Search

Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder that primarily affects persons aged 65 years and above. It causes dementia with memory loss and deterioration in thinking and language skills. AD is characterized by specific pathology resulting from the accumulation in the brain of extracellular plaques of amyloid-β and intracellular tangles of phosphorylated tau. The importance of mitochondrial dysfunction in AD pathogenesis, while previously underrecognized, is now more and more appreciated. Mitochondria are an essential organelle involved in cellular bioenergetics and signaling pathways. Mitochondrial processes crucial for synaptic activity such as mitophagy, mitochondrial trafficking, mitochondrial fission, and mitochondrial fusion are dysregulated in the AD brain. Excess fission and fragmentation yield mitochondria with low energy production. Reduced glucose metabolism is also observed in the AD brain with a hypometabolic state, particularly in the temporo-parietal brain regions. This review addresses the multiple ways in which abnormal mitochondrial structure and function contribute to AD. Disruption of the electron transport chain and ATP production are particularly neurotoxic because brain cells have disproportionately high energy demands. In addition, oxidative stress, which is extremely damaging to nerve cells, rises dramatically with mitochondrial dyshomeostasis. Restoring mitochondrial health may be a viable approach to AD treatment. [ABSTRACT FROM AUTHOR]

Although there are many biochemical methods to measure amyloid-β (Aβ)42 concentration, one of the critical issues in the study of the effects of Aβ42 on the nervous system is a simple physiological measurement. The in vitro rat sciatic nerve model is employed and the nerve action potential (NAP) is quantified with different stimuli while exposed to different concentrations of Aβ42. Aβ42 predominantly reduces the NAP amplitude with minimal effects on other parameters except at low stimulus currents and short inter-stimulus intervals. The effects of Aβ42 are significantly concentration-dependent, with a maximum reduction in NAP amplitude at a concentration of 70 nM and smaller effects on the NAP amplitude at higher and lower concentrations. However, even physiologic concentrations in the range of 70 pM did reduce the NAP amplitude. The effects of Aβ42 became maximal 5–8 h after exposure and did not reverse during a 30 min washout period. The in vitro rat sciatic nerve model is sensitive to the effects of physiologic concentrations of Aβ42. These experiments suggest that the effect of Aβ42 is a very complex function of concentration that may be the result of amyloid-related changes in membrane properties or sodium channels. [ABSTRACT FROM AUTHOR]

SARS-CoV-2, a single-stranded RNA coronavirus, causes an illness known as coronavirus disease 2019 (COVID-19). Long-term complications are an increasing issue in patients who have been infected with COVID-19 and may be a result of viral-associated systemic and central nervous system inflammation or may arise from a virus-induced hypercoagulable state. COVID-19 may incite changes in brain function with a wide range of lingering symptoms. Patients often experience fatigue and may note brain fog, sensorimotor symptoms, and sleep disturbances. Prolonged neurological and neuropsychiatric symptoms are prevalent and can interfere substantially in everyday life, leading to a massive public health concern. The mechanistic pathways by which SARS-CoV-2 infection causes neurological sequelae are an important subject of ongoing research. Inflammation- induced blood-brain barrier permeability or viral neuro-invasion and direct nerve damage may be involved. Though the mechanisms are uncertain, the resulting symptoms have been documented from numerous patient reports and studies. This review examines the constellation and spectrum of nervous system symptoms seen in long COVID and incorporates information on the prevalence of these symptoms, contributing factors, and typical course. Although treatment options are generally lacking, potential therapeutic approaches for alleviating symptoms and improving quality of life are explored. [ABSTRACT FROM AUTHOR]

The Guidelines for Qualifications of Neurodiagnostic Personnel (QNP) document has been created through the collaboration of the American Clinical Neurophysiology Society (ACNS), the American Society of Neurophysiological Monitoring (ASNM), the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM), and ASET The Neurodiagnostic Society (ASET). The quality of patient care is optimized when neurophysiological procedures are performed and interpreted by appropriately trained and qualified practitioners at every level. These societies recognize that neurodiagnostics is a large field with practitioners who have entered the field through a variety of training paths. This document suggests job titles, associated job responsibilities, and the recommended levels of education, certification, experience, and ongoing education appropriate for each job. This is important because of the growth and development of standardized training programs, board certifications, and continuing education in recent years. This document matches training, education, and credentials to the various tasks required for performing and interpreting neurodiagnostic procedures. This document does not intend to restrict the practice of those already working in neurodiagnostics. It represents recommendations of these societies with the understanding that federal, state, and local regulations, as well as individual hospital bylaws, supersede these recommendations. Because neurodiagnostics is a growing and dynamic field, the authors fully intend this document to change over time. [ABSTRACT FROM AUTHOR]

As the search for modalities to cure Alzheimer's disease (AD) has made slow progress, research has now turned to innovative pathways involving neural and peripheral inflammation and neuro-regeneration. Widely used AD treatments provide only symptomatic relief without changing the disease course. The recently FDA-approved anti-amyloid drugs, aducanumab and lecanemab, have demonstrated unclear real-world efficacy with a substantial side effect profile. Interest is growing in targeting the early stages of AD before irreversible pathologic changes so that cognitive function and neuronal viability can be preserved. Neuroinflammation is a fundamental feature of AD that involves complex relationships among cerebral immune cells and pro-inflammatory cytokines, which could be altered pharmacologically by AD therapy. Here, we provide an overview of the manipulations attempted in pre-clinical experiments. These include inhibition of microglial receptors, attenuation of inflammation and enhancement of toxin-clearing autophagy. In addition, modulation of the microbiome-brain-gut axis, dietary changes, and increased mental and physical exercise are under evaluation as ways to optimize brain health. As the scientific and medical communities work together, new solutions may be on the horizon to slow or halt AD progression. [ABSTRACT FROM AUTHOR]

Although dementia is a common and devastating disease that has been studied intensely for more than 100 years, no effective disease modifying treatment has been found. At this impasse, new approaches are important. The purpose of this paper is to provide, in the context of current research, one clinician's perspective regarding important challenges in the field in the form of specific challenges. These challenges not only illustrate the scope of the problems inherent in finding treatments for dementia, but can also be specific targets to foster discussion, criticism and new research. One common theme is the need to transform research activities from small projects in individual laboratories/clinics to larger multinational projects, in which each clinician and researcher works as an integral part. This transformation will require collaboration between researchers, large corporations, regulatory/governmental authorities and the general population, as well as significant financial investments. However, the costs of transforming the approach are small in comparison with the cost of dementia. [ABSTRACT FROM AUTHOR]

There is conflicting information on the relationship between diet and dementia. The purposes of this pilot study were twofold. First, to use publicly available data regarding food consumption (United Kingdom Family Food), dementia, risk and demographic factors to find relationships between the consumption of various foods to dementia prevalence. The second purpose was to identify elements of study design that had important effects on the results. Multiple analyses were performed on different data sets derived from the existing data. Statistical testing began with univariate correlation analyses corrected for multiple testing followed by global tests for significance. Subsequently, a number of multivariate techniques were applied including stepwise linear regression, cluster regression, regularized regression, and principal components analysis. Permutation tests and simulations highlighted the strength and weakness of each technique. The univariate analyses demonstrated that the consumption of certain foods was highly associated with the prevalence of dementia. However, because of the complexity of the data set and the high degree of correlation between variables, different multivariate analyses yielded different results, explainable by the correlations. Some factors identified as having potential associations were the consumption of rice, sugar, fruit, potatoes, meat products and fish. However, within a given dietary category there were often a number of different elements with different relations to dementia. This pilot study demonstrates some critical elements for a future study: (1) dietary factors must be very narrowly defined, (2) large numbers of cases are needed to support multivariable analyses. (3) Multiple statistical methods along with simulations must be used to confirm results. [ABSTRACT FROM AUTHOR]

Despite intensive research, effective treatments for many common and devastating diseases are lacking. For example, huge efforts and billions of dollars have been invested in Alzheimer’s disease (AD), which affects over 50 million people worldwide. However, there is still no effective drug that can slow or cure AD. This relates, in part, to the absence of an animal model or cellular system that incorporates all the relevant features of the disease. Therefore, large scale studies on human populations and tissues will be key to better understanding dementia and developing methods to prevent or treat it. This is especially difficult because the dementia phenotype can result from many different processes and is likely to be affected by multiple personal and environmental variables. We hypothesize that analyzing massive volumes of demographic data that are currently available and combining this with genomic, proteomic, and metabolomic profiles of AD patients and their families, new insights into pathophysiology and treatment of AD may arise. While this requires much coordination and cooperation among large institutions, the potential for advancement would be lifechanging for millions of people. In many ways this represents the next step in the information revolution started by the Human Genome Project. [ABSTRACT FROM AUTHOR]

Abstract In this paper, the acute changes in the compound motor action potential (CMAP) during mechanical stretch were studied in hamster sciatic nerve and compared to the changes that occur during compression. In response to stretch, the nerve physically broke when a mean force of 331 gm (3.3 N) was applied while the CMAP disappeared at an average stretch force of 73 gm (0.73 N). There were 5 primary measures of the CMAP used to describe the changes during the experiment: the normalized peak to peak amplitude, the normalized area under the curve (AUC), the normalized duration, the normalized velocity and the normalized velocity corrected for the additional path length the impulses travel when the nerve is stretched. Each of these measures was shown to contain information not available in the others. During stretch, the earliest change is a reduction in conduction velocity followed at higher stretch forces by declines in the amplitude of the CMAP. This is associated with the appearance of spontaneous EMG activity. With stretch forces < 40 gm (0.40 N), there is evidence of increased excitability since the corrected velocities increase above baseline values. In addition, there is a remarkable increase in the peak to peak amplitude of the CMAP after recovery from stretch < 40 gm, often to 20% above baseline. Multiple means of predicting when a change in the CMAP suggests a significant stretch are discussed and it is clear that a multifactorial approach using both velocity and amplitude parameters is important. In the case of pure compression, it is only the amplitude of the CMAP that is critical in predicting which changes in the CMAP are associated with significant compression.

Abstract Detecting acute nerve compression using neurophysiologic studies is an important part of the practice of clinical intra-operative neurophysiology. The goal of this paper was to study the changes in the compound muscle action potential (CMAP) during acute mechanical compression. This is the type of injury most likely to occur during surgery. Thus, understanding the changes in the CMAP during this type of injury will be useful in the detection and prevention using intra-operative neurophysiologic monitoring. The model involved compression of the hamster sciatic nerve over a region of 1.3 mm with pressures up to 2000 mmHg for times on the order of 3 minutes. In this model CMAP amplitude dropped to 50% of its baseline value when a pressure of roughly 1000 mmHg is applied while, at the same time, nerve conduction velocities decline by only 5%. The ability to detect statistically significant changes in the CMAP at low force levels using other descriptors of the CMAP including duration, latency variation, etc alone or in conjunction with amplitude and velocity measures was investigated. However, these other parameters did not allow for earlier detection of significant changes. This study focused on a model in which nerve injury on a short time scale is purely mechanical in origin. It demonstrated that a pure compression injury produced large changes in CMAP amplitude prior to large changes in conduction velocity. On the other hand, ischemic and stretch injuries are associated with larger changes in conduction velocity for a given value of CMAP amplitude reduction.

Abstract Background Measurements of auto and cross covariance functions are frequently used to investigate neural systems. In interpreting this data, it is commonly assumed that the largest contribution to the recordings comes from sources near the electrode. However, the potential recorded at an electrode represents the superimposition of the potentials generated by large numbers of active neural structures. This creates situations under which the measured auto and cross covariance functions are dominated by the activity in structures far from the electrode and in which the distance dependence of the cross-covariance function differs significantly from that describing the activity in the actual neural structures. Methods Direct application of electrostatics to calculate the theoretical auto and cross covariance functions that would be recorded from electrodes immersed in a large volume filled with active neural structures with specific statistical properties. Results It is demonstrated that the potentials recorded from a monopolar electrode surrounded by dipole sources in a uniform medium are predominantly due to activity in neural structures far from the electrode when neuronal correlations drop more slowly than 1/r3 or when the size of the neural system is much smaller than a known correlation distance. Recordings from quadrupolar sources are strongly dependent on distant neurons when correlations drop more slowly than 1/r or the size of the system is much smaller than the correlation distance. Differences between bipolar and monopolar recordings are discussed. It is also demonstrated that the cross covariance of the recorded in two spatially separated electrodes declines as a power-law function of the distance between them even when the electrical activity from different neuronal structures is uncorrelated. Conclusion When extracellular electrophysiologic recordings are made from systems containing large numbers of neural structures, it is important to interpret measured auto and cross covariance functions cautiously in light of the long range nature of the electric fields. Using recording electrodes that are bipolar or quadrupolar minimizes or eliminates these effects and hence these electrodes are preferred when electrical recordings are made for the purpose of auto and cross correlation analysis of local electrical activity.