Mitochondria in Alzheimer's Disease Pathogenesis.

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-ß 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.

Amyloid-ß Effects on Peripheral Nerve: A New Model System.

Although there are many biochemical methods to measure amyloid-ß (Aß)42 concentration, one of the critical issues in the study of the effects of Aß42 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 Aß42. Aß42 predominantly reduces the NAP amplitude with minimal effects on other parameters except at low stimulus currents and short inter-stimulus intervals. The effects of Aß42 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 Aß42 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 Aß42. These experiments suggest that the effect of Aß42 is a very complex function of concentration that may be the result of amyloid-related changes in membrane properties or sodium channels.

Efficient extraction of data from intra-operative evoked potentials: 1.-Theory and simulations.

Quickly and efficiently extracting evoked potential information from noise is critical to the clinical practice of intraoperative neurophysiologic monitoring (IONM). Currently this is primarily done using trained professionals to interpret averaged waveforms. The purpose of this paper is to evaluate and compare multiple means of electronically extracting simple to understand evoked potential characteristics with minimum averaging. A number of evoked potential models are studied and their performance evaluated as a function of the signal to noise level in simulations. Methods: which extract the least number of parameters from the data are least sensitive to the effects of noise and are easiest to interpret. The simplest model uses the baseline evoked potential and the correlation receiver to provide an amplitude measure. Amplitude measures extracted using the correlation receiver show superior performance to those based on peak to peak amplitude measures. In addition, measures of change in latency or shape of the evoked potential can be extracted using the derivative of the baseline evoked response or other methods. This methodology allows real-time access to amplitude measures that can be understood by the entire OR staff as they are small, dimensionless numbers of order unity which are simple to interpret. The IONM team can then adjust averaging and other parameters to allow for visual interpretation of waveforms as appropriate.

Long COVID, the Brain, Nerves, and Cognitive Function.

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.

Alzheimer's Disease Treatment: The Search for a Breakthrough.

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.

Guidelines for Qualifications of Neurodiagnostic Personnel: A Joint Position Statement of the American Clinical Neurophysiology Society, the American Association of Neuromuscular & Electrodiagnostic Medicine, the American Society of Neurophysiological Monitoring, and ASET The Neurodiagnostic Society.

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.

Guidelines for Qualifications of Neurodiagnostic Personnel: A Joint Position Statement of the American Clinical Neurophysiology Society, the American Association of Neuromuscular & Electrodiagnostic Medicine, the American Society of Neurophysiological Monitoring, and ASET - The Neurodiagnostic Society.

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. As Neurodiagnostics is a growing and dynamic field, we fully intend this document to change over time.

Guidelines for Qualifications of Neurodiagnostic Personnel: A Joint Position Statement of the American Clinical Neurophysiology Society, the American Association of Neuromuscular & Electrodiagnostic Medicine, the American Society of Neurophysiological Monitoring, and ASET-The Neurodiagnostic Society.

SUMMARY: 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.

The role of massive demographic databases in intractable illnesses: Denomics for dementia.

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 life-changing for millions of people. In many ways this represents the next step in the information revolution started by the Human Genome Project.

A Perspective: Challenges in Dementia Research.

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.

Dementia and Diet, Methodological and Statistical Issues: A Pilot Study.

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.

Monitoring cardiac and ascending aortic procedures.

Although cardiac and aortic operations have been successfully performed for more than 60 years, the risk of neurologic complications remains high. In particular, the rate of stroke with cardiac operations continues to be significant in the 1%-5% range. Similarly, the risk of stroke with aortic operations remains in the range of 7%-10% despite many years of improving techniques. Because of this persistently high risk, the use of intra-operative neurophysiologic monitoring (IONM) has the potential of improving outcomes. This chapter provides an overview of cardiac/aortic arch procedures from the neurophysiologic standpoint and discusses the roles of different monitoring modalities in detecting injury.

The role of mitochondrial dysfunction in Alzheimer's disease: A potential pathway to treatment.

BACKGROUND: Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and is characterized by progressive memory loss and cognitive impairment. Our understanding of AD pathogenesis is limited and no effective disease-modifying treatment is available. Mitochondria are cytoplasmic organelles critical to the homeostatic regulation of glucose and energy in the cell. METHODS: Mitochondrial abnormalities are found early in the course of AD and dysfunctional mitochondria are involved in AD progression. The resulting respiratory chain impairment, neuronal apoptosis, and generation of reactive oxygen species are highly damaging to neurons. Restoration of mitochondrial function may provide a novel therapeutic strategy for AD. RESULTS: This review discusses the specifics of mitochondrial fragmentation, imbalances in fission and fusion, and DNA damage seen in AD and the contribution of compromised mitochondrial activity to AD etiopathogenesis. It explores how an understanding of the processes underlying mitochondrial failure may lead to urgently needed treatment innovations. It considers individual mitochondrial proteins that have emerged as promising drug targets and evaluates neuroprotective agents that could improve the functional state of mitochondria in the setting of AD. CONCLUSIONS: There is great promise in exploring original approaches to preserving mitochondrial viability as a means to achieve breakthroughs in treating AD.

Effect of 2,6-xylidine (DMA) on secretion of biomarkers for inflammation and neurodevelopment by the placenta.

Cigarette smoke enhances placental inflammation and interferes with steroidogenesis. However, the chemicals in the smoke responsible for these biological activities are unclear. 2,6 xylidine (also called 2,6 Dimethylaniline, DMA) is a component of cigarette smoke that has carcinogenic properties but its effects on the placenta are unknown. Therefore, we hypothesized that DMA may interfere with placental steroidogenesis or enhance placental inflammation. Placental explant cultures were treated with 0-50,000 nM DMA and concentrations of progesterone (P4), estradiol (E2), testosterone (T), IL-1ß, TNF-α, IL-6, sgp130, HO-1, IL-10, 8-Isoprostane (8-IsoP), and BDNF in the conditioned medium were quantified. Since many environmental toxins enhance the proinflammatory host response to infection, we also performed experiments on placental cultures co-stimulated with 107 heat-killed E. coli. DMA alone significantly reduced P4 and T secretion but enhanced E2 secretion. The toxin also reduced placental secretion of IL-6, sgp130, and BDNF. For bacteria-stimulated cultures, DMA increased secretion of P4 and T, and proinflammatory cytokines (IL-1ß, TNF-α) but had mixed effects on anti-inflammatory markers, increasing some (sgp130, IL-10) and reducing others (HO-1). However, DMA enhanced 8-IsoP levels by bacteria-stimulated placental cultures, suggesting that it increases oxidative stress by the tissues. These studies suggest that DMA affects secretion of biomarkers by the placenta and may promote inflammation. Further studies are needed to determine if these observed changes occur in vivo and the extent to which DMA exposure increases the risk of adverse pregnancy outcomes associated with smoking in pregnancy.

Alzheimer Disease Clinical Trials Targeting Amyloid: Lessons Learned From Success in Mice and Failure in Humans.

BACKGROUND: The goal of slowing or halting the development of Alzheimer disease (AD) has resulted in the huge allocation of resources by academic institutions and pharmaceutical companies to the development of new treatments. The etiology of AD is elusive, but the aggregation of amyloid-ß and tau peptide and oxidative processes are considered critical pathologic mechanisms. The failure of drugs with multiple mechanisms to meet efficacy outcomes has caused several companies to decide not to pursue further AD studies and has left the field essentially where it has been for the past 15 years. Efforts are underway to develop biomarkers for detection and monitoring of AD using genetic, imaging, and biochemical technology, but this is of minimal use if no intervention can be offered. REVIEW SUMMARY: In this review, we consider the natural progression of AD and how it continues despite present attempts to modify the amyloid-related machinery to alter the disease trajectory. We describe the mechanisms and approaches to AD treatment targeting amyloid, including both passive and active immunotherapy as well as inhibitors of enzymes in the amyloidogenic pathway. CONCLUSION: Lessons learned from clinical trials of amyloid reduction strategies may prove crucial for the leap forward toward novel therapeutic targets to treat AD.

Alzheimer's disease: many failed trials, so where do we go from here?

Alzheimer's disease (AD) is a neurodegenerative brain disorder associated with relentlessly progressive cognitive impairment and memory loss. AD pathology proceeds for decades before cognitive deficits become clinically apparent, opening a window for preventative therapy. Imbalance of clearance and buildup of amyloid ß and phosphorylated tau proteins in the central nervous system is believed to contribute to AD pathogenesis. However, multiple clinical trials of treatments aimed at averting accumulation of these proteins have yielded little success, and there is still no disease-modifying intervention. Here, we discuss current knowledge of AD pathology and treatment with an emphasis on emerging biomarkers and treatment strategies.

Case-Control Study of Paresthesia Among World Trade Center-Exposed Community Members.

OBJECTIVE: To investigate whether paresthesia of the lower extremities following exposure to the World Trade Center (WTC) disaster was associated with signs of neuropathy, metabolic abnormalities, or neurotoxin exposures. METHODS: Case-control study comparing WTC-exposed paresthesia cases with "clinic controls" (WTC-exposed subjects without paresthesias), and "community controls" (WTC-unexposed persons). RESULTS: Neurological histories and examination findings were significantly worse in cases than controls. Intraepidermal nerve fiber densities were below normal in 47% of cases and sural to radial sensory nerve amplitude ratios were less than 0.4 in 29.4%. Neurologic abnormalities were uncommon among WTC-unexposed community controls. Metabolic conditions and neurotoxin exposures did not differ among groups. CONCLUSIONS: Paresthesias among WTC-exposed individuals were associated with signs of neuropathy, small and large fiber disease. The data support WTC-related exposures as risk factors for neuropathy, and do not support non-WTC etiologies.

Prevalence of electrographic seizure in dogs and cats undergoing electroencephalography and clinical characteristics and outcome for dogs and cats with and without electrographic seizure: 104 cases (2009-2015).

OBJECTIVE: To determine the prevalence of electrographic seizure (ES) and electrographic status epilepticus (ESE) in dogs and cats that underwent electroencephalography (EEG) because of suspected seizure activity and to characterize the clinical characteristics, risk factors, and in-hospital mortality rates for dogs and cats with ES or ESE. DESIGN: Retrospective case series. ANIMALS: 89 dogs and 15 cats. PROCEDURES: Medical records of dogs and cats that underwent EEG at a veterinary neurology service between May 2009 and April 2015 were reviewed. Electrographic seizure was defined as ictal discharges that evolved in frequency, duration, or morphology and lasted at least 10 seconds, and ESE was defined as ES that lasted ≥ 10 minutes. Patient signalment and history, physical and neurologic examination findings, diagnostic test results, and outcome were compared between patients with and without ES or ESE. RESULTS: Among the 104 patients, ES and ESE were diagnosed in 21 (20%) and 12 (12%), respectively. Seventeen (81%) patients with ES had no or only subtle signs of seizure activity. The in-hospital mortality rate was 48% and 50% for patients with ES and ESE, respectively, compared with 19% for patients without ES or ESE. Risk factors for ES and ESE included young age, overt seizure activity within 8 hours before EEG, and history of cluster seizures. CONCLUSIONS AND CLINICAL REVELANCE: Results indicated that ES and ESE were fairly common in dogs and cats with suspected seizure activity and affected patients often had only subtle clinical signs. Therefore, EEG is necessary to detect patients with ES and ESE.