Abnormal Serum Iron-Status Indicator Changes in Amyotrophic Lateral Sclerosis (ALS) Patients: A Meta-Analysis

Objective. The aim of this study was to assess iron status in a cohort of amyotrophic lateral sclerosis (ALS) patients compared to controls in order to evaluate these parameters as a risk factor or a modifying factor of ALS. Methods. We collected serum iron, ferritin, transferrin, total iron-binding capacity, and transferrin saturation coefficient (TSC) from 104 ALS patients at the time of diagnosis and from 145 controls. We reported phenotypic characteristics and evolution parameters such as ALSFRS-R and forced vital capacity at diagnosis and after one year of follow-up. In a first step we compared iron status between ALS patients and controls, and then we evaluated the relation between iron status and disease evolution of ALS patients using univariate and multivariate analysis. Results. We observed increased concentrations of serum iron (P = 0.002) and ferritin (P < 0.0001) and increased TSC (P = 0.017) in ALS patients. We also showed an association between markers of iron status and high body weight loss in ALS patients. The multivariate analysis of survival highlighted a significant relation between ferritin level and disease duration (P = 0.038). Conclusion. This is the first study showing a higher concentration of serum iron in ALS patients, strengthening the involvement of a deregulation of iron metabolism in ALS.

Further studies on the erythrocyte uptake of lead in vitro in amyotrophic lateral sclerosis (ALS) patients and controls: Abnormal eythrocyte fragility in ALS

Proper transportation of mitochondria to sites with high energy demands is critical for neuronal function and survival. Impaired mitochondrial movement has been repeatedly reported in motor neurons of amyotrophic lateral sclerosis (ALS) patients and indicated as an important mechanism contributing to motor neuron degeneration in ALS. Miro1, a RhoGTPase also referred to as Rhot1, is a key regulator of mitochondrial movement linking mitochondria and motor proteins. In this study, we investigated whether the expression of Miro1 was altered in ALS patients and ALS animal models. Immunoblot analysis revealed that Miro1 was significantly reduced in the spinal cord tissue of ALS patients. Consistently, the decreased expression of Miro1 was also noted only in the spinal cord, and not in the brain tissue of transgenic mice expressing ALS-associated SOD1 G93A or TDP-43 M337V. Glutamate excitotoxicity is one of the major pathophysiological mechanisms implicated in the pathogenesis of ALS, and we found that excessive glutamate challenge lead to significant reduction of Miro1 expression in spinal cord motor neurons both in vitro and in mice. Taken together, these findings show Miro1 deficiency in ALS patients and ALS animal models and suggest glutamate excitotoxicity as a likely cause of Miro1 deficiency.

Immunological disturbances have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Chemokines are involved in the recruitment of immune cells. Regulated upon activation, normal T-cell expressed and secreted (RANTES) is a C-C beta-chemokine with strong chemo-attractant activity for T-lymphocytes and monocytes. We examined serum levels of RANTES in 20 patients with amyotrophic lateral sclerosis (ALS), 14 patients with non-inflammatory neurological disorders (NIND) and 13 control subjects (CTRL) and cerebrospinal fluid (CSF) levels of RANTES in ALS and NIND group patients in order to investigate whether RANTES as index of immune activation is present in ALS patients. Patients with ALS had higher RANTES levels compared with the NIND patients and CTRL subjects (p = 0.005 and p = 0.02, respectively). CSF RANTES levels were also higher compared with the NIND patients (p = 0.007). No correlation of serum and CSF RANTES levels with disease duration was found. These results may suggest an activated microglia induced recruitment of peripheral inflammatory cells to sites of inflammation in ALS patients.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motor neuron (MN) degeneration, frequently overlapping with frontotemporal dementia (FTD). Protein aggregation is a hallmark of these disorders, yet the role of aggregates in ALS pathogenesis remains unclear. Previously, stomatin-like protein 2 (SLP2) and prohibitin (PHB) aggregates were identified in a model of CHCHD10-related ALS (Chchd10S59L/+ mice). This study raises the question of the presence and possible involvement of these aggregates in ALS beyond CHCHD10-associated motor neuron disease (MND). Using immunohistofluorescence, we analyzed SLP2/PHB expression in the spinal MNs and hippocampus of two ALS mouse models: FusΔNLS and Sod1G86R. Additionally, post-mortem spinal cord tissues from 27 ALS and ALS-FTD patients were analyzed. SLP2/PHB aggregates were identified in spinal MNs and the hippocampus of FusΔNLS mice but not in Sod1G86R mice. In ALS patients, SLP2/PHB aggregation was observed in four cases, including two with C9ORF72 mutations. Interestingly, aggregates were absent in SOD1-associated ALS patients. These findings suggest that SLP2/PHB aggregation is not specific to CHCHD10 variants but may contribute to the pathogenesis of ALS from different origins. The age-related accumulation of these aggregates highlights their potential role in disease progression and as therapeutic targets. Future studies should investigate their mechanistic contributions across different ALS subtypes.

Background:High expressions of galectin-3 were identified recently in the end stage of amyotrophic lateral sclerosis (ALS) patients, which suggested that immune reactivity and inflammatory mechanisms might play an important role in the pathogenesis of ALS. The purpose of this study was to investigate plasma galectin-3 levels in different groups and stages of ALS patients and the association with related clinical characteristics.Methods:A total of 51 patients with ALS and 60 normal controls (NCs) were recruited in this study. Plasma galectin-3 levels were determined using the enzyme-linked immunosorbent assay. Patients with ALS were divided into several groups according to their clinical characteristics: gender, type of disease onset, duration of disease, and clinical conditions of disease. Statistical analyses of the differences of galectin-3 levels between groups and the association with the clinical characteristics of disease were performed.Results:As compared with the NCs (201.64 [22.35–401.63] ng/ml), plasma galectin-3 levels were significantly elevated in the patients with duration >12 months (341.17 [69.12–859.22] ng/ml, P < 0.05), and the patients with limb onset of disease (254.14 [69.12–859.22] ng/ml, P < 0.05); however, no difference was found in the patients with duration ≤12 months (250.62 [109.77–334.92] ng/ml, P > 0.05), and the patients with bulbar onset of disease (251.79 [109.20–404.76] ng/ml, P > 0.05). In addition, galectin-3 levels were significantly increased in the female patients (263.27 [123.32–859.22] ng/ml, P < 0.05) while no difference was found in the male patients (220.39 [69.12–748.73] ng/ml, P > 0.05). The further statistical analyses showed that plasma galectin-3 levels were positively correlated with the duration of disease (r = 0.293, P = 0.037).Conclusions:Plasma galectin-3 levels were significantly increased in ALS patients with limb onset of disease, especially in ALS female patients, and positively correlated with the duration of disease, which suggested that plasma galectin-3 might be an interesting and useful factor associated with ALS.

Objective The coronavirus disease 2019 (COVID-19) pandemic has resulted in a shortage of medical resources, including ventilators, personal protective equipment, medical staff, and hospital beds. We investigated the impact of COVID-19 in amyotrophic lateral sclerosis (ALS) patients, their families, caregivers, and medical experts. Methods We conducted a nationwide ALS webinar about COVID-19 in May 2020 and sent a questionnaire to those enrolled. Results A total of 135 participants (31 ALS patients; 23 families and caregivers of ALS patients; 81 medical experts) responded to this cross-sectional self-report questionnaire. The results showed that tracheostomy and invasive ventilation (TIV) was used in 22.6% of ALS patients, whereas 77.4% of ALS patients were not under TIV. Among non-TIV patients (n=24), 79.2% did not want TIV in the future. However, 47.4% of non-TIV patients not wanting a tracheostomy in advanced stages replied that they would want an emergency tracheostomy if they developed COVID-19-related pneumonia. These results suggest that ALS patients may be receptive to emergency treatments for reasons other than ALS. In addition, approximately half of the ALS patients agreed with the policy of not ventilating the elderly or ALS patients in case of a ventilator shortage. Furthermore, compared with medical experts, few ALS patients reported that the chance for ALS patients to obtain work was higher due to the increasing availability of remote work. Conclusions This survey indicates that the COVID-19 pandemic might be associated with increased distress about access to care and work, inducing contradictory responses and potential hopelessness among ALS patients.

Blood Superoxide Dismutase, Catalase and Glutathione Peroxidase Activities in Familial and Sporadic Amyotrophic Lateral Sclerosis

Objective To characterize the brain microstructure changes of amyotrophic lateral sclerosis (ALS) patients with various levels of cognitive impairment as measured by diffusion tensor imaging (DTI). Methods A total of 55 ALS patients and 20 healthy controls (HC) were enrolled in the Department of Neurology of Peking Union Medical College Hospital From September 2013 to March 2017, and all participants underwent neuropsychological assessments and DTI scans. According to their cognitive performance, ALS patients were further subclassified into ALS with normal cognition (ALS-Cn, n=27), ALS with cognitive impairment (ALS-Ci, n=17) and ALS-frontotemporal dementia (ALS-FTD, n=11) subgroups. Comparisons of voxel-based and atlas-based fractional anisotropy (FA) and mean diffusivity (MD) data were conducted among the four subgroups. Results In the voxel-based analyses, the FA showed significant differences in cingulate gyrus, corpus callosum, brain stem and cerebellum, and MD showed significant differences in bilateral frontal lobe, temporal lobe, cingulate gyrus, corpus callosum, and cerebellum among the four subgroups. Besides, when compared to ALS-Ci, ALS-Cn and HC groups in the order, the areas of involvement were larger and differences were more significant in ALS-FTD group. In the atlas-based analyses, the FA and MD of the corticospinal tracts revealed no difference within the patients groups, but decreased FA and increased MD were found compared to HC group. The ALS-FTD patients manifested widespread white matter fiber integrity damage and microstructure impairment in the extramotor areas compared to other three groups. Conclusion The brain white matter structural patterns of ALS patients correlate with their cognitive function, and there is a gradient of alterations across the ALS-Cn, ALS-Ci and ALS-FTD continuum. Key words: Amyotrophic lateral sclerosis; Cognition disorders; Frontotemporal dementia; Diffusion tensor imaging

BackgroundFasciculation is an important sign for the diagnosis of amyotrophic lateral sclerosis (ALS). Our study aimed to analyze the difference in fasciculation detected with muscle ultrasonography (MUS) between ALS patients and non-ALS patients with symptoms resembling ALS.MethodsEighty-eight ALS patients and fifty-four non-ALS (eight multifocal motor neuropathy, 32 chronic inflammatory demyelinating polyneuropathy/Charcot-Marie-Tooth, and 14 cervical spondylopathy or lumbar spondylopathy) patients were recruited. MUS was performed on 19 muscle groups in cervical, lumbosacral, bulbar, and thoracic regions for each patient. The intensity of fasciculation was divided into five grades based on firing frequency and number in the involved muscle groups.ResultsThe overall detection rates were 72.8% in ALS and 18% in non-ALS patients. The fasciculation grades (median [IQR]) were 2 (0–3) in ALS and 0 (0–0) in non-ALS patients (P < 0.001). Fasciculations were observed in four regions for ALS patients and primarily distributed in proximal limbs. Fasciculations in non-ALS patients were primarily low-grade and mostly distributed in distal limbs.DiscussionThe fasciculation grade was higher in ALS than non-ALS patients. The distribution pattern of fasciculation was different between ALS and non-ALS patients.ConclusionsThe fasciculation grade and distribution pattern detected with MUS could help distinguish ALS from non-ALS patients.

Reproductive and developmental behaviour in sheep: A.F. Fraser (Editor), in the Series Developments in Animal and Veterinary Sciences, Vol. 18. Elsevier Science Publishers, Amsterdam, 1985, 439 pp., Dfl. 160.00, US$59.25, ISBN 0-444-42444-X

BackgroundUsing in vivo neuroimaging techniques, growing evidence has demonstrated that the choroid plexus (CP) volume is enlarged in patients with several neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. However, although animal and postmortem findings suggest that CP abnormalities are likely important pathological mechanisms underlying amyotrophic lateral sclerosis (ALS), the third most common neurodegenerative disease, no available study has been conducted to thoroughly assess CP abnormalities and their clinical relevance in vivo in ALS patients to date. Thus, we aimed to determine whether in vivo CP enlargement may occur in ALS patients. We also aimed to identify the relationships of CP volume with clinical disabilities and blood-CSF barrier (BCSFB) permeability in ALS patients.MethodsIn this retrospective study, based on structural MRI data, CP volume was assessed using a Gaussian mixture model and underwent further manual correction in 155 ALS patients and 105 age- and sex-matched HCs from October 2021 to April 2023. The ALS Functional Rating Scale-Revised (ALSFRS-R) was used to assess clinical disability. The CSF/serum albumin quotient (Qalb) was used to assess BCSFB permeability. Moreover, all the ALS patients completed genetic testing, and according to genetic testing, the ALS patients were further divided into genetic ALS subgroup and sporadic ALS subgroup.ResultsWe found that compared with HCs, ALS patients had a significantly higher CP volume (p < 0.001). Moreover, compared with HCs, CP volume was significantly increased in both ALS patients with and without known genetic mutations after family-wise error correction (p = 0.006 and p < 0.001, respectively), while there were no significant differences between the two ALS groups. Furthermore, the CP volume was significantly correlated with the ALSFRS-r score (r = -0.226; p = 0.005) and the Qalb (r = 0.479; p < 0.001) in ALS patients.ConclusionOur study first demonstrates CP enlargement in vivo in ALS patients, and continues to suggest an important pathogenetic role for CP abnormalities in ALS. Moreover, assessing CP volume is likely a noninvasive and easy-to-implement approach for screening BCSFB dysfunction in ALS patients.

A hexanucleotide repeat expansion in C9ORF72 causes familial and sporadic ALS in Taiwan

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with loss of muscle function. The pathogenesis is still unclear and the heterogeneity of ALS phenotypes is huge. We investigated a large population of ALS patients and controls concerning comorbidities and medications to detect specific risk or protective factors regarding onset and progression of ALS. We investigated a cohort of 200 ALS patients pro- and retrospectively compared to a control group. For comparison of frequencies of comorbidities and medication intake, uni- and multivariate binary logistic regressions were performed. To analyze the influence of comorbidities and medication on the progression of ALS, we used linear regression analysis. ALS patients showed a relevantly higher prevalence of strokes and depression compared to controls. Moreover, ALS patients reported relevantly more often regular physical activity and their BMI was lower. The coexistence of coronary heart disease was associated with a relevantly faster disease progression. Intake of contraceptives was relevantly higher in controls compared with ALS patients. Our results suggest stroke, lower BMI, and regular physical activity as risk factors for ALS. Strokes could be a possible trigger of the pathogenetic pathway of ALS and the lower BMI with consecutively lower rate of hyperlipidemia supports the hypothesis of premorbid hypermetabolism in ALS patients. Coexistence of coronary heart disease possibly has a negative influence on respiratory involvement. Contraceptives could be beneficial due to a protective effect of estrogen. Information on influencing factors can help to elucidate the pathogenesis of ALS or provide approaches for possible therapeutic options.

Objectives: Excitotoxicity is thought to be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). One possible source of excitotoxicity is the presence of sulphur amino acids (SAAs). In the brain of subjects with ALS, there are increased levels of taurine. In the metabolism of methionine to taurine, excitatory sulphur amino acids (SAAs) are formed. These could potentially contribute to excitotoxicity in ALS. The present study has examined whether plasma levels of SAAs in 38 ALS patients differ from those of 30 healthy controls. Methods: Plasma levels of SAAs were measured by liquid chromatography mass spectrometry. Results: There were no significant changes in plasma cysteic acid, cysteine sulfinic acid, and homocysteic acid in ALS patients compared to healthy subjects. Significant elevations in plasma homocysteinesulfinic acid (HCSA) levels (p < 0.0001) were observed in the ALS patients (75.91 ± 15.38 nM) compared to healthy controls (54.06 ± 8.503 nM); 50% of the ALS patients had HCSA levels that were 1.5–2-folds higher than those of controls. Plasma levels of HCSA differed significantly (p = 0.0440) between patients with bulbar onset and spinal onset (68.57 ± 14.20 vs. 79.30 ± 14.95 nM, respectively). Conclusion: HCSA is elevated in the blood of subjects with ALS. Since HCSA can be transported from the blood to the CNS by active transport, has neurotransmitter properties, and can activate synaptic receptors including NMDAR and metabotropic glutamate receptor, it is possible that increases in HCSA could influence glutamatergic neurotransmission and potentially contribute to excitotoxicity in some ALS patients.