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Challenges and Opportunities in Amyotrophic Lateral Sclerosis

Challenges and Opportunities in Amyotrophic Lateral Sclerosis

Cezar FC, Cantarini KV, Gaspar HA, and Oliveira CF

Abstract

Introduction: Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disease that causes significant and progressive functional loss, leading to a high degree of dependence. The disease’s consequences include hypoventilation, inefficient cough, dysphagia, and malnutrition, which predispose patients to recurrent respiratory infections and reduced life expectancyA growing number of Amyotrophic Lateral Sclerosis patients are being treated with mechanical ventilation at home. Ventilatory support can be invasive or non-invasive. Since little has been reported on the association between ventilatory support type and the incidence of pneumonia in patients with Amyotrophic Lateral Sclerosis, this study aims to evaluate the incidence density of pneumonia in Brazilian patients with Amyotrophic Lateral Sclerosis who received private home care, correlating it with ventilatory support type and comparing it with the global incidence among home care patients.

Methods: This observational retrospective cohort study analyzed the electronic medical records of patients treated between January and December 2022.

Results: A total of 91 patients with Amyotrophic Lateral Sclerosis were treated between January and December 2022 with mean age of 63.3 years. Of these 91 patients, 56 (62%) were tracheostomized. 33 (36%) developed pneumonia during the study period, of whom 20 had more than one infectious episode, totaling 69 pneumonia events. The incidence density of pneumonia among Amyotrophic Lateral Sclerosis patients was 3.1 cases/1000 patient days. A total of 56 (62%) Amyotrophic Lateral Sclerosis patients received invasive mechanical ventilation, and the incidence density of pneumonia was 4.1 cases/1000 ventilation days. The incidence density of pneumonia among Amyotrophic Lateral Sclerosis patients who received non-invasive ventilatory support was 1.6 cases/1000 non-invasive ventilation days and Amyotrophic Lateral Sclerosis patients who did not receive ventilatory support was 0.3 cases/1000 patient days.

Conclusions: Amyotrophic Lateral Sclerosis patients who receive specialized home care in Brazil often receive invasive mechanical ventilation. The modality of ventilatory support is correlated with the incidence of pneumonia, and those who receive invasive ventilatory support are more affected.

Righi Marco, Morara Stefano, Petrillo Giulia, Perota Andrea, Cagnotti Giulia, and Corona Cristiano

Abstract

Amyotrophic Lateral Sclerosis is still a poorly understood neurological syndrome showing muscle impairment and leading to death because of respiratory failure. Recently, a new, transgenic swine model overexpressing the human superoxide-dismutase 1 gene, promised the chance to investigate animals before disease onset, and we planned to investigate vascular alterations that we recently learned to quantify. In order to address for feasibility, we checked angioarchitectures in spinal cord samples of at least one animal for each of three health conditions: healthy, asymptomatic, clear motor symptoms. Furthermore, analyses were carried out in three different regions: cervical, thoracic and lumbar districts.

In our approach, we relied on described ImageJ automatic routines, measuring amounts and dispersion of microvascular structures, classified according to their calibers and in spite of the low height of the sample slice. As in previous papers, we investigated the amount and volume dispersion of 7 progressively reconstructed angioarchitectures, built from larger calibers through addition of vessels or voxels of smaller and smaller caliber. Results were processed by linear regression to depict a 2D summary pattern, specific to that micro-angioarchitecture.

Healthy samples presented well-dispersed vascular layouts, depicted by near-flat linear regressions. However, they were characterized by large dispersion variances, apparently due to district of origin of the sample itself. On the contrary, results from pathological samples presented lines with increased slopes while retaining the observed inter-sample dispersion variances. Absence of samples from different animals in the same health status prevented us to observe inter-animal variances. Therefore, we could not derive significant biological conclusions on reduced vascularization. Nevertheless, results demonstrated the success of our image analysis approach and provided a “tantalizing” observation of vascular alterations in a swine model for Amyotrophic Lateral Sclerosis.

Jae-kook Yoo, Soon-Hee Kwon, Jong-Eun Jeon, Sul-Hee Yoon, Jung-Eun Lee, and Sang-Yoon Lee

Abstract

This case report from the Rodem Hospital introduces a pioneering intervention for muscle rigidity in Amyotrophic Lateral Sclerosis (ALS), featuring a unique placental extract injection and glucose injection therapy combined with lidocaine. This novel approach has demonstrated significant muscle regeneration and sustained relaxation in 47 ALS patients. Unlike traditional treatments, this protocol offers a more sustainable and regenerative outcome. The treatment involved injections of a mixture containing glucose, lidocaine, and placental extract, targeting severely rigid muscles. Remarkably, 42 of the 47 patients showed considerable improvements in knee flexion and a dramatic reduction in pain. The other two also experienced notable progress. This method stands out for its cost efficiency, impact on muscle suppleness, and reduced pain, suggesting a potential paradigm shift in ALS management. This case series highlights the importance of continued innovation and personalized treatment strategies in ALS care, aiming to improve patient quality of life and functional abilities.

This case report from the Rodem Hospital introduces a pioneering intervention for muscle rigidity in Amyotrophic Lateral Sclerosis (ALS), featuring a unique placental extract injection and glucose injection therapy combined with lidocaine. This novel approach has demonstrated significant muscle regeneration and sustained relaxation in 47 ALS patients. Unlike traditional treatments, this protocol offers a more sustainable and regenerative outcome. The treatment involved injections of a mixture containing glucose, lidocaine, and placental extract, targeting severely rigid muscles. Remarkably, 42 of the 47 patients showed considerable improvements in knee flexion and a dramatic reduction in pain. The other two also experienced notable progress. This method stands out for its cost efficiency, impact on muscle suppleness, and reduced pain, suggesting a potential paradigm shift in ALS management. This case series highlights the importance of continued innovation and personalized treatment strategies in ALS care, aiming to improve patient quality of life and functional abilities.

Ryan Shoemaker, A Heyman, and D Lark

Abstract

Beginning with Possible Estuarine Associated Syndrome (PEAS) in 1998 and followed by numerous studies on similar types of exposures, patients with illness associated with biotoxin exposure routinely have had symptom rosters dominated by executive cognitive dysfunction, including recent memory deficits, difficulty in concentration, difficulty with word finding, decreased assimilation of new knowledge, confusion and disorientation, tremors, headaches, vertigo, and unusual pains. In addition, tremors, headaches, vertigo, unusual pains and metallic taste. Toxins involved variously have included those found in toxin-forming dinoflagellates, including Pfiesteria and ciguatera; cyanobacteria, including Microcystis, Cylindrospermopsis and Lyngbya wollei; post Lyme syndrome and Babesia; as well as organisms found in damp buildings, including Aspergillus versicolor and A. penicillioides, Stachybotrys chartarum, Chaetomium globosum, Wallemia sebi, Actinobacteria species, especially Corynebacteria tuberculostearicum and Propionibacterium acnes; as well as bacterial endotoxins and beta-glucans. These illnesses have been called chronic inflammatory response syndromes (CIRS).

The mechanism of neurologic findings has remained elusive despite studies showing successful treatment with intranasal vasoactive intestinal polypeptide (VIP). Neurocognitive testing has only been performed in PEAS patients, showing profound deficits in learning and higher cognitive functioning. These CIRS patients have had brain imaging without consistent findings, including MRI, EEG, and CT of the brain. NeuroQuant has shown findings that fit a “fingerprint” found in patients with specific causation and confirmed exposure to Actinobacteria and endotoxins. Fungal exposure shows disproportionate enlargement due to interstitial edema in the forebrain parenchyma and cortical grey, with a diminished caudate nucleus size. These findings have not been found in controls. The recent inclusion of transcriptomic studies using GENIE has confirmed that specific causation can be identified for Actinobacteria (48% of total confirmed cases), bacterial endotoxins (28%) and fungi (7%) in CIRS patients. The combination of NeuroQuant and GENIE has implicated excessive production of cytoskeletal tubulin genes TUBA4A and TUBB1 as risk factors for specific fingerprints for die-back degenerative central nervous system (CNS) injury in patients with illnesses associated variously with exposure to Actinobacteria, fungi and endotoxins.

This study seeks to implicate a causal abnormality of excessive expression of tubulin genes TUBA4A and TUBB1. Given the role of these genes in die-back CNS degenerative diseases, such as Alzheimer’s, amyotrophic lateral sclerosis and Parkinson’s disease, and anecdotal successful treatment of CIRS patients with elevated TUBA4A and TUBB1, we suggest the possibility of treatment of tubulin excess may have a role in clinical improvement seen in die-back CNS degenerative diseases. Elevated levels of MAPK are also risk factors when combined with elevated levels of TUBA4A and TUBBI.

William Kirkpatrick Reid, MD

Abstract

Three neurodegenerative disorders- Alzheimer’s dementia (ALZ), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS)- share a common feature in their pathogenesis: evidence of mitochondrial dysfunction and reactive oxygen stress. Their pathologic classifications are based on the findings at autopsy based on patterns of protein aggregates in neurons and glial cells. This pathology supports the concept that neurotoxins are a major factor in the etiology of these disorders. There is value in exploring the similarities in the pathogenesis of ALS, Parkinson Disease and Alzheimer Dementia based on non-genetic etiologies.

The nose to olfactory pathway feeds sensory input from the nasal cavity to the olfactory bulb and the entorhinal lobe. Another component of these pathways involves two branches of the trigeminal nerve with sensory input to the pons and midbrain. A key factor is their capacity to bypass the blood-brain barrier (BBB). The protection of the brain by the BBB diminishes with age and can be lost with damage from insults as with viral infections. The olfactory nerve is the only cranial nerve with direct exposure to the ambient environment and has a high rate of turnover of sensory receptors.

The nasal cavity is being studied for drug delivery and can be used to deliver medications into the central nervous system (CNS. The nose-to-brain pathway may represent a critical avenue of exposure to oxidative neurotoxins. Neurotoxic mycotoxins are a major risk to humans. Neurotoxins may be amplified by the nose-to-brain pathway. The pathology shows similarities to prion disease. These neurotoxins are highly fat-soluble and tend to accumulate in mitochondria and synaptic vesicles. Neurotoxins in synaptic vesicles can migrate from neuron to neuron.

There is evidence of chronic fungal infections in ALS patients that secret neurotoxic and immunotoxic mycotoxins leading to progressive immune suppression. The nose-to-olfactory pathway may amplify neurotoxins levels in the brain. If Parkinson Disease and ALZ are due to systemic poisonings, the source of neurotoxins may be episodic and lead to autoimmune disease.

Marion C. Hogg

Abstract

Transfer RNAs play a crucial role in protein translation where they bring amino acids to the ribosome to be incorporated into nascent polypeptide chains. During stress conditions tRNAs can be cleaved to generate tRNA-derived fragments. Several ribonucleases have been identified that cleave tRNA, however mutations in the stress-induced ribonuclease Angiogenin have been identified in a range of neurological disorders including Amyotrophic Lateral Sclerosis, Parkinson’s Disease, and Alzheimer’s Disease, suggesting that tRNA cleavage may be dysregulated in neurological disease. tRNA fragments have been detected in biofluids indicating they may be of use as biomarkers for neurological diseases. There is considerable variability in the methods used to quantify tRFs from size selection, adapter ligation, removal of RNA modifications, and sequence analysis approaches which can make it difficult to reconcile multiple studies. Here we review the biology of transfer RNAs and the biogenesis of tRNA-derived fragments, with a focus on the methods used to identify and quantify tRNA fragments and how different methodological approaches can influence tRNA fragment detection. We provide an overview of current literature on the identification of tRNA fragments in neurological disease models and patient samples, with a focus on circulating tRNA fragments as potential biomarkers of neurological diseases.