Journal articles: 'Motoer Neuron Disease – Therapy'

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Sendtner, Michael. "Gene therapy for motor neuron disease." Nature Medicine 3, no. 4 (April 1997): 380–81. http://dx.doi.org/10.1038/nm0497-380.

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Kiernan, Matthew C. "Progress towards therapy in motor neuron disease." Nature Reviews Neurology 14, no. 2 (January 19, 2018): 65–66. http://dx.doi.org/10.1038/nrneurol.2017.186.

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&NA;. "Gene therapy helps mice with motor neuron disease." Inpharma Weekly &NA;, no. 1085 (May 1997): 10. http://dx.doi.org/10.2165/00128413-199710850-00026.

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Messina, Sonia. "New Directions for SMA Therapy." Journal of Clinical Medicine 7, no. 9 (August 31, 2018): 251. http://dx.doi.org/10.3390/jcm7090251.

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Spinal muscular atrophy (SMA) is a severe disorder of motor neurons and the most frequent genetic cause of mortality in childhood, due to respiratory complications. The disease occurs due to mutations in the survival motor neuron 1 (SMN1) gene that leads to a reduction in the SMN protein, causing degeneration of lower motor neurons, muscle weakness and atrophy. Recently, the Food and Drug Administration (FDA) and the European Medical Agency (EMA) approved the antisense oligonucleotide nusinersen, the first disease-modifying treatment for SMA. Encouraging results from SMN1 gene therapy studies have raised hope for other therapeutic approaches that might arise in the coming years. However, nusinersen licensing has created ethical, medical, and financial implications that will need to be addressed. In this review, the history and challenges of the new SMA therapeutic strategies are highlighted.

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Rosenfeld, Jeffrey, and Amy Ellis. "Nutrition and Dietary Supplements in Motor Neuron Disease." Physical Medicine and Rehabilitation Clinics of North America 19, no. 3 (August 2008): 573–89. http://dx.doi.org/10.1016/j.pmr.2008.03.001.

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Mackinnon, H. "Motor neuron disease and music therapy - a holistic approach." BMJ Supportive & Palliative Care 1, no. 2 (September 1, 2011): 204. http://dx.doi.org/10.1136/bmjspcare-2011-000100.16.

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Werner, Jana, Ilijas Jelcic, Esther Irene Schwarz, Elisabeth Probst-Müller, Jakob Nilsson, Bernhard Schwizer, Konrad Ernst Bloch, Andreas Lutterotti, Hans-Heinrich Jung, and Bettina Schreiner. "Anti-IgLON5 Disease." Neurology - Neuroimmunology Neuroinflammation 8, no. 2 (February 2, 2021): e962. http://dx.doi.org/10.1212/nxi.0000000000000962.

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ObjectiveTo expand the spectrum of anti-IgLON5 disease by adding 5 novel anti-IgLON5–seropositive cases with bulbar motor neuron disease-like phenotype.MethodsWe characterized the clinical course, brain MRI and laboratory findings, and therapy response in these 5 patients.ResultsPatients were severely affected by bulbar impairment and its respiratory consequences. Sleep-related breathing disorders and parasomnias were common. All patients showed clinical or electrophysiologic signs of motor neuron disease without fulfilling the diagnostic criteria for amyotrophic lateral sclerosis. One patient regained autonomy in swallowing and eating, possibly related to immunotherapy.ConclusionIgLON5 disease is an important differential diagnosis to evaluate in patients with bulbar motor neuron disease-like phenotype and sleep disorders. There is need for a deeper understanding of the underlying pathobiology to determine whether IgLON5 disease is an immunotherapy-responsive condition.

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Manzano, Raquel, Gianni Sorarú, Christopher Grunseich, Pietro Fratta, Emanuela Zuccaro, Maria Pennuto, and Carlo Rinaldi. "Beyond motor neurons: expanding the clinical spectrum in Kennedy’s disease." Journal of Neurology, Neurosurgery & Psychiatry 89, no. 8 (January 20, 2018): 808–12. http://dx.doi.org/10.1136/jnnp-2017-316961.

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Kennedy’s disease, or spinal and bulbar muscular atrophy (SBMA), is an X-linked neuromuscular condition clinically characterised by weakness, atrophy and fasciculations of the limb and bulbar muscles, as a result of lower motor neuron degeneration. The disease is caused by an abnormally expanded triplet repeat expansions in the ubiquitously expressed androgen receptor gene, through mechanisms which are not entirely elucidated. Over the years studies from both humans and animal models have highlighted the involvement of cell populations other than motor neurons in SBMA, widening the disease phenotype. The most compelling aspect of these findings is their potential for therapeutic impact: muscle, for example, which is primarily affected in the disease, has been recently shown to represent a valid alternative target for therapy to motor neurons. In this review, we discuss the emerging study of the extra-motor neuron involvement in SBMA, which, besides increasingly pointing towards a multidisciplinary approach for affected patients, deepens our understanding of the pathogenic mechanisms and holds potential for providing new therapeutic targets for this disease.

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Villalón, E., R. A. Kline, C. E. Smith, Z. C. Lorson, E. Y. Osman, S. O’Day, L. M. Murray, and C. L. Lorson. "AAV9-Stathmin1 gene delivery improves disease phenotype in an intermediate mouse model of spinal muscular atrophy." Human Molecular Genetics 28, no. 22 (July 31, 2019): 3742–54. http://dx.doi.org/10.1093/hmg/ddz188.

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Abstract Spinal muscular atrophy (SMA) is a devastating infantile genetic disorder caused by the loss of survival motor neuron (SMN) protein that leads to premature death due to loss of motor neurons and muscle atrophy. The approval of an antisense oligonucleotide therapy for SMA was an important milestone in SMA research; however, effective next-generation therapeutics will likely require combinatorial SMN-dependent therapeutics and SMN-independent disease modifiers. A recent cross-disease transcriptomic analysis identified Stathmin-1 (STMN1), a tubulin-depolymerizing protein, as a potential disease modifier across different motor neuron diseases, including SMA. Here, we investigated whether viral-based delivery of STMN1 decreased disease severity in a well-characterized SMA mouse model. Intracerebroventricular delivery of scAAV9-STMN1 in SMA mice at P2 significantly increased survival and weight gain compared to untreated SMA mice without elevating Smn levels. scAAV9-STMN1 improved important hallmarks of disease, including motor function, NMJ pathology and motor neuron cell preservation. Furthermore, scAAV9-STMN1 treatment restored microtubule networks and tubulin expression without affecting tubulin stability. Our results show that scAAV9-STMN1 treatment improves SMA pathology possibly by increasing microtubule turnover leading to restored levels of stable microtubules. Overall, these data demonstrate that STMN1 can significantly reduce the SMA phenotype independent of restoring SMN protein and highlight the importance of developing SMN-independent therapeutics for the treatment of SMA.

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Francis, Kathleen, John R. Bach, and Joel A. DeLisa. "Evaluation and rehabilitation of patients with adult motor neuron disease." Archives of Physical Medicine and Rehabilitation 80, no. 8 (August 1999): 951–63. http://dx.doi.org/10.1016/s0003-9993(99)90089-8.

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Goodall, Emily F., and Karen E. Morrison. "Amyotrophic lateral sclerosis (motor neuron disease): proposed mechanisms and pathways to treatment." Expert Reviews in Molecular Medicine 8, no. 11 (May 24, 2006): 1–22. http://dx.doi.org/10.1017/s1462399406010854.

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterised by loss of motor neurons. The cause of disease is unknown other than in the rare cases of familial disease arising from mutations in the superoxide dismutase 1 gene. Many theories for pathogenesis have been proposed – including oxidative stress, excitotoxicity, mitochondrial dysfunction and abnormal protein aggregation – based on studies of human post mortem tissue, research on animal models, and in vitro work. Here we review the evidence for the main pathogenic mechanisms and outline how they might interact to cause motor neuron death. Clinical trials have as yet failed to identify any truly effective therapies in ALS, with only riluzole providing a modest improvement in survival. Ongoing trials are exploring the value of antiglutamatergic agents, including the cephalosporin antibiotic ceftriaxone, as well as antioxidants, mitochondrial enhancers and anti-apoptotic drugs. It is likely that effective therapy will involve combinations of agents acting on different mechanisms. Gene therapy with neurotrophic factors will soon be in clinical trials, while work on stem cell therapy remains preclinical. In addition to finding effective therapies, research also needs to identify early disease markers because therapy is likely to be of most benefit when given early in the course of disease.

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Nizzardo, Monica, Chiara Simone, Federica Rizzo, Sabrina Salani, Sara Dametti, Paola Rinchetti, Roberto Del Bo, et al. "Gene therapy rescues disease phenotype in a spinal muscular atrophy with respiratory distress type 1 (SMARD1) mouse model." Science Advances 1, no. 2 (March 2015): e1500078. http://dx.doi.org/10.1126/sciadv.1500078.

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Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive motor neuron disease affecting children. It is caused by mutations in theIGHMBP2gene (11q13) and presently has no cure. Recently, adeno-associated virus serotype 9 (AAV9)–mediated gene therapy has been shown to rescue the phenotype of animal models of another lower motor neuron disorder, spinal muscular atrophy 5q, and a clinical trial with this strategy is ongoing. We report rescue of the disease phenotype in a SMARD1 mouse model after therapeutic delivery via systemic injection of an AAV9 construct encoding the wild-typeIGHMBP2to replace the defective gene. AAV9-IGHMBP2administration restored protein levels and rescued motor function, neuromuscular physiology, and life span (450% increase), ameliorating pathological features in the central nervous system, muscles, and heart. To test this strategy in a human model, we transferred wild-typeIGHMBP2into human SMARD1-induced pluripotent stem cell–derived motor neurons; these cells exhibited increased survival and axonal length in long-term culture. Our data support the translational potential of AAV-mediated gene therapies for SMARD1, opening the door for AAV9-mediated therapy in human clinical trials.

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Gordon, Brian, Eimear Joyce, and Timothy J. Counihan. "Stridor: a rare presentation of motor neuron disease." BMJ Case Reports 14, no. 7 (July 2021): e241923. http://dx.doi.org/10.1136/bcr-2021-241923.

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A 74-year-old farmer presented to the emergency department with a subacute history of progressive dyspnoea, wheeze and dysphonia. He was treated for an exacerbation of asthma with poor response to pharmacological therapy. Investigation of dysphonia via laryngoscopy identified a bilateral vocal cord palsy. Subsequently, the patient developed an episode of life-threatening stridor and hypercapnic respiratory failure requiring an emergency tracheostomy. Neurology input identified evidence of widespread muscle fasciculations on clinical examination. MRI of the brain and cervical spine were unremarkable. Electromyogram testing identified changes of acute denervation in several limbs consistent with a diagnosis of motor neuron disease (MND). Bilateral vocal cord palsy has been rarely reported in the literature as the heralding symptom resulting in the diagnosis of MND. In patients with a subacute onset of dysphonia, dyspnoea and stridor, MND should be a differential diagnosis.

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Spasić, Snežana, Aleksandra Nikolić-Kokić, Srđan Miletić, Zorana Oreščanin-Dušić, Mihajlo B. Spasić, Duško Blagojević, and Zorica Stević. "Edaravone May Prevent Ferroptosis in ALS." Current Drug Targets 21, no. 8 (June 20, 2020): 776–80. http://dx.doi.org/10.2174/1389450121666200220123305.

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Radicava™ (Edaravone) was approved the Food and Drug Administration (FDA) as a new treatment for amyotrophic lateral sclerosis (ALS). Edaravone is a synthetic antioxidant that specifically targets oxidative damage interacting with lipid radicals in the cell. In ALS disease the multiple cell types are involved in devastating loss of motor neurons. Mutations and biochemical changes in various cell types jointly contribute to motor neuron death, disease onset, and disease progression. The overall mechanism of neurodegeneration in ALS is still not completely understood. Dying motor neurons have been reported to exhibit features of apoptosis. However, non-apoptotic features of dying motor neurons have also been reported such as ferroptosis. The role of Edaravone in the prevention of ferroptosis in parallel with other therapeutic approaches to ALS therapy is discussed.

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Satin, Zachary Aaron, and Elham Bayat. "ALS-Like Disorder in Three HIV-Positive Patients: Case Series." Case Reports in Neurology 13, no. 1 (January 28, 2021): 59–64. http://dx.doi.org/10.1159/000511203.

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There appears to be a relationship between retroviruses such as HIV and the development of an ALS-like syndrome. Few cases have been reported; however, there exists evidence of a higher frequency of motor neuron disease in HIV-infected patients, as well as potential slowing and reversibility of disease course with combination antiretroviral therapy. We conducted a retrospective chart review of patients presenting to the George Washington University ALS Clinic from September 2006 to June 2018 to identify patients with HIV receiving HAART who were subsequently diagnosed with ALS or an ALS-like disorder. Our goals were to describe our patients’ disease course and compare them to general characteristics of ALS. We report three cases of HIV-positive individuals, all male, who were subsequently diagnosed with ALS. Each presented with symptoms of limb onset ALS with involvement of upper and lower motor neurons and whose disease originated at the cervical level. All three had been diagnosed with HIV prior to presentation and were presumably compliant with antiretroviral therapy throughout. Our patients demonstrated effective control of their HIV infection. Each experienced relatively slow progression of motor impairment compared to general ALS characteristics. Our study offers a distinct profile of HIV-positive patients compliant with HAART subsequently diagnosed with an ALS-like disorder. Further study should aim to uncover pathophysiological similarities between motor neuron disease both in the presence and absence of retroviral infection and to develop effective medical therapy for each.

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Harvey, W. T., and D. Martz. "Motor neuron disease recovery associated with IV ceftriaxone and anti-Babesia therapy." Acta Neurologica Scandinavica 115, no. 2 (February 2007): 129–31. http://dx.doi.org/10.1111/j.1600-0404.2006.00727.x.

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Lee, Ni-Chung, Wuh-Liang Hwu, Shin-Ichi Muramatsu, Darin J. Falk, Barry J. Byrne, Chia-Hao Cheng, Nien-Chu Shih, Kai-Ling Chang, Li-Kai Tsai, and Yin-Hsiu Chien. "A Neuron-Specific Gene Therapy Relieves Motor Deficits in Pompe Disease Mice." Molecular Neurobiology 55, no. 6 (September 11, 2017): 5299–309. http://dx.doi.org/10.1007/s12035-017-0763-4.

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Cappella, Marisa, Chiara Ciotti, Mathilde Cohen-Tannoudji, and Maria Grazia Biferi. "Gene Therapy for ALS—A Perspective." International Journal of Molecular Sciences 20, no. 18 (September 6, 2019): 4388. http://dx.doi.org/10.3390/ijms20184388.

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Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) with no cure. Recent advances in gene therapy open a new perspective to treat this disorder—particularly for the characterized genetic forms. Gene therapy approaches, involving the delivery of antisense oligonucleotides into the central nervous system (CNS) are being tested in clinical trials for patients with mutations in SOD1 or C9orf72 genes. Viral vectors can be used to deliver therapeutic sequences to stably transduce motor neurons in the CNS. Vectors derived from adeno-associated virus (AAV), can efficiently target genes and have been tested in several pre-clinical settings with promising outcomes. Recently, the Food and Drug Administration (FDA) approved Zolgensma, an AAV-mediated treatment for another MND—the infant form of spinal muscular atrophy. Given the accelerated progress in gene therapy, it is potentially a promising avenue to develop an efficient and safe cure for ALS.

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Cai, Mudan, and Eun Jin Yang. "Hochu-Ekki-To Improves Motor Function in an Amyotrophic Lateral Sclerosis Animal Model." Nutrients 11, no. 11 (November 4, 2019): 2644. http://dx.doi.org/10.3390/nu11112644.

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Hochu-ekki-to (Bojungikgi-Tang (BJIGT) in Korea; Bu-Zhong-Yi-Qi Tang in Chinese), a traditional herbal prescription, has been widely used in Asia. Hochu-ekki-to (HET) is used to enhance the immune system in respiratory disorders, improve the nutritional status associated with chronic diseases, enhance the mucosal immune system, and improve learning and memory. Amyotrophic lateral sclerosis (ALS) is pathologically characterized by motor neuron cell death and muscle paralysis, and is an adult-onset motor neuron disease. Several pathological mechanisms of ALS have been reported by clinical and in vitro/in vivo studies using ALS models. However, the underlying mechanisms remain elusive, and the critical pathological target needs to be identified before effective drugs can be developed for patients with ALS. Since ALS is a disease involving both motor neuron death and skeletal muscle paralysis, suitable therapy with optimal treatment effects would involve a motor neuron target combined with a skeletal muscle target. Herbal medicine is effective for complex diseases because it consists of multiple components for multiple targets. Therefore, we investigated the effect of the herbal medicine HET on motor function and survival in hSOD1G93A transgenic mice. HET was orally administered once a day for 6 weeks from the age of 2 months (the pre-symptomatic stage) of hSOD1G93A transgenic mice. We used the rota-rod test and foot printing test to examine motor activity, and Western blotting and H&E staining for evaluation of the effects of HET in the gastrocnemius muscle and lumbar (L4–5) spinal cord of mice. We found that HET treatment dramatically inhibited inflammation and oxidative stress both in the spinal cord and gastrocnemius of hSOD1G93A transgenic mice. Furthermore, HET treatment improved motor function and extended the survival of hSOD1G93A transgenic mice. Our findings suggest that HET treatment may modulate the immune reaction in muscles and neurons to delay disease progression in a model of ALS.

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Marques, Viviane, Marco Orsini, Rossano Fiorelli, Victor Hugo Bastos, Silmar Teixeira, Stenio Fiorelli, Andréa Povedano, et al. "Early gastrostomy associated with speech therapy in patients with amyotrophic lateral sclerosis." Fisioterapia Brasil 19, no. 3 (July 13, 2018): 414. http://dx.doi.org/10.33233/fb.v19i3.2437.

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Amyotrophic Lateral Sclerosis (ALS) is a degenerative disease that occurs with the deterioration of motor neurons. The beginning of clinical impairment may be bulbar with the average life time, after the first symptoms, between 2 to 5 years, presenting serious swallowing, speech and breathing disorders. Deglutition disorders can lead to malnutrition, dehydration, aspiration, displeasure, and more serious complications such as aspiration pneumonia and death. With the evolution of the disease, the patient needs procedures that generate doubts in the professionals and family, as the correct moment of indication of the use of alternative long-term feeding routes called gastrostomies (GTT). The objective of this article is to analyze the impact of dysphagias and the most favorable moment for the placement of gastrostomies. Early GTT placement may help prevent the patient from clinically debilitating more quickly, respond better to multidisciplinary team therapeutics, and feel more comfortable.Key-words: dysphagia, enteral nutrition, gastrostomy, deglutition disorders, motor neuron disease, amyotrophic lateral sclerosis.

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Bromberg, Mark B., and Alexander A. Brownell. "Motor Unit Number Estimation in the Assessment of Performance and Function in Motor Neuron Disease." Physical Medicine and Rehabilitation Clinics of North America 19, no. 3 (August 2008): 509–32. http://dx.doi.org/10.1016/j.pmr.2008.02.006.

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Haase, G., P. Kennel, B. Pettmann, E. Vigne, S. Akli, F. Revah, H. Schmalbruch, and A. Kahn. "Gene therapy of murine motor neuron disease using adenoviral vectors for neurotrophic factors." Nature Medicine 3, no. 4 (April 1997): 429–36. http://dx.doi.org/10.1038/nm0497-429.

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Venkova-Hristova, Kalina, Alexandar Christov, Zarine Kamaluddin, Peter Kobalka, and Kenneth Hensley. "Progress in Therapy Development for Amyotrophic Lateral Sclerosis." Neurology Research International 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/187234.

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that cannot be slowed substantially using any currently-available clinical tools. Through decades of studying sporadic and familial ALS (SALS and FALS), researchers are coming to understand ALS as a complex syndrome with diverse genetic and environmental etiologies. It is know appreciated that motor neuron degeneration in ALS requires active (gain of function) and passive (loss of function) events to occur in non-neuronal cells, especially astrocytes and microglia. These neuroinflammatory processes produce paracrine factors that detrimentally affect motor neurons, precipitating protein aggregation and compromising cytoskeletal integrity. The result is a loss of neuronal homeostasis and progressive die-back of motor axons culminating in death of the afflicted motor neurons. This review will discuss experimental therapeutics that have been tested in murine ALS models, with an emphasis on those that have progressed to human clinical trials. Reasons will be considered for the frequent failure of preclinical successes to translate into positive clinical outcomes. Finally, this review will explore current trends in experimental therapeutics for ALS with emphasis on the emerging interest in axon guidance signaling pathways as novel targets for pharmacological support of neural cytoskeletal structure and function in order to slow ALS.

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Lasiene, Jurate, and Koji Yamanaka. "Glial Cells in Amyotrophic Lateral Sclerosis." Neurology Research International 2011 (2011): 1–7. http://dx.doi.org/10.1155/2011/718987.

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Amyotrophic lateral sclerosis (ALS) is an adult motor neuron disease characterized by premature death of upper and lower motor neurons. Two percent of ALS cases are caused by the dominant mutations in the gene for superoxide dismutase 1 (SOD1) through a gain of toxic property of mutant protein. Genetic and chimeric mice studies using SOD1 models indicate that non-neuronal cells play important roles in neurodegeneration through non-cell autonomous mechanism. We review the contribution of each glial cell type in ALS pathology from studies of the rodent models and ALS patients. Astrogliosis and microgliosis are not only considerable hallmarks of the disease, but the intensity of microglial activation is correlated with severity of motor neuron damage in human ALS. The impaired astrocytic functions such as clearance of extracellular glutamate and release of neurotrophic factors are implicated in disease. Further, the damage within astrocytes and microglia is involved in accelerated disease progression. Finally, other glial cells such as NG2 cells, oligodendrocytes and Schwann cells are under the investigation to determine their contribution in ALS. Accumulating knowledge of active role of glial cells in the disease should be carefully applied to understanding of the sporadic ALS and development of therapy targeted for glial cells.

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Corbett, Joel, Stephen Walsh, Sandeep Bhuta, and Arman Sabet. "105 Snake eyes in the thoracic spine." Journal of Neurology, Neurosurgery & Psychiatry 89, no. 6 (May 24, 2018): A41.3—A42. http://dx.doi.org/10.1136/jnnp-2018-anzan.104.

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IntroductionBilateral anterior horn cell hyperintensity on spinal imaging (‘snake eyes’ sign) is seen in pathologies including cervical spondylosis, spinal cord infarction and Hirayama’s disease. Below is the first report of lower limb monomelic amyotrophy (MMA) with thoracic spine snake eyes sign. We present a case report of lower limb MMA with bilateral anterior horn hyperintensity, and literature review of cases with this clinico-radiologic presentation.CaseA 47 year old man presented with an 11 year history of asymmetric, progressive, proximal right lower limb weakness and wasting following traumatic back injury. Eight years into the disease course left leg changes developed. There was no upper limb, bulbar nor respiratory involvement. Examination revealed widespread lower limb wasting, normal tone, marked proximal weakness, brisk reflexes and non-sustained clonus bilaterally. Upper limb and cranial nerve examinations were normal. MRI demonstrated T11–12 bilateral anterior horn cell hyper-intensity. Electromyography demonstrated denervation/re-innervation changes in the right vastus lateralis and to a lesser extent tibialis anterior. Muscle biopsy showed chronic denervation atrophy. Anti-ganglioside GM1 IgM was elevated. Further autoimmune testing, infectious screen, cerebrospinal fluid and neuromuscular disease gene analysis were negative. Steroid and intravenous immunoglobulin therapy were ineffective.Case series describing lower motor neuron diseases (LMND) including MMA have not previously reported snake eyes sign in association with lower limb disease.1 Two recent publications describing thirty-two cases of LMND with cervical spine snake eyes sign report that all cases were associated with a relatively benign course and many were misdiagnosed as motor neuron disease (MND).2 3 The authors propose this as a previously unidentified mimic of motor neuron disease.ConclusionThis is the first reported case of thoracic snake eyes sign with corresponding lower limb MMA. Lower motor neuron diseases with bilateral anterior horn cell hyper-intensity may represent a unique clinical form of MND with relatively slower progression.References. Nalini A, Gourie-Devi, Thennarasu K, et al. Monomelic Amyotrophy: Clinical profile and natural history of 279 cases seen over 35 years (1976–2010). Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration2014;15:457–465.. Saski S. Sporadic lower motor neuron disease with a snake eyes appearance on the cervical anterior horns by MRI. Clinical Neurology and Neurosurgery2015;136:122–131.. Lebouteux M, Franques J, Guillevin R, et al. Revisiting the Spectrum of Lower Motor Neuron Diseases with Snake Eyes Appearance on Magnetic Resonance Imaging. European Journal of Neurology2014;21:1233–1241.

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Sokolova, Mariia G., Sergei V. Lobzin, Andrey A. Zuev, Vladimir G. Pustozerov, Nicolay Yu Aleksandrov, and Artur V. Gavrichenko. "On the question of differential diagnosis of multifocal motor neuropathy." HERALD of North-Western State Medical University named after I.I. Mechnikov 12, no. 1 (May 28, 2020): 89–96. http://dx.doi.org/10.17816/mechnikov202012189-96.

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Differential diagnostics of multifocal motor neuropathy (MMN) has many difficulties associated with a number of factors: rare nature of disease, polymorphic clinical forms and a phenotypic picture similar to peripheral motor neuron diseases. Such diseases also include rare nosological forms: amyotrophic lateral sclerosis, hereditary myopathies and neuropathies; their general phenotypic picture has a form of progressive flaccid paralysis, age of the disease onset and the nature of its course. However, different pathogenesis of these diseases requires a differentiated approach to therapy. This article deals with differential diagnostics of multifocal motor neuropathy, gives examples of modern diagnostic criteria necessary for diagnosing multifocal motor neuropathy and analyzes a clinical case with an incorrect diagnosis of multifocal motor neuropathy.

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Rolland, Jenny Pernilla, Mari-Anne Myrberget, and Tore Wergeland Meisingset. "The Assistive Device Situation for ALS Patients in Norway." Occupational Therapy International 2021 (August 18, 2021): 1–5. http://dx.doi.org/10.1155/2021/5563343.

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Aims. There are limited analytical descriptions of the assistive device situation in Norway for patients with ALS and other motor neuron diseases. This study is aimed at investigating how patients, caregivers, and healthcare professionals (occupational therapists and physiotherapists) experience the assistive device situation. Methods. Twenty-four interviews were conducted with patients with motor neuron disease, caregivers, and healthcare professionals involved in procurement and adaptation of assistive devices. Systematic text condensation was used to analyse the interviews. Results. The majority of patients and caregivers had positive experiences of follow-up by the specialist healthcare service. Several found follow-up by the primary health service to be deficient owing to inadequate expertise, continuity, and resources. Healthcare professionals reported having a proactive approach to identifying needs for assistive devices, but for various reasons, application processes were often delayed. Several patients indicated a reluctance to use assistive devices and were ambivalent regarding proactivity. The availability of assistive devices for some functional impairments was described as inadequate. Some patients felt there was too little focus on sexuality in the follow-up. The respondents had a number of suggestions for improving the assistive device situation. Conclusions. Multidisciplinary ALS teams are found to ensure follow-up expertise and continuity. Healthcare professionals wish to take a proactive approach to assistive devices, but a number of bureaucratic obstacles occur. The study findings are preliminary and should be validated through a prospective national quality registry for motor neuron diseases.

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Bonanno, Silvia, Stefania Marcuzzo, Claudia Malacarne, Eleonora Giagnorio, Riccardo Masson, Riccardo Zanin, Maria Teresa Arnoldi, et al. "Circulating MyomiRs as Potential Biomarkers to Monitor Response to Nusinersen in Pediatric SMA Patients." Biomedicines 8, no. 2 (January 26, 2020): 21. http://dx.doi.org/10.3390/biomedicines8020021.

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Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by mutations in survival motor neuron (SMN) 1 gene, resulting in a truncated SMN protein responsible for degeneration of brain stem and spinal motor neurons. The paralogous SMN2 gene partially compensates full-length SMN protein production, mitigating the phenotype. Antisense oligonucleotide nusinersen (Spinraza®) enhances SMN2 gene expression. SMN is involved in RNA metabolism and biogenesis of microRNA (miRNA), key gene expression modulators, whose dysregulation contributes to neuromuscular diseases. They are stable in body fluids and may reflect distinct pathophysiological states, thus acting as promising biomarkers. Muscle-specific miRNAs (myomiRs) as biomarkers for clinical use in SMA have not been investigated yet. Here, we analyzed the expression of miR-133a, -133b, -206 and -1, in serum of 21 infantile SMA patients at baseline and after 6 months of nusinersen treatment, and correlated molecular data with response to therapy evaluated by the Hammersmith Functional Motor Scale Expanded (HFMSE). Our results demonstrate that myomiR serological levels decrease over disease course upon nusinersen treatment. Notably, miR-133a reduction predicted patients’ response to therapy. Our findings identify myomiRs as potential biomarkers to monitor disease progression and therapeutic response in SMA patients.

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James, Rachel, Helena Chaytow, Leire M. Ledahawsky, and Thomas H. Gillingwater. "Revisiting the role of mitochondria in spinal muscular atrophy." Cellular and Molecular Life Sciences 78, no. 10 (April 5, 2021): 4785–804. http://dx.doi.org/10.1007/s00018-021-03819-5.

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AbstractSpinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease of variable clinical severity that is caused by mutations in the survival motor neuron 1 (SMN1) gene. Despite its name, SMN is a ubiquitous protein that functions within and outside the nervous system and has multiple cellular roles in transcription, translation, and proteostatic mechanisms. Encouragingly, several SMN-directed therapies have recently reached the clinic, albeit this has highlighted the increasing need to develop combinatorial therapies for SMA to achieve full clinical efficacy. As a subcellular site of dysfunction in SMA, mitochondria represents a relevant target for a combinatorial therapy. Accordingly, we will discuss our current understanding of mitochondrial dysfunction in SMA, highlighting mitochondrial-based pathways that offer further mechanistic insights into the involvement of mitochondria in SMA. This may ultimately facilitate translational development of targeted mitochondrial therapies for SMA. Due to clinical and mechanistic overlaps, such strategies may also benefit other motor neuron diseases and related neurodegenerative disorders.

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Nakao, Naoyuki, Koji Kakishita, Yuji Uematsu, Tatsuya Yoshimasu, Toshiya Bessho, Kunio Nakai, Yasuaki Naito, and Toru Itakura. "Enhancement of the response to levodopa therapy after intrastriatal transplantation of autologous sympathetic neurons in patients with Parkinson disease." Journal of Neurosurgery 95, no. 2 (August 2001): 275–84. http://dx.doi.org/10.3171/jns.2001.95.2.0275.

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Object. There is growing evidence to indicate that tissue transplantation can potentially be a restorative neurosurgical treatment for patients with Parkinson disease (PD). In this study the authors investigated the clinical effect of unilateral intrastriatal grafting of autologous sympathetic neurons in patients with PD. Methods. Four patients with PD who had been observed for 1 year after graft placement of autologous sympathetic neurons were selected for an analysis of the effect of that procedure. Sympathetic ganglion tissue was endoscopically excised from the thoracic sympathetic trunk and grafted into the unilateral caudate head and putamen of the PD patients. No changes were made in the patients' preoperative regimens of antiparkinsonian medications, and clinical evaluations were made principally according to those established by the Core Assessment Program for Intracerebral Transplantation Committee. Whereas the sympathetic neuron grafts failed to affect clinical scores reflecting the patients' motor performance, which was evaluated during either the “on” or “off” phases, the grafts significantly increased the duration of the levodopa-induced on period with consequent reduction in the percentage of time spent in the off phase. This beneficial effect may be explained by the results of the present in vitro experiment, which show that human sympathetic neurons have the ability to convert exogenous levodopa to dopamine and to store this synthesized dopamine. Conclusions. Sympathetic neuron autografts were found to improve performance status in patients with PD by reducing the time spent in the off phase. This clearly indicates that sympathetic ganglion tissue, the use of which involves few ethical issues, can be an efficacious donor source in cell transplantation therapy for PD. Further studies are needed to determine whether the grafts may provide long-lasting clinical benefits.

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Hanakawa, T., M. Nakamura, T. Suenaga, and S. Hashimoto. "Response to corticosteroid therapy in a patient with HTLV-I-associated motor neuron disease." Neurology 50, no. 4 (April 1, 1998): 1188–89. http://dx.doi.org/10.1212/wnl.50.4.1188.

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Hansel, Anna, Johannes Dorst, Angela Rosenbohm, Annemarie Hübers, and Albert Ludolph. "ALS Mimics." Neurology International Open 02, no. 01 (January 2018): E60—E71. http://dx.doi.org/10.1055/s-0043-119960.

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AbstractAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Most patients die within 2–5 years of symptom onset due to the lack of effective therapy options. A diagnostic delay is encountered quite often, since disease progression as well as site and speed of onset may vary significantly. Some diseases can mimic features of ALS, especially in early stages. It is very important to differentiate those mimics from ALS as potentially treatable conditions might be missed otherwise. ALS typically affects the upper as well as the lower motor neuron, which implies that diseases sharing at least one of these clinical features have to be considered in the differential diagnosis. The following conditions should be taken into account as a differential diagnosis for ALS with predominant affection of the lower motor neuron: Immune mediated neuropathies such as multifocal motor neuropathy (MMN) with pronounced distal paresis without striking atrophy signs and conduction blocks in electroneurography, and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with common signs of sensibility disturbances, areflexia and cytoalbuminologic dissociation in the cerebrospinal fluid (CSF). Sporadic inclusion body myositis (sIBM) with typical biopsy findings and clinically predominant affection of the finger flexors. Spinal and bulbar muscular atrophy (SBMA), in which androgen receptor (AR-)gene testing and clinical signs of androgen insensitivity will help to differentiate the disease from ALS. Hirayama disease shows cold paresis; a cervical MRI scan and a normal neurography will help to confirm the diagnosis. In benign fasciculation syndrome, there is no muscle paresis or atrophy, and acute denervation cannot be detected in the EMG. In spinal muscular atrophy (SMA), testing for the SMN gene will help to differentiate the condition from ALS; furthermore, SMA is a very rare disease in adults. As a differential diagnosis for ALS with both clinical affection of the upper and lower motor neuron e. g. metabolic diseases such as adrenoleukodystrophy, metachromatic leukodystrophy and Tay-Sachs disease should be taken into account. Here, laboratory tests are the most important steps for a correct diagnosis. Cervical myelopathy is also capable of affecting the upper and lower motor neuron, but can easily be differentiated by a cervical MRI scan. As a differential diagnosis of ALS with predominant affection of the upper motor neuron, we discuss hereditary spastic paraparesis (HSP) which presents with a symmetric spasticity of the legs. The MRI often shows atrophy of the spinal cord, and SPG gene testing is done to differentiate HSP from ALS.

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Huang, Zifeng, Wenwen Si, Xinrong Li, Shanyu Ye, Xuelei Liu, Yichun Ji, Xiaoqian Hao, Dongfeng Chen, and Meiling Zhu. "Moxibustion Protects Dopaminergic Neurons in Parkinson’s Disease through Antiferroptosis." Evidence-Based Complementary and Alternative Medicine 2021 (April 16, 2021): 1–11. http://dx.doi.org/10.1155/2021/6668249.

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Ferroptosis is associated with neural degeneration of dopaminergic neurons in Parkinson’s disease (PD). However, how to control the level of ferroptosis in PD remains unclear. Clinically, moxibustion has been used to treat PD and has an apparent therapeutic effect on improving the motor symptoms of PD. In the present study, the PD rat model was constructed by two-point stereotactic 6-hydroxydopamine injection. Then, moxibustion was used to treat the PD rats. The expression of glutathione peroxidase 4 (GPX4) and Ferritin Heavy Chain 1 (FTH1), the level of reactive oxygen species (ROS), and the morphology of mitochondrial were detected to evaluate the level of ferroptosis. The results showed that moxibustion treatment of Shi’s moxa sticks could reduce the behavioral score, alleviate the level of ferroptosis, decrease mitochondrial damage, and improve dopaminergic neuron survival. In conclusion, the present study results indicated that Shi’s moxa sticks could effectively suppress the level of ferroptosis, thereby improving the survival of dopaminergic neurons in the SNpc of PD rats, which may provide a promising complementary and alternative therapy for PD patients.

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Ravi, Bhavya, Michelle Harran Chan-Cortés, and Charlotte J. Sumner. "Gene-Targeting Therapeutics for Neurological Disease: Lessons Learned from Spinal Muscular Atrophy." Annual Review of Medicine 72, no. 1 (January 27, 2021): 1–14. http://dx.doi.org/10.1146/annurev-med-070119-115459.

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The last few decades have seen an explosion in identification of genes that cause monogenetic neurological diseases, as well as advances in gene-targeting therapeutics. Neurological conditions that were once considered incurable are now increasingly tractable. At the forefront is the motor neuron disease spinal muscular atrophy (SMA), historically the leading inherited cause of infant mortality. In the last 5 years, three SMA treatments have been approved by the US Food and Drug Administration (FDA): intrathecally delivered splice-switching antisense oligonucleotide (nusinersen), systemically delivered AAV9-based gene replacement therapy (onasemnogene abeparvovec), and an orally bioavailable, small-molecule, splice-switching drug (risdiplam). Despite this remarkable progress, clinical outcomes in patients are variable. Therapeutic optimization will require improved understanding of drug pharmacokinetics and target engagement in neurons, potential toxicities, and long-term effects. We review current progress in SMA therapeutics, clinical trials, shortcomings of current treatments, and implications for the treatment of other neurogenetic diseases.

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Petri, Susanne, Sonja Körner, and Mahmoud Kiaei. "Nrf2/ARE Signaling Pathway: Key Mediator in Oxidative Stress and Potential Therapeutic Target in ALS." Neurology Research International 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/878030.

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Nrf2 (nuclear erythroid 2-related factor 2) is a basic region leucine-zipper transcription factor which binds to the antioxidant response element (ARE) and thereby regulates the expression of a large battery of genes involved in the cellular antioxidant and anti-inflammatory defence as well as mitochondrial protection. As oxidative stress, inflammation and mitochondrial dysfunctions have been identified as important pathomechanisms in amyotrophic lateral sclerosis (ALS), this signaling cascade has gained interest both with respect to ALS pathogenesis and therapy. Nrf2 and Keap1 expressions are reduced in motor neurons in postmortem ALS tissue. Nrf2-activating compounds have shown therapeutic efficacy in the ALS mouse model and other neurodegenerative disease models. Alterations in Nrf2 and Keap1 expression and dysregulation of the Nrf2/ARE signalling program could contribute to the chronic motor neuron degeneration in ALS and other neurodegenerative diseases. Therefore, Nrf2 emerges as a key neuroprotective molecule in neurodegenerative diseases. Our recent studies strongly support that the Nrf2/ARE signalling pathway is an important mediator of neuroprotection and therefore represents a promising target for development of novel therapies against ALS, Parkinson’s disease (PD), Huntington’s disease (HD), and Alzheimer’s disease (AD).

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Morris, Meg E., Alison Perry, Belinda Bilney, Andrea Curran, Karen Dodd, Joanne E. Wittwer, and Gregory W. Dalton. "Outcomes of Physical Therapy, Speech Pathology, and Occupational Therapy for People with Motor Neuron Disease: A Systematic Review." Neurorehabilitation and Neural Repair 20, no. 3 (September 2006): 424–34. http://dx.doi.org/10.1177/1545968305285092.

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This article describes a systematic review and critical evaluation of the international literature on the effects of physical therapy, speech pathology, and occupational therapy for people with motor neuron disease (PwMND). The results were interpreted using the framework of the International Classification of Functioning, Disability and Health. This enabled us to summarize therapy outcomes at the level of body structure and function, activity limitations, participation restrictions, and quality of life. Databases searched included MEDLINE, PUBMED, CINAHL, PSYCInfo, Data base of Abstracts of Reviews of Effectiveness (DARE), The Physiotherapy Evidence data base (PEDro), Evidence Based Medicine Reviews (EMBASE), the Cochrane database of systematic reviews, and the Cochrane Controlled Trials Register. Evidence was graded according to the Harbour and Miller classification. Most of the evidence was found to be at the level of “clinical opinion” rather than of controlled clinical trials. Several nonrandomized small group and “observational studies” provided low-level evidence to support physical therapy for improving muscle strength and pulmonary function. There was also some evidence to support the effectiveness of speech pathology interventions for dysarthria. The search identified a small number of studies on occupational therapy for PwMND, which were small, noncontrolled pre-post-designs or clinical reports.

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Wang, Mengmeng, King-Hwa Ling, Jun Tan, and Cheng-Biao Lu. "Development and Differentiation of Midbrain Dopaminergic Neuron: From Bench to Bedside." Cells 9, no. 6 (June 18, 2020): 1489. http://dx.doi.org/10.3390/cells9061489.

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Parkinson’s Disease (PD) is a neurodegenerative disorder affecting the motor system. It is primarily due to substantial loss of midbrain dopamine (mDA) neurons in the substantia nigra pars compacta and to decreased innervation to the striatum. Although existing drug therapy available can relieve the symptoms in early-stage PD patients, it cannot reverse the pathogenic progression of PD. Thus, regenerating functional mDA neurons in PD patients may be a cure to the disease. The proof-of-principle clinical trials showed that human fetal graft-derived mDA neurons could restore the release of dopamine neurotransmitters, could reinnervate the striatum, and could alleviate clinical symptoms in PD patients. The invention of human-induced pluripotent stem cells (hiPSCs), autologous source of neural progenitors with less ethical consideration, and risk of graft rejection can now be generated in vitro. This advancement also prompts extensive research to decipher important developmental signaling in differentiation, which is key to successful in vitro production of functional mDA neurons and the enabler of mass manufacturing of the cells required for clinical applications. In this review, we summarize the biology and signaling involved in the development of mDA neurons and the current progress and methodology in driving efficient mDA neuron differentiation from pluripotent stem cells.

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Liss, Birgit, and Jörg Striessnig. "The Potential of L-Type Calcium Channels as a Drug Target for Neuroprotective Therapy in Parkinson's Disease." Annual Review of Pharmacology and Toxicology 59, no. 1 (January 6, 2019): 263–89. http://dx.doi.org/10.1146/annurev-pharmtox-010818-021214.

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The motor symptoms of Parkinson's disease (PD) mainly arise from degeneration of dopamine neurons within the substantia nigra. As no disease-modifying PD therapies are available, and side effects limit long-term benefits of current symptomatic therapies, novel treatment approaches are needed. The ongoing phase III clinical study STEADY-PD is investigating the potential of the dihydropyridine isradipine, an L-type Ca2+channel (LTCC) blocker, for neuroprotective PD therapy. Here we review the clinical and preclinical rationale for this trial and discuss potential reasons for the ambiguous outcomes of in vivo animal model studies that address PD-protective dihydropyridine effects. We summarize current views about the roles of Cav1.2 and Cav1.3 LTCC isoforms for substantia nigra neuron function, and their high vulnerability to degenerative stressors, and for PD pathophysiology. We discuss different dihydropyridine sensitivities of LTCC isoforms in view of their potential as drug targets for PD neuroprotection, and we conclude by considering how these aspects could guide further drug development.

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Turner, Martin R., Richard J. Barohn, Philippe Corcia, John K. Fink, Matthew B. Harms, Matthew C. Kiernan, John Ravits, et al. "Primary lateral sclerosis: consensus diagnostic criteria." Journal of Neurology, Neurosurgery & Psychiatry 91, no. 4 (February 6, 2020): 373–77. http://dx.doi.org/10.1136/jnnp-2019-322541.

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Primary lateral sclerosis (PLS) is a neurodegenerative disorder of the adult motor system. Characterised by a slowly progressive upper motor neuron syndrome, the diagnosis is clinical, after exclusion of structural, neurodegenerative and metabolic mimics. Differentiation of PLS from upper motor neuron-predominant forms of amyotrophic lateral sclerosis remains a significant challenge in the early symptomatic phase of both disorders, with ongoing debate as to whether they form a clinical and histopathological continuum. Current diagnostic criteria for PLS may be a barrier to therapeutic development, requiring long delays between symptom onset and formal diagnosis. While new technologies sensitive to both upper and lower motor neuron involvement may ultimately resolve controversies in the diagnosis of PLS, we present updated consensus diagnostic criteria with the aim of reducing diagnostic delay, optimising therapeutic trial design and catalysing the development of disease-modifying therapy.

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Stavrovskaya, А. V., D. N. Voronkov, E. A. Artyomova, B. V. Belugin, М. М. Shmarov, N. G. Yamshchikova, А. S. Gushchina, А. S. Olshansky, B. S. Naroditskiy, and S. N. Illarioshkin. "Genetic model of motor neuron disease in B6SJL-Tg mice: new data on the dynamics of motor symptoms and immunohistochemical manifestations of the neurodegenerative process." Neuromuscular Diseases 10, no. 3 (December 6, 2020): 63–73. http://dx.doi.org/10.17650/2222-8721-2020-10-3-63-73.

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Introduction. Over the past several decades, the study of mutations associated with motor neuron disease has led to the development of a number of transgenic animal models of motor neuron disease. One of the causes of the familial form of this disorder is mutations in the gene encoding Cu/Zn superoxide dismutase 1. The B6SJL-Tg (SOD1*G93A) mouse strain expresses a mutant form of human superoxide dismutase 1. Aim of study. To assess motor functions, dynamics of survival, and morphological changes in the spinal cord of transgenic B6SJL-Tg (SOD1*G93A) mice. Material and methods. In total, 31 animals have been studied. Starting from the age of 22 weeks, once every two weeks, the “open field” and “beam walking” motor tests were performed. The morphological changes in the spinal cord were evaluated at intermediate (26–35 weeks) and late stages (40–45 weeks). Neuronal proteins NeuN and PGP9.5, gliofibrillar protein, cyclonucleotide phosphatase (a marker of oligodendroglia) and a marker protein of microglia IBA1 were detected by immunohistochemistry; antibodies MTC02 to the outer membrane protein were used to detect mitochondria. Results. Motor problems appeared at the age of 24–26 weeks and steadily progressed; one could see consistent paresis of the hindlimbs, then the forelimbs, which was accompanied by general hypotrophy of the animals. There was a greater variability in the timing of symptom onset and life expectancy in males compared to females. The neurodegenerative process with damage to motor neurons was accompanied by the activation of micro- and astroglia. A sharp decrease in immunoreactivity to the mitochondrial marker MTC02 was found. Conclusion. The obtained results demonstrate new details of the development of a complex of motor and pathomorphological changes characteristic of motor neuron disease in B6SJL-Tg (SOD1*G93A) mice. Clarification of the fine dynamics of the neurodegenerative process in these animals is of great importance for monitoring the course of the disease during preclinical trials of new drugs and methods of gene therapy.

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Naveed, Aimen, and Hillary Calderon. "Onasemnogene Abeparvovec (AVXS-101) for the Treatment of Spinal Muscular Atrophy." Journal of Pediatric Pharmacology and Therapeutics 26, no. 5 (June 28, 2021): 437–44. http://dx.doi.org/10.5863/1551-6776-26.5.437.

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Spinal muscular atrophy (SMA) is a debilitating disorder characterized by degeneration of large motor neurons. It is a heterogeneous group of disorders caused by a homozygous deletion in the survival motor neuron (SMN) gene on chromosome 5, resulting in a SMN protein deficiency. Small amounts of SMN protein are also produced by the SMN2 gene, which that differs from SMN1 by a single nucleotide. Spinal muscular atrophy types and phenotypic severity depend on the number of variations of the SMN2 gene and the amount of SMN2 protein produced. Because the SMN protein deficiency is the root cause of the disease, treatment strategies for SMA revolve around increasing SMN protein production. Nusinersen (Spinraza, Biogen, Cambridge, MA) was the only treatment option available for SMA until the FDA approved onasemnogene abeparvovec-xioi (Zolgensma, AveXis Inc, Bannockburn, IL), a one-time–administered adeno-associated viral vector–based gene therapy that delivers the SMN gene to the motor neuron cells. Data from clinical studies show significant improvement in motor milestone achievements and ventilator-free survival but are limited by approximately 5 years' worth of results. This one-time intravenous injection of this new gene therapy also bears a hefty price tag; however, it may be more cost effective in the long run versus the multiple intrathecal administrations needed with nusinersen. Drug access and use are hindered by drug cost, payer reimbursement issues, and lack of long-term data from clinical studies. Questions also remain regarding the safety and efficacy of repeated drug administration for patients with advanced disease.

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Aoun, Samar M., Harvey M. Chochinov, and Linda J. Kristjanson. "Dignity Therapy for People with Motor Neuron Disease and Their Family Caregivers: A Feasibility Study." Journal of Palliative Medicine 18, no. 1 (January 2015): 31–37. http://dx.doi.org/10.1089/jpm.2014.0213.

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Lo, Yi-Ching, Yu-Tzu Shih, Yu-Ting Tseng, and Hung-Te Hsu. "Neuroprotective Effects of San-Huang-Xie-Xin-Tang in the MPP+/MPTP Models of Parkinson’s DiseaseIn VitroandIn Vivo." Evidence-Based Complementary and Alternative Medicine 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/501032.

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San-Huang-Xie-Xin-Tang (SHXT), composed ofCoptidis rhizoma, Scutellariae radix, andRhei rhizoma, is a traditional Chinese medicine used for complementary and alternative therapy of cardiovascular and neurodegenerative diseases via its anti-inflammatory and antioxidative effects. The aim of this study is to investigate the protective effects of SHXT in the 1–methyl–4–phenylpyridinium (MPP+)/1–methyl–4–phenyl–1,2,3,6–tetrahydropyridine (MPTP) models of Parkinson’s disease. Rat primary mesencephalic neurons and mouse Parkinson disease model were used in this study. Oxidative stress was induced by MPP+in vitroand MPTPin vivo. In MPP+-treated mesencephalic neuron cultures, SHXT significantly increased the numbers of TH-positive neurons. SHXT reduced apoptotic signals (cytochrome and caspase) and apoptotic death. MPP+-inducedgp91phoxactivation and ROS production were attenuated by SHXT. In addition, SHXT increased the levels of GSH and SOD in MPP+-treated neurons. In MPTP animal model, SHXT markedly increased TH-positive neurons in the substantia nigra pars compacta (SNpc) and improved motor activity of mice. In conclusion, the present results reveal the evidence that SHXT possesses beneficial protection against MPTP-induced neurotoxicity in this model of Parkinson’s disease via its antioxidative and antiapoptotic effects. SHXT might be a potentially alternative and complementary medicine for neuroprotection.

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Messina, Sonia, and Maria Sframeli. "New Treatments in Spinal Muscular Atrophy: Positive Results and New Challenges." Journal of Clinical Medicine 9, no. 7 (July 13, 2020): 2222. http://dx.doi.org/10.3390/jcm9072222.

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Spinal muscular atrophy (SMA) is one of the most common autosomal recessive diseases with progressive weakness of skeletal and respiratory muscles, leading to significant disability. The disorder is caused by mutations in the survival motor neuron 1 (SMN1) gene and a consequent decrease in the SMN protein leading to lower motor neuron degeneration. Recently, Food and Drug Administration (FDA) and European Medical Agency (EMA) approved the antisense oligonucleotide nusinersen, the first SMA disease-modifying treatment and gene replacement therapy by onasemnogene abeparvovec. Encouraging results from phase II and III clinical trials have raised hope that other therapeutic options will enter soon in clinical practice. However, the availability of effective approaches has raised up ethical, medical and financial issues that are routinely faced by the SMA community. This review covers the available data and the new challenges of SMA therapeutic strategies.

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Tang, Bor Luen. "The use of mesenchymal stem cells (MSCs) for amyotrophic lateral sclerosis (ALS) therapy – a perspective on cell biological mechanisms." Reviews in the Neurosciences 28, no. 7 (October 26, 2017): 725–38. http://dx.doi.org/10.1515/revneuro-2017-0018.

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AbstractRecent clinical trials of mesenchymal stem cells (MSCs) transplantation have demonstrated procedural safety and clinical proof of principle with a modest indication of benefit in patients with amyotrophic lateral sclerosis (ALS). While replacement therapy remained unrealistic, the clinical efficacy of this therapeutic option could be potentially enhanced if we could better decipher the mechanisms underlying some of the beneficial effects of transplanted cells, and work toward augmenting or combining these in a strategic manner. Novel ways whereby MSCs could act in modifying disease progression should also be explored. In this review, I discuss the known, emerging and postulated mechanisms of action underlying effects that transplanted MSCs may exert to promote motor neuron survival and/or to encourage regeneration in ALS. I shall also speculate on how transplanted cells may alter the diseased environment so as to minimize non-neuron cell autonomous damages by immune cells and astrocytes.

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Gagliardi, Delia, Megi Meneri, Domenica Saccomanno, Nereo Bresolin, Giacomo Pietro Comi, and Stefania Corti. "Diagnostic and Prognostic Role of Blood and Cerebrospinal Fluid and Blood Neurofilaments in Amyotrophic Lateral Sclerosis: A Review of the Literature." International Journal of Molecular Sciences 20, no. 17 (August 25, 2019): 4152. http://dx.doi.org/10.3390/ijms20174152.

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting upper and lower motor neurons (MNs) that still lacks an efficacious therapy. The failure of recent therapeutic trials in ALS, other than depending on the poor knowledge of pathogenic mechanisms responsible for MNs loss, is largely due to diagnostic delay and the lack of reliable biomarkers for diagnosis, prognosis and response to pharmacologic intervention. Neurofilaments (Nfs) are neuron-specific cytoskeletal proteins, whose levels increased in biological fluids proportionally to the degree of axonal damage, both in normal and in pathologic conditions, representing potential biomarkers in various neurological disorders, such as motor neuron disorder (MND). Growing evidence has shown that phosphorylated neurofilaments heavy chain (p-NfH) and neurofilaments light chain (NfL) are increased in blood and cerebrospinal fluid (CSF) of ALS patients compared to healthy and neurological controls and are found to correlate with disease progression. In this review, we reported the most relevant studies investigating the diagnostic and prognostic role of Nfs in ALS. Given their reliability and reproducibility, we consider Nfs as promising and useful biomarkers in diagnosis of MND, early patient identification for inclusion in clinical trials, prediction of disease progression, and response to pharmacological intervention, and we suggest the validation of their measurement in clinical activity.

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Farrar, Michelle, Kathryn J. Swoboda, Meredith Schultz, Hugh McMillan, Julie Parsons, Ian E. Alexander, Elaine Kernbauer, et al. "014 AVXS-101 gene-replacement therapy (GRT) in presymptomatic spinal muscular atrophy (SMA): study update." Journal of Neurology, Neurosurgery & Psychiatry 90, e7 (July 2019): A5.3—A6. http://dx.doi.org/10.1136/jnnp-2019-anzan.14.

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IntroductionSMA is a neurodegenerative disease caused by biallelic deletion/mutation of the survival motor neuron 1 gene (SMN1). Copies of a similar gene (SMN2) modify disease severity. In a phase 1 study, SMN GRT onasemnogene abeparvovec (AVXS-101) improved outcomes of symptomatic SMA patients with two SMN2 copies (2xSMN2) dosed ≤6 months. Because motor neuron loss can be insidious and disease progression is rapid, early intervention is critical. This study evaluates AVXS-101 in presymptomatic SMA newborns.MethodsSPR1NT is a multicenter, open-label, phase 3 study (NCT03505099) enrolling ≥27 SMA patients with 2–3xSMN2. Asymptomatic infants ≤6 weeks receive a one-time intravenous AVXS-101 infusion (1.1×1014 vg/kg). Safety and efficacy are assessed through study end (18 [2xSMN2] or 24 months [3xSMN2]). Primary outcomes: independent sitting for ≥30 seconds (18 months [2xSMN2]) or assisted standing (24 months [3xSMN2]).ResultsFrom April–September 2018, 7 infants received AVXS-101 (4 female; 6 with 2xSMN2) at ages 8–37 days. Mean baseline Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score was 41.7 (n=6), which increased by 6.8, 11.0, 18.0, and 22.5 points at day 14 (n=4), month 1 (n=3), 2 (n=3), and 3 (n=2). As of January 31, 2019, 15 asymptomatic infants have been enrolled in SPR1NT and dosed with AVXS-101. Updated data available at the time of the congress will be presented.ConclusionsPreliminary data from SPR1NT show rapid motor function improvements in presymptomatic SMA patients.

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Rui, Wenjuan, Sheng Li, Hong Xiao, Ming Xiao, and Jingping Shi. "Baicalein Attenuates Neuroinflammation by Inhibiting NLRP3/Caspase-1/GSDMD Pathway in MPTP-Induced Mice Model of Parkinson’s Disease." International Journal of Neuropsychopharmacology 23, no. 11 (August 6, 2020): 762–73. http://dx.doi.org/10.1093/ijnp/pyaa060.

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Abstract Background Inflammasome-induced neuroinflammation is a major pathogenic mechanism underlying the degeneration of nigral dopaminergic neurons in Parkinson’s disease (PD). Baicalein is a flavonoid isolated from the traditional Chinese medicinal herbal Scutellaria baicalensis Georgi with known anti-inflammatory and neuroprotective efficacy in models of neurodegenerative diseases, including PD. However, its effects on inflammasome-induced neuroinflammation during PD remain unclear. Methods We used N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD-like pathology in mice. Behavioral assessments including the pole test, rotarod test, and open field test were conducted to evaluate the effects of baicalein on MPTP-induced motor dysfunction. The efficacies of baicalein against MPTP-induced dopaminergic neuron loss and glial cell activation in the substantia nigra compact were examined by immunohistochemistry, effects on proinflammatory cytokines by quantitative real-time PCR and enzyme-linked immunosorbent assay, and effects on inflammasome pathway activation by immunoblotting and flow cytometry. Results Administration of baicalein reversed MPTP-induced motor dysfunction, loss of dopaminergic neurons, and pro-inflammatory cytokine elevation. Baicalein also inhibited NLRP3 and caspase-1 activation and suppressed gasdermin D-dependent pyroptosis. Additionally, baicalein inhibited the activation and proliferation of disease-associated proinflammatory microglia. Conclusions These findings suggest that baicalein can reverse MPTP-induced neuroinflammation in mice by suppressing NLRP3/caspase-1/gasdermin D pathway. Our study provides potential insight into the use of baicalein in PD therapy.

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Calza, L., R. Manfredi, E. Freo, B. Farneti, L. Tampellini, G. d'orsi, and F. Chiodo. "Transient Reversal of HIV-Associated Motor Neuron Disease Following the Introduction of Highly Active Antiretroviral Therapy." Journal of Chemotherapy 16, no. 1 (February 2004): 98–101. http://dx.doi.org/10.1179/joc.2004.16.1.98.

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Deguise, Marc-Olivier, Lucia Chehade, and Rashmi Kothary. "Metabolic Dysfunction in Spinal Muscular Atrophy." International Journal of Molecular Sciences 22, no. 11 (May 31, 2021): 5913. http://dx.doi.org/10.3390/ijms22115913.

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Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder leading to paralysis, muscle atrophy, and death. Significant advances in antisense oligonucleotide treatment and gene therapy have made it possible for SMA patients to benefit from improvements in many aspects of the once devastating natural history of the disease. How the depletion of survival motor neuron (SMN) protein, the product of the gene implicated in the disease, leads to the consequent pathogenic changes remains unresolved. Over the past few years, evidence toward a potential contribution of gastrointestinal, metabolic, and endocrine defects to disease phenotype has surfaced. These findings ranged from disrupted body composition, gastrointestinal tract, fatty acid, glucose, amino acid, and hormonal regulation. Together, these changes could have a meaningful clinical impact on disease traits. However, it is currently unclear whether these findings are secondary to widespread denervation or unique to the SMA phenotype. This review provides an in-depth account of metabolism-related research available to date, with a discussion of unique features compared to other motor neuron and related disorders.

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Journal articles on the topic 'Motoer Neuron Disease – Therapy'

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