Early Diagnosis Of Amyotrophic Lateral Sclerosis Research Articles

A Machine Learning Approach for Highlighting microRNAs as Biomarkers Linked to Amyotrophic Lateral Sclerosis Diagnosis and Progression.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons in the brain and spinal cord. The early diagnosis of ALS can be challenging, as it usually depends on clinical examination and the exclusion of other possible causes. In this regard, the analysis of miRNA expression profiles in biofluids makes miRNAs promising non-invasive clinical biomarkers. Due to the increasing amount of scientific literature that often provides controversial results, this work aims to deepen the understanding of the current state of the art on this topic using a machine-learning-based approach. A systematic literature search was conducted to analyze a set of 308 scientific articles using the MySLR digital platform and the Latent Dirichlet Allocation (LDA) algorithm. Two relevant topics were identified, and the articles clustered in each of them were analyzed and discussed in terms of biomolecular mechanisms, as well as in translational and clinical settings. Several miRNAs detected in the tissues and biofluids of ALS patients, including blood and cerebrospinal fluid (CSF), have been linked to ALS diagnosis and progression. Some of them may represent promising non-invasive clinical biomarkers. In this context, future scientific priorities and goals have been proposed.

Diagnosis of amyotrophic lateral sclerosis by respiratory function test.

The diagnostic criterion for amyotrophic lateral sclerosis (ALS) based on the findings of concomitant clinical and electrophysiological evidence of upper and lower motor neuron involvement may remain unsatisfied for months and in some patients, even for years in the early stage of the disease. Since respiratory involvement is an onset symptom of ALS in only 1-3% of patients, pulmonary assessment has never been considered useful in the early diagnosis of ALS. However, studies on pulmonary function are lacking, especially in those early stages where neurologic tests are also inconclusive. In contrast to the scarcity of data in the early stages, as the disease progresses, it is increasingly enriched by a rich set of symptoms and positive respiratory tests until respiratory failure occurs, which represents the main cause of death in ALS. Hereby we analyze the main pulmonary function tests (PFT) in the various stages of the disease, up to the recent evidence for the possibility of an early diagnosis.

Breaking the amyotrophic lateral sclerosis early diagnostic barrier: the promise of general markers

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that is associated with selective and progressive loss of motor neurons. As a consequence, the symptoms of ALS are muscle cramps and weakness, and it eventually leads to death. The general markers for early diagnosis can assist ALS patients in receiving early intervention and prolonging their survival. Recently, some novel approaches or previously suggested methods have validated the potential for early diagnosis of ALS. The purpose of this review is to summarize the status of current general markers discovery and development for early diagnosis of ALS, including genes, proteins neuroimaging, neurophysiology, neuroultrasound, and machine learning models. The main genetic markers evaluated are superoxide dismutase 1 (SOD1), chromosome 9 open reading frame 72 (C9orf72), transactivation-responsive DNA binding protein 43 (TARDBP), and fused in sarcoma (FUS) genes. Among proteins, neurofilament light chain is still the most established disease-specific adaptive change in ALS. The expression of chitinases, glial fibrillary acidic protein (GFAP), and inflammatory factors are changed in the early stage of ALS. Besides, more patient-friendly and accessible feature assays are explored by the development of neuroimaging, neurophysiology, and neuroultrasound techniques. The novel disease-specific changes exhibited the promising potential for early diagnosis of ALS. All of these general markers still have limitations in the early diagnosis, therefore there is an urgent need for the validation and development of new disease-specific features for ALS.

Current State and Future Directions in the Diagnosis of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of upper and lower motor neurons, resulting in progressive weakness of all voluntary muscles and eventual respiratory failure. Non-motor symptoms, such as cognitive and behavioral changes, frequently occur over the course of the disease. Considering its poor prognosis with a median survival time of 2 to 4 years and limited causal treatment options, an early diagnosis of ALS plays an essential role. In the past, diagnosis has primarily been determined by clinical findings supported by electrophysiological and laboratory measurements. To increase diagnostic accuracy, reduce diagnostic delay, optimize stratification in clinical trials and provide quantitative monitoring of disease progression and treatment responsivity, research on disease-specific and feasible fluid biomarkers, such as neurofilaments, has been intensely pursued. Advances in imaging techniques have additionally yielded diagnostic benefits. Growing perception and greater availability of genetic testing facilitate early identification of pathogenic ALS-related gene mutations, predictive testing and access to novel therapeutic agents in clinical trials addressing disease-modified therapies before the advent of the first clinical symptoms. Lately, personalized survival prediction models have been proposed to offer a more detailed disclosure of the prognosis for the patient. In this review, the established procedures and future directions in the diagnostics of ALS are summarized to serve as a practical guideline and to improve the diagnostic pathway of this burdensome disease.

Early initiation of riluzole may improve absolute survival in amyotrophic lateral sclerosis.

Riluzole improves survival in amyotrophic lateral sclerosis (ALS), but optimal time and duration of treatment are unknown. The aim of this study was to examine if timing of riluzole initiation and duration of treatment modified its effect on survival. Patients from the PRO-ACT dataset with information on ALS Functional Rating Scale, time from onset to enrollment (TFOE), and riluzole use were selected for analysis. Survival from enrollment was the outcome. Multivariable Cox proportional hazard models were examined for interactions between riluzole and TFOE. Inverse probability of treatment weighting (IPTW) was used to assess average treatment effect. Of 4778 patients, 3446 (72.1%) had received riluzole. In unadjusted analyses, riluzole improved median survival significantly (22.6 vs. 20.2months, log-rank p < 0.001). In multivariable analyses, no significant interaction between TFOE and riluzole was found. Riluzole effect was uniform during follow-up. By IPTW, estimated riluzole hazard ratio was 0.798 (95% confidence interval 0.686-0.927). Delaying riluzole initiation by 1y (6 to 18 months from onset) may translate to reducing median survival from onset by 1.9months (40.1 to 38.2months). Riluzole appears to reduce risk of death uniformly, regardless of time from onset to treatment, and duration of treatment. Earlier treatment with riluzole may be associated with greater absolute survival gain from onset. Early diagnosis of ALS will facilitate early treatment and is expected to improve survival.

Amyotrofik lateral skleroz erken tanısında sinir iletim çalışmaları ve ayrık el bulgusunun önemi

Aim: The heterogeneity of the Amyotrophic Lateral Sclerosis (ALS) clinical phenotypes leads to difficulties in early diagnosis. The ‘split hand’ sign is defined as the thenar muscles that are more prominently affected by hypothenar. In this study, the results of the initial nerve conduction study of the patients were compared with those of the controls in order to increase the findings supporting early diagnosis.&#x0D; Material and Method: Seventy-five patients who were diagnosed with ALS in our clinic were included in the study. The initial ENMG findings of the patients were compared with those of 70 healthy controls: Distal motor latency (DML), the compound muscle action potential (CMAP) amplitude, velocity in the motor conduction of median, ulnar, peroneal and tibial nerves; distal latency, amplitude, velocity in sensorial conduction were evaluated. Ulnar/median DML and ulnar/median CMAP amplitude ratios were examined.&#x0D; Results: In ALS group, DMLs of the median, ulnar, peroneal, and tibial nerves were significantly longer, and CMAP amplitudes were significantly smaller than those of the controls. The sensory conductions of the median, ulnar, and sural nerves were not statistically different between the groups. The ulnar/median DML ratio of the patients was lower than the ratio of controls (0.73/0.80;p=0.003); while the ulnar/median CMAP amplitude ratio was greater (1.40/1.11; p=0.002).&#x0D; Conclusion: Prolonged DML and reduced amplitudes were observed in the motor nerve conduction of ALS patients in the early period. The results of the present study also support the presence of split-hand phenomenon even in early period of limb-onset ALS (both upper and lower). These findings suggest that nerve conduction studies and electrophysiologically detected split-hand sign are important clues for the early diagnosis of ALS in case of heterogeneous clinical phenotype.

Serum NfL and CHI3L1 for ALS and parkinsonian disorders in the process of diagnosis.

Serum neurofilament light chain (NfL) and chitinase 3-like 1 (CHI3L1, also called YKL-40) concentrations are attractive candidate biomarkers for neurodegenerative disorders, which include amyotrophic lateral sclerosis (ALS) and parkinsonian disorders. We aimed to assess the diagnostic power of serum NfL and CHI3L1 concentrations with regard to the early diagnosis of ALS and Parkinson's disease (PD). We studied 157 individuals, which included 41 healthy controls, 8 patients with ALS mimics, 18 patients initially diagnosed with ALS (ID-ALS), 32 patients late-diagnosed with ALS (LD-ALS), 29 patients with PD, 12 patients with PD mimics, and 17 patients initially diagnosed with atypical parkinsonian disorders (ID-APDs) at the initial stage of diagnosis. Electrochemiluminescence was used to measure the concentrations of serum NfL and CHI3L1, the diagnostic performance of which was assessed using the area under the receiver operating curves (AUCs). The AUCs of serum NfL were 0.90 for discriminating ALS mimics from LD-ALS at the initial stage of diagnosis and 0.89 for discriminating ALS mimics from ALS (LD/ID-ALS). The AUCs of serum NfL were 0.76 for discriminating PD from PD mimics at the initial stage of diagnosis, and 0.80 for discriminating PD from APD. No significant difference existed in serum CHI3L1 concentrations between individuals with suspected ALS or parkinsonism (p = 0.14, and p = 0.44, respectively). Serum NfL had excellent and almost good diagnostic performances for patients with ALS and PD, respectively, at the initial stage of diagnosis, whereas no significant difference existed in serum CHI3L1 between any groups.

Characteristics of serum metabolites in sporadic amyotrophic lateral sclerosis patients based on gas chromatography-mass spectrometry

To identify differential metabolites and metabolic pathways and provide guidance for the novel biomarkers for diagnosis and prognosis of amyotrophic lateral sclerosis (ALS). ALS patients and people without nervous diseases were recruited. Metabolomic analysis was performed using gas chromatography-mass spectrometry (GC/MS). The orthogonal projections to latent structures discriminant analysis (OPLS-DA) were used to identify differential metabolites. Kyoto Encyclopedia of Genes and Genomes and MetaboAnalyst were used to identify metabolic pathways. 75 metabolites were detected and aligned. The OPLS-DA showed the metabolomic profile of ALS patients and those in the fast-progression and slow-progression ALS groups differed from that of CTRL (p < 0.05). The levels of maltose, glyceric acid, lactic acid, beta-alanine, phosphoric acid, glutamic acid, ethanolamine and glycine in ALS were significantly higher, while 2,4,6-tri-tert-butylbenzenethiol was lower. Glycine, serine and threonine metabolism, D-glutamine and D-glutamate metabolism, alanine, aspartate, and glutamate metabolism, beta-alanine metabolism, and pyruvate metabolism were significantly altered metabolic pathways in ALS. ROC was used to discriminate ALS from CTRL with an AUC of 0.898 (p < 0.001) using 2,4,6-tri-tert-butylbenzenethiol, beta-alanine, glycine, and ethanolamine. The serum metabolites and metabolic pathways in ALS patients are significantly altered compared with CTRL. These findings may contribute to the early diagnosis of ALS.

Early diagnosis of amyotrophic lateral sclerosis by threshold tracking and conventional transcranial magnetic stimulation.

Background and purposeShort‐interval intracortical inhibition by threshold tracking (T‐SICI) has been proposed as a diagnostic tool for amyotrophic lateral sclerosis (ALS) but has not been compared directly with conventional amplitude measurements (A‐SICI). This study compared A‐SICI and T‐SICI for sensitivity and clinical usefulness as biomarkers for ALS.MethodsIn all, 104 consecutive patients referred with suspicion of ALS were prospectively included and were subsequently divided into 62 patients with motor neuron disease (MND) and 42 patient controls (ALS mimics) by clinical follow‐up. T‐SICI and A‐SICI recorded in the first dorsal interosseus muscle (index test) were compared with recordings from 53 age‐matched healthy controls. The reference standard was the Awaji criteria. Clinical scorings, conventional nerve conduction studies and electromyography were also performed on the patients.ResultsMotor neuron disease patients had significantly reduced T‐SICI and A‐SICI compared with the healthy and patient control groups, which were similar. Sensitivity and specificity for discriminating MND patients from patient controls were high (areas under the receiver operating characteristic curves 0.762 and 0.810 for T‐SICI and A‐SICI respectively at 1–3.5 ms). Paradoxically, T‐SICI was most reduced in MND patients with the fewest upper motor neuron (UMN) signs (Spearman ρ = 0.565, p = 4.3 × 10−6).ConclusionsAmplitude‐based measure of cortical inhibition and T‐SICI are both sensitive measures for the detection of cortical involvement in MND patients and may help early diagnosis of ALS, with T‐SICI most abnormal before UMN signs have developed. The gradation in T‐SICI from pathological facilitation in patients with minimal UMN signs to inhibition in those with the most UMN signs may be due to progressive degeneration of the subset of UMNs experiencing facilitation.

PND53 Predictive Models Leveraging Machine Learning and Real-World Data for Early Diagnosis: An Application in Amyotrophic Lateral Sclerosis

To assess the utility of machine learning for predicting early diagnosis of amyotrophic lateral sclerosis (ALS) based on real-world data (RWD). We identified 4779 patients with ALS and without primary lateral sclerosis from the Optum® de-identified Electronic Health Record (EHR) dataset (2007-2020), and 47,781 patients as the control cohort who did not have ALS and were demographically matched by age and gender in a 1:10 target to control ratio. Mutual information was used to explore and identify features in RWD, including lab, microbiology, and natural language processing biomarkers available in EHR, by comparing the target population (ALS patients) with the demographically matched control cohort. We trained various machine learning models (eg, logistic regression, random forest, gradient boosting, support vector machines, neural networks, soft voting) spanning different periods of time relative to a defined index date and compared their performance in predicting early diagnosis of ALS. Predictive models trained with gradient boosting on data closer to the defined index date, including lab tests from EHR, performed the best and had a very low false positive rate (AUC=0.9463). This model suggested that the top 5 predictors of an undiagnosed ALS patient were muscle weakness (generalized), normal thyroid stimulating hormone levels, dysphagia (unspecified), cramp of limb/abnormal involuntary movements, and other musculoskeletal symptoms referable to limbs. Many of the features were diagnoses that could be considered for an earlier evaluation of ALS in clinical practice. Indeed, the model had a sensitivity of 1%, specificity >99.0%, and was able to identify with a precision of 63% patients not yet identified with ALS, suggesting that early screening for ALS would be beneficial. This study highlights opportunities of leveraging machine learning utilizing EHR RWD to identify features that predict early diagnosis of ALS.

Sensitivity of Awaji Criteria and Revised El Escorial Criteria in the Diagnosis of Amyotrophic Lateral Sclerosis (ALS) at First Visit in a Tunisian Cohort.

Background Amyotrophic lateral sclerosis (ALS) is a fatal disease whose diagnosis and early management can improve survival. The most used diagnostic criteria are the revised El Escorial criteria (rEEC) and Awaji criteria (AC). The comparison of their sensitivities showed contradictory results. Our study aimed to compare the sensitivities of these two criteria in the diagnosis of definite ALS, at first visit, in a Tunisian hospital cohort. Materials and Methods This was a retrospective study including 173 patients diagnosed with ALS at the Department of Neurology of the Razi Hospital between January 2003 and April 2018.After studying the clinical features of the disease in our study population,each patient was categorized according to the rEEC and AC based on data collected in his medical record during his first visit to our department. Then, we compared the sensitivities of these two criteria in the diagnosis of definite ALS. Results Our Tunisian cohort was characterized by a slower disease progression. The sensitivity of the AC (69.4%) was significantly higher than that of the rEEC (40.5%) (p < 0.001). When the clinical signs evolved for less than 6 months, the sensitivities were 61% for AC and 12% for rEEC (p < 0.001). After 24 months of disease progression, the sensitivities were 78.2% for AC and 69.1% for rEEC (p = 0.063). It was impossible to categorize seventeen patients by the two criteria. Conclusion Our study demonstrated that patients in AC are more sensitive than rEEC in the early diagnosis of ALS in our Tunisian cohort. However, this superiority is gradually reduced during the evolution of the disease.

Evaluation of Motor Neuron Injury in ALS by Different Parameters of Diffusion Tensor Imaging

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving upper and lower motoneurons selectively. The injury of lower motoneurons is closely related to the onset, progression and prognosis of ALS. Therefore, the assessment of the injury of lower motoneurons is of great significance to ALS. Diffusion tensor imaging (DTI) is a new imaging method improved and developed on the basis of diffusion weighted imaging. It uses the anisotropic principle of diffusion movement of water molecules to quantify it from multiple directions, so as to reflect the changes of fine structure and function of living tissues. It can be more objective to find the damage of the upper motor neurons, help the early diagnosis of ALS, and objectively monitor and evaluate the development and treatment of ALS. In this paper, the research and application of different parameters of diffusion tensor imaging to evaluate the motor neuron injury in ALS were studied. Patients with motor neuron injury in ALS were collected as case group and healthy volunteers as control group. The diagnostic value of different parameters of axial DTI in ALS was discussed. The FA and MD values of the pyramidal tract in ALS patients have obvious changes compared with those in healthy people. It can objectively and quantitatively evaluate the pathological changes of the pyramidal tract in ALS patients, and provide valuable information for the diagnosis of ALS. The FA value is more sensitive, and the posterior limb of the internal capsule may be the best place to evaluate the damage of the pyramidal tract. In a word, DTI can objectively and quantitatively evaluate the lesions of pyramidal tract, provide valuable information for the diagnosis of ALS, and hope to provide help for the establishment, diagnosis, evaluation, prognosis, scientific research and drug test of ALS motor nerve injury.

New molecular diagnostic trends and biomarkers for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurodegenerative disorder. Two forms are recognized, familial (FALS) that accounts for 5-10% of ALS cases, and sporadic (SALS) that accounts for the rest. Early diagnosis of ALS is important because it improves their therapeutic efficacy. Current diagnosis is based on clinical assessment and requires approximately 12 months, leading to a significant delay in drug administration. Therefore, new methods are required for the earlier diagnosis of ALS. Screening for pathogenic variants in known ALS-associated genes is already exploited as a diagnostic tool in ALS but cannot be applied for population-based screening. New circulating biomarkers (proteins or small molecules) are needed for initial screening, whereas specific diagnostic methods can be applied to confirm the presence of pathogenic variants in the selected population subgroup. Lipids appear as promising biomarkers for population-based screening and for monitoring disease progression. Genetic analysis can also assist in the prediction of disease progression by analyzing disease-modifying genes, for example, EPHA4 and CHGB. Furthermore, molecular diagnosis will aid the stratification of ALS patients for improved pharmacological approaches. Here, we discuss current and novel diagnostic strategies and how they can be applied to revolutionize the field of ALS molecular diagnosis.

Identification of molecular signatures and pathways common to blood cells and brain tissue of amyotrophic lateral sclerosis patients

Abstract Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that is characterized by the death of neurons controlling voluntary muscles. Early diagnosis of ALS is difficult and detection is limited in sensitivity and specificity as well as by cost. Therefore, detecting ALS from blood cell analysis could improve the early diagnosis and treatment of the disease. The present study aimed to identify blood cell transcripts that reflect brain expression levels of factors linked to ALS progression. We analyzed blood cell and brain transcriptomics gene expression datasets (RNA-seq and microarray) in blood and brain. We identified 13 differentially expressed genes (DEG; ALS versus controls) common to blood cells and brain (DNAH6, HLA-DMB, HLA-A, EHD2, CMKLR1, PROS1, GAPT, CCR1, THBS1, CDK2, RAB27A, ITGB3 and C1orf162) that were commonly dysregulated between ALS blood and brain tissues. These data revealed significant neurodegeneration-associated molecular pathways in the signaling systems. Integration of these different analyses revealed dysregulation of a number of transcription factors, namely SP1, MYC, TP3, CTCF and SRF. In addition, we identified microRNAs altered in ALS: miR-29c, miR-21, let-7a, miR-377, miR-103, miR-369-3p, miR-494, miR-204, miR-29a. Thus, we have identified possible new links between pathological processes in the brain and transcripts in blood cells in ALS subjects that may enable the use of blood samples to diagnose and monitor ALS onset and progression.

O21 Peak ratio and motor unit potential analyses in detection of chronic neurogenic changes in amyotrophic lateral sclerosis

Objectives Peak ratio analysis is a quantitative way of analyzing interference pattern by turns-amplitude analysis. We aimed in this study to compare the sensitivities of peak ratio analysis and quantitative motor unit potential (MUP) analysis in detecting chronic neurogenic changes in amyotrophic lateral sclerosis (ALS). Methods Twenty-two patients (1 definite, 7 probable, and 9 possible ALS according to Awaji criteria as reference standard, and 5 progressive muscular atrophy) were prospectively included. Quantitative MUP and peak ratio analyses were done in 22 biceps brachialis (BB), 22 tibialis anterior (TA) and 18 abductor pollicis brevis (APB) muscles on the least affected side. Results were compared to laboratory controls. The sensitivity of MUP duration and peak ratio was compared using the McNemar chi-square test. Results Peak ratio analysis was more frequently abnormal than MUP analysis in BB (59% vs. 23%), and TA (59% vs. 18%) muscles ( p Discussion Peak ratio analysis sampled at stronger effort detected more frequently chronic neurogenic changes than MUP analysis recruited at weak effort. Conclusions Peak ratio analysis may provide earlier detection of chronic neurogenic changes, thereby facilitating earlier diagnosis of ALS. Significance Peak ratio analysis which is available in commercial EMG machines should be considered in the electrodiagnostic investigation of ALS.

14. Pre-symptomatic detection of cytoplasmic TDP-43 accumulation using tissue-engineered skin model derived from C9ORF72-FALS patients

Amyotrophic lateral sclerosis (ALS) is an adult-onset disease characterized by the selective degeneration of motor neurons in the brain and spinal cord resulting in progressive paralysis and death. Current diagnosis of ALS is based on clinical assessment of related symptoms, which appear only late in the disease course after degeneration of a significant number of motor neurons. As a result, the identification and development of disease-modifying therapies is difficult, making ALS an incurable disease. Novel strategies for early diagnosis of ALS, to monitor disease progression and to assess response to existing and future treatments are urgently needed.Many neurological disorders, including ALS, are accompanied by skin changes that often precede the onset of neurological symptoms. We have developed a unique ALS tissue-engineered skin model (ALS-TES), derived from the cells of ALS patients, in order to study the earliest stages of ALS-related skin pathology. For each participant, two skin biopsies were collected using a 6-mm diameter punch biopsy. Tissue-engineered skin was then generated from isolated keratinocytes and fibroblasts, and examined by routine histochemistry and immunohistochemistry, as well as by confocal microscopy. The ALS-TES model presents a number of striking features including altered epidermal differentiation, abnormal dermo-epidermal junction, delamination, keratinocyte infiltration, collagen disorganization and cytoplasmic TDP-43 inclusions, which are not seen in skin models derived from healthy subjects. The same abnormal skin model changes were detected skin models derived from the cells of pre- symptomatic C9orf72-linked ALS patients carrying the GGGGCC DNA repeat expansion. Consequently, our ALS-TES skin model could represent a renewable source of human tissue to better understand the physiopathological mechanisms underlying this disease, including cytoplasmic TDP43 accumulation, and lead to better tools for early diagnosis and disease monitoring.

Diffusion tensor imaging (DTI) correlates with transcranial magnetic stimulation (TMS) findings in early ALS (Amyotrophic Lateral Sclerosis) diagnostic

The onset of ALS is insidious and symptoms may be disregarded by the patient for several months. The diagnosis of ALS is based on clinical features and EMG findings. DTI offers the advantage of the revealing in vivo macroscopic geometrical arrangement of white matter bundles that becomes apparent through diffusion measurements of water molecules. DTI findings could correlate with prolonged cortical MEP, sustaining the early diagnosis of ALS, revealing upper motor neurons involvement.

1H-NMR-Based Metabolomic Profiling of CSF in Early Amyotrophic Lateral Sclerosis

BackgroundPathophysiological mechanisms involved in amyotrophic lateral sclerosis (ALS) are complex and none has identified reliable markers useful in routine patient evaluation. The aim of this study was to analyze the CSF of patients with ALS by 1H NMR (Nuclear Magnetic Resonance) spectroscopy in order to identify biomarkers in the early stages of the disease, and to evaluate the biochemical factors involved in ALS.MethodologyCSF samples were collected from patients with ALS at the time of diagnosis and from patients without neurodegenerative diseases. One and two-dimensional 1H NMR analyses were performed and metabolites were quantified by the ERETIC method. We compared the concentrations of CSF metabolites between both groups. Finally, we performed principal component (PCA) and discriminant analyses.Principal FindingsFifty CSF samples from ALS patients and 44 from controls were analyzed. We quantified 17 metabolites including amino-acids, organic acids, and ketone bodies. Quantitative analysis revealed significantly lower acetate concentrations (p = 0.0002) in ALS patients compared to controls. Concentration of acetone trended higher (p = 0.015), and those of pyruvate (p = 0.002) and ascorbate (p = 0.003) were higher in the ALS group. PCA demonstrated that the pattern of analyzed metabolites discriminated between groups. Discriminant analysis using an algorithm of 17 metabolites revealed that patients were accurately classified 81.6% of the time.Conclusion/SignificanceCSF screening by NMR spectroscopy could be a useful, simple and low cost tool to improve the early diagnosis of ALS. The results indicate a perturbation of glucose metabolism, and the need to further explore cerebral energetic metabolism.

Utility of trapezius EMG for diagnosis of amyotrophic lateral sclerosis

Needle electromyography (EMG) of the tongue is traditionally used as a key to the diagnosis of amyotrophic lateral sclerosis (ALS), although relaxation of the tongue is often difficult to achieve. Recently, frequent abnormalities in the EMGs of the sternocleidomastoid (SCM) and upper trapezius muscles in ALS have been reported. To elucidate the diagnostic utility of these muscles we performed a multicenter prospective study to examine EMGs of the tongue (genioglossus), SCM, and trapezius in 104 ALS or suspected ALS patients. We also examined EMGs of the SCM and trapezius in 32 cervical spondylosis (CS) patients. We mainly evaluated fibrillation potentials/positive sharp waves (Fib/PSWs) and fasciculation potentials. Complete relaxation was achieved in 85% of ALS patients in the trapezius, but in only 6% of patients in the tongue. Fib/PSWs were observed in 8%, 13%, and 45% of ALS patients in the tongue, SCM, and trapezius, respectively, whereas fasciculation potentials were observed in 1%, 7%, and 39%, respectively. Abnormal spontaneous activity of any type was found in 9%, 17%, and 63% of patients, respectively. The high frequency of abnormal spontaneous activity in the trapezius was similar among the different diagnostic categories, and even 72% of clinically suspected ALS (progressive muscular atrophy) patients showed them in their trapezius. We did not observe Fib/PSWs or fasciculation potentials in any of our CS patients, thus these findings have excellent specificity. Tongue EMG added little utility over the clinical sign of tongue atrophy. Abnormal spontaneous activity in the trapezius would be more useful for the early diagnosis of ALS.

Early diagnosis of ALS: The search for signs of denervation in clinically normal muscles

We prospectively investigated whether early diagnosis of amyotrophic lateral sclerosis (ALS) could be facilitated by demonstrating signs of denervation in a muscle of a clinical and electromyographical unaffected region. Muscle fibre conduction velocity (MFCV) was determined in 18 patients in whom the diagnosis ALS was considered but not established beyond a level of clinically possible ALS according to the revised El Escorial criteria. A muscle biopsy was obtained from the same muscle, to demonstrate neurogenic changes. The study followed the guidelines from the STARD initiative. Results were analysed with respect to the final diagnosis. After a mean follow-up of 16 months, 9 patients developed probable or definite ALS. Sensitivity of abnormal MFCV for developing ALS was 89%. Muscle biopsy confirmed that denervation was the cause of abnormal MFCV. We concluded that MFCV can be used to detect denervation in muscles that show no clinical or electromyographical signs of lower motor neuron disease, and thus may contribute to early diagnosis of probable laboratory-supported ALS.