with revised ALS Functional Rating Scale scores (r = 0.26; r2 = 7%; P = .049). NF in the sciatic nerve showed a significant correlation with MRC scores (r = 0.35; r2 = 12%; P = .008). ConclusionMT measurements derived from dynamic testing together with NF and FD may be useful biomarkers for monitoring patients with ALS and establishing a prognosis.

Maximum Phonation Time as a Surrogate Marker for Airway Clearance Physiologic Capacity and Pulmonary Function in Individuals With Amyotrophic Lateral Sclerosis.

The increased use of telehealth practices has created a critical need for home-based surrogate markers for prognostic respiratory indicators of disease progression in persons with amyotrophic lateral sclerosis (pALS). Given that phonation relies on the respiratory subsystem of speech production, we aimed to examine the relationships between maximum phonation time (MPT), forced vital capacity, and peak cough flow and to determine the discriminant ability of MPT to detect forced vital capacity and peak cough flow impairments in pALS. MPT, peak cough flow, forced vital capacity, and ALS Functional Rating Scale scores were obtained from 62 pALS (El-Escorial Revised) every 3 months as part of a longitudinal natural history study. Pearson's correlations, linear regressions, and receiver operator characteristic curve analyses with the area under the curve (AUC), sensitivity, specificity, and likelihood ratios were calculated. The mean age of pALS was 63.14 ± 10.95 years, 49% were female, and 43% had bulbar onset. MPT predicted forced vital capacity, F(1, 225) = 117.96, p < .0001, and peak cough flow, F(1, 217) = 98.79, p < .0001. A significant interaction was noted between MPT and ALS Functional Rating Scale-Revised respiratory subscore for forced vital capacity, F(1, 222) = 6.7, p = .010, and peak cough flow, F(1, 215) = 4.37, p = .034. The discriminant ability of MPT was excellent for peak cough flow (AUC = 0.88) and acceptable for forced vital capacity (AUC = 0.78). MPT is a simple clinical test that can be measured via telehealth and represents a potential surrogate marker for important respiratory and airway clearance indices. Further larger studies are required to validate these findings with remote data collection. https://doi.org/10.23641/asha.22186408.

Spatial-temporal pattern of propagation in amyotrophic lateral sclerosis and effect on survival: A cohort study.

Clarification of propagation patterns in amyotrophic lateral sclerosis (ALS) is challenging, but understanding these has implications for individual prognostication and clinical trial design. However, systematic knowledge in this area is lacking. The aim of this study was to characterize the spatial and temporal features of propagation patterns in ALS, and to evaluate the association between propagation patterns and survival. A cohort of 833 patients with ALS, diagnosed between January 2018 and December 2019 and followed to August 2021, was analysed. Spatial and temporal features of propagation patterns were determined based on the involved functional regions (bulbar, cervical, thoracic/respiratory and lumbar) in time order. The final propagation pattern was identified in patients with at least three functional regions involved. Kaplan-Meier analysis and Cox regression analysis were performed. During a median follow-up of 21.2months, 19 final propagation patterns were identified in 657 patients (78.9%). In survival analysis, we found that the earlier the respiratory functional region becomes involved, the higher the risk of death (time order: 1st: hazard ratio [HR], 3.35, 95% confidence interval [CI] 1.23-9.15; 2nd: HR 2.45, 95% CI 1.55-3.87; 3rd: HR 1.94, 95% CI 1.52-2.49), adjusting for age, sex, diagnostic delay, revised ALS Functional Rating Scale score, cognitive impairment and riluzole. Shorter interval time between involved regions was an independent adverse prognostic factor. The propagation patterns of ALS are varied. The order in which the respiratory region becomes involved and the interval time between involvement of functional regions are predictors for prognosis.

Characteristics of Dysphagia Based on the Type of ALS in Korean Patients Evaluated Using Videofluoroscopic Study: A Retrospective Analysis.

Dysphagia is one of the main serious issues for amyotrophic lateral sclerosis (ALS) patients because of causing malnutrition and aspiration pneumonia. Early detection and management of dysphagia are essential for the long-term survival. In this study, videofluoroscopic swallowing study (VFSS) results of bulbar and spinal onset ALS patients were compared. VFSS results and revised ALS Functional Rating Scale (ALSFRS-R) score were also analyzed to assess the correlation between dysphagia and functional status of patients. ALS patients with swallowing difficulties who underwent VFSS were recruited retrospectively. Two oral, seven pharyngeal, and two esophageal components of VFSS were evaluated. An ALSRFRS-R bulbar subtype score < 9 was used to divide the groups with severe bulbar symptoms. Total 109 Korean ALS patients (39 bulbar vs 70 spinal) were included. Bulbar ALS patients exhibited a significantly longer oral transit time (OTT) then spinal ALS patients, especially in severe bulbar patients with low ALSRFRS-R bulbar subscale. In bulbar ALS patients, penetration (thick liquid), aspiration, OTT, and Penetration-Aspiration Scale (PAS) were significantly correlated with ALSFRS-R bulbar subscale score. However, in spinal ALS patients, only OTT (thin liquid) and aspiration (thick liquid) were significantly correlated with ALSFRS-R bulbar subscale score. Bulbar ALS patients demonstrated significantly longer OTT than spinal ALS patients, and ALSFRS-R bulbar subscale score also correlated well with bulbar ALS patients. Therefore, high vigilance and aggressive treatment for dysphagia especially in bulbar ALS patients rather than spinal ALS patients are mandatory.

Análisis dinámico muscular y de la estructura interna del nervio periférico como biomarcadores para la esclerosis lateral amiotrófica: estudio piloto mediante ecografía

IntroductionThe aim of this study was to determine the behaviour of ultrasound biomarkers of fascicle density and muscle strength in patients with amyotrophic lateral sclerosis (ALS). MethodsWe conducted an observational, cross-sectional pilot study of 14 patients with ALS (28.6% women) and 14 controls. Bilateral cross-sectional ultrasound scans were performed in the abductor pollicis brevis (APB) and tibialis anterior (TA) muscles, with recording of muscle thickness (MT) at rest and in contraction, and the difference in thickness. In the median, sciatic, and common peroneal nerves, we analysed the cross-sectional area (CSA), number of fascicles (NF) and fascicle density (FD). Analyses were nested by laterality. ResultsIntra- and interrater agreement regarding NF was very good, with a minimum detectable error of < 0.7%. In patients with ALS, MT was lower in the APB both at rest (P = .003; g-Hedges = 1.03) and in contraction (P = .017; g-Hedges = 0.78) and in TA at rest (P = .002; g-Hedges = 0.15) and in contraction (P = .001; g-Hedges = 0.46), with lower thickening capacity. In the nerves, patients displayed lower CSA, with lower NF and higher FD. Significant correlations were found between MT of the ABP and Medical Research Council (MRC) scores for muscle strength (r = 0.34; r2 = 12%; P = .011) and with revised ALS Functional Rating Scale scores (r = 0.44; r2 = 19%; P < .001). The difference in TA thickening correlated with MRC scores (r = 0.30; r2 = 15%; P = .003) and with revised ALS Functional Rating Scale scores (r = 0.26; r2 = 7%; P = .049). NF in the sciatic nerve showed a significant correlation with MRC scores (r = 0.35; r2 = 12%; P = .008). ConclusionMT measurements derived from dynamic testing together with NF and FD may be useful biomarkers for monitoring patients with ALS and establishing a prognosis.

Inflammatory Cytokine Levels in Patients with Sporadic Amyotrophic Lateral Sclerosis

Objectives: In the present study, inflammatory factors, including interleukin (IL) and tumor necrosis factor-α (TNF-α) in the peripheral blood of patients with sporadic amyotrophic lateral sclerosis (sALS), were evaluated, and the issue of whether these variables were associated with the progression and severity of the disease examined. Methods: Data on inflammatory factors, including IL-1, IL-2, IL-6, IL-8, IL-10, and TNF-α, were retrospectively collected from 248 sALS patients admitted to the Chinese PLA General Hospital between March 2018 and March 2021. The relationships between the variables and clinical features, including gender, age at onset, site of onset, time from onset to hospital admission, ALS functional rating scale score, and diagnostic category were analyzed. Results: IL-1, IL-2, IL-6, IL-8, IL-10, and TNF-α levels were elevated in 43.75%, 7.04%, 16.42%, 25.35%, 1.41%, and 50.72% of ALS patients, respectively, compared with the normal value range. IL-2 and IL-6 levels were inversely associated with the ALS functional rating scale score (r = −0.280, p = 0.004 and r = −0.198, p = 0.048). Conclusion: Elevated levels of inflammatory cytokines support the hypothesis of an inflammatory response in ALS, and IL-2 and IL-6 may be used as an inflammation-related biomarker for disease severity.

Assessment of Therapeutic Response of Edaravone and Riluzole Combination Therapy in Amyotrophic Lateral Sclerosis Patients.

Background:Amyotrophic lateral sclerosis (ALS) is a progressive disease characterized by chronic degeneration of upper and lower motor neurons and finally death within 3–5 years usually because of respiratory failure. Riluzole and edaravone are presently available treatments. It may be better to try combination therapy rather than taking individual medications.Objectives:To compare the effectiveness of (edaravone + riluzole) combination therapy versus riluzole therapy alone in slowing down the progression of ALS and to evaluate the role of serum creatinine as a marker of disease progression.Materials and Methods:Observational, randomized, parallel assignment, open label study. Thirty patients with definite and probable ALS were randomly assigned to two treatment groups. The case group received (riluzole + edaravone) for the initial 6 months, followed by riluzole for the next 6 months. The control group received riluzole for 12 months. After 6 and 12 months, changes in ALS functional rating scale (ALSFRS-R), mRS, and Japanese ALS scores were determined. P value <.05 was considered significant.Results:An increase in mRS at 6 months in the case group versus control group was 0.07 versus 0.20, respectively (p =0.02). At 12 months, it was 0.47 versus 0.53, respectively (p =0.17). A decrease in serum creatinine at 6 months in case group versus control group was 0.08 versus 0.09, respectively (p =.82). There was no change in ALS FRS for bulbar symptoms (salivation), 3.46 versus 3.46 in the case group (p =.018) for the first 6 months.Conclusions:Combined with riluzole, edaravone slows disease progression and is safe, but the effect is short-term. Bulbar symptoms respond better to combination therapy. The serum creatinine is helpful in monitoring disease progression.

Efficacy and Safety of Plasma Exchange with Albumin Replacement as a Therapy for Amyotrophic Lateral Sclerosis

Background: Neuroinflammation is being increasingly recognized as a key factor in the pathogenesis of amyotrophic lateral sclerosis (ALS). A therapeutic approach for ALS using plasma exchange with albumin replacement (PE-A) has been proposed to remove antibody complexes, inflammatory mediators, and toxins to decrease neuronal damage caused by inflammation. Methods: In this pilot study, 15 patients underwent 24 weeks of PE-A with 5% albumin and their revised ALS Functional Rating Scale (ALSFRS-R) scores and Forced Vital Capacity (FVC) were tracked for 48 weeks to evaluate the efficacy of PE-A as a therapy for ALS. Results: There was a statistically significant decline of ALSFRS-R scores as well as FVC (%) throughout the study. A post hoc comparison with clinically matched control patients showed no statistically significant difference. Likewise, no significant differences were found when the rate of ALSFRS-R decline in the PE-A-treated patients was compared to the European Medicines Agency (EMA) guideline estimate of a −1 point/month decrease in untreated patients. However, 50% of the PE-A-treated patients showed a slow rate of decline of &lt; −0.8 points/month. PE was safe and well tolerated in ALS patients. Conclusion: In conclusion, results of this study indicated that PE-A performed in this manner was safe but showed a considerable heterogeneity in the response to treatment when it comes to slowing the ALS deterioration, with no overall clinical benefit. Further investigation focused on the characterization of ALS patients suitable for PE-A therapy is warranted. Registration: ClinicalTrials.gov ID: NCT02872142.

Using the ALSFRS-R in multicentre clinical trials for amyotrophic lateral sclerosis: potential limitations in current standard operating procedures

Objective: Uniform data collection is fundamental for multicentre clinical trials. We aim to determine the variability, between ALS trial centers, in the prevalence of unexpected or implausible improvements in the revised ALS functional rating scale (ALSFRS-R) score, and its associations with individual patient and item characteristics. Methods: We used data from two multicentre studies to estimate the prevalence of an unexpected increase or implausible improvement in the ALSFRS-R score, defined as an increase of 5 points or more between two consecutive, monthly visits. For each patient with a 5-point or more increase, we evaluated the individual contribution of each ALSFRS-R item. Results: Longitudinal ALSFRS-R scores, originating from 114 trial centers enrolling a total of 1,240 patients, were analyzed. A 5-point or more increase in ALSFRS-R total score was found in 151 (12.2%) patients, with prevalence per study center ranging from 0% to 83%. Bulbar onset, faster disease progression at enrollment, and a lower ALSFRS-R score at baseline were associated with a sudden 5-point or more increase in the ALSFRS-R total score. ALSFRS-R items 2 (saliva), 9 (stairs), 10 (dyspnea), and 11 (orthopnea) were the primary drivers when a 5-point or more increase occurred. Conclusions: Sudden 5-point or more increases in ALSFRS-R total scores between two consecutive visits are relatively common. These sudden increases were not found to occur with equal frequency in trial centers; which underscores the need for amending existing standard operating procedures toward a universal version and monitoring of data quality during the study, in multicentre research.

Assessing the upper motor neuron in amyotrophic lateral sclerosis using the triple stimulation technique: A multicenter prospective study

ObjectiveTo evaluate the relevance of transcranial magnetic stimulation (TMS) using triple stimulation technique (TST) to assess corticospinal function in amyotrophic lateral sclerosis (ALS) in a large-scale multicenter study. MethodsSix ALS centers performed TST and conventional TMS in upper limbs in 98 ALS patients during their first visit to the center. Clinical evaluation of patients included the revised ALS Functional Rating Scale (ALSFRS-R) and upper motor neuron (UMN) score. ResultsTST amplitude ratio was decreased in 62% of patients whereas conventional TMS amplitude ratio was decreased in 25% of patients and central motor conduction time was increased in 16% of patients. TST amplitude ratio was correlated with ALSFRS-R and UMN score. TST amplitude ratio results were not different between the centers. ConclusionsTST is a TMS technique applicable in daily clinical practice in ALS centers for the detection of UMN dysfunction, more sensitive than conventional TMS and related to the clinical condition of the patients. SignificanceThis multicenter study shows that TST can be a routine clinical tool to evaluate UMN dysfunction at the diagnostic assessment of ALS patients.

P 48. Cerebrospinal fluid neurofilaments predict disease aggressiveness in Amyotrophic Lateral Sclerosis: an application of the D50 disease progression model

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder. As previous therapeutic trials in ALS have been severely hampered by high inter-individual heterogeneity in clinical phenotype, progression speed and survival, the identification of biomarkers that reliably reflect disease progression represents a priority in current ALS research. Here, we aimed to use the D50 disease progression model to investigate correlations between Cerebrospinal fluid (CSF) Neurofilament light chain (NfL) levels and disease aggressiveness in ALS patients. The D50 model quantifies patients“ individual disease trajectories and is calculated based on consecutively assessed ALS functional rating scale scores. The derived value D50 is defined as the time taken in months for a patient to lose 50% of his/her functionality and thus provides a unified measure of a patient”s overall disease aggressiveness. The relative D50 (rD50) reflects the individual disease covered and can be calculated for any timepoint in the disease course. The application of the D50 model enabled us to generate a large-scale pseudo-longitudinal analysis thereby overcoming the persistent difficulties in obtaining longitudinal CSF samples from heterogenous ALS patient cohorts. We analyzed detailed clinical data from a well-defined cohort of 156 patients with ALS. The concentration of NfL in CSF samples was measured at two different laboratories using the same procedure. Based on patients“ individual D50 values, we defined subgroups with high (<20), intermediate (20–40) or low (>40) disease aggressiveness. NfL levels were compared between these subgroups via analysis of covariance, using an array of confounding factors: age, gender, clinical phenotype, frontotemporal dementia, rD50-derived disease Phase and analysis laboratory. We found highly significant differences in NfL concentrations between all three D50 subgroups ( p < 0.001), representing an increase of NfL levels with increasing disease aggressiveness, as revealed in post-hoc analyses. The conducted analysis of covariance showed that this correlation was independent of gender, disease phenotype and Phase; however, age, analyzing laboratory, and dementia significantly influenced NfL concentration. We could show that CSF NfL is independent of patients“ individual disease covered (rD50 or derived disease Phase). Our results provided strong evidence for the potential of NfL to reflect disease aggressiveness in ALS and in addition proofed to remain at stable levels throughout the disease course. Implementation of CSF NfL as a potential read-out for future multi-center therapeutic trials in ALS is currently constrained by its demonstrated susceptibility to (pre-)analytical variations. Here we show that the D50 model is a sensitive tool that enables the discovery of correlations between clinical characteristics and CSF analytes and can accordingly recommended for future studies evaluating potential biomarkers.

Novel STMN2 Variant Linked to Amyotrophic Lateral Sclerosis Risk and Clinical Phenotype.

ObjectiveThere is a critical need to establish genetic markers that explain the complex phenotypes and pathogenicity of ALS. This study identified a polymorphism in the Stathmin-2 gene and investigated its association with sporadic ALS (sALS) disease risk, age-of onset and survival duration.MethodsThe candidate CA repeat was systematically analyzed using PCR, Sanger sequencing and high throughput capillary separation for genotyping. Stathmin-2 expression was investigated using RT-PCR in patient olfactory neurosphere-derived (ONS) cells and RNA sequencing in laser-captured spinal motor neurons.ResultsIn a case-control analysis of a combined North American sALS cohort (n = 321) and population control group (n = 332), long/long CA genotypes were significantly associated with disease risk (p = 0.042), and most strongly when one allele was a 24 CA repeat (p = 0.0023). In addition, longer CA allele length was associated with earlier age-of-onset (p = 0.039), and shorter survival duration in bulbar-onset cases (p = 0.006). In an Australian longitudinal sALS cohort (n = 67), ALS functional rating scale scores were significantly lower in carriers of the long/long genotype (p = 0.034). Stathmin-2 mRNA expression was reduced in sporadic patient ONS cells. Additionally, sALS patients and controls exhibited variable expression of Stathmin-2 mRNA according to CA genotype in laser-captured spinal motor neurons.ConclusionsWe report a novel non-coding CA repeat in Stathmin-2 which is associated with sALS disease risk and has disease modifying effects. The potential value of this variant as a disease marker and tool for cohort enrichment in clinical trials warrants further investigation.

Clinical and electrophysiological examination of pinch strength in patients with amyotrophic lateral sclerosis.

The split-hand concept has highlighted the preferential wasting of the thenar side of the hand in amyotrophic lateral sclerosis (ALS). Our objective is to re-explore pinch grip strength to assess whether it has the potential to be a practical biomarker of ALS. We measured different pinch grip strengths (thumb, index, and fifth) using a pinch gauge from both hands of 54 ALS patients and correlated this with the Medical Research Council (MRC) score, the upper-limb component of the revised ALS Functional Rating Scale - Revised (ALSFRS-R) score, and compound muscle action potentials (CMAPs) that comprise the split-hand index. Pinch grip strength using any of the three fingers showed a positive correlation with its corresponding CMAP, MRC grading, and upper-limb ALSFRS-R score. The thumb pinch showed the strongest correlation with the split-hand index and MRC grading. Pinch grip strength test using a simple gauge deserves further study as a potentially practical biomarker of ALS.

Prolonged distal latency of the median motor nerve is associated with poor prognosis in amyotrophic lateral sclerosis

ABSTRACT A nerve conduction study (NCS) is routinely undertaken for the differential diagnosis of amyotrophic lateral sclerosis (ALS). Prolonged median motor distal latency (MMDL) has been reported in a subset of patients with ALS. This study aimed to investigate the clinical importance of NCS characteristics in patients with ALS. A total of 75 patients who underwent NCS were enrolled in this study. The frequency of ALS patients with prolonged motor DL was higher in the median than ulnar NCS. The multivariate analysis revealed that shorter diagnostic latency, prolonged MMDL, and higher disease progression rate were significantly associated with poor prognosis. When ALS patients were divided into two groups according to the cut-off value (4.2 ms) of the MMDL, the group with prolonged MMDL had lower ALS functional rating scale and frontal assessment battery scores, upper limbs subscore, and shorter survival time than the group with shorter MMDL. In conclusion, patients with ALS that have prolonged MMDL may have upper limb dysfunction and shorter survival. MMDL can be a useful prognostic marker for patients with ALS. Abbreviations: ADM = abductor digiti minimi; APB = abductor pollicis brevis; ALS = amyotrophic lateral sclerosis; ALSFRS-R = revised ALS Functional Rating Scale; CI = confidence interval; CMAP = compound muscle action potential; CTS = carpal tunnel syndrome; DL = distal latency; ΔFS = disease progression rate; FAB = frontal assessment battery; FVC = forced vital capacity; HR = hazard ratio; MCV = motor nerve conduction velocity; MMDL = median motor distal latency; MMSE = mini-mental state examination; NCS = nerve conduction study; PaCO2 = partial pressure of arterial carbon dioxide; SBMA = spinal and bulbar muscular atrophy; SCV = sensory nerve conduction velocity; SD = standard deviation; SMA = spinal muscular atrophy; SNAP = sensory nerve action potential; SOD1 = superoxide dismutase 1; UMDL = ulnar motor distal latency.