Cellular mechanisms underlying neurological/neuropsychiatric manifestations of COVID-19.

Patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection manifest mainly respiratory symptoms. However, clinical observations frequently identified neurological symptoms and neuropsychiatric disorders related to COVID-19 (Neuro-SARS2). Accumulated robust evidence indicates that Neuro-SARS2 may play an important role in aggravating the disease severity and mortality. Understanding the neuropathogenesis and cellular mechanisms underlying Neuro-SARS2 is crucial for both basic research and clinical practice to establish effective strategies for early detection/diagnosis, prevention, and treatment. In this review, we comprehensively examine current evidence of SARS-CoV-2 infection in various neural cells including neurons, microglia/macrophages, astrocytes, pericytes/endothelial cells, ependymocytes/choroid epithelial cells, and neural stem/progenitor cells. Although significant progress has been made in studying Neuro-SARS2, much remains to be learned about the neuroinvasive routes (transneuronal and hematogenous) of the virus and the cellular/molecular mechanisms underlying the development/progression of this disease. Future and ongoing studies require the establishment of more clinically relevant and suitable neural cell models using human induced pluripotent stem cells, brain organoids, and postmortem specimens.

Lymphotoxin ß receptor-mediated NFκB signaling promotes glial lineage differentiation and inhibits neuronal lineage differentiation in mouse brain neural stem/progenitor cells.

BACKGROUND: Lymphotoxin (LT) is a lymphokine mainly expressed in lymphocytes. LTα binds one or two membrane-associated LTß to form LTα2ß1 or LTα1ß2 heterotrimers. The predominant LTα1ß2 binds to LTß receptor (LTßR) primarily expressed in epithelial and stromal cells. Most studies on LTßR signaling have focused on the organization, development, and maintenance of lymphoid tissues. However, the roles of LTßR signaling in the nervous system, particularly in neurogenesis, remain unknown. Here, we investigated the role of LTßR-mediated NFκB signaling in regulating neural lineage differentiation. METHODS: The C57BL/6J wild-type and GFAP-dnIκBα transgenic mice were used. Serum-free embryoid bodies were cultured from mouse embryonic stem cells and further induced into neural stem/progenitor cells (NSCs/NPCs). Primary neurospheres were cultured from embryonic and adult mouse brains followed by monolayer culture for amplification/passage. NFκB activation was determined by adenovirus-mediated NFκB-firefly-luciferase reporter assay and p65/RelB/p52 nuclear translocation assay. LTßR mRNA expression was evaluated by quantitative RT-PCR and LTßR protein expression was determined by immunohistochemistry and Western blot analysis. Multilabeled immunocytochemistry or immunohistochemistry followed by fluorescent confocal microscopy and quantitative analysis of neural lineage differentiation were performed. Graphing and statistical analysis were performed with GraphPad Prism software. RESULTS: In cultured NSCs/NPCs, LTα1ß2 stimulation induced an activation of classical and non-classical NFκB signaling. The expression of LTßR-like immunoreactivity in GFAP+/Sox2+ NSCs was identified in well-established neurogenic zones of adult mouse brain. Quantitative RT-PCR and Western blot analysis validated the expression of LTßR in cultured NSCs/NPCs and brain neurogenic regions. LTßR expression was significantly increased during neural induction. LTα1ß2 stimulation in cultured NSCs/NPCs promoted astroglial and oligodendrocytic lineage differentiation, but inhibited neuronal lineage differentiation. Astroglial NFκB inactivation in GFAP-dnIκBα transgenic mice rescued LTßR-mediated abnormal phenotypes of cultured NSCs/NPCs. CONCLUSION: This study provides the first evidence for the expression and function of LTßR signaling in NSCs/NPCs. Activation of LTßR signaling promotes glial lineage differentiation. Our results suggest that neurogenesis is regulated by the adaptive immunity and inflammatory responses.

Phoenixin: a novel brain-gut-skin peptide with multiple bioactivity.

In this brief review we summarize the current fndings relative to the discovery of a small peptide ligand, phoenixin (PNX). Using a bioinformatic approach, two novel peptides PNX-14 and PNX-20 containing 14 and 20 amino acids, respectively, were isolated from diverse tissues including the brain, heart, lung and stomach. Mass spectrometry analysis identified a major and minor peak corresponding to PNX-14 and PNX-20, in rat or mouse spinal cord extracts. With the use of a rabbit polyclonal antiserum, phoenixin immunoreactivity (irPNX) was detected in discrete areas of the rodent brain including several hypothalamic subnuclei and dorsal motor nucleus of the vagus. In addition, irPNX was detected in a population of sensory ganglion cells including dorsal root ganglion, nodose ganglion and trigeminal ganglion, and in cell processes densely distributed to the superficial layers of the dorsal horn, nucleus of the solitary tract and spinal trigeminal tract. irPNX cell processes were also detected in the skin and myenteric plexus, suggesting a brain-gut and/or brain-skin connection. Pharmacological studies show that PNX-14 injected subcutaneously to the nape of the neck of mice provoked dose-dependent repetitive scratching bouts directed to the back of the neck with the hindpaws. Our result suggests that the peptide PNX-14 and/or PNX-20, may serve as one of the endogenous signal molecules transducing itch sensation. Additionally, results from other laboratories show that exogenous PNX may affect a number of diverse behaviors such as memory formation, depression, reproduction, food-intake and anxiolytic-like behaviors.

Innate immunity of vascular smooth muscle cells contributes to two-wave inflammation in atherosclerosis, twin-peak inflammation in aortic aneurysms and trans-differentiation potential into 25 cell types.

Introduction: Vascular smooth muscle cells (VSMCs) are the predominant cell type in the medial layer of the aorta, which plays a critical role in aortic diseases. Innate immunity is the main driving force for cardiovascular diseases. Methods: To determine the roles of innate immunity in VSMC and aortic pathologies, we performed transcriptome analyses on aortas from ApoE-/- angiotensin II (Ang II)-induced aortic aneurysm (AAA) time course, and ApoE-/- atherosclerosis time course, as well as VSMCs stimulated with danger-associated molecular patterns (DAMPs). Results: We made significant findings: 1) 95% and 45% of the upregulated innate immune pathways (UIIPs, based on data of 1226 innate immune genes) in ApoE-/- Ang II-induced AAA at 7 days were different from that of 14 and 28 days, respectively; and AAA showed twin peaks of UIIPs with a major peak at 7 days and a minor peak at 28 days; 2) all the UIIPs in ApoE-/- atherosclerosis at 6 weeks were different from that of 32 and 78 weeks (two waves); 3) analyses of additional 12 lists of innate immune-related genes with 1325 cytokine and chemokine genes, 2022 plasma membrane protein genes, 373 clusters of differentiation (CD) marker genes, 280 nuclear membrane protein genes, 1425 nucleoli protein genes, 6750 nucleoplasm protein genes, 1496 transcription factors (TFs) including 15 pioneer TFs, 164 histone modification enzymes, 102 oxidative cell death genes, 68 necrotic cell death genes, and 47 efferocytosis genes confirmed two-wave inflammation in atherosclerosis and twin-peak inflammation in AAA; 4) DAMPs-stimulated VSMCs were innate immune cells as judged by the upregulation of innate immune genes and genes from 12 additional lists; 5) DAMPs-stimulated VSMCs increased trans-differentiation potential by upregulating not only some of 82 markers of 7 VSMC-plastic cell types, including fibroblast, osteogenic, myofibroblast, macrophage, adipocyte, foam cell, and mesenchymal cell, but also 18 new cell types (out of 79 human cell types with 8065 cell markers); 6) analysis of gene deficient transcriptomes indicated that the antioxidant transcription factor NRF2 suppresses, however, the other five inflammatory transcription factors and master regulators, including AHR, NF-KB, NOX (ROS enzyme), PERK, and SET7 promote the upregulation of twelve lists of innate immune genes in atherosclerosis, AAA, and DAMP-stimulated VSMCs; and 7) both SET7 and trained tolerance-promoting metabolite itaconate contributed to twin-peak upregulation of cytokines in AAA. Discussion: Our findings have provided novel insights on the roles of innate immune responses and nuclear stresses in the development of AAA, atherosclerosis, and VSMC immunology and provided novel therapeutic targets for treating those significant cardiovascular and cerebrovascular diseases.

A tough trek in the development of an anti-amyloid therapy for Alzheimer's disease: Do we see hope in the distance?

The search for a clinically effective therapy for patients with Alzheimer's disease (AD) has been long and arduous. In some circles the recent US Food and Drug Administration (FDA) approval of the human monoclonal antibody, Aducanumab, was viewed as a welcome advance. However, the administrative decision, in the face of a negative review by the members of the FDA neurology advisory board raised many questions concerning its appropriateness. In response the FDA has modified the conditions under which the drug should be administered. Currently, the etiology of AD remains unknown. Thus, application of therapies based on the still controversial amyloid hypothesis deserves critical scrutiny. While successful animal studies based on the hypothesis have stimulated many clinical trials in humans, none of these have shown statistically clinical benefit, raising questions regarding the intrinsic validity of the hypothesis itself. However, each successive trial has benefited from the experiences of those which preceded it. Given these caveats, the relevance of an apparent beneficial response in a subset of Aducanumab treated study participants must be weighed carefully. There are competing hypotheses regarding the etiology and pathophysiology responsible for the development of AD, including tau protein aggregation, acetylcholine deficiency, neuroinflammation, among others, all of which remain controversial. Nonetheless, the newly approved agent, Aducanumab did show some subtle benefit in some mild AD patients. Understanding the current hypotheses and controversies may help better evaluate the limitations and challenges in anti-amyloid therapy and in exploration of more efficacious therapies in treating patients with AD in the future.

Comparison of BNT162b2-, mRNA-1273- and Ad26.COV2.S-Elicited IgG and Neutralizing Titers against SARS-CoV-2 and Its Variants.

Because the vaccine-elicited antibody and neutralizing activity against spike protein of SARS-CoV-2 are associated with protection from COVID-19, it is important to determine the levels of specific IgG and neutralization titers against SARS-CoV-2 elicited by the vaccines. While three widely used vaccine brands (Pfizer-BNT162b2, Moderna-mRNA-1273 and Johnson-Ad26.COV2.S) are effective in preventing SARS-CoV-2 infection and alleviating COVID-19 illness, they have different efficacy against COVID-19. It is unclear whether the differences are due to varying ability of the vaccines to elicit a specific IgG antibody response and neutralization activity against spike protein of the virus. In this study, we compared the plasma IgG and neutralization titers against spike proteins of wild-type SARS-CoV-2 and eight variants in healthy subjects who received the mRNA-1273, BNT162b2 or Ad26.COV2.S vaccine. We demonstrated that subjects vaccinated with Ad26.COV2.S vaccine had significantly lower levels of IgG and neutralizing titers as compared to those who received the mRNA vaccines. While the linear regression analysis showed a positive correlation between IgG levels and neutralizing activities against SARS-CoV-2 WT and the variants, there was an overall reduction in neutralizing titers against the variants in subjects across the three groups. These findings suggest that people who received one dose of Ad26.COV2.S vaccine have a more limited IgG response and lower neutralization activity against SARS-CoV-2 WT and its variants than recipients of the mRNA vaccines. Thus, monitoring the plasma or serum levels of anti-SARS-CoV-2 spike IgG titer and neutralization activity is necessary for the selection of suitable vaccines, vaccine dosage and regimens.

Comparative study on clinical, laboratory and electrodiagnostic findings of peripheral neuropathy in patients with hypocupremia and hypercupremia, and literature review.

Copper deficiency (hypocupremia) or toxicosis (hypercupremia) may cause disorders of central and peripheral nervous systems. Hypocupremia causes myeloneuropathy resembling vitamin B12 deficiency. However, the clinical manifestations, particularly peripheral neuropathy (PN), of hypercupremia have not been adequately evaluated. To compare clinical, laboratory and electrodiagnositc features of PN between patients with hypocupremia and hypercupremia, we retrospectively reviewed the charts of patients with abnormal copper levels. Subjects with zinc abnormalities were excluded. Five hypocupremia (Male/Female = 4/1; age: 54.6 ±â€¯17.1 years; copper = 55.0 ±â€¯8.5 µg/dL [normal = 72-175]; zinc = 74.4 ±â€¯15.5 µg/dL [normal = 60-130]) and 3 hypercupremia (M/F = 1/2; age: 57.0 ±â€¯8.2 years; copper = 215.0 ±â€¯10.8 µg/dL; zinc = 72.3 ±â€¯14.6 µg/dL) were studied. The notable clinical findings included ambulatory difficulty in hypocupremia (2/5); paresthesia in both hypocupremia (3/5) and hypercupremia (2/3) but pain was only seen in (3/3) hypercupremia patients. Tendon reflexes were decreased in hypocupremia (3/5) and hypercupremia (1/3) but hyperreflexias in hypocupremia (2/5) only. Preexisting comorbidity such as diarrhea were observed in (2/3) hypercupremia but not in hypocupremia patients. Laboratory findings showed vitamin D deficiency (16.4 ±â€¯5.6 ng/mL) in (2/2) hypercupremia but normal (40.4 ±â€¯4.7 ng/mL) in (2/2) hypocupremia. Neurophysiologic studies showed evidence of neuropathy in (3/5) hypocupremia only. Different patterns of clinical, neurological examination and electrophysiologic findings between hypocupremia and hypercupremia suggest different underlying pathophysiologies.

Low-contrast visual evoked potential and early detection of optic demyelination.

Visual Evoked Potential (VEP) is a useful tool in identifying abnormality relative to the integration of optic pathways, and aids the diagnosis of central nervous system demyelinating disorders, such as multiple sclerosis (MS). However, the sensitivity of VEP in detecting early optic abnormality as a visual function surrogate remains questionable. Recent studies showed that low-contrast VEP increases sensitivity in early detection of optic demyelination. In order to evaluate the applicability of low-contrast VEP to our electrodiagnostic protocol, we tested whether low-contrast VEP may provide an improved sensitivity in identifying early optic demyelination. We performed low-contrast VEP with different stimulation intensities in 42 subjects. Twenty-three were patients (age: 44.0 ±â€¯13.6 year-old, range 26-69) with a clinical diagnosis of clinically isolated syndrome, a subtype of MS, and 19 subjects were normal volunteers (age: 34.4 ±â€¯14.3 year-old, range: 18-59) without any neurological disorders. Neither of them had a history of optic neuritis. Our preliminary data indicate that the low-contrast VEP is not superior over the conventional high-contrast VEP, and may not provide improved sensitivity in early detection of optic demyelination.

Clinical Manifestations of Isolated Elevated Homocysteine-Induced Peripheral Neuropathy in Adults.

OBJECTIVE: To characterize the clinical features of isolated elevated plasma homocysteine (eHcy)-induced peripheral neuropathy (IHIN) in adults. METHODS: Charts of subjects with the diagnosis of IHIN who visited neuromuscular clinic from January 01, 2012 to September 30, 2014 were reviewed. Subjects with identifiable etiologies for neuropathy, such as B12/folate deficiency; metabolic, toxic, endocrinologic, infectious/inflammatory renal or liver diseases; or traumatic nerve injury, were excluded. Their clinical presentations were recorded and analyzed. RESULTS: Thirty subjects (age: 63.2 ± 14.8 years, 13 males) were included. They all had an isolated increased homocysteine level (15.4 ± 5.3 µmol/L) but normal levels of B12, folate, and methylmalonic acid. Of 30, 14 (46.7%) had numb feet, 11 (36.7%) had numb hands, 7 (23.3%) had pain in lower extremities, and 10 (33.3%) had tingling in feet. Distal sensory deficits were present in 18/30 (60%) patients. Distal limb weakness was seen in 4 and decreased tendon reflexes in 12 patients. CONCLUSIONS: Sensory deficits are predominant components of IHIN. Characterizing clinical features of IHIN would help better understand eHcy-related neuropathy and improve its management.

Concomitant presentation of Anderson-Tawil syndrome and myasthenia gravis in an adult patient: A case report.

Andersen-Tawil syndrome (ATS) is an autosomal dominant, multisystem channelopathy characterized by periodic paralysis, ventricular arrhythmias and distinctive dysmorphic facial or skeletal features. The disorder displays marked intrafamilial variability and incomplete penetrance. Myasthenia gravis (MG) is an autoimmune disorder that demonstrates progressive fatigability, in which the nicotinic acetylcholine receptor (AChR) at neuromuscular junctions is the primary autoantigen. The present study reports a rare case of a 31-year-old woman with a history of morbid obesity and periodic weakness, who presented with hemodynamic instability, cardiogenic shock and facial anomalies. Laboratory results revealed hypokalemia and an elevated anti-AChR antibody expression levels. Electrocardiography demonstrated prolonged QT-interval, ST-elevation, and subsequent third-degree atrioventricular block. Neurological examination revealed bilateral ptosis, horizontal diplopia, dysarthria and generalized weakness. No mutations in the potassium channel inwardly rectifying subfamily J member 2 gene were detected in the present case. The patient was treated with oral potassium supplementation and an acetylcholinesterase inhibitor (pyridostigmine), after which the symptoms were improved. To the best of our knowledge, the present case report was the first to describe concomitant presentation of both ATS and MG, which represents a diagnostic and therapeutic challenge.

Erratum: hyperhomocysteinemia and neurologic disorders: a review.

[This corrects the article on p. 281 in vol. 10, PMID: 25324876.].

Ketamine - A Multifaceted Drug.

There is a petition for tight control of ketamine from the Chinese government to classify ketamine as a Schedule I drug, which is defined as a drug with no currently accepted medical use but a high potential for abuse. However, ketamine has unique properties that can benefit different patient populations. Scholars from the Translational Perioperative and Pain Medicine and the International Chinese Academy of Anesthesiology WeChat groups had an interactive discussion on ketamine, including its current medical applications, future research priorities, and benefits versus risks. The discussion is summarized in this manuscript with some minor edits.