Urinary metabolomic changes and microbiotic alterations in presenilin1/2 conditional double knockout mice

Background Given the clinical low efficient treatment based on mono-brain-target design in Alzheimer’s disease (AD) and an increasing emphasis on microbiome-gut-brain axis which was considered as a crucial pathway to affect the progress of AD along with metabolic changes, integrative metabolomic signatures and microbiotic community profilings were applied on the early age (2-month) and mature age (6-month) of presenilin1/2 conditional double knockout (PS cDKO) mice which exhibit a series of AD-like phenotypes, comparing with gender and age-matched C57BL/6 wild-type (WT) mice to clarify the relationship between microbiota and metabolomic changes during the disease progression of AD. Materials and methods Urinary and fecal samples from PS cDKO mice and gender-matched C57BL/6 wild-type (WT) mice both at age of 2 and 6 months were collected. Urinary metabolomic signatures were measured by the gas chromatography-time-of-flight mass spectrometer, as well as 16S rRNA sequence analysis was performed to analyse the microbiota composition at both ages. Furthermore, combining microbiotic functional prediction and Spearman’s correlation coefficient analysis to explore the relationship between differential urinary metabolites and gut microbiota. Results In addition to memory impairment, PS cDKO mice displayed metabolic and microbiotic changes at both of early and mature ages. By longitudinal study, xylitol and glycine were reduced at both ages. The disturbed metabolic pathways were involved in glycine, serine and threonine metabolism, glyoxylate and dicarboxylate metabolism, pentose and glucuronate interconversions, starch and sucrose metabolism, and citrate cycle, which were consistent with functional metabolic pathway predicted by the gut microbiome, including energy metabolism, lipid metabolism, glycan biosynthesis and metabolism. Besides reduced richness and evenness in gut microbiome, PS cDKO mice displayed increases in Lactobacillus, while decreases in norank_f_Muribaculaceae, Lachnospiraceae_NK4A136_group, Mucispirillum, and Odoribacter. Those altered microbiota were exceedingly associated with the levels of differential metabolites. Conclusions The urinary metabolomics of AD may be partially mediated by the gut microbiota. The integrated analysis between gut microbes and host metabolism may provide a reference for the pathogenesis of AD.

Chronic, Multi-Site Recordings Supported by Two Low-Cost, Stationary Probe Designs Optimized to Capture Either Single Unit or Local Field Potential Activity in Behaving Rats

Rodent models of cognitive behavior have greatly contributed to our understanding of human neuropsychiatric disorders. However, to elucidate the neurobiological underpinnings of such disorders or impairments, animal models are more useful when paired with methods for measuring brain function in awake, behaving animals. Standard tools used for systems-neuroscience level investigations are not optimized for large-scale and high-throughput behavioral battery testing due to various factors including cost, time, poor longevity, and selective targeting limited to measuring only a few brain regions at a time. Here we describe two different “user-friendly” methods for building extracellular electrophysiological probes that can be used to measure either single units or local field potentials in rats performing cognitive tasks. Both probe designs leverage several readily available, yet affordable, commercial products to facilitate ease of production and offer maximum flexibility in terms of brain-target locations that can be scalable (32–64 channels) based on experimental needs. Our approach allows neural activity to be recorded simultaneously with behavior and compared between micro (single unit) and more macro (local field potentials) levels of brain activity in order to gain a better understanding of how local brain regions and their connected networks support cognitive functions in rats. We believe our novel probe designs make collecting electrophysiology data easier and will begin to fill the gap in knowledge between basic and clinical research.

TAP: Targeting and analysis pipeline for optimization and verification of TMS coil placement

Transcranial magnetic stimulation (TMS) offers possibilities to modulate function in regions of interest (ROI) in the brain via an induced electric field (E-field). The ROI E-field can be maximized using individualized computational head modeling to find an optimal scalp coil placement. We present a TMS targeting and analysis pipeline (TAP) software that uses an MRI/fMRI-derived brain target to optimize a coil placement considering experimental requirements such as subjects hair thickness and coil placement restriction. The coil placement optimization is implemented in SimNIBS 3.2 for which an additional graphical user interface (TargetingNavigator) is provided to visualize and adjust procedural parameters. The optimized coil placement information is prepared for neuronavigation software (Brainsight) which supports the targeting during the TMS experiment. The neuronavigation system can record the coil placement during the experiment and these data can be processed in TAP to evaluate retrospectively and visualize the TMS targeting accuracy.

Combustion-Derived Nanoparticles in Key Brain Target Cells and Organelles in Young Urbanites: Culprit Hidden in Plain Sight in Alzheimer’s Disease Development

Millions of children and young adults are exposed to fine particulate matter (PM2.5) and ozone, associated with Alzheimer’s disease (AD) risk. Mexico City (MC) children exhibit systemic and brain inflammation, low cerebrospinal fluid (CSF) Aβ1-42, breakdown of nasal, olfactory, alveolar-capillary, duodenal, and blood-brain barriers, volumetric and metabolic brain changes, attention and short-term memory deficits, and hallmarks of AD and Parkinson’s disease. Airborne iron-rich strongly magnetic combustion-derived nanoparticles (CDNPs) are present in young urbanites’ brains. Using transmission electron microscopy, we documented CDNPs in neurons, glia, choroid plexus, and neurovascular units of young MC residents versus matched clean air controls. CDNPs are associated with pathology in mitochondria, endoplasmic reticulum (ER), mitochondria-ER contacts (MERCs), axons,and dendrites. There is a significant difference in size and numbers between spherical CDNPs (>85%) and the angular, euhedral endogenous NPs (<15%). Spherical CDNPs (dogs 21.2 ± 7.1 nm in diameter versus humans 29.1 ± 11.2 nm, p = 0.002) are present in neurons, glia, choroid plexus, endothelium, nasal and olfactory epithelium, and in CSF at significantly higher in numbers in MC residents (p < 0.0001). Degenerated MERCs, abnormal mitochondria, and dilated ER are widespread, and CDNPs in close contact with neurofilaments, glial fibers, and chromatin are a potential source for altered microtubule dynamics, mitochondrial dysfunction, accumulation and aggregation of unfolded proteins, abnormal endosomal systems, altered insulin signaling, calcium homeostasis, apoptotic signaling, autophagy, and epigenetic changes. Highly oxidative, ubiquitous CDNPs constitute a novel path into AD pathogenesis. Exposed children and young adults need early neuroprotection and multidisciplinary prevention efforts to modify the course of AD at early stages.

Global Variability in Deep Brain Stimulation Practices for Parkinson’s Disease

IntroductionDeep brain stimulation (DBS) has become a standard treatment option for select patients with Parkinson’s disease (PD). The selection process and surgical procedures employed have, to date, not been standardized.MethodsA comprehensive 58-question web-based survey was developed with a focus on DBS referral practices and peri-operative management. The survey was distributed to the Parkinson’s Foundation Centers of Excellence, members of the International Parkinson’s Disease and Movement Disorders Society, and the Parkinson Study Group (Functional Neurosurgery Working Group) between December 2015 and May 2016.ResultsThere were 207 individual respondents (20% response rate) drawn from 59 countries and 6 continents, of whom 64% received formal training in DBS. Thirteen percent of centers reported that DBS could proceed despite a confidence level of &lt; 50% for PD diagnosis. A case-based approach to DBS candidacy was applied in 51.3% of centers without a cut-off for levodopa-responsiveness. Surprisingly, 33% of centers regularly used imaging for diagnostic confirmation of idiopathic PD. Thirty-one percent of centers reported that neuropsychological evaluation did not affect DBS target selection. Approximately half of the respondents reported determination of DBS candidacy based on a multidisciplinary committee evaluation and 1/3rd reported that a committee was used for target selection. Eight percent of respondents felt that psychosocial factors should not impact DBS candidacy nor site selection. Involvement of allied health professionals in the preoperative process was sparse. There was high variability in preoperative education about DBS outcome expectations. Approximately half of the respondents did not utilize a “default brain target,” though STN was used more commonly than GPi. Specific DBS procedure techniques applied, as well as follow-up timelines, were highly variable.ConclusionResults revealed high variability on the best approaches for DBS candidate selection, brain target selection, procedure type, and postoperative practices. Cognitive and mood assessments were underutilized. There was low reliance on multidisciplinary teams or psychosocial factors to impact the decision-making process. There were small but significant differences in practice across global regions, especially regarding multidisciplinary teams. The wide variability of responses across multiple facets of DBS care highlights the need for prospective studies to inform evidence-based guidelines.

Deep brain stimulation in the caudal zona incerta in patients with essential tremor: effects on cognition 1 year after surgery

OBJECTIVEThe ventral intermediate nucleus (VIM) of the thalamus is currently the established target in the use of deep brain stimulation (DBS) to treat essential tremor (ET). In recent years, the caudal zona incerta (cZi), a brain target commonly used during the lesional era, has been revived as the primary target in a number of DBS studies that show evidence of the efficacy of cZi targeting in DBS treatment for controlling the symptoms of ET. The authors sought to obtain comprehensive neuropsychological data and thoroughly investigate the cognitive effects of cZi targeting in patients with ET treated with DBS.METHODSTwenty-six consecutive patients with ET who received DBS with cZi as the target at our department from December 2012 to February 2017 were included in this study. All patients were assessed using a comprehensive neuropsychological test battery covering the major cognitive domains both preoperatively and 12 months postoperatively.RESULTSThe results show no major adverse effects on patient performance on the tests of cognitive function other than a slight decline of semantic verbal fluency.CONCLUSIONSThis study indicates that the cZi is a safe target from a cognitive perspective in the treatment of ET with DBS.

TREATMENT-RESISTANT OBSESSIVE COMPULSIVE DISORDER: AN EVALUATION STUDY OF THE AUGMENTATION EFFECT OF LOW-FREQUENCY REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION

Background: Thelifetime prevalence of obsessive-compulsive disorders (OCD) is estimated to be around 3% in the general population. Selective serotonin reuptake inhibitors (SSRIs) are considered to be the primary treatment strategy of OCD in addition to psychotherapy. Unfortunately, current medications, augmentation strategies, and behavioral therapies fail to provide adequate benefits in many cases. A large percentage of patients (40-60%) do not show satisfactory response to the standard treatments, some of them experiencing a chronically deteriorating course, leading to marked interpersonal and occupational impairments. In recent years, non-invasive neuromodulatory techniques such as repetitive transcranial magnetic stimulation have been increasingly studied as potential adjunct or alternative therapies for a wide range of neurological and psychiatric conditions including pain disorder, depression, and stroke rehabilitation and OCD. Aims: the aim of this work to evaluate rTMS as an augmentation strategy in treatment-resistant OCD, to test the potential value oflow frequency rTMS to SMA,orbitofrontal cortex and right DLPFC in the treatment of resistant OCD and to compare between the therapeutic values of applying the TMS coil to those different areas of the cortex. Patients and Methods: This study was carried out in Psychiatry, Neurology and Neurosurgery Center, Tanta University from September 2017 to November 2019. Eighty patients (52 females and 28 males) aging between 18 and 65 years underwent complete psychiatric evaluation, including full medical history, psychiatric and physical examination and diagnosed as having OCD accordingto DSM-5 with failure of at least two adequate therapeutic trials of SRIs. Results: Before rTMS sessions there was no statistical significant difference between the three active groups and the sham group regarding the scores onYale-Brown obsessive compulsive scale,Hamilton anxiety rating scale, Hamilton depression rating scale and Clinical global impression scale. Results after rTMS sessions revealed the following: Active rTMS on the SMA, the left OFC and right DLPFC was associated with marked improvement in YBOCS, Hamilton anxiety rating scale, Hamilton Depression rating scale and clinical global impression scale. The most significant improvement in Yale Brown Obsessive Compulsive scale was obtained when the brain target was the SMA. The most significant improvement in anxiety rating scale and depression ratingscale was obtained when the brain target was the left OFC. Sham group didnt have significant improvement through the study. Conclusions: We can thus conclude that low frequency rTMS is significantly effective as an adjunctive treatment for resistant OCD and that the SMA is the most effective brain target.