- Erratum to: Regulation of Caveolin-1 and Junction Proteins by bFGF Contributes to the Integrity of Blood-Spinal Cord Barrier and Functional Recovery. [Published Erratum]
- NNeurotherapeutics 2016 Dec 01
- Magnetic Resonance Imaging-Guided Laser Interstitial Thermal Therapy for Treatment of Drug-Resistant Epilepsy. [Journal Article]
- NNeurotherapeutics 2016 Nov 30
- Surgery is the most effective treatment for drug-resistant epilepsy. Long-term studies demonstrate that about 60% to 80% of patients become seizure-free after anterior temporal lobectomy and a majori...
Surgery is the most effective treatment for drug-resistant epilepsy. Long-term studies demonstrate that about 60% to 80% of patients become seizure-free after anterior temporal lobectomy and a majority of patients (about 95%) report significant seizure reduction after surgery. In the last few years, there has been significant advances in minimally invasive surgical techniques to treat drug-resistant epilepsy. These minimally invasive procedures have significant advantages over open surgery in that they produce less immediate discomfort and disability, while allowing for greater preservation of functional tissue. Laser interstitial thermal therapy (LiTT) is an example of such a procedure. Recent advances in imaging, surgical navigation, and real-time thermal monitoring have made LiTT safer and easier to implement, offering an effective and powerful neurosurgical tool for drug-resistant epilepsy. This article will review the technical considerations, uses, and potential future directions for LiTT in drug-resistant epilepsy.
- Axonal Excitability in Amyotrophic Lateral Sclerosis : Axonal Excitability in ALS. [Review]
- NNeurotherapeutics 2016 Nov 22
- Axonal excitability testing provides in vivo assessment of axonal ion channel function and membrane potential. Excitability techniques have provided insights into the pathophysiological mechanisms un...
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 Ca(2+)-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.
- Tau Imaging in Alzheimer's Disease Diagnosis and Clinical Trials. [Review]
- NNeurotherapeutics 2016 Nov 21
- In vivo imaging of the tau protein has the potential to aid in quantitative diagnosis of Alzheimer's disease, corroborate or dispute the amyloid hypothesis, and demonstrate biomarker engagement in cl...
In vivo imaging of the tau protein has the potential to aid in quantitative diagnosis of Alzheimer's disease, corroborate or dispute the amyloid hypothesis, and demonstrate biomarker engagement in clinical drug trials. A host of tau positron emission tomography agents have been designed, validated, and tested in humans. Several agents have characteristics approaching the ideal imaging tracer with some limitations, primarily regarding off-target binding. Dozens of clinical trials evaluating imaging techniques and several pharmaceutical trials have begun to integrate tau imaging into their protocols.
- Transcranial Magnetic Stimulation for the Assessment of Neurodegenerative Disease. [Review]
- NNeurotherapeutics 2016 Nov 09
- Transcranial magnetic stimulation (TMS) is a noninvasive technique that has provided important information about cortical function across an array of neurodegenerative disorders, including Alzheimer'...
Transcranial magnetic stimulation (TMS) is a noninvasive technique that has provided important information about cortical function across an array of neurodegenerative disorders, including Alzheimer's disease, frontotemporal dementia, Parkinson's disease, and related extrapyramidal disorders. Application of TMS techniques in neurodegenerative diseases has provided important pathophysiological insights, leading to the development of pathogenic and diagnostic biomarkers that could be used in the clinical setting and therapeutic trials. Abnormalities of TMS outcome measures heralding cortical hyperexcitability, as evidenced by a reduction of short-interval intracortical inhibition and increased in motor-evoked potential amplitude, have been consistently identified as early and intrinsic features of amyotrophic lateral sclerosis (ALS), preceding and correlating with the ensuing neurodegeneration. Cortical hyperexcitability appears to form the pathogenic basis of ALS, mediated by trans-synaptic glutamate-mediated excitotoxic mechanisms. As a consequence of these research findings, TMS has been developed as a potential diagnostic biomarker, capable of identifying upper motor neuronal pathology, at earlier stages of the disease process, and thereby aiding in ALS diagnosis. Of further relevance, marked TMS abnormalities have been reported in other neurodegenerative diseases, which have varied from findings in ALS. With time and greater utilization by clinicians, TMS outcome measures may prove to be of utility in future therapeutic trial settings across the neurodegenerative disease spectrum, including the monitoring of neuroprotective, stem-cell, and genetic-based strategies, thereby enabling assessment of biological effectiveness at early stages of drug development.
- Electrical Impedance Myography and Its Applications in Neuromuscular Disorders. [Review]
- NNeurotherapeutics 2016 Nov 03
- Electrical impedance myography (EIM) refers to the specific application of electrical bioimpedance techniques for the assessment of neuromuscular disorders. In EIM, a weak, high-frequency electrical ...
Electrical impedance myography (EIM) refers to the specific application of electrical bioimpedance techniques for the assessment of neuromuscular disorders. In EIM, a weak, high-frequency electrical current is applied to a muscle or muscle group of interest and the resulting voltages measured. Among its advantages, the technique can be used noninvasively across a variety of disorders and requires limited subject cooperation and evaluator training to obtain accurate and repeatable data. Studies in both animals and human subjects support its potential utility as a primary diagnostic tool, as well as a biomarker for clinical trial or individual patient use. This review begins by providing an overview of the current state and technological advances in electrical impedance myography and its specific application to the study of muscle. We then provide a summary of the clinical and preclinical applications of EIM for neuromuscular conditions, and conclude with an evaluation of ongoing research efforts and future developments.
- The Spectrum of Functional Rating Scales in Neurology Clinical Trials. [Review]
- NNeurotherapeutics 2016 Oct 27
- The selection of an appropriate outcome measure is crucial to the success of a clinical trial, in order to obtain accurate results, which, in turn, influence patient care and future research. Outcome...
The selection of an appropriate outcome measure is crucial to the success of a clinical trial, in order to obtain accurate results, which, in turn, influence patient care and future research. Outcomes that can be directly measured are mortality/survival. More frequently, neurology clinical trials evaluate outcomes that cannot be directly measured, such as disability, cognitive function, or change in symptoms of the condition under study. These complex outcomes are abstract ideas or latent constructs and are measured using rating scales. Functional rating scales typically assess the ability of patients to perform tasks and roles for everyday life. Rating scales should be valid (measure what they are supposed to measure), reliable (provide similar results if administered under the same conditions), and responsive (able to detect clinically important changes over time). The clinical relevance of rating scales depends on their ability to detect a minimal clinically important difference, and should be distinguished from statistical significance. Most rating scales are ordinal scales and have limitations. Modern psychometric methods of Rasch analysis and item response theory, termed latent trait theory, are increasingly being utilized to convert ordinal data to interval measurements, both to validate existing scales and to develop new scales. Patient-reported outcomes are being increasingly used in clinical trials and have a role in clinical quality assessment. The PROMIS and NeuroQoL databases are excellent resources for rigorously developed and validated patient-reported outcomes.
- EGAR, A Food Protein-Derived Tetrapeptide, Reduces Seizure Activity in Pentylenetetrazole-Induced Epilepsy Models Through α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionate Receptors. [Journal Article]
- NNeurotherapeutics 2016 Oct 25
- A primary pathogeny of epilepsy is excessive activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPARs). To find potential molecules to inhibit AMPARs, high-throughput screeni...
A primary pathogeny of epilepsy is excessive activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPARs). To find potential molecules to inhibit AMPARs, high-throughput screening was performed in a library of tetrapeptides in silico. Computational results suggest that some tetrapeptides bind stably to the AMPAR. We aligned these sequences of tetrapeptide candidates with those from in vitro digestion of the trout skin protein. Among salmon-derived products, Glu-Gly-Ala-Arg (EGAR) showed a high biological affinity toward AMPAR when tested in silico. Accordingly, natural EGAR was hypothesized to have anticonvulsant activity, and in vitro experiments showed that EGAR selectively inhibited AMPAR-mediated synaptic transmission without affecting the electrophysiological properties of hippocampal pyramidal neurons. In addition, EGAR reduced neuronal spiking in an in vitro seizure model. Moreover, the ability of EGAR to reduce seizures was evaluated in a rodent epilepsy model. Briefer and less severe seizures versus controls were shown after mice were treated with EGAR. In conclusion, the promising experimental results suggest that EGAR inhibitor against AMPARs may be a target for antiepilepsy pharmaceuticals. Epilepsy is a common brain disorder characterized by the occurrence of recurring, unprovoked seizures. Twenty to 30 % of persons with epilepsy do not achieve adequate seizure control with any drug. Here we provide a possibility in which a natural and edible tetrapeptide, EGAR, can act as an antiepileptic agent. We have combined computation with in vitro experiments to show how EGAR modulates epilepsy. We also used an animal model of epilepsy to prove that EGAR can inhibit seizures in vivo. This study suggests EGAR as a potential pharmaceutical for the treatment of epilepsy.
- Blood Biomarkers as Outcome Measures in Inflammatory Neurologic Diseases. [Review]
- NNeurotherapeutics 2016 Oct 18
- Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system. Only a few biomarkers are available in MS clinical practice, such as cerebrospinal fluid oligoclonal ban...
Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system. Only a few biomarkers are available in MS clinical practice, such as cerebrospinal fluid oligoclonal bands and immunoglobulin index, serum anti-aquaporin 4 antibodies, and serum anti-John Cunningham virus antibodies. Thus, there is a significant unmet need for biomarkers to assess prognosis, response to therapy, or potential treatment complications. Here we describe emerging biomarkers that are in development, focusing on those from peripheral blood. There are several limitations in the process of discovery and validation of a good biomarker, such as the pathophysiological complexity of MS and the technical difficulties in globally standardizing methods for sampling, processing, and conserving biological specimens. In spite of these limitations, ongoing international collaborations allow the exploration of many interesting molecules and markers to validate diagnostic, prognostic, and therapeutic-response biomarkers.
- Inflammation and Stroke: An Overview. [Review]
- NNeurotherapeutics 2016; 13(4):661-670
- The immune response to acute cerebral ischemia is a major factor in stroke pathobiology and outcome. While the immune response starts locally in occluded and hypoperfused vessels and the ischemic bra...