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MielniczekKatarzyna. Botulinum toxin in the treatment of neuralgia and neuropathic pain.Journal of Education, Health and Sport. 2021;11(9):310-314. eISSN 2391-8306. DOI http://dx.doi.org/10.12775/JEHS.2021.11.09.038 https://apcz.umk.pl/JEHS/article/view/JEHS.2021.11.09.038 https://zenodo.org/record/5515785 The journal has had 5 points in Ministry of Science and Higher Education parametric evaluation. § 8. 2) and § 12. 1. 2) 22.02.2019. © The Authors 2021; This article is published with open access at Licensee Open Journal Systems of Nicolaus Copernicus University in Torun, Poland Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author (s) and source are credited. This is an open access article licensed under the terms of the Creative Commons Attribution Non commercial license Share alike. (http://creativecommons.org/licenses/by-nc-sa/4.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited. The authors declare that there is no conflict of interests regarding the publication of this paper. Received: 05.09.2021. Revised: 18.09.2021. Accepted: 18.09.2021. Botulinum toxin in the treatment of neuralgia and neuropathic pain Katarzyna Mielniczek; ORCID Id: https://orcid.org/0000-0003-2575-3642; kasiamielniczek@gmail.com Medical University of Lublin, Faculty of Medicine, Lublin, Poland Abstract Introduction:Botulinum toxin is one of the most powerful neurotoxins currently known, with high affinity to the cholinergic synapse, which sufficiently inhibits the release of acetylcholine. Its use has proved to be effective in the treatment of many diseases of the musculoskeletal system. Although most of the therapeutic effects of botulinum toxin are due to the temporary relaxation of skeletal muscles (caused by inhibition of acetylcholine release), research is ongoing into its effects on the nervous system. Purpose of the work:The aim of the study is to analyze the effectiveness of botulinum toxin in the treatment of neuralgia and neuropathic pain. Method: The relevant samples were accessed by means of an electronic search in the PubMed database. The analysis used reviews and meta-analyzes posted on the platform over the last 10 years. Conclusions:Botulinum toxin has great potential in the treatment of pain. It is multitasking due to its favorable safety profile and long-lasting relief from a single injection compared to other pain medications. The side effects caused by it were assessed to be mild to moderate and included a local skin reaction (swelling), injection site pain, muscle weakness, flu symptoms, nausea and vomiting. Keywords:botulinum toxin; neuropathic pain; pain treatment; neuralgia; BoNT / A

Non-small cell lung cancer (NSCLC) is one of the most malignant tumors worldwide. The main treatment for NSCLC is based on Western medicine; however, the overall effect is unsatisfactory. This study aimed to investigate the potential therapeutic targets and pharmacological mechanisms of action of the traditional Chinese medicine Corydalis decumbens (Thunb.) Pers. in NSCLC based on network pharmacology and bioinformatics. The overlapping genes between Corydalis decumbens (Thunb.) Pers. and NSCLCs were screened using Venn analysis. Cytoscape 3.7.1 software was used to analyze the overlapping target protein-protein interaction (PPI) network. Gene ontology and pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomics database were performed to exploring biological functions of the overlapping genes. The gene expression profiling interactive analysis dataset was used to analyze the correlation between hub gene expression and disease. This study revealed 38 nodes with 191 edges, which may be therapeutic targets for NSCLC. PPI network analysis showed that the most likely association was between the genes AR and NCOA2, NCOA2, and RXRA and ESR1 and NCOA2. These overlapping genes were mainly enriched in the estrogen signaling pathway, calcium signaling pathway, cholinergic synapse, and PI3K-Akt signaling pathway. ESR2 mRNA levels were significantly downregulated in patients with lung adenocarcinoma (LUAD) getting worse, and KDR levels were lower in lung squamous cell carcinoma (LUSC) than those in normal tissue. PTGS2 expression was correlated with the median survival time of LUAD, and ESR1 expression was correlated with the median survival time of LUSC. The application of network pharmacology revealed the potential mechanism underlying the effects of Corydalis decumbens (Thunb.) Pers. in NSCLC treatment and provided a theoretical basis for further in-depth research in this field.

Background X-linked dystonia parkinsonism is a generalized, progressive dystonia followed by parkinsonism with onset in adulthood and accompanied by striatal neurodegeneration. Causative mutations are located in a noncoding region of the TATA-box binding protein-associated factor 1 (TAF1) gene and result in aberrant splicing. There are 2 major TAF1 isoforms that may be decreased in symptomatic patients, including the ubiquitously expressed canonical cTAF1 and the neuronal-specific nTAF1. Objective The objective of this study was to determine the behavioral and transcriptomic effects of decreased cTAF1 and/or nTAF1 in vivo. Methods We generated adeno-associated viral (AAV) vectors encoding microRNAs targeting Taf1 in a splice-isoform selective manner. We performed intracerebroventricular viral injections in newborn mice and rats and intrastriatal infusions in 3-week-old rats. The effects of Taf1 knockdown were assayed at 4 months of age with evaluation of motor function, histology, and RNA sequencing of the striatum, followed by its validation. Results We report motor deficits in all cohorts, more pronounced in animals injected at P0, in which we also identified transcriptomic alterations in multiple neuronal pathways, including the cholinergic synapse. In both species, we show a reduced number of striatal cholinergic interneurons and their marker mRNAs after Taf1 knockdown in the newborn. Conclusion This study provides novel information regarding the requirement for TAF1 in the postnatal maintenance of striatal cholinergic neurons, the dysfunction of which is involved in other inherited forms of dystonia. © 2021 International Parkinson and Movement Disorder Society.

Gut microbiome and plasma metabolome serve a role in the pathogenesis of ischemic stroke (IS). However, the relationship between the microbiota and metabolites remains unclear. This study aimed to reveal the specific asso-ciation between the microbiota and the metabolites in IS using integrated 16S rRNA gene sequencing and liquid chromatography-mass spectrometry (LC-MS) analysis. Male Sprague Dawley (SD) rats were divided into three groups: normal group (n = 8, Normal), model group (n = 9, IS), and sham-operated group (n = 8, Sham). Rats in the IS group were induced by middle cerebral artery occlusion (MCAO), and rats in the Sham group received an initial anesthesia and neck incision only. A neurological function test and 2,3,5-triphenyltetrazolium chloride (TTC) staining were used to assess the IS rat model. Then, the plasma samples were analyzed using untargeted LC-MS. The cecum samples were collected and analyzed using 16S rRNA sequencing. Pearson correlation analysis was performed to explore the association between the gut microbiota and the plasma metabolites. The 16S rRNA sequencing showed that the composition and diversity of the microbiota in the IS and control rats were significantly different. Compared with the Sham group, the abundance of the Firmicutes phylum was decreased, whereas Proteobacteria and Deferribacteres were increased in the IS group. Ruminococcus_sp_15975 and Lachnospiraceae_UCG_001 might be considered as biomarkers for the IS and Sham groups, respectively. LC-MS analysis revealed that many metabolites, such as L-leucine, L-valine, and L-phenylalanine, displayed different patterns between the IS and Sham groups. Pathway analysis indicated that these metabolites were mainly involved in mineral absorption and cholinergic synapse. Furthermore, integrated analysis correlated IS-related microbes with metabolites. For example, Proteobacteria were positively correlated with L-phenylalanine, while they were negatively correlated with eicosapentaenoic acid (EPA). Our results provided evidence of the relationship between the gut microbiome and plasma metabolome in IS, suggesting that these microflora-related metabolites might serve as potential diagnostic and therapeutic markers.

Withania somnifera is a Rasayana of the Ayurvedic system of medicine that is widely used to treat stress-related neurological disorders. Although its anti-stress activity is reported in experimentally-induced stress models, the probable mechanism for neuroprotection has not been elucidated yet. Hence, the present study aimed to evaluate the effect of Withania somnifera against two neurodegenerative diseases (Parkinson’s and Alzheimer’s diseases) using a network pharmacology followed by molecular docking. The bioactives were retrieved from ChEBI and PCIDB databases; targets were predicted using BindingDB and were enriched via STRING. The combination synergy analysis of the constructed network was performed using Cytoscape. Similarly, molecular docking was performed using autodock4.0. Out of 45 phytoconstituents, 23 were predicted to modulate the proteins involved in the pathogenesis of Parkinson’s disease and Alzheimer’s disease. The combination synergy identified 10 and 6 targets interacting with 22 and 18 compounds in Parkinson’s disease and Alzheimer’s disease respectively. Pathways involved in Parkinson’s disease was cholinergic synapse; further cholinergic synapse and neuroactive ligand-receptor interaction were primarily involved in Alzheimer’s disease. Further, phytoconstituents-target-pathway interaction revealed that the highly modulated protein(s) involved in Parkinson’s disease was PRKCD whereas COX-1 and 2 in Alzheimer’s disease along with some common proteins in both. Network pharmacology analysis elucidated the probable molecular mechanisms of Withania somnifera in the management of stress-associated neurodegenerative diseases, identified the lead molecules, their targets, and possible pathways. However, the current findings are based on processor simulations and further experimental validation of the constructed network is still required to confirm the present findings.

Purpose: To screen for bioactive anti-functional dyspepsia compounds from Magnoliae officinalis Cortex (Hou Po) and to identify the mechanism(s) of action involved.Methods: The compounds of Hou Po were collected from the literature. The related target proteins were identified from DrugBank. Through “Libdock” module of Discovery Studio 3.5, the compounds were matched with related target proteins. Taking the Libdock score of the original ligand with target protein as standard, components with higher scores than this standard were considered as potential bioactive compounds. Based on Cytoscape software, the interaction networks of the bioactive compound-target protein complexes were mapped. On the other hand, the online DAVID database was used to analyze the GO enrichment and KEGG pathway of each target.Results: A total of 199 chemical constituents and 13 correlated target proteins were obtained. One hundred and thirty-nine (139) potential bioactive constituents were acquired based on molecular docking. Thirty-one (31) bioactive compounds were selected based on degree values in networkanalysis. “Palmitone” and “magnolignan G” which had the highest degree values were considered promising and leading compounds. The result of gene enrichment analysis showed that the bioactive compounds exerted their effects mainly via “neuroactive ligand-receptor interaction” pathway and “Cholinergic synapse” pathways.Conclusion: Based on molecular docking and network pharmacology technique, the material basis for the use of Hou Po in the treatment of FD has been revealed. This finding provides a useful guide in the development of Hou Po-based anti-FD drugs. Keywords: Magnolia officinalis, Hou Po, Molecular docking, Functional dyspepsia, Network pharmacology

A kinetic model describing the dynamics of synaptic “discharge”, taking into account the kinetics of the neurotransmitter injection into the synaptic cleft, pH dependence of the enzyme catalytic activity, and proton removal by diffusion was proposed and studied. In the framework of the kinetic model, functioning of the cholinergic synapse was considered. The results of mathematical modeling of the change in the acetylcholine level, induced pH impulse, and the effect of the impulse transmission frequency and acetylcholinesterase inhibition are presented. A physicochemical interpretation was given for a number of key important physiological phenomena, such as neuromuscular paralysis, the mechanism of information recording and storage in the neurological memory, the action of nerve poisons and toxins, and Alzheimer’s disease.

Background Alzheimer’s disease (AD) is a neurodegenerative disease that primarily manifests as progressive memory loss and cognitive impairment. Traditional herbal medicines may be helpful in the discovery of new anti-AD drugs. Studies have shown that Ferula assafoetida has neuroprotective and memory-enhancing effects, which may be beneficial for the treatment of AD. However, the combination of active ingredients and their mechanisms remain unclear. Therefore, we aimed to identify potential active ingredients in F. assafoetida and their mechanisms of action against AD by using network pharmacology. Methods In our study, an integrated network pharmacological approach, that included adsorption, distribution, metabolism and excretion screening, target identification, network construction, topological analysis, gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, and molecular docking, was used to predict the pharmacological material basis and potential mechanisms through which these ingredients may treat and prevent AD. Results The results indicated that 12 key active ingredients, obtained by topological analysis (including farnesiferol a, conferol, farnesiferol b, ferulic acid, etc.), may be the primary pharmacological components that may ameliorate AD. The 2 key significant pathways identified are the cholinergic synapse signaling pathway (critical targets include ACHE, CHRM1, CHRM2, MAPK1, PIK3CA, PIK3CB, PIK3CD, and PIK3CG) and the AD signaling pathway (critical targets include APP, BACE1, GSK3B, MAPK1, NCSTN, NOS1, PSEN1). These critical targets are closely related to the regulation of three typical pathological features of AD [central nervous system (CNS) cholinergic hypofunction, amyloid-β (Aβ) plaques, and hyperphosphorylated tau proteins]. Finally, 14 critical targets in the 2 key significant pathways were validated by molecular docking analysis. Conclusion F. assafoetida may be effective for alleviating AD symptoms, through multi-component, multi-target, and multi-pathway synergistic effects, associated with the multiple pathogenesis hypotheses of AD. Our study may provide certain clues for the further development and utilization of this natural herbal medicine.

A kinetic model describing the dynamics of synaptic "discharge" taking into account the kinetics of the injection of the neurotransmitter into the synaptic cleft, the pH-dependence of the catalytic activity of the enzyme, and diffusion withdrawal of protons is proposed. The model provides a physicochemical explanation for a number of important physiological phenomena, such as the neuromuscular paralysis, the molecular mechanism of neurological memory, and the effect of some neurotoxins and drugs.

Sub-acute ruminal acidosis is a type of metabolic disorder in which affected cattle show a considerable depression of rumen pH. This leads to a dramatic decline in productivity and consequent loss of income for many dairy farms. The objective of the present study is to identify and characterize novel long non-coding RNAs (lncRNAs) in Holstein cattle affected by sub-acute ruminal acidosis. Two replicates from six animals were sequenced that bioinformatically analyzed. Results showed 6679 novel lncRNAs among which 12 intergenic lncRNAs showed differential expression (p value ≤0.05). GO and KEGG analysis revealed that calcium signaling and G protein couple-receptor pathways may be involved in regulating metabolic processes during sub-acute ruminal acidosis. Furthermore, other biological processes including transmembrane transport, adult behavior, neuroactive ligand-receptor interaction, GABAergic synapse, cholinergic synapse were significantly enriched. The present data suggest that these differentially expressed lncRNAs may play regulatory roles in modulating biological processes associated with sub-acute ruminal acidosis in cattle rumen.

Background Alzheimer's disease is the major cause of dementia by two main factors includes an accumulation of acetylcholinesterase enzyme at cholinergic synapse and deposition of β-amyloid protein at neurofibrillary tangles. The present investigation explores the binding affinities of phytoconstituents present in the methanolic leaf extract of Erytrhroxylum monogynum identified by gas chromatography-mass spectrometry against selected targets, i.e., β-amyloid and acetylcholinesterase. Objectives The main objective of present study was to explore anti-Alzheimer's potential of phytoconstituents from methanolic leaf extract of Erytrhroxylum monogynum. Methods Erytrhroxylum monogynum leaf material was subjected to Soxhlet extraction by three different solvents, namely n-hexane, chloroform and methanol. The methanolic leaf extract was subjected to Gas chromatography–mass spectrometric analysis for identification of novel phytoconstituents and chromatogram revealed the presence of 45 novel phytoconstituents. These phytoconstituents were not reported earlier from any part of this plant material. These phytoconstituents were explored for their anti-Alzheimer’s potential by iGEMDOCK software against selected targets, namely recombinant human acetylcholinesterase (protein data bank ID: 3LII) and β-amyloid (protein data bank ID: 2LMN). Results From the results of docking analysis, the top five phytoconstituents with the highest binding affinity towards the selected targets were further subjected to ADMET prediction by in silico admetSAR web portal. Conclusions Molecular docking analysis revealed the presence of 7 phytoconstituents are having the highest binding affinity towards the selected targets when compared to their respective standard compounds namely 9, 12-octa-decadienoic acid, methyl ester, (E, E); octadecanoic acid, methyl ester; hexadecanoic acid, 2-hydroxy-1-(hydroxymethyl) ethyl ester; 3, 6-ditigloyloxy-7-hydroxytropane; 3, 7,11, 15-tetramethyl-2-hexa-decen-1-ol; neophytadiene and phytol. The lead hits were further subjected to LigPlot analysis to understand their intermolecular interactions. Thus the result collectively obtained from the in silico studies using computational approaches may become prospective novel lead compounds against the selected targets of Alzheimer's disease.

Allergic rhinitis (AR) is characterized by an early-phase response (EPR), and in a subgroup of individuals, a late-phase response (LPR). We sought to investigate polymorphisms in cholinergic synapse pathway genes, previously associated with late-asthmatic responses, in the LPR. Twenty healthy participants and 74 participants with AR underwent allergen exposure using the Environmental Exposure Unit. Allergic participants were sub-phenotyped using self-reported nasal congestion scores; congestion is the predominant symptom experienced during the LPR. Acute congestion (AC, n = 36) participants developed only an EPR, while persistent congestion (PC, n = 38) participants developed both allergic responses. We interrogated blood samples collected before allergen exposure with genotyping and gene expression assays. Twenty-five SNPs located in ADCY3, AKT3, CACNA1S, CHRM3, CHRNB2, GNG4, and KCNQ4 had significantly different allele frequencies (P < 0.10) between PC and AC participants. PC participants had increased minor allele content (P = 0.009) in the 25 SNPs compared to AC participants. Two SNPs in AKT3 were associated with gene expression differences (FDR < 0.01) in PC participants. This study identified an association between the LPR and polymorphisms in the cholinergic synapse pathway genes, and developed a novel method to sub-phenotype AR using self-reported nasal congestion scores.

Background Methionine has been proven to inhibit addictive behaviors of cocaine dependence. However, the mechanism of methionine response to cocaine CPP is unknown. Recent evidence highlights piRNAs to regulate genes via a miRNA‐like mechanism. Here, next‐generation sequencing is used to study mechanism on methionine response to drug‐induced behaviors though piRNA. Methods l‐methionine treatment cocaine CPP animal model was used to do non‐coding RNA sequencing. There were four groups to sequence: saline+saline (SS), MET+saline (MS), MET+cocaine (MC), and cocaine+saline. Combining mRNA sequencing data, the network and regulation of piRNA were analyzed with their corresponding mRNA and miRNA. Results Analysis of the piRNAome reveals that piRNAs inversely regulated their target mRNA genes. KEGG analysis of DE‐piRNA target mRNA genes were enriched in Morphine addiction, GABAergic synapse and Cholinergic synapse pathway. Furthermore, four significantly differential expressed genes Cacna2d3, Epha6, Nedd4l, and Vav2 were identified and regulated by piRNAs in the process of l‐methionine inhibits cocaine CPP. Thereinto, Vav2 was regulated by multiple DE piRNAs by sharing the common sequence: GTCTCTCCAGCCACCTT. Meanwhile, it was found that piRNA positively regulates miRNA and three genes Bcl3, Il20ra, and Insrr were identified and regulated by piRNA through miRNA. Conclusion The results showed that piRNA negatively regulated target mRNA genes and positively regulated target miRNA genes. Genes located in substance dependence, signal transduction and also nervous functions pathways were identified. When taken together, these data may explain the roles of l‐methionine in counteracting the effects of cocaine CPP via piRNAs., our results showed piRNA negatively regulated target mRNA genes and positively regulated target miRNA genes. Genes located in substance dependence, Signal transduction and also nervous functions pathways were down‐regulated: Cacna2d3, Epha6, Nedd4l and Vav2. Thereinto, Vav2 was targeted by multiple piRNAs by sharing the common target sequence: GTCTCTCCAGCCACCTT. Taken together, these data may explain the roles of L‐methionine in counteracting the effects of cocaine CPP via piRNAs.

The neuromuscular junction is a highly specialized cholinergic synapse, essential for initiating nerve-evoked muscle contractions by means of neuromuscular transmission. Loss or dysfunction of any component of this junction might affect synaptic performance. Congenital Myasthenic Syndromes (CMSs) are rare heterogeneous disorders of autosomal inheritance caused by genetic defects affecting neuromuscular transmission that results in skeletal muscle weakness and abnormal fatigability on exertion. The onset is usually from birth to childhood. CMSs are more uncommon than autoimmune myasthenia gravis. CMSs are classified based on their genetic and clinical presentations into presynaptic, synaptic basal lamina, and postsynaptic CMSs. To date, mutations in more than 25 genes have been implicated in the pathogenesis of CMSs. In this review article, different CMSs diagnostic procedures are investigated, and the genetic, clinical, and molecular aspects of CMSs are outlined.

Allergen inhalation challenge triggers well-defined airway responses in mild, allergic asthmatics. Some individuals develop only an isolated early response (early responders (ERs)) characterised by acute airway smooth muscle constriction immediately following allergen inhalation. Others develop a late response (dual responders (DRs)) that begins 3–4 h later, resulting in prolonged reduction of airway function, associated with cellular infiltration, inflammation and hyperresponsiveness of the airways [1]. It is not well understood how certain individuals are protected from developing a late response. Our previous research identified novel RNA transcripts in peripheral blood that are predictive of asthmatics who could develop a late response. Our findings pointed towards the presence of inherent differences underlying molecular mechanisms that predispose asthmatic individuals to the late response [2]., Cholinergic synapse pathway gene polymorphisms may play a role in regulating a type of asthmatic airway response triggered upon allergen challenge http://bit.ly/2lJx1VG

This study was aimed to identify hub genes associated with the development of glioblastoma (GBM) by conducting a bioinformatic analysis. The raw gene expression data were downloaded from the Gene Expression Omnibus database and The Cancer Genome Atlas project. After the differentially expressed genes (DEGs) were identified, the functional enrichment analysis of DEGs was conducted. Subsequently, the protein-protein interaction (PPI) network, molecular complex detection clusters, and transcriptional factor (TF)-miRNA-target regulatory network were constructed, respectively. Furthermore, the survival analysis of prognostic outcomes and genes was analyzed. In addition, the expression of key genes was validated by quantitative real-time PCR (qRT-PCR) analysis. A total of 884 DEGs, including 418 upregulated and downregulated genes, were identified between GBM and normal samples. The PPI network comprised a set of 3418 pairs involving 751 nodes, and AKT1 and CDK2 were the critical genes in the network. A total of seven clusters were identified, the genes in which were intensively associated with cell cycle, cholinergic synapse, and extracellular matrix (ECM)-receptor interaction. qRT-PCR analysis indicated that AKT1 and CDK2 were significantly upregulated, and NRXN3 and NPTX2 were significantly downregulated in GBM samples. The TF-miRNA-target regulatory networks were built, in which CCNB1, RFC5, microRNA524, and microRNA34b were key regulators. There were 43 genes, including NPTX2 and NRXN3, significantly related to the prognostic outcomes of GBM patients. These crucial genes might be promising options for GBM treatment.

Based on epidemiological data it was believed that botulinumtoxin type D (BT-D) may not block human cholinergic synapses. We wanted to investigate BT-D’s effect on the autonomic cholinergic synapse in humans. For this, we compared in four volunteers intraindividually the hypohidrotic effect of intradermal BT-D and BT-A in Minor’s iodine starch sweat test. Altogether, we studied BT-D in doses of 4, 8, 16 and 32MU and BT-A in doses of 2, 4, 8 and 16MU at weekly intervals throughout a period of 13 weeks. All BT doses were diluted in 0.2 ml 0.9% NaCl/H2O. Overall 704 data points were collected. Combined over all four subjects and all four doses BT-D’s hypohidrotic effect intensity was half of BT-A’s. BT-D’s effect peaked around 5 weeks, BT-A’s around 7 weeks. BT-D’s effect duration was around 12 weeks, of BT-A’s was around 14 weeks. For both BT types the hypohidrotic effect was dose dependent. BT-D, when injected intradermally, can block autonomic cholinergic synapses in humans. Compared to BT-A, BT-D’s effect intensity was half and its effect duration was some 2 weeks shorter. With its weaker and shorter effect BT-D does not seem to promise therapeutic effects superior to BT-A.

Accumulation of normal or mutant human Tau isoforms in Central Nervous System (CNS) neurons of vertebrate and invertebrate models underlies pathologies ranging from behavioral deficits to neurodegeneration that broadly recapitulate human Tauopathies. Although some functional differences have begun to emerge, it is still largely unclear whether normal and mutant Tau isoforms induce differential effects on the synaptic physiology of CNS neurons. We use the oligosynaptic Giant Fiber System in the adult Drosophila CNS to address this question and reveal that 3R and 4R isoforms affect distinct synaptic parameters. Whereas 0N3R increased failure rate upon high frequency stimulation, 0N4R compromised stimulus conduction and response speed at a specific cholinergic synapse in an age-dependent manner. In contrast, accumulation of the R406W mutant of 0N4R induced mild, age-dependent conduction velocity defects. Because 0N4R and its mutant isoform are expressed equivalently, this demonstrates that the defects are not merely consequent of exogenous human Tau accumulation and suggests distinct functional properties of 3R and 4R isoforms in cholinergic presynapses.

Objective Postural instability and gait difficulties (PIGDs) represent debilitating disturbances in Parkinson's disease (PD). Past acetylcholinesterase positron emission tomography (PET) imaging studies implicate cholinergic changes as significant contributors to PIGD features. These studies were limited in quantification of striatal cholinergic synapse integrity. Vesicular acetylcholine transporter (VAChT) PET ligands are better suited for evaluation of high binding areas. We examined associations between regional VAChT expression and freezing of gait (FoG) and falls. Methods Ninety-four PD subjects underwent clinical assessment and VAChT ([18 F]FEOBV) PET. Results Thirty-five subjects (37.2%) reported a history of falls, and 15 (16%) had observed FoG. Univariate volume-of-interest analyses demonstrated significantly reduced thalamic (p = 0.0016) VAChT expression in fallers compared to nonfallers. VAChT expression was significantly reduced in the striatum (p = 0.0012) and limbic archicortex (p = 0.004) in freezers compared to nonfreezers. Whole-brain voxel-based analyses of FEOBV PET complemented these findings and showed more granular changes associated with falling history, including the right visual thalamus (especially the right lateral geniculate nucleus [LGN]), right caudate nucleus, and bilateral prefrontal regions. Freezers had prominent VAChT expression reductions in the bilateral striatum, temporal, and mesiofrontal limbic regions. Interpretation Our findings confirm and extend on previous PET findings of thalamic cholinergic deficits associated with falling history and now emphasize right visual thalamus complex changes, including the right LGN. FoG status is associated with reduced VAChT expression in striatal cholinergic interneurons and the limbic archicortex. These observations suggest different cholinergic systems changes underlying falls and FoG in PD. Ann Neurol 2019;85:538-549.

This special issue of the Journal of Neurochemistry, entitled "Cholinergic Mechanisms," presents 15 reviews and two original papers, which have been selected to cover the broad spectrum of topics and disciplines presented at the XVIth International Symposium on Cholinergic Mechanisms (ISCM-XVI), ranging from the molecular and the cellular to the clinical and the cognitive mechanisms of cholinergic transmission. The authors discuss recent developments in the field, for instance, the association of cholinergic transmission with a number of important neurological and neuromuscular diseases in the central and peripheral nervous systems.