Onset Of Amyotrophic Lateral Sclerosis Research Articles

ATXN2 intermediate expansions in amyotrophic lateral sclerosis.

Intermediate CAG (polyQ) expansions in the gene ataxin-2 (ATXN2) are now recognized as a risk factor for amyotrophic lateral sclerosis. The threshold for increased risk is not yet firmly established, with reports ranging from 27 to 31 repeats. We investigated the presence of ATXN2 polyQ expansions in 9268 DNA samples collected from people with amyotrophic lateral sclerosis, amyotrophic lateral sclerosis with frontotemporal dementia, frontotemporal dementia alone, Lewy body dementia and age matched controls. This analysis confirmed ATXN2 intermediate polyQ expansions of ≥31 as a risk factor for amyotrophic lateral sclerosis with an odds ratio of 6.31. Expansions were an even greater risk for amyotrophic lateral sclerosis with frontotemporal dementia (odds ratio 27.59) and a somewhat lesser risk for frontotemporal dementia alone (odds ratio 3.14). There was no increased risk for Lewy body dementia. In a subset of 1362 patients with amyotrophic lateral sclerosis with complete clinical data, we could not confirm previous reports of earlier onset of amyotrophic lateral sclerosis or shorter survival in 25 patients with expansions. These new data confirm ≥31 polyQ repeats in ATXN2 increase the risk for amyotrophic lateral sclerosis, and also for the first time show an even greater risk for amyotrophic lateral sclerosis with frontotemporal dementia. The lack of a more aggressive phenotype in amyotrophic lateral sclerosis patients with expansions has implications for ongoing gene-silencing trials for amyotrophic lateral sclerosis.

Respiratory onset in amyotrophic lateral sclerosis: clinical features and spreading pattern

Objective To describe the clinical features and progression of patients with respiratory onset amyotrophic lateral sclerosis (ALS). Methods: We analyzed the clinical features, including respiratory tests, functional score, noninvasive ventilation (NIV) time and survival of ALS patients with respiratory-onset in our database consisting of 1688 patients. In a subset of 625 ALS patients we analyzed the spreading pattern to other bodily regions. Results: We included 1579 patients with ALS. Sixty-three patients (4%) presented respiratory-onset (79.4% men, mean onset-age 67.7 ± 8.9yrs). All had predominant LMN involvement, and significant weight loss (>10%) was identified in 38.9%. The respiratory tests were abnormal in these respiratory-onset patients (p < 0.001). ALSFRS-R respiratory subscore was lower in this population (p < 0.001). NIV was adapted in 84.1%, sooner than in the larger group of ALS patients (p < 0.001), and survival from disease onset was shorter (p < 0.001). Respiratory-onset was a predictor of time to NIV (X 2=42.0, p < 0.001) and of survival (X 2=7.1, p = 0.008). The spreading pattern was studied in 18 patients with isolated respiratory-onset. The progression interval to the 2nd region was 4.7 ± 5.7mo and to a 3rd region 6.1 ± 8.7mo. Different patterns of spread had no impact on survival. Conclusions: This phenotype is typically seen in emaciated older men with predominant lower motor neuron involvement, and is associated with diaphragm paresis and central respiratory involvement. NIV adaptation is rapid but total survival is shorter than in the other patients. Spreading pattern did not affect time to NIV adaptation or total survival, as NIV support is a modifying treatment in the course of ALS.

Risk Factors of Amyotrophic Lateral Sclerosis (ALS): An Updated Systematic Review

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease impacting the voluntary motor nervous system. While the origin of ALS remains unclear, existing literature suggests multifactorial pathogenesis. Most cases appear sporadically, implicating the existence of environmental factors, while others suggest an underlying genetic mechanism. This study aims to summarize risk factors associated with the onset and progression of ALS. Methods: Three reviewers searched Medline database for English-language articles published between January 1, 2017 and November 6, 2021. Keywords included, but were not limited to, ALS, motor neuron disease, biomarkers, expos*, risk factors, and others. Included studies directly examined the effect of risk factors on ALS patients. Results were summarized descriptively following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Results: Overall, 310 unique articles were identified, of which 66 articles spanning 18 countries met the inclusion criteria. Thirty-five articles discussed environmental factors and reported 3 personal characteristics, 13 lifestyle factors, and 22 clinical factors being associated with ALS. Nineteen different genes were also discovered to be associated with ALS, while 13 genes were found to have no association. Discussion: Among environmental factors, lower socioeconomic status occupations were found to have a higher occurrence of ALS. Traumatic brain injuries are another clinical risk factor commonly associated with ALS. There are inconsistent associations between alcohol intake and ALS, and the link between ALS and viruses needs to be further explored due to a potential causal relationship. Some of the genes identified in this review are definitive ALS genes, but others are novel or have little supporting evidence, necessitating further research. Conclusion: With over 90% of ALS cases appearing sporadically, a great amount of research has gone into identifying the risk factors of the fatal illness. This study provides an updated systematic review that encompasses findings from 66 of the most current articles surrounding environmental and genetic risk factors of ALS. This paper provides researchers with a comprehensive summary of these risk factors to provide a springboard for future studies.

The Impact of Profilin‐1 Mutations on Protein Homeostasis in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal disease characterized by the dysfunction and degeneration of motor neurons in the central nervous system. ALS has been linked to a number of genetic mutations, including point mutations in the actin‐binding protein profilin‐1 (Pfn1). While the prevalence of Pfn1 mutations is low, around 1% of inherited forms of the disease, an understanding of their impact on motor neuron cell death can provide insight into the mechanisms underlying ALS onset and progression. As Pfn1 is an important regulator of the actin cytoskeleton, we hypothesize that ALS‐linked mutations of Pfn1 promote defects in protein homeostasis and synaptic communication. To test this hypothesis, neuronal cells were transfected with Pfn1 constructs (including wild‐type, C71G, and M118V) and subjected to cellular stressors (including heat shock and sodium arsenite treatments). Immunostaining was then used to visualize and quantify differences in protein aggregation and stress granule formation. Our results have established the baseline response with the wild‐type construct and indicate that there is an increase in protein aggregation as well as in the number and size of stress granules with the mutant constructs. Our ongoing studies are aimed at validating these preliminary results, and our goal is to provide mechanistic insight pertaining to Pfn1’s role in ALS disease pathogenesis.

Genetic Variability of Inflammation and Oxidative Stress Genes Affects Onset, Progression of the Disease and Survival of Patients with Amyotrophic Lateral Sclerosis.

Inflammation and oxidative stress are recognized as important contributors to amyotrophic lateral sclerosis (ALS) disease pathogenesis. Our aim was to evaluate the impact of selected single-nucleotide polymorphisms in genes involved in inflammation and oxidative stress on ALS susceptibility and modification. One-hundred-and-eighty-five ALS patients and 324 healthy controls were genotyped for nine polymorphisms in seven antioxidant and inflammatory genes using competitive allele-specific PCR. Logistic regression; nonparametric tests and survival analysis were used in the statistical analysis. Investigated polymorphisms were not associated with ALS susceptibility. Carriers of at least one polymorphic SOD2 rs4880 T or IL1B rs1071676 C allele more often had bulbar ALS onset (p = 0.036 and p = 0.039; respectively). IL1B rs1071676 was also associated with a higher rate of disease progression (p = 0.015). After adjustment for clinical parameters; carriers of two polymorphic IL1B rs1071676 C alleles had shorter survival (HR = 5.02; 95% CI = 1.92–13.16; p = 0.001); while carriers of at least one polymorphic CAT rs1001179 T allele had longer survival (HR = 0.68; 95% CI = 0.47–0.99; p = 0.046). Our data suggest that common genetic variants in the antioxidant and inflammatory pathways may modify ALS disease. Such genetic information could support the identification of patients that may be responsive to the immune or antioxidant system—based therapies.

The Multifaceted Role of GPCRs in Amyotrophic Lateral Sclerosis: A New Therapeutic Perspective?

Amyotrophic lateral sclerosis (ALS) is a degenerating disease involving the motor neurons, which causes a progressive loss of movement ability, usually leading to death within 2 to 5 years from the diagnosis. Much effort has been put into research for an effective therapy for its eradication, but still, no cure is available. The only two drugs approved for this pathology, Riluzole and Edaravone, are onlyable to slow down the inevitable disease progression. As assessed in the literature, drug targets such as protein kinases have already been extensively examined as potential drug targets for ALS, with some molecules already in clinical trials. Here, we focus on the involvement of another very important and studied class of biological entities, G protein-coupled receptors (GPCRs), in the onset and progression of ALS. This workaimsto give an overview of what has been already discovered on the topic, providing useful information and insights that can be used by scientists all around the world who are putting efforts into the fight against this very important neurodegenerating disease.

Clinical and electrophysiological characteristics of respiratory onset amyotrophic lateral sclerosis: a single-centre study.

We compared the clinical characteristics of patients with respiratory, bulbar and limb onset amyotrophic lateral sclerosis (ALS) who visited a single tertiary centre for 8years. Total of 115 ALS patients with respiratory, bulbar and limb onset ALS, including sex, body mass index (BMI), presence of lung disease, age at diagnosis, disease duration after initial symptoms, ALS Functional Rating Scale (ALSFRS-R) and progression rate (Delta-FS), pulmonary function, amplitude and distal latency (DL) of the phrenic nerves and blood creatine kinase (CK) and uric acid levels were collected. The prevalence of respiratory, bulbar and limb onset ALS were 5.2%, 28.7% and 66.1%, respectively. The mean age at diagnosis and ALSFRS-R were 67.8 ± 5.5, 63.8 ± 10.1 and 59.2 ± 11.7 in the descending order. The mean amplitude (0.18 ± 0.10mV) and DL (9.5 ± 1.7ms) of the phrenic nerves were significantly decreased and prolonged in respiratory onset ALS compared with other types of ALS patients. Patients with respiratory onset ALS had normal creatine kinase (CK) levels, whereas patients with other types of ALS had increased CK levels. Although rare, respiratory onset ALS may occur and should be considered during the initial differential diagnosis. In this study, patients with respiratory onset ALS were characterised by male predominance, with a higher baseline ALSFRS-R, lower BMI and phrenic nerve study well discriminated respiratory onset ALS from bulbar or limb onset ALS patients.

Statin Medications and Amyotrophic Lateral Sclerosis Incidence and Mortality.

Studies of statins and amyotrophic lateral sclerosis (ALS) incidence and survival have had conflicting findings possibly related to difficulties with confounding by indication. We considered potency of statins used and duration of use to explore confounding by indication. Within the Clalit Health Services in Israel, we identified 948 ALS case patients from 2004 through 2017 and matched them with 1,000 control subjects each. Any statin use up to 3 years before ALS onset was not associated with ALS incidence but was associated with a reduced hazard ratio (HR) for death. Odds of ALS did not vary by statin potency, but use of only lower-potency statins was associated with longer survival (HR = 0.82, 95% CI: 0.68, 0.98), whereas the association with higher-potency statins was null compared with those case patients who did not use statins. However, duration of statin use appeared to account for these findings. Those who used statins only up to 3 years had longer survival (HR = 0.77, 95% CI: 0.61, 0.96) than did case patients who did not use statins, but those who used statins for >3 years did not. Although other explanations are possible, these findings could suggest a protective effect of statins on ALS survival that is partially masked by a worse prognosis from underlying reasons for taking statins that deserves further exploration.

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.

Alveolar Ventilation-Targeted Versus Spontaneous/Timed Mode for Home Noninvasive Ventilation in Amyotrophic Lateral Sclerosis.

Home noninvasive ventilation (NIV) is increasingly used in amyotrophic lateral sclerosis (ALS) to improve symptoms and survival. Our primary objective was to compare intelligent volume-assured pressure support (iVAPS) versus spontaneous/timed (S/T) modes regarding time to first change in ventilator parameters and the number of interventions over 6 months in subjects with ALS in a respiratory therapist (RT)-led program. In this study, 30 subjects with ALS meeting criteria for NIV initiation were randomized to iVAPS or S/T. NIV was initiated using standardized protocols targeting optimal tidal volume and comfort in a daytime session. Download data were recorded at 1 week and 1 and 6 months. Any changes in ventilator parameters were recorded. Of the 30 subjects, 56.7% had bulbar onset ALS, 8 died, and 11 in each group completed the study. Median time to first parameter change was 33.5 (interquartile range [IQR] 7.7-96.0) d versus 41.0 (IQR 12.5-216.5) d for iVAPS versus S/T groups, respectively, (P = .48). The average number of RT interventions was similar between groups (1.1 ± 1.1 vs 0.9 ± 0.9 at 1 month, P = .72; 2.4 ± 2.1 vs 2.4 ± 2.3 at 6 months, P = .95, for iVAPS vs S/T, respectively). Adherence was significantly lower with iVAPS than S/T at 1 week but not at 1 or 6 months. Download parameters were similar between groups at 1 week and 6 months except for higher residual apnea-hypopnea index (AHI) and less spontaneously triggered breaths with iVAPS at 6 months. The time to first change of parameters and the number of interventions at 6 months from NIV initiation were similar for the iVAPS and S/T modes in subjects with ALS. With iVAPS, adherence was lower transiently at NIV initiation, and the residual AHI was higher at 6 months. Alveolar ventilation-targeted NIV may require a longer adaptation period and result in greater upper-airway instability predominantly in patients with bulbar ALS.

Lack of an association between SCFD1 rs10139154 polymorphism and amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Through a genome-wide association study (GWAS), the Sec1 family domain-containing protein 1 (SCFD1) rs10139154 variant at 14q12 has emerged as a risk factor gene for ALS. Moreover, it has been reported to influence the age at onset (AAO) of patients with ALS. The aim of the present study was to assess the association of the SCFD1 rs10139154 polymorphism with the risk of developing ALS. For this purpose, 155 patients with sporadic ALS and 155 healthy controls were genotyped for the SCFD1 rs10139154. The effect of the SCFD1 rs10139154 polymorphism was then examined on the following parameters: i) The risk of developing ALS; ii) the AAO of ALS; iii) the site of ALS onset (patients with bulbar onset ALS vs. healthy controls; and patients with limb onset ALS vs. healthy controls); and iv) the AAO of ALS onset with subgroup analyses based on the site of onset (bulbar and limb, crude and adjusted for sex). The analysis of all the outcomes was performed assuming five genetic models. Crude and adjusted analyses were applied. The threshold for statistical significance was set at 0.05. The results revealed no association between SCFD1 rs10139154 and any of the examined phenotypes in any of the models examined. On the whole, based on the findings of the present study, SCFD1 rs10139154 does not appear to play a determining role in the risk of developing ALS.

Natural history and remarkable psychiatric state of late-onset amyotrophic lateral sclerosis in China.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. The proportion of late-onset ALS in China were low and may have distinct clinical and genetic manifestations. We aimed to investigate the natural history and remarkable psychiatric state of ALS with age at onset over 60years in China. We collected all ALS cases from 2017 to 2020 in our center and focused on late-onset ALS patients particularly, by analyzing the clinical data, including the ALS onset and disease progression. Anxiety, depression, cognitive function, and sleep quality were assessed to reflect the psychiatric state. A total of 193late-onset ALS patients were included in this study. The median age at onset of late-onset ALS was 65years with the quartile from 62 to 68years. When compared with 446 non-late-onset ALS, late-onset ALS showed distinct clinical presentation, with lower ALS Functional Rating Scale-Revised at diagnosis and faster rate of progression. Remarkably, late-onset ALS were suffering from worse psychiatric state, including serious anxiety and depression, as well as worse cognitive function with sleep quality. The abnormal psychiatric state was more pronounced in female patients of late-onset. In the current study, ALS patients with late-onset showed unique clinical features. Severe psychiatric conditions and faster progression in the early stage of the disease of late-onset ALS indicated the need for more social and psychiatric support in this population.

The Involvement of RAGE and Its Ligands during Progression of ALS in SOD1 G93A Transgenic Mice.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive degeneration of upper and lower motor neurons that causes paralysis and muscle atrophy. The pathogenesis of the disease is still not elucidated. Receptor for Advanced Glycation End Product (RAGE) is a major component of the innate immune system and has implications in ALS pathogenesis. Multiple studies suggest the role of RAGE and its ligands in ALS. RAGE and its ligands are overexpressed in human and murine ALS motor neurons, astrocytes, and microglia. Here, we demonstrated the expression of RAGE and its ligands during the progression of the disease in the transgenic SOD1 G93A mouse lumbar spinal cord. We observed the highest expression of HMGB1 and S100b proteins at ALS onset. Our results highlight the potential role of RAGE and its ligands in ALS pathogenesis and suggest that some of the RAGE ligands might be used as biomarkers in early ALS diagnosis and potentially be useful in targeted therapeutic interventions at the early stage of this devastating disease.

Previous psychiatric disorders in the multistep hypothesis of amyotrophic lateral sclerosis: a South Korean population study

Objective: There is accumulating evidence about an association between amyotrophic lateral sclerosis (ALS) and psychiatric disorders. We aimed to investigate the prevalence of previous psychiatric disorders before ALS onset and evaluate the contribution of psychiatric disorders to the number of steps toward developing ALS. Methods: We analyzed the National Health Insurance claims data from 2011 to 2017 and calculated the incidence of ALS. We created a multistep model using the linear least squares method with regression of the log incidence against the log age. Results: The mean annual incidence of ALS was 0.95/100,000 and frequency of familial ALS (fALS) was 5.89%. The proportions of patients who had psychiatric disorders before ALS diagnosis were 36.8% and 47.0% in fALS and sporadic ALS (sALS), respectively (p = 0.009). In both fALS and sALS, depressive disorders and anxiety and stress disorders were relatively frequent, whereas psychotic disorders and bipolar disorders were rare. Further, the slope estimates for regression analyses were 3.50 (R2 = 0.94) and 3.56 (R2 = 0.99) for fALS and sALS, respectively, suggesting a 4–5-step process to ALS onset. However, slope estimates did not differ between sALS patients with pre-symptomatic psychiatric disorders and those without. Conclusions: The incidence of ALS is relatively low in Korea and fewer steps are required to develop ALS compared to Western populations (all 6 steps). Although the prevalence of previous depression or anxiety is seemingly high, the multistep model provides no evidence that these conditions modify the risk of developing ALS in our cohort.

Different saccadic profile in bulbar versus spinal-onset amyotrophic lateral sclerosis.

Two clinical phenotypes characterize the onset of amyotrophic lateral sclerosis (ALS): the spinal variant, with symptoms beginning in the limbs, and the bulbar variant, affecting firstly speech and swallowing. The two variants show some distinct features in the histopathology, localization and prognosis, but to which extent they really differ clinically and pathologically remains to be clarified. Recent neuropathological and neuroimaging studies have suggested a broader spreading of the neurodegenerative process in ALS, extending beyond the motor areas, toward other cortical and deep grey matter regions, many of which are involved in visual processing and saccadic control. Indeed, a wide range of eye movement deficits have been reported in ALS, but they have never been used to distinguish the two ALS variants. Since quantifying eye movements is a very sensitive and specific method for the study of brain networks, we compared different saccadic and visual search behaviours across spinal ALS patients (n = 12), bulbar ALS patients (n = 6) and healthy control subjects (n = 13), along with cognitive and MRI measures, with the aim to define more accurately the two patients subgroups and possibly clarify a different underlying neural impairment. We found separate profiles of visually-guided saccades between spinal (short saccades) and bulbar (slow saccades) ALS, which could result from the pathologic involvement of different pathways. We suggest an early involvement of the parieto-collicular-cerebellar network in spinal ALS and the fronto-brainstem circuit in bulbar ALS. Overall, our data confirm the diagnostic value of the eye movements analysis in ALS and add new insight on the involved neural networks.

Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis

There is a strong genetic contribution to Amyotrophic lateral sclerosis (ALS) risk, with heritability estimates of up to 60%. Both Mendelian and small effect variants have been identified, but in common with other conditions, such variants only explain a little of the heritability. Genomic structural variation might account for some of this otherwise unexplained heritability. We therefore investigated association between structural variation in a set of 25 ALS genes, and ALS risk and phenotype. As expected, the repeat expansion in the C9orf72 gene was identified as associated with ALS. Two other ALS-associated structural variants were identified: inversion in the VCP gene and insertion in the ERBB4 gene. All three variants were associated both with increased risk of ALS and specific phenotypic patterns of disease expression. More than 70% of people with respiratory onset ALS harboured ERBB4 insertion compared with 25% of the general population, suggesting respiratory onset ALS may be a distinct genetic subtype.

Analysis of disease progression rate and related factors in amyotrophic lateral sclerosis patients at initial visit

Objective: To find out the relationship of the progression rate of amyotrophic lateral sclerosis (ALS) patients with relevant clinical indicators at initial visit so as to enrich the knowledge of ALS at its early stage. Methods: The clinical data of 282 patients diagnosed with ALS at Neurology Department of the First Medical Center, Chinese PLA General Hospital from June 2016 to March 2021 were collected in order to make a retrospective analysis of the dynamic change of the progression rate (ΔFS) and influencing factors, and thus a classification of the progression rate will be summarized. Results: Among 282 patients, 164 were males and 118 were females. The age of onset was (53±11) years old. The ΔFS had a negative exponential relationship with delay time of diagnosis no matter what kinds of onset the patients experienced (upper limb onset, lower limb onset or bulbar onset). The ΔFS for the limb function sub-group had a similar functional relationship with diagnostic delay in patients with either upper limb onset or lower limb onset. The statistical model indicated that the disease progression rate of ALS at initial visit can be classified into three types (high speed type: ΔFS≥1.0 score/month; moderate speed type: 0.5≤ΔFS<1.0 score/month; low speed type: ΔFS<0.5 score/month). The critical values of the three types in patients with upper limb onset were 8 and 20 months, while 9 and 24 months for lower limb onset patients, and 9 and 36 months for bulbar onset patients. At initial visit, there were significant statistical differences among these three types in age at onset (P=0.008), diagnostic delay (P<0.001), ALS functional rating scale-revised (ALSFRS-R) score (P<0.001) and onset site (P=0.006). The age at onset in moderate speed type was significantly greater than that of the slow speed type [(54.9±10.4) years vs (50.2±9.6) years, P=0.002]. The diagnostic delay in high speed type [6 (4, 10) months] was significantly shorter than that in moderate speed type [12 (8, 19) months, P<0.001] and low speed type [22 (14, 36) months, P<0.001], and the moderate speed type was shorter in comparison with low speed type (P<0.001). As for the ALSFRS-R score, the high speed type [36(32, 39)] was significantly lower than the moderate speed type [39 (36, 42), P<0.001] and low speed type [42 (39, 44), P<0.001], and the moderate speed type was lower in comparison with low speed type (P=0.002). The proportion of cases with upper limb onset in high speed type (20.3%) was significantly lower than that in low speed type (42.2%, P<0.001) and moderate speed type (37.5%, P=0.014). By contrast, the proportion of cases with lower limb onset in high speed type (39.2%) was significantly higher than that in low speed type (28.9%, P=0.023), however no difference was shown between the fast speed type and moderate speed type (32.0%, P=0.061). There was no difference among these three progression types in patients with bulbar onset. Conclusions: The disease progression rate of ALS at initial visit can be classified into three types including high speed, moderate speed and low speed. At early stage of ALS, ΔFS is affected by onset age, onset site, diagnostic delay and ALSFRS-R score.

From Physiological Properties to Selective Vulnerability of Motor Units in Amyotrophic Lateral Sclerosis.

Spinal alpha-motoneurons are classified in several types depending on the contractile properties of the innervated muscle fibers. This diversity is further displayed in different levels of vulnerability of distinct motor units to neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS). We summarize recent data suggesting that, contrary to the excitotoxicity hypothesis, the most vulnerable motor units are hypoexcitable and experience a reduction in their firing prior to symptoms onset in ALS. We suggest that a dysregulation of activity-dependent transcriptional programs in these motoneurons alter crucial cellular functions such as mitochondrial biogenesis, autophagy, axonal sprouting capability and re-innervation of neuromuscular junctions.

Amyotrophic Lateral Sclerosis: A Diet Review.

Amyotrophic lateral sclerosis (ALS) is a fatal disease related to upper and lower motor neurons degeneration. Although the environmental and genetic causes of this disease are still unclear, some factors involved in ALS onset such as oxidative stress may be influenced by diet. A higher risk of ALS has been correlated with a high fat and glutamate intake and β-methylamino-L-alanine. On the contrary, a diet based on antioxidant and anti-inflammatory compounds, such as curcumin, creatine, coenzyme Q10, vitamin E, vitamin A, vitamin C, and phytochemicals could reduce the risk of ALS. However, data are controversial as there is a discrepancy among different studies due to a limited number of samples and the many variables that are involved. In addition, an improper diet could lead to an altered microbiota and consequently to an altered metabolism that could predispose to the ALS onset. In this review we summarized some research that involve aspects related to ALS such as the epidemiology, the diet, the eating behaviour, the microbiota, and the metabolic diseases. Further research is needed to better comprehend the role of diet and the metabolic diseases in the mechanisms leading to ALS onset and progression.

The split-elbow index: A biomarker of the split elbow sign in ALS

ObjectiveThe split elbow sign is a clinical feature of amyotrophic lateral sclerosis (ALS), characterised by preferential weakness of biceps brachii muscle compared to triceps. A novel neurophysiological index, termed the split elbow index (SEI), was developed to quantify the split-elbow sign, and assess its utility in ALS. MethodsClinical and neurophysiological assessment was prospectively undertaken on 34 ALS patients and 32 ALS mimics. Compound muscle action potential (CMAP) amplitude was recorded from biceps brachii and triceps muscles from which the SEI was calculated using the following formula:SEI=CMAPamplitudeBICEPSBRACHIICMAPamplitudeTRICEPSBRACHII ResultsThe split elbow sign was significantly more common in ALS patients when compared to ALS mimic patients (P < 0.05). The SEI was significantly reduced in ALS patients when compared to ALS mimics (P < 0.01). This reduction was evident in spinal and bulbar onset ALS. A SEI cut-off value of ≤0.62 exhibited a sensitivity of 71% and specificity of 61%. ConclusionsThe split elbow sign is significantly more common in ALS patients, and was supported by a reduction in the SEI. SignificanceThe SEI may be utilised as a surrogate biomarker of the split elbow sign in future ALS studies.