scholarly journals Extracellular Vesicles as Innovative Treatment Strategy for Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 9 ◽  
Author(s):  
Ke Wang ◽  
Yu Li ◽  
Chao Ren ◽  
Yongjing Wang ◽  
Wenshan He ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Extracellular Vesicles ◽  
Treatment Strategy ◽  
Early Stage ◽  
Membrane Vesicles ◽  
Bioactive Substances ◽  
Innovative Treatment ◽  
Application Potential ◽  
Als Patients ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron degenerative disease, and it is hard to diagnose in the early stage, and treatment means are limited, and the treatment effect is unsatisfactory. Therefore, exploring a new effective treatment strategy is urgently needed for ALS patients. Extracellular vesicles (EVs) are a heterogeneous group of natural membrane vesicles containing many bioactive substances, and they play important roles in the paracrine pathway and exhibit neuroprotection effects. A growing body of evidence shows that EVs have great application potential in diagnosis, treatment, and drug delivery in ALS, and they represent an innovative treatment strategy for ALS. In this review, we will briefly introduce the biogenesis of EVs and focus on discussing the role of EVs in ALS treatment to further enrich and boost the development of EVs as an innovative treatment strategy for ALS.

scholarly journals Cognitive dysfunction in amyotrophic lateral sclerosis: can we predict it?

2021 ◽  
Author(s):  
Fabiola De Marchi ◽  
◽  
Claudia Carrarini ◽  
Antonio De Martino ◽  
Luca Diamanti ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Time Course ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Multisystem Disorder ◽  
Behavioral Impairment ◽  
Behavioral Impairments ◽  
Als Patients ◽  
Disease Stages ◽  
Lateral Sclerosis

Abstract Background and aim Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of both upper and lower motoneurons in the brain and spinal cord leading to motor and extra-motor symptoms. Although traditionally considered a pure motor disease, recent evidences suggest that ALS is a multisystem disorder. Neuropsychological alterations, in fact, are observed in more than 50% of patients: while executive dysfunctions have been firstly identified, alterations in verbal fluency, behavior, and pragmatic and social cognition have also been described. Detecting and monitoring ALS cognitive and behavioral impairment even at early disease stages is likely to have staging and prognostic implications, and it may impact the enrollment in future clinical trials. During the last 10 years, humoral, radiological, neurophysiological, and genetic biomarkers have been reported in ALS, and some of them seem to potentially correlate to cognitive and behavioral impairment of patients. In this review, we sought to give an up-to-date state of the art of neuropsychological alterations in ALS: we will describe tests used to detect cognitive and behavioral impairment, and we will focus on promising non-invasive biomarkers to detect pre-clinical cognitive decline. Conclusions To date, the research on humoral, radiological, neurophysiological, and genetic correlates of neuropsychological alterations is at the early stage, and no conclusive longitudinal data have been published. Further and longitudinal studies on easily accessible and quantifiable biomarkers are needed to clarify the time course and the evolution of cognitive and behavioral impairments of ALS patients.

scholarly journals Practical Measures for Dealing With the Struggles of Nurses Caring for People With Amyotrophic Lateral Sclerosis Comorbid With Cognitive Impairment in Japan

2021 ◽  
Vol 12 ◽  
Author(s):  
Mitsuko Ushikubo ◽  
Emiko Nashiki ◽  
Tadahiro Ohtani ◽  
Hiromi Kawabata
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cognitive Impairment ◽  
Early Stage ◽  
Care Delivery ◽  
Care Quality ◽  
Daily Lives ◽  
Free Writing ◽  
Group Interviews ◽  
Als Patients ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which there is currently no cure. This study aimed to explore the situations with which nurses struggled, their implemented practical measures, and the challenges they experienced when caring for patients with ALS comorbid with cognitive impairment (hereinafter, targeted patients). In this qualitative study, we conducted a survey with nurses (n = 121) experienced in caring for ALS patients; the survey contained a free-writing section in which participants described their struggles regarding care delivery for these patients. To collect data on practical measures that nurses had already implemented or wanted to propose regarding care delivery for the targeted patients, we conducted four focus group interviews (n = 22). We used a qualitative inductive approach to extract the categories. Fifty-eight nurses (49.6%) completed the free-writing survey section. The situations in which nurses struggled in care for the targeted patients were organized into three categories: “Patients’ strong persistency on specific requirements for nursing assistance in their daily lives,” “Patients’ problematic behaviors toward nurses,” and “Struggles in communicating with and understanding patients’ wishes.” Nurses reported these situations as stressful, and they affected care quality. The practical measures implemented when caring for the targeted patients were organized into five categories: “Cognitive impairment assessment,” “Care delivery to deal with patients’ strong persistency on specific requirements for assistance in their daily lives,” “Communication,” “Supporting the decision-making process,” and “Collaboration between the hospital and the community.” Multidisciplinary collaboration in the hospital, and collaboration between the hospital and the community from an early stage is necessary to share the results of the assessment and diagnosis of cognitive impairment. Our evidence underlines that guideline and care manual establishment may lead to improved care delivery and to the unification of care deliveries to respond to patients’ strong persistency.

scholarly journals Decoding distinctive features of plasma extracellular vesicles in amyotrophic lateral sclerosis

2020 ◽  
Author(s):  
Laura Pasetto ◽  
Stefano Callegaro ◽  
Deborah Ferrara ◽  
Laura Brunelli ◽  
Giovanna Sestito ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Size Distribution ◽  
Extracellular Vesicles ◽  
Disease Diagnosis ◽  
Machine Learning Techniques ◽  
Multidimensional Data ◽  
Distribution Data ◽  
Pathological State ◽  
Als Patients ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis is a multifactorial and multisystem motor neuron disease with currently no effective treatment. There is an urgent need to identify biomarkers that can tackle the disease's complexity and help in early diagnosis, prognosis, and therapy development. Extracellular vesicles (EVs) are nanostructures that are released by any cell type into body fluids. Their variable biophysical and biochemical characteristics reflect the parent cell's physiological and pathological state and make them an attractive source of multidimensional data for patient classification and stratification. To test whether EVs could be exploited as diagnostic and prognostic biomarkers in ALS, we analyzed plasma-derived EVs of ALS patients and relative healthy and diseased controls. Using the nickel-based isolation, a recently developed EV purification method, we unmasked peculiar features in plasma EVs of ALS patients with a potential straightforward application in a clinical setting. We report that the number of particles is increased in the plasma of ALS patients and two mouse models of ALS while the average diameter is decreased. Proteins like HSP90 and phosphorylated TDP-43 are differentially represented in ALS patients and mice compared to the controls. In terms of disease progression, the levels of phosphorylated TDP-43 and cyclophilin A, along with the EV size distribution, discriminated fast and slow disease progressors suggesting a new means for patient stratification. Finally, we conceived an innovative mathematical model based on machine learning techniques that integrating EV size distribution data with biochemical EV parameters resulted in very high prediction rates for disease diagnosis and prognosis.

scholarly journals The Japanese Early-Stage Trial of High-Dose Methylcobalamin for Amyotrophic Lateral Sclerosis (JETALS): Protocol for a Randomized Controlled Trial (Preprint)

2018 ◽  
Author(s):  
Ryosuke Oki ◽  
Yuishin Izumi ◽  
Hiroyuki Nodera ◽  
Yasutaka Sato ◽  
Hiroshi Nokihara ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Early Stage ◽  
Phase Iii ◽  
High Dose ◽  
Efficacy And Safety ◽  
Double Blind ◽  
One Year ◽  
Als Patients ◽  
To Receive ◽  
Lateral Sclerosis

BACKGROUND Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons. Currently, only riluzole and edaravone are approved as drugs to treat ALS and new agents with larger effect sizes are warranted. Exploratory analyses in our previous study (study ID #E0302-J081-761) have suggested that high-dose methylcobalamin (E0302) prolonged the overall survival of ALS patients and suppressed ALS progression in patients with a disease duration of less than 12 months. OBJECTIVE This clinical trial aims to evaluate the efficacy and safety of E0302 for treatment of ALS patients within one year of onset. METHODS The Japanese early-stage trial of high-dose methylcobalamin for ALS (JETALS) is a prospective, multicenter, placebo-controlled, double-blind, randomized phase III study conducted at 24 tertiary neurology centers and is funded by the Japan Agency for Medical Research and Development. A total of 128 ALS patients within one year of onset were randomized at a 1:1 ratio to receive intramuscular injection with E0302 50 mg or placebo twice a week for 16 weeks. The primary endpoint is changes in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score at 16 weeks. If patients wish to receive E0302 50 mg after the double-blind administration period, E0302 will be provided to them until March 2020 during the continuous administration period. RESULTS This study began in October 2017 and is being conducted at 24 participating institutions in Japan. The study is in progress and the patient enrollment period is scheduled to end in August 2019, with follow-up scheduled to end in March 2020. CONCLUSIONS This study is being performed to revalidate the efficacy and safety of E0302 in patients with early-stage ALS in the first year of symptom onset. If positive results are obtained, the aim is to apply for E0302 approval as a new drug for the treatment of ALS. CLINICALTRIAL ClinicalTrials.gov NCT03548311; https://clinicaltrials.gov/ct2/show/NCT03548311 (Archived by WebCite at http://www.webcitation.org/74Fw3rDzb) INTERNATIONAL REGISTERED REPOR PRR1-10.2196/12046

Support needs of caregivers of patients with amyotrophic lateral sclerosis: A qualitative study

2018 ◽  
Vol 17 (2) ◽  
pp. 195-201 ◽  
Author(s):  
Jessica de Wit ◽  
Carin D. Schröder ◽  
Julia el Mecky ◽  
Anita Beelen ◽  
Leonard H. van den Berg ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Early Stage ◽  
Care Process ◽  
Support Needs ◽  
Structured Interviews ◽  
Personal Time ◽  
Proactive Approach ◽  
Short Period ◽  
Als Patients ◽  
Lateral Sclerosis

AbstractObjectiveThe aim of this study was to explore the support needs of Dutch informal caregivers of patients with amyotrophic lateral sclerosis (ALS).MethodIndividual semi-structured interviews were conducted with 21 caregivers of ALS patients. Audio-taped interviews were transcribed and data were analyzed thematically.ResultA total of four global support needs emerged: “more personal time”, “assistance in applying for resources”, “counseling”, and “peer contact”. Despite their needs, caregivers are reluctant to apply for and accept support. They saw their own needs as secondary to the needs of the patients.Significance of resultsALS seems to lead to an intensive caregiving situation with multiple needs emerging in a short period. This study offers targets for the development of supportive interventions. A proactive approach seems essential, acknowledging the importance of the role of the caregivers in the care process at an early stage, informing them about the risk of burden, monitoring their wellbeing, and repeatedly offering support opportunities. Using e-health may help tailor interventions to the caregivers’ support needs.

scholarly journals Selective and Inverse U-Shaped Curve Alteration of the Retinal Nerve in Amyotrophic Lateral Sclerosis: A Potential Mirror of the Disease

2022 ◽  
Vol 13 ◽  
Author(s):  
Yixuan Zhang ◽  
Xiangyi Liu ◽  
Jiayu Fu ◽  
Yuanjin Zhang ◽  
Xue Yang ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Early Stage ◽  
Compound Muscle Action Potential ◽  
Progression Rate ◽  
Fiber Layer ◽  
Abductor Pollicis Brevis ◽  
Thickness Change ◽  
Als Patients ◽  
Lateral Sclerosis

Introduction: Alterations in the visual pathway involving the retina have been reported in amyotrophic lateral sclerosis (ALS) but they lack consistency and subgroup analysis. We aimed to assess the retinal nerve fiber layer (RNFL) and retinal ganglion cells (RGCs) alterations in different stages of ALS patients and their association with ALS progression parameters.Methods: The study population consisted of 70 clinically diagnosed ALS patients and 55 age, sex matched controls. All of them underwent ophthalmic assessments and optical coherence tomography imaging. Four quadrants of the peripapillary RNFL and ganglion cell/inner plexiform complex (GCIP) were observed and automatically measured. Early-stage distal motor neuron axon dysfunction in ALS was detected by compound muscle action potential (CMAP) of the distal limbs within 12 months. The ALS disease parameters included the ALSFRS-R score and the disease progression rate (ΔFS).Results: Generally compared with controls, the nasal (p = 0.016) quadrant of the RNFL was thicker in ALS patients. When controlling for age and ΔFS, the RNFL(r = 0.37, p = 0.034) and GCIP(r = 0.40, p = 0.021) were significantly thickened as disease progressed within 12 months, while the RNFL declined with time after one year (r = −0.41, p = 0.037). ALS patients was subclassified into thickened RNFL (T-RNFL, >95th percentile of normal), impaired RNFL (I-RNFL, <5th percentile of normal) and normal RNFL. There were significant differences in the GCIP among the three groups (p < 0.001). In the T-RNFL group (n = 18), the RNFL was negatively correlated with the abductor pollicis brevis-CMAP amplitude within 12 months (r = −0.56, p = 0.01). Patients within 12 months in this group progressed faster than others (p = 0.039). In the normal RNFL group (n = 22), 13 patients were diagnosed beyond 12 months, whose ΔFS was remarkably lower (p = 0.007). In I-RNFL group (n = 30), the early stage patients (<12 months) had significant higher ΔFS (p = 0.006). One patient was with SOD1 pathogenic variant (p.A5V).Conclusion: Alterations of retinal nerve were not consistent in ALS patients with diverse phenotypes and progression rates. Generally speaking, the RNFL thickened during the first year and then gradually declined, which is related to but preceding the thickness change of the RGCs. Patients with a significant RNFL thinning in the early stage may have a faster progression rate. The inverse U-shaped curve transformation might be in accordance with early-stage motor neuron axonopathy.

scholarly journals Decoding distinctive features of plasma extracellular vesicles in amyotrophic lateral sclerosis

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Laura Pasetto ◽  
Stefano Callegaro ◽  
Alessandro Corbelli ◽  
Fabio Fiordaliso ◽  
Deborah Ferrara ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Machine Learning ◽  
Amyotrophic Lateral Sclerosis ◽  
Size Distribution ◽  
Mouse Models ◽  
Extracellular Vesicles ◽  
Multidimensional Data ◽  
Diagnosis And Prognosis ◽  
Als Patients ◽  
Lateral Sclerosis

Abstract Background Amyotrophic lateral sclerosis (ALS) is a multifactorial, multisystem motor neuron disease for which currently there is no effective treatment. There is an urgent need to identify biomarkers to tackle the disease’s complexity and help in early diagnosis, prognosis, and therapy. Extracellular vesicles (EVs) are nanostructures released by any cell type into body fluids. Their biophysical and biochemical characteristics vary with the parent cell’s physiological and pathological state and make them an attractive source of multidimensional data for patient classification and stratification. Methods We analyzed plasma-derived EVs of ALS patients (n = 106) and controls (n = 96), and SOD1G93A and TDP-43Q331K mouse models of ALS. We purified plasma EVs by nickel-based isolation, characterized their EV size distribution and morphology respectively by nanotracking analysis and transmission electron microscopy, and analyzed EV markers and protein cargos by Western blot and proteomics. We used machine learning techniques to predict diagnosis and prognosis. Results Our procedure resulted in high-yield isolation of intact and polydisperse plasma EVs, with minimal lipoprotein contamination. EVs in the plasma of ALS patients and the two mouse models of ALS had a distinctive size distribution and lower HSP90 levels compared to the controls. In terms of disease progression, the levels of cyclophilin A with the EV size distribution distinguished fast and slow disease progressors, a possibly new means for patient stratification. Immuno-electron microscopy also suggested that phosphorylated TDP-43 is not an intravesicular cargo of plasma-derived EVs. Conclusions Our analysis unmasked features in plasma EVs of ALS patients with potential straightforward clinical application. We conceived an innovative mathematical model based on machine learning which, by integrating EV size distribution data with protein cargoes, gave very high prediction rates for disease diagnosis and prognosis.

Riluzole Exhibits No Therapeutic Efficacy on a Transgenic Rat model of Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 17 (3) ◽  
pp. 275-285 ◽  
Author(s):  
Si Chen ◽  
Qiao Liao ◽  
Ke Lu ◽  
Jinxia Zhou ◽  
Cao Huang ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Rat Model ◽  
Microglial Activation ◽  
Transgenic Rat ◽  
Intragastric Administration ◽  
Behavioral Deficits ◽  
Als Patients ◽  
Lateral Sclerosis ◽  
Transgenic Rat Model

Background: Amyotrophic lateral sclerosis (ALS) is a neurological disorder clinically characterized by motor system dysfunction, with intraneuronal accumulation of the TAR DNAbinding protein 43 (TDP-43) being a pathological hallmark. Riluzole is a primarily prescribed medicine for ALS patients, while its therapeutical efficacy appears limited. TDP-43 transgenic mice are existing animal models for mechanistic/translational research into ALS. Methods: We developed a transgenic rat model of ALS expressing a mutant human TDP-43 transgene (TDP-43M337V) and evaluated the therapeutic effect of Riluzole on this model. Relative to control, rats with TDP-43M337V expression promoted by the neurofilament heavy subunit (NEF) gene or specifically in motor neurons promoted by the choline acetyltransferase (ChAT) gene showed progressive worsening of mobility and grip strength, along with loss of motor neurons, microglial activation, and intraneuronal accumulation of TDP-43 and ubiquitin aggregations in the spinal cord. Results: Compared to vehicle control, intragastric administration of Riluzole (30 mg/kg/d) did not mitigate the behavioral deficits nor alter the neuropathologies in the transgenics. Conclusion: These findings indicate that transgenic rats recapitulate the basic neurological and neuropathological characteristics of human ALS, while Riluzole treatment can not halt the development of the behavioral and histopathological phenotypes in this new transgenic rodent model of ALS.

Plasma Creatinine Level Does Not Predict Respiratory Function in Amyotrophic Lateral Sclerosis

2021 ◽  
pp. 1-5
Author(s):  
João Morgadinho ◽  
Ana Catarina Pronto-Laborinho ◽  
Vasco A. Conceição ◽  
Marta Gromicho ◽  
Susana Pinto ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Creatinine Level ◽  
Cox Regression ◽  
Functional Decline ◽  
Plasma Creatinine ◽  
Plasma Creatinine Level ◽  
Decline Rate ◽  
Respiratory Outcome ◽  
Als Patients ◽  
Lateral Sclerosis

In amyotrophic lateral sclerosis (ALS) lower plasma creatinine level has been associated with shorter survival and faster functional decline. It has not been clear if creatinine is associated with respiratory outcome. We analyzed retrospectively a population of unselected ALS patients. Multiple-regression and Cox-regression analyses were performed. We included 233 patients, mean age 62.8, mean disease duration of 18.6 months. At baseline, creatinine was significantly associated with ALSFRS-R, but not with its decline rate. No predictive value was disclosed for FVC, or their decline rate, or with survival. We did not confirm that creatinine is a marker of respiratory outcome.

Coping strategies among amyotrophic lateral sclerosis (ALS) patients: an integrative review

2021 ◽  
Author(s):  
Georgiana Soares Leandro ◽  
Mário Emílio Teixeira Dourado Júnior ◽  
Glauciane Costa Santana ◽  
Luan Samy Xavier Dantas
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Coping Strategies ◽  
Integrative Review ◽  
Als Patients ◽  
Lateral Sclerosis
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