Dysfunction In Motor Neuron Disease Research Articles

Effects of Hyperbaric Oxygen Therapy in Treatment on Diverse Diseases

INTRODUCTION: Hyperbaric oxygen therapy (HBOT) indeed holds significant therapeutic potential across various medical conditions, primarily by increasing the concentration of oxygen delivered to tissues under pressure. Saturating tissues with oxygen allows for the effective alleviation of underlying hypoxia, facilitating healing, tissue repair and mechanisms of action leads to reducing concentration of pro-inflammatory acute phase proteins, interleukins, and cytokines. Conversely, HBOT while also boosting levels of growth factors and other cytokines that promote angiogenesis. REVIEW METHODS: The article was complied by analyzing data from PubMed and Google Scholar regarding effects of hyperbaric therapy. THE STATE OF KNOWLEDGE: Studies indicate that HBOT provides numerous opportunities in the treatment of extensive diseases acress various systems. Neurodegenerative disorders involve progressive nerve cell damage leading to motor or cognitive decline, exacerbated by oxidative stress and inflammation. HBOT has shown promise in delaying disease onset by improving mitochondrial dysfunction in motor neuron disease. In case of intestinal obstruction HBOT reduces intestinal gas volume, diameter of obstructed loops, and improves intestinal contractility. Significant benefits have been observed in conditions such as Crohn's disease and ulcerative colitis. Hyperbaric therapy presents potential benefits for the infertility, improving the environment for blastocyst implantation and pregnancy. CONCLUSION: There is no doubt that HBOT has a beneficial impact on treatment of many systems such as the nervous, cardiovascular, digestive, and skeletal. This innovative approach of hyperbaric therapy extends to selected disorders such as neurodegenerative diseases, Crohn's disease, ulcerative colitis, and infertility.

Metabolic Dysfunction in Motor Neuron Disease: Shedding Light through the Lens of Autophagy.

Amyotrophic lateral sclerosis (ALS) patients show a myriad of energetic abnormalities, such as weight loss, hypermetabolism, and dyslipidaemia. Evidence suggests that these indices correlate with and ultimately affect the duration of survival. This review aims to discuss ALS metabolic abnormalities in the context of autophagy, the primordial system acting at the cellular level for energy production during nutrient deficiency. As the primary pathway of protein degradation in eukaryotic cells, the fundamental role of cellular autophagy is the adaptation to metabolic demands. Therefore, autophagy is tightly coupled to cellular metabolism. We review evidence that the delicate balance between autophagy and metabolism is aberrant in ALS, giving rise to intracellular and systemic pathophysiology observations. Understanding the metabolism autophagy crosstalk can lead to the identification of novel therapeutic targets for ALS.

Axonal Excitability in Amyotrophic Lateral Sclerosis : Axonal Excitability in ALS.

Axonal excitability testing provides in vivo assessment of axonal ion channel function and membrane potential. Excitability techniques have provided insights into the pathophysiological mechanisms underlying the development of neurodegeneration and clinical features of amyotrophic lateral sclerosis (ALS) and related neuromuscular disorders. Specifically, abnormalities of Na+ and K+ conductances contribute to development of membrane hyperexcitability in ALS, thereby leading to symptom generation of muscle cramps and fasciculations, in addition to promoting a neurodegenerative cascade via Ca2+-mediated processes. Modulation of axonal ion channel function in ALS has resulted in significant symptomatic improvement that has been accompanied by stabilization of axonal excitability parameters. Separately, axonal ion channel dysfunction evolves with disease progression and correlates with survival, thereby serving as a potential therapeutic biomarker in ALS. The present review provides an overview of axonal excitability techniques and the physiological mechanisms underlying membrane excitability, with a focus on the role of axonal ion channel dysfunction in motor neuron disease and related neuromuscular diseases.

Changes in cortical β-oscillation dynamics across the clinical spectrum of motor neuron disease

BackgroundNovel biomarker discovery and validation are essential to the development and appraisal of emerging therapies for the devastating cerebral neurodegenerative disorder motor neuron disease (MND), the commonest phenotype of which is amyotrophic lateral sclerosis (ALS). MND pathology (and strong genetic risk of MND prior to symptoms) was hypothesised to be manifested by changes in movement-related cortical neuronal β-oscillations. MethodsWe used magnetoencephalography (MEG) to investigate both symptomatic patients and asymptomatic mutation carriers at risk of developing ALS. MEG data were acquired during a visually cued lateralised motor preparation task that included infrequent movement inhibition trials. Data from 11 patients with ALS, ten with the upper motor neuron-only phenotype primary lateral sclerosis (PLS), and 12 asymptomatic mutation carriers were age-matched against healthy controls. Source-space MEG analysis used a combination of functionally defined voxels of interest and whole brain data to measure β-power before, during, and after movement execution or inhibition. FindingsPatients with PLS were slower to respond to targets relative to controls (663 ms [SD 189] vs 440 [124], p=0·008), but the task was otherwise comparably performed across groups. Source reconstructed MEG data revealed excessive β-desynchronisation relative to controls in the motor cortices of both patients with ALS (p=0·012) and in asymptomatic mutation carriers (p=0·043). In only those patients with PLS, β-desynchronisation was inadequately lateralised to the contralateral motor cortex during response preparation. Transition to β-rebound was slowed in patients with ALS relative to controls (p=0·028). During successfully performed inhibition trials asymptomatic mutation carrier (p=0·046) groups demonstrated reduced inhibitory β-power relative to controls immediately before their expected response time to GO trials. InterpretationMEG is sensitive to cortical dysfunction in MND through changes in neural β-oscillations related to motor pathology. These abnormalities differ by phenotype, yet may be detectable before the development of overt symptoms in those at genetic risk. FundingWellcome Trust, Medical Research Council.

13.: More than just dysarthria: Language dysfunction in motor neuron disease

Motor neuron disease (MND) and frontotemporal dementia (FTD) share clinical, genetic, and pathological features. Executive and behavioural disturbances are now recognised in MND, but non-executive cognitive impairments such as language dysfunction – a characteristic clinical feature of FTD – have not been explored to our knowledge. The present study investigated language in MND using tools specifically designed for use in different FTD phenotypes, including semantic dementia (SD) and progressive non-fluent aphasia (PNFA). Specifically, semantic deficits were assessed and compared to SD, whereas ability to interpret grammar was compared to PNFA. The study was performed in two parts. In part A, the Sydney language battery was used to assess aspects of semantic knowledge such as object naming, and results were compared to SD. In part B, interpretation of grammar was assessed using the test of reception of grammar (TROG), and results were compared to PNFA. Voxel-based morphometry was used to correlate patterns of cortical atrophy with performance on language measures. In total, 84 participants were included in part A (17 MND, 19 FTD-MND, 22 SD, and 26 controls) and 71 participants in part B (18 MND, 16 FTD-MND, 28 PNFA, and 9 controls). Part A demonstrated semantic deficits in MND and FTD-MND. For example, MND and FTD-MND were impaired on object naming (MND 25 ± 2.9, FTD-MND 17.1 ± 6.6, SD 5.4 ± 3.9, and controls 27 ± 1.9; p

Associations between laryngeal and cough dysfunction in motor neuron disease with bulbar involvement.

True vocal fold (TVF) dysfunction may lead to cough ineffectiveness. In individuals with motor neuron disease (MND), cough impairment in the context of dysphagia increases risk for aspiration and respiratory failure. This study characterizes differences and associations between TVF kinematics and airflow during cough in individuals with bulbar MND. Sequential glottal angles associated with TVF movements during volitional cough were analyzed from laryngeal video endoscopy examinations of adults with bulbar MND (n = 12) and healthy controls (n = 12) and compared with simultaneously collected cough-related airflow measures. Significant group differences were observed with airflow and TVF measures: volume acceleration (p ≤ 0.001) and post-compression abduction TVF angle average velocity (p = 0.002) were lower and expiratory phase rise time (p = 0.001) was higher in the MND group. Reductions in maximum TVF angle during post-compression abduction in the MND group approached significance (p = 0.09). All subjects demonstrated complete TVF and supraglottic closure during the compression phase of cough, except for incomplete supraglottic closure in 2/12 MND participants. A strong positive relationship between post-compression maximum TVF abduction angle and peak expiratory cough flow was observed in the MND group, though it was not statistically significant (r = 0.55; p = 0.098). Reductions in the speed and extent of TVF abduction are seen during the expulsion phase of cough in individuals with MND. This may contribute to cough impairment and morbidity.

Androgen receptors in muscle fibers induce rapid loss of force but not mass: Implications for spinal bulbar muscular atrophy

Testosterone (T) induces motor dysfunction in transgenic (Tg) mice that overexpress wild-type androgen receptor (AR) in skeletal muscles. Because many genes implicated in motor neuron disease are expressed in skeletal muscle, mutant proteins may act in muscle to cause dysfunction in motor neuron disease. We examined contractile properties of the extensor digitorum longus (EDL) and soleus (SOL) muscles in vitro after 5 and 3 days of T treatment in motor-impaired Tg female mice. Both muscles showed deficits in tetanic force after 5 days of T treatment, without losses in muscle mass, protein content, or fiber number. After 3 days of T treatment, only SOL showed a deficit in tetanic force comparable to that of 5 days of treatment. In both treatments, EDL showed slowed twitch kinetics, whereas SOL showed deficits in the twitch/tetanus ratio. These results suggest calcium-handling mechanisms in muscle fibers are defective in motor-impaired mice.

Beta-band intermuscular coherence: a novel biomarker of upper motor neuron dysfunction in motor neuron disease

In motor neuron disease, the focus of therapy is to prevent or slow neuronal degeneration with neuroprotective pharmacological agents; early diagnosis and treatment are thus essential. Incorporation of needle electromyographic evidence of lower motor neuron degeneration into diagnostic criteria has undoubtedly advanced diagnosis, but even earlier diagnosis might be possible by including tests of subclinical upper motor neuron disease. We hypothesized that beta-band (15–30 Hz) intermuscular coherence could be used as an electrophysiological marker of upper motor neuron integrity in such patients. We measured intermuscular coherence in eight patients who conformed to established diagnostic criteria for primary lateral sclerosis and six patients with progressive muscular atrophy, together with 16 age-matched controls. In the primary lateral sclerosis variant of motor neuron disease, there is selective destruction of motor cortical layer V pyramidal neurons and degeneration of the corticospinal tract, without involvement of anterior horn cells. In progressive muscular atrophy, there is selective degeneration of anterior horn cells but a normal corticospinal tract. All patients with primary lateral sclerosis had abnormal motor-evoked potentials as assessed using transcranial magnetic stimulation, whereas these were similar to controls in progressive muscular atrophy. Upper and lower limb intermuscular coherence was measured during a precision grip and an ankle dorsiflexion task, respectively. Significant beta-band coherence was observed in all control subjects and all patients with progressive muscular atrophy tested, but not in the patients with primary lateral sclerosis. We conclude that intermuscular coherence in the 15–30 Hz range is dependent on an intact corticospinal tract but persists in the face of selective anterior horn cell destruction. Based on the distributions of coherence values measured from patients with primary lateral sclerosis and control subjects, we estimated the likelihood that a given measurement reflects corticospinal tract degeneration. Therefore, intermuscular coherence has potential as a quantitative test of subclinical upper motor neuron involvement in motor neuron disease.

161 15–30 Hz intermuscular coherence as a potential biomarker of upper motor neuron dysfunction in motor neuron disease

Motor neuron disease (MND) involves the degeneration of variable proportions of upper and lower motor neurons (UMNs, LMNs). Electrophysiological tests for LMN degeneration are well established but an analogous biomarker...

Ventilatory dysfunction in motor neuron disease: when and how to act?

Amyotrophic lateral sclerosis is a devastating progressive neurodegenerative disorder, involving motor neurons in the cerebral cortex, brainstem and spinal cord. Mean duration of survival from the time of diagnosis is around 15 months, being pulmonary complications and respiratory failure responsible for more than 85% of deaths. Albeit the inevitability of respiratory failure and short-term death, standardized intervention protocols have been shown to significantly delay the need for invasive ventilatory support, thus prolonging survival and enhancing quality of life. The authors present an intervention protocol based on clinical progression and respiratory parameters. Decisions regarding initiation of non-invasive positive pressure ventilation (NIPPV) and mechanically assisted coughing, depend on development of symptoms of hypoventilation and on objective deterioration of respiratory parameters especially in what concerns bulbar muscle function. These include maximum inspiratory capacity (MIC), difference between MIC and vital capacity (MIC-VC), and assisted peak cough flow (PCF). These standardized protocols along with patient and caregivers education, allow for improved quality of life, prolonged survival and delay or eventually prevent the need for tracheotomy and invasive ventilatory support. Supplemental oxygen should be avoided in these patients, since it precludes use of oxymetry as feedback for titrating NIPPV and MAC, and is associated with decreased ventilatory drive and aggravated hypercapnia.

Impairment of mitochondrial anti-oxidant defence in SOD1-related motor neuron injury and amelioration by ebselen

There is now compelling evidence of mitochondrial dysfunction in motor neuron disease (MND), but the molecular basis of these abnormalities is unknown. It is also unclear whether the observed mitochondrial dysfunction plays a central role in disease pathogenesis, and if so, whether its amelioration might present therapeutic opportunities. We adopted a candidate generation approach using proteomics to screen for changes in mitochondrial protein expression in a well-validated cell-culture model of superoxide dismutase 1 (SOD1) related familial MND (fMND). Changed proteins were identified by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectroscopy. Protein candidates included apoptotic regulators, anti-oxidants and components of the electron transport chain. Confirmatory Western blotting was performed, and validated protein expression changes were further investigated. Peroxiredoxin 3 (Prx3), a mitochondrial thioredoxin-dependent hydroperoxidase, is downregulated in the presence of mutant SOD1 in both our cell-culture model and in the spinal cord mitochondria of mutant SOD1 transgenic mice. We confirm the expression of Prx3 within the mitochondria of spinal motor neurons in mouse and humans by immunohistochemistry. Using quantitative real-time PCR (Q-PCR), we show that Prx3 is also downregulated in spinal motor neurons from patients with both sporadic (sMND) and SOD1-related fMND. In a disease characterized by oxidative stress, this represents a potentially important deficit in mitochondrial anti-oxidant defence. Recent evidence suggests that oxidative stress from aberrant copper chemistry may not play a major part in the pathogenesis of SOD1-related fMND. From the results of this study we propose disruption of mitochondrial anti-oxidant defence as an alternative mechanism whereby mutant SOD1 may generate oxidative stress within motor neurons. We further demonstrate that ebselen, an anti-oxidant drug already safely used in human studies and that acts as a Prx mimic, is able to ameliorate the toxicity of mutant SOD1 in our cell-culture model. We conclude by showing that ebselen is capable of inducing transcription of the anti-oxidant response element (ARE) and postulate that ebselen may act both by the transcriptional upregulation of anti-oxidant proteins, and directly as an anti-oxidant in its own right.

Respiratory complications related to bulbar dysfunction in motor neuron disease

Bulbar dysfunction resulting from corticobulbar pathway or brainstem neuron degeneration is one of the most important clinical problems encountered in motor neuron disease (MND) and contributes to various respiratory complications which are major causes of morbidity and mortality. Chronic malnutrition as a consequence of bulbar muscle weakness may have a considerable bearing on respiratory muscle function and survival. Abnormalities of the control and strength of the laryngeal and pharyngeal muscles may cause upper airway obstruction increasing resistance to airflow. Bulbar muscle weakness prevents adequate peak cough flows to clear airway debris. Dysphagia can lead to aspiration of microorganisms, food and liquids and hence pneumonia. MND patients with bulbar involvement commonly display an abnormal respiratory pattern during swallow characterized by inspiration after swallow, prolonged swallow apnoea and multiple swallows per bolus. Volitional respiratory function tests such as forced vital capacity can be inaccurate in patients with bulbofacial weakness and/or impaired volitional respiratory control. Bulbar muscle weakness with abundant secretions may increase the risk of aspiration and make successful non-invasive assisted ventilation more difficult. We conclude that an evaluation of bulbar dysfunction is an essential element in the assessment of respiratory dysfunction in MND.

Respiratory complications related to bulbar dysfunction in motor neuron disease

Respiratory complications related to bulbar dysfunction in motor neuron disease

Olfactory Disorder in Motor Neuron Disease

In Parkinson's disease and Alzheimer's disease there is profound disorder of olfaction. The extent to which this modality is involved in motor neuron disease (MND) has been studied little. To address this further we assessed olfaction by three methods—a smell identification test (“UPSIT”) in 58 patients and 135 controls; olfactory-evoked response (OEP) to H2S in 15 patients, and pathological examination of olfactory bulbs obtained from 8 cadavers. It was found that smell identification compared with the controls was slightly worse overall in the MND group as a whole, but only the bulbar patients scored significantly less on the UPSIT. Patients displayed a subtle defect in cheese odor recognition. OEPs were normal in 9 subjects and delayed in 1 subject. The remaining 5 OEPs were unsuccessful. Histopathological studies of olfactory bulbs showed excess lipofuscin deposition in all 8 cases examined, indicating subclinical neuronal damage. Olfactory neurons with a degree of antioxidant defect may be more susceptible to cellular damage than other neuronal groups because of their direct relationship to environmental agents. Overall we found the degree of olfactory dysfunction in MND to be mild and in contrast with the marked changes described by others.