scholarly journals CSF Diagnostics: A Potentially Valuable Tool in Neurodegenerative and Inflammatory Disorders Involving Motor Neurons: A Review

Diagnostics ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1522
Author(s):  
Karsten Krause ◽  
Maximilian Wulf ◽  
Paula Sommer ◽  
Katalin Barkovits ◽  
Matthias Vorgerd ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Muscular Atrophy ◽  
Neurological Diseases ◽  
Neuromuscular Disorders ◽  
Disease Onset ◽  
Neuromuscular Diseases ◽  
Promising Alternative ◽  
Alternative Techniques ◽  
Subordinate Role ◽  
Lateral Sclerosis

Cerebrospinal fluid (CSF) diagnostics has emerged as a valid tool for a variety of neurological diseases. However, CSF diagnostics has been playing a subordinate role in the diagnosis of many neurological conditions. Thus, in the multitude of neuromuscular diseases in which motor neurons are affected, a CSF sample is rarely taken routinely. However, CSF diagnostics has the potential to specify the diagnosis and monitor the treatment of neuromuscular disorders. In this review, we therefore focused on a variety of neuromuscular diseases, among them amyotrophic lateral sclerosis (ALS), peripheral neuropathies, and spinal muscular atrophy (SMA), for which CSF diagnostics has emerged as a promising option for determining the disease itself and its progression. We focus on potentially valuable biomarkers among different disorders, such as neurofilaments, cytokines, other proteins, and lipids to determine their suitability, differentiating between different neurological disorders and their potential to determine early disease onset, disease progression, and treatment outcome. We further recommend novel approaches, e.g., the use of mass spectrometry as a promising alternative techniques to standard ELISA assays, potentially enhancing biomarker significance in clinical applications.

scholarly journals Genetic approaches to the treatment of inherited neuromuscular diseases

2019 ◽  
Vol 28 (R1) ◽  
pp. R55-R64 ◽  
Author(s):  
Bhavya Ravi ◽  
Anthony Antonellis ◽  
Charlotte J Sumner ◽  
Andrew P Lieberman
Keyword(s):  
Motor Neurons ◽  
Viral Vectors ◽  
Age Of Onset ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Neuromuscular Diseases ◽  
Clinical Severity ◽  
Charcot Marie Tooth Disease ◽  
Degenerative Disorders ◽  
Clinical Benefits

Abstract Inherited neuromuscular diseases are a heterogeneous group of developmental and degenerative disorders that affect motor unit function. Major challenges toward developing therapies for these diseases include heterogeneity with respect to clinical severity, age of onset and the primary cell type that is affected (e.g. motor neurons, skeletal muscle and Schwann cells). Here, we review recent progress toward the establishment of genetic therapies to treat inherited neuromuscular disorders that affect both children and adults with a focus on spinal muscular atrophy, Charcot–Marie–Tooth disease and spinal and bulbar muscular atrophy. We discuss clinical features, causative mutations and emerging approaches that are undergoing testing in preclinical models and in patients or that have received recent approval for clinical use. Many of these efforts employ antisense oligonucleotides to alter pre-mRNA splicing or diminish target gene expression and use viral vectors to replace expression of mutant genes. Finally, we discuss remaining challenges for optimizing the delivery and effectiveness of these approaches. In sum, therapeutic strategies for neuromuscular diseases have shown encouraging results, raising hope that recent strides will translate into significant clinical benefits for patients with these disorders.

scholarly journals Lipidomics study of plasma from patients suggest that ALS and PLS are part of a continuum of motor neuron disorders

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Estela Area-Gomez ◽  
D. Larrea ◽  
T. Yun ◽  
Y. Xu ◽  
J. Hupf ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Cell Structure ◽  
Disease Onset ◽  
Point Of View ◽  
Motor Dysfunction ◽  
Cellular Processes ◽  
Progressive Muscle Weakness ◽  
Human Pathology ◽  
Lateral Sclerosis

AbstractMotor neuron disorders (MND) include a group of pathologies that affect upper and/or lower motor neurons. Among them, amyotrophic lateral sclerosis (ALS) is characterized by progressive muscle weakness, with fatal outcomes only in a few years after diagnosis. On the other hand, primary lateral sclerosis (PLS), a more benign form of MND that only affects upper motor neurons, results in life-long progressive motor dysfunction. Although the outcomes are quite different, ALS and PLS present with similar symptoms at disease onset, to the degree that both disorders could be considered part of a continuum. These similarities and the lack of reliable biomarkers often result in delays in accurate diagnosis and/or treatment. In the nervous system, lipids exert a wide variety of functions, including roles in cell structure, synaptic transmission, and multiple metabolic processes. Thus, the study of the absolute and relative concentrations of a subset of lipids in human pathology can shed light into these cellular processes and unravel alterations in one or more pathways. In here, we report the lipid composition of longitudinal plasma samples from ALS and PLS patients initially, and after 2 years following enrollment in a clinical study. Our analysis revealed common aspects of these pathologies suggesting that, from the lipidomics point of view, PLS and ALS behave as part of a continuum of motor neuron disorders.

scholarly journals Poor Corticospinal Motor Neuron Health Is Associated with Increased Symptom Severity in the Acute Phase Following Repetitive Mild TBI and Predicts Early ALS Onset in Genetically Predisposed Rodents

2021 ◽  
Vol 11 (2) ◽  
pp. 160
Author(s):  
Mor R. Alkaslasi ◽  
Noell E. Cho ◽  
Navpreet K. Dhillon ◽  
Oksana Shelest ◽  
Patricia S. Haro-Lopez ◽  
...  
Keyword(s):  
Risk Factor ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Disease Onset ◽  
Poor Health ◽  
Disease Symptoms ◽  
Established Risk Factor ◽  
Early Injury ◽  
Corticospinal Motor Neurons ◽  
Lateral Sclerosis

Traumatic brain injury (TBI) is a well-established risk factor for several neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease, however, a link between TBI and amyotrophic lateral sclerosis (ALS) has not been clearly elucidated. Using the SOD1G93A rat model known to recapitulate the human ALS condition, we found that exposure to mild, repetitive TBI lead ALS rats to experience earlier disease onset and shortened survival relative to their sham counterparts. Importantly, increased severity of early injury symptoms prior to the onset of ALS disease symptoms was linked to poor health of corticospinal motor neurons and predicted worsened outcome later in life. Whereas ALS rats with only mild behavioral injury deficits exhibited no observable changes in corticospinal motor neuron health and did not present with early onset or shortened survival, those with more severe injury-related deficits exhibited alterations in corticospinal motor neuron health and presented with significantly earlier onset and shortened lifespan. While these studies do not imply that TBI causes ALS, we provide experimental evidence that head injury is a risk factor for earlier disease onset in a genetically predisposed ALS population and is associated with poor health of corticospinal motor neurons.

scholarly journals The Skeletal Muscle Emerges as a New Disease Target in Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 11 (7) ◽  
pp. 671
Author(s):  
Oihane Pikatza-Menoio ◽  
Amaia Elicegui ◽  
Xabier Bengoetxea ◽  
Neia Naldaiz-Gastesi ◽  
Adolfo López de Munain ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amyotrophic Lateral Sclerosis ◽  
Muscle Tissue ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
Fine Tuning ◽  
Current State ◽  
The Central Nervous System ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that leads to progressive degeneration of motor neurons (MNs) and severe muscle atrophy without effective treatment. Most research on ALS has been focused on the study of MNs and supporting cells of the central nervous system. Strikingly, the recent observations of pathological changes in muscle occurring before disease onset and independent from MN degeneration have bolstered the interest for the study of muscle tissue as a potential target for delivery of therapies for ALS. Skeletal muscle has just been described as a tissue with an important secretory function that is toxic to MNs in the context of ALS. Moreover, a fine-tuning balance between biosynthetic and atrophic pathways is necessary to induce myogenesis for muscle tissue repair. Compromising this response due to primary metabolic abnormalities in the muscle could trigger defective muscle regeneration and neuromuscular junction restoration, with deleterious consequences for MNs and thereby hastening the development of ALS. However, it remains puzzling how backward signaling from the muscle could impinge on MN death. This review provides a comprehensive analysis on the current state-of-the-art of the role of the skeletal muscle in ALS, highlighting its contribution to the neurodegeneration in ALS through backward-signaling processes as a newly uncovered mechanism for a peripheral etiopathogenesis of the disease.

scholarly journals Utility of Transcranial Magnetic Simulation in Studying Upper Motor Neuron Dysfunction in Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 11 (7) ◽  
pp. 906
Author(s):  
Nimeshan Geevasinga ◽  
Mehdi Van den Bos ◽  
Parvathi Menon ◽  
Steve Vucic
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Cortical Excitability ◽  
Muscular Atrophy ◽  
Close Relationship ◽  
Bulbar Onset ◽  
Als Patients ◽  
Transcranial Magnetic Simulation ◽  
Cortical Dysfunction ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is characterised by progressive dysfunction of the upper and lower motor neurons. The disease can evolve over time from focal limb or bulbar onset to involvement of other regions. There is some clinical heterogeneity in ALS with various phenotypes of the disease described, from primary lateral sclerosis, progressive muscular atrophy and flail arm/leg phenotypes. Whilst the majority of ALS patients are sporadic in nature, recent advances have highlighted genetic forms of the disease. Given the close relationship between ALS and frontotemporal dementia, the importance of cortical dysfunction has gained prominence. Transcranial magnetic stimulation (TMS) is a noninvasive neurophysiological tool to explore the function of the motor cortex and thereby cortical excitability. In this review, we highlight the utility of TMS and explore cortical excitability in ALS diagnosis, pathogenesis and insights gained from genetic and variant forms of the disease.

scholarly journals Cerebrospinal Fluid Chitinases as Biomarkers for Amyotrophic Lateral Sclerosis

Diagnostics ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1210
Author(s):  
Júlia Costa ◽  
Marta Gromicho ◽  
Ana Pronto-Laborinho ◽  
Conceição Almeida ◽  
Ricardo A. Gomes ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cerebrospinal Fluid ◽  
Motor Neurons ◽  
Neurological Diseases ◽  
Disease Diagnosis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Progression Rate ◽  
Therapeutic Trials ◽  
Als Patients ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative neuromuscular disease that affects motor neurons controlling voluntary muscles. Survival is usually 2–5 years after onset, and death occurs due to respiratory failure. The identification of biomarkers would be very useful to help in disease diagnosis and for patient stratification based on, e.g., progression rate, with implications in therapeutic trials. Neurofilaments constitute already-promising markers for ALS and, recently, chitinases have emerged as novel marker targets for the disease. Here, we investigated cerebrospinal fluid (CSF) chitinases as potential markers for ALS. Chitotriosidase (CHIT1), chitinase-3-like protein 1 (CHI3L1), chitinase-3-like protein 2 (CHI3L2) and the benchmark marker phosphoneurofilament heavy chain (pNFH) were quantified by an enzyme-linked immunosorbent assay (ELISA) from the CSF of 34 ALS patients and 24 control patients with other neurological diseases. CSF was also analyzed by UHPLC-mass spectrometry. All three chitinases, as well as pNFH, were found to correlate with disease progression rate. Furthermore, CHIT1 was elevated in ALS patients with high diagnostic performance, as was pNFH. On the other hand, CHIT1 correlated with forced vital capacity (FVC). The three chitinases correlated with pNFH, indicating a relation between degeneration and neuroinflammation. In conclusion, our results supported the value of CHIT1 as a diagnostic and progression rate biomarker, and its potential as respiratory function marker. The results opened novel perspectives to explore chitinases as biomarkers and their functional relevance in ALS.

scholarly journals The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration

2020 ◽  
Author(s):  
Paymaan Jafar-nejad ◽  
Berit Powers ◽  
Armand Soriano ◽  
Hien Zhao ◽  
Daniel A Norris ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Muscular Atrophy ◽  
Neurological Diseases ◽  
Cell Types ◽  
Rnase H ◽  
Central Administration ◽  
Spinal Motor Neurons ◽  
New Class ◽  
Wide Range ◽  
Therapeutic Development

Abstract Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing efforts to develop ASOs for other neurological diseases. While SMA specifically affects spinal motor neurons, other neurological diseases affect different central nervous system (CNS) regions, neuronal and non-neuronal cells. Therefore, it is important to characterize ASO distribution and activity in all major CNS structures and cell types to have a better understanding of which neurological diseases are amenable to ASO therapy. Here we present for the first time the atlas of ASO distribution and activity in the CNS of mice, rats, and non-human primates (NHP), species commonly used in preclinical therapeutic development. Following central administration of an ASO to rodents, we observe widespread distribution and target RNA reduction throughout the CNS in neurons, oligodendrocytes, astrocytes and microglia. This is also the case in NHP, despite a larger CNS volume and more complex neuroarchitecture. Our results demonstrate that ASO drugs are well suited for treating a wide range of neurological diseases for which no effective treatments are available.

scholarly journals LanCL1 promotes motor neuron survival and extends the lifespan of amyotrophic lateral sclerosis mice

2019 ◽  
Vol 27 (4) ◽  
pp. 1369-1382 ◽  
Author(s):  
Honglin Tan ◽  
Mina Chen ◽  
Dejiang Pang ◽  
Xiaoqiang Xia ◽  
Chongyangzi Du ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Neuronal Survival ◽  
Disease Onset ◽  
Alternative Mechanism ◽  
Specific Expression ◽  
Motor Neuron Survival ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Improving neuronal survival in ALS remains a significant challenge. Previously, we identified Lanthionine synthetase C-like protein 1 (LanCL1) as a neuronal antioxidant defense gene, the genetic deletion of which causes apoptotic neurodegeneration in the brain. Here, we report in vivo data using the transgenic SOD1G93A mouse model of ALS indicating that CNS-specific expression of LanCL1 transgene extends lifespan, delays disease onset, decelerates symptomatic progression, and improves motor performance of SOD1G93A mice. Conversely, CNS-specific deletion of LanCL1 leads to neurodegenerative phenotypes, including motor neuron loss, neuroinflammation, and oxidative damage. Analysis reveals that LanCL1 is a positive regulator of AKT activity, and LanCL1 overexpression restores the impaired AKT activity in ALS model mice. These findings indicate that LanCL1 regulates neuronal survival through an alternative mechanism, and suggest a new therapeutic target in ALS.

scholarly journals Motor Unit Number Estimation in Neuromuscular Disease

2008 ◽  
Vol 35 (2) ◽  
pp. 153-159 ◽  
Author(s):  
Omid Rashidipour ◽  
K. Ming Chan
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Unit ◽  
Neuromuscular Disease ◽  
Muscular Atrophy ◽  
Neuromuscular Diseases ◽  
Neuronal Loss ◽  
Response To Treatment ◽  
Motor Unit Number Estimation ◽  
Electrophysiological Method ◽  
Lateral Sclerosis

Motor unit number estimation (MUNE) is an electrophysiological method designed to quantify motor unit loss in target muscles of interest. Most of the techniques are noninvasive and are therefore well suited for longitudinal monitoring. In this brief review, we describe the more commonly used techniques and their applications in amyotrophic lateral sclerosis, poliomyelitis, spinal muscular atrophy and hereditary sensorimotor neuropathies. Findings in some of these studies offer important pathophysiological insights. Since conventional electrophysiologic methods are not sensible measures of motor neuronal loss, MUNE could play a potentially important role in the diagnosis, monitoring of disease progression and response to treatment in neuromuscular diseases in which motor unit loss is a major feature.

scholarly journals Pulmonary function in patients with Amyotrophic Lateral Sclerosis at disease onset

2015 ◽  
Vol 77 (3-4) ◽  
Author(s):  
B. Chandrasoma ◽  
D. Balfe ◽  
T. Naik ◽  
A. Elsayegh ◽  
M. Lewis ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Pulmonary Function ◽  
Muscle Weakness ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Pulmonary Function Tests ◽  
Disease Onset ◽  
Group Versus ◽  
Combination Methods ◽  
Lateral Sclerosis

Background. Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder affecting both the upper and lower motor neurons. Deteriorating pulmonary function as a reflection of progressive respiratory muscle weakness is a common feature, accounting for the majority of deaths. The aim of the study was to describe a trend in initial pulmonary function tests (PFT) of Amyotrophic Lateral Sclerosis (ALS) patients, in addition, differentiating between the types of disease onset, bulbar, limb muscle, and a combination. Methods. Initial PFT were gathered from 32 consecutive patients in our clinic with the diagnosis of ALS, they were categorized by the type of disease onset. Values obtained were referenced to the 95% confidence limits for normality. Results. There was evidence of significant reductions in both the FEV1 (64.7% predicted) and FVC (61.2%), with preservation of the FEV1/FVC (81.7%). The MVV was significantly reduced(43%). Total lung capacity was 93.2%, the residual volumes was increased at 145.7%. Subgroup analysis failed to show significant differences between types of disease onset. In the bulbar onset group (versus the limb group) there was a trend for the MVV to be further reduced (p=0.15) and the RV to be higher (157.4% versus 135.9%, P=0.24). Conclusions. ALS is a devastating disease that invariably leads to respiratory failure. Abnormal spirometric variables such as the FVC and MVV, likely reflect inspiratory muscle weakness and increased RV likely reflect expiratory muscle weakness. The type of disease onset did not result in a different pattern of PFT abnormalities.

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