Artificial intelligence and machine learning in aneurysmal subarachnoid hemorrhage: Future promises, perils, and practicalities.

INTRODUCTION: Aneurysmal subarachnoid hemorrhage (SAH) is a subtype of hemorrhagic stroke with thirty-day mortality as high as 40%. Given the expansion of Machine Learning (ML) and Artificial intelligence (AI) methods in health care, SAH patients desperately need an integrated AI system that detects, segments, and supports clinical decisions based on presentation and severity. OBJECTIVES: This review aims to synthesize the current state of the art of AI and ML tools for the management of SAH patients alongside providing an up-to-date account of future horizons in patient care. METHODS: We performed a systematic review through various databases such as Cochrane Central Register of Controlled Trials, MEDLINE, Scopus, Cochrane Database of Systematic Reviews, and Embase. RESULTS: A total of 507 articles were identified. Following extensive revision, only 21 articles were relevant. Two studies reported improved mortality prediction using Glasgow Coma Scale and biomarkers such as Neutrophil to Lymphocyte Ratio and glucose. One study reported that ffANN is equal to the SAHIT and VASOGRADE scores. One study reported that metabolic biomarkers Ornithine, Symmetric Dimethylarginine, and Dimethylguanidine Valeric acid were associated with poor outcomes. Nine studies reported improved prediction of complications and reduction in latency until intervention using clinical scores and imaging. Four studies reported accurate prediction of aneurysmal rupture based on size, shape, and CNN. One study reported AI-assisted Robotic Transcranial Doppler as a substitute for clinicians. CONCLUSION: AI/ML technologies possess tremendous potential in accelerating SAH systems-of-care. Keeping abreast of developments is vital in advancing timely interventions for critical diseases.

A Novel Approach to Posterior Lateral Nasal Neurectomy.

Background Allergic rhinitis (AR) is a major health concern throughout the world. By severing the parasympathetic supply to the lateral wall of the nose, posterior lateral nasal neurectomy (PLNN), a form of highly selective vidian neurectomy, decreases nasal allergy symptoms. This study attempts to characterize the demographic and surgical characteristics of study participants in relation to PLNN, as well as to identify the risk factors associated with these characteristics. Methodology A five-year, cross-sectional study was undertaken among patients diagnosed with AR at a tertiary care center in Tamaka, Kolar. Case sheets accessible in the department of medical records were used to compile a list of 50 study patients. SPSS version 21 was used for data analysis (IBM Corp., Armonk, NY, USA). Results The study revealed that the average age of the sample population was 30.4 years. The majority of the study participants were less than or equal to 30 years old (54%). In our study, the majority of the participants were male (60%). This study revealed that around 46% of the surgeries were independent PLNNs and that most of them (76%) were observed to have four nerves following surgery. The average intraoperative blood loss during PLNN surgery was 43.14 mL. The mean hemoglobin levels before and after surgery were 13.11 and 12.78 g/dL, respectively. The average duration of the surgical procedure was 62 minutes. The average duration of PLNN surgery in females was 52.75 minutes, whereas the average duration in males was 68.33 minutes. According to an independent t-test (p = 0.045), this difference in mean was statistically significant. Approximately 85% of female study participants were identified with four nerves during PLNN surgery compared to 70% of male study participants. According to the chi-square test (p = 0.018), this proportional difference was statistically significant. Conclusions The majority of the participants in this study were male and younger. The typical PLNN surgical procedure lasted one hour. Males and females require different amounts of time, with females requiring less time. During PLNN surgery, most females detected four nerves, as opposed to most males.

Association of Obesity With COVID-19 Severity and Mortality: An Updated Systemic Review, Meta-Analysis, and Meta-Regression.

Background: Obesity affects the course of critical illnesses. We aimed to estimate the association of obesity with the severity and mortality in coronavirus disease 2019 (COVID-19) patients. Data Sources: A systematic search was conducted from the inception of the COVID-19 pandemic through to 13 October 2021, on databases including Medline (PubMed), Embase, Science Web, and Cochrane Central Controlled Trials Registry. Preprint servers such as BioRxiv, MedRxiv, ChemRxiv, and SSRN were also scanned. Study Selection and Data Extraction: Full-length articles focusing on the association of obesity and outcome in COVID-19 patients were included. Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were used for study selection and data extraction. Our Population of interest were COVID-19 positive patients, obesity is our Intervention/Exposure point, Comparators are Non-obese vs obese patients The chief outcome of the study was the severity of the confirmed COVID-19 positive hospitalized patients in terms of admission to the intensive care unit (ICU) or the requirement of invasive mechanical ventilation/intubation with obesity. All-cause mortality in COVID-19 positive hospitalized patients with obesity was the secondary outcome of the study. Results: In total, 3,140,413 patients from 167 studies were included in the study. Obesity was associated with an increased risk of severe disease (RR=1.52, 95% CI 1.41-1.63, p<0.001, I2 = 97%). Similarly, high mortality was observed in obese patients (RR=1.09, 95% CI 1.02-1.16, p=0.006, I2 = 97%). In multivariate meta-regression on severity, the covariate of the female gender, pulmonary disease, diabetes, older age, cardiovascular diseases, and hypertension was found to be significant and explained R2 = 40% of the between-study heterogeneity for severity. The aforementioned covariates were found to be significant for mortality as well, and these covariates collectively explained R2 = 50% of the between-study variability for mortality. Conclusions: Our findings suggest that obesity is significantly associated with increased severity and higher mortality among COVID-19 patients. Therefore, the inclusion of obesity or its surrogate body mass index in prognostic scores and improvement of guidelines for patient care management is recommended.

Hyperthyroidism and the Risk of Cardiac Arrhythmias: A Narrative Review.

Hyperthyroidism directly affects the cardiovascular system, altering the heart's normal function and leading to high cardiovascular mortality. Excess thyroid hormones are associated with significantly increased risk and prevalence of cardiac arrhythmias, particularly atrial fibrillation (AF). This article reviewed the hemodynamic changes and the risk of cardiac arrhythmias, including atrial and ventricular arrhythmias associated with hyperthyroidism. It has also discussed the multi-level pathophysiology of thyrotoxic AF, sinus tachycardia, and different treatment modalities such as anti-thyroid drugs, beta-blockers, and the role of cardioversion and catheter ablation. This article has explored different studies that have concluded that AF and sinus tachycardia are the most common arrhythmias associated with thyrotoxicosis.

Probiotics in Irritable Bowel Syndrome: A Review of Their Therapeutic Role.

Irritable bowel syndrome (IBS) is a chronic collection of symptoms and lowers the quality of life. The management of such patients has always involved mitigating the symptoms produced by this disorder. This article reviews the role of probiotics in IBS by compiling various studies to deduce the possible symptomatic relief that probiotics may provide to IBS patients. Given the encouraging part of probiotics in abundant other gastrointestinal conditions, this article focuses on understanding the specific functional effects (if any) that are brought about by adding probiotics in patients with different types of IBS such as IBS with predominant constipation, IBS with predominant diarrhea, and even the unclassified type of IBS. The purpose of analyzing the role of probiotics is to study the changes brought about by them at the level of the gut microbiota in patients suffering from IBS, as this may prove to be of prime importance in managing such conditions with time. This article has also furnished an overview of the pathogenesis, diagnostic criteria, treatment modalities, sources of probiotics, and their therapeutic significance in IBS patients.

Cyclin-Dependent Kinase 4 and 6 Inhibitors: A Quantum Leap in the Treatment of Advanced Breast Cancers.

Breast cancer (BC) is defined as an uncontrolled growth of breast cells that affected 2.3 million women in 2020 alone. Until a few years earlier, radiotherapy and chemotherapy were the most commonly used treatments in treating BC; however, many trials and studies were conducted to test the competence of cyclin-dependent kinases 4/6 (CDK4/6) in arresting the cell cycle, and it was found that they were highly influential in halting the disease from progressing. Palbociclib, ribociclib, and abemaciclib are the three drugs that have been approved by the US Food and Drug Administration (FDA) and are even more efficient when used in combination with aromatase inhibitors and fulvestrant. This article aimed to explain the effect of CDK4/6 inhibitors on tumor cells and their efficacy in combination with other drugs. We further explored the development of resistance to these treatments and future possibilities.

Cardiovascular Magnetic Resonance Imaging: A Prospective Modality in the Diagnosis and Prognostication of Heart Failure.

Heart failure (HF) is a clinical syndrome resulting from structural cardiac remodeling and altered function that impairs tissue perfusion. This article aimed to highlight the current diagnostic and prognostic value of cardiac magnetic resonance (CMR) in the management of HF and prospective future applications. Reviewed are the physics associated with CMR, its use in ischemic and non-ischemic causes of HF, and its role in quantifying left ventricular ejection fraction. It also emphasized that CMR allows for noninvasive morphologic and functional assessment, tissue characterization, blood flow, and perfusion evaluation in patients with suspected or diagnosed HF. CMR has become a crucial instrument for the diagnosis, prognosis, and therapy planning in patients with HF and cardiomyopathy due to its accuracy in quantifying cardiac volumes and ejection fraction (considered the gold standard) as well as native and post-contrast myocardial tissue characterization.

Multiple Sclerosis and Autoimmunity: A Veiled Relationship.

Multiple sclerosis (MS) is an autoimmune inflammatory illness that affects the central nervous system (CNS) when the body's immune system attacks its tissue. It is characterized by demyelination and varying degrees of axonal loss. This article has compiled various studies elaborating MS and other autoimmune diseases (ADs) co-occurrence. Several conditions that fall into this category, including type 1 diabetes (T1D), rheumatoid arthritis (RA), Guillain-Barre syndrome (GBS), myasthenia gravis (MG), and many others, are found in MS patients and their relatives, suggesting one or more common etiologic mechanisms, including genetic, environmental, and immunological factors, supporting the concept of a possible influence of poly-autoimmunity on MS and the rest of ADs, as well as providing a significant feature for early detection of the disease and also a potential treatment option by clinical neurologists.

Malignancy and Endocarditis: Divulging Into the Intertwined Association.

Cancer is an immunosuppressive disorder with characteristic features of unchecked cell growth, invasion, and sometimes thromboembolism leading to multiple systemic sequelae, including infective endocarditis. This article has compiled some of the crucial mechanisms by which infective endocarditis occurs in cancer patients, its risk factors, and the existing treatment interventions. It has focused on the necessity of being aware that these multiple pathogeneses are involved in the development of infective endocarditis (IE) in cancer patients, which would help delineate the risk factors associated with the condition and help physicians screen better for specific red flags. Identifying these risk factors and patient-oriented therapy, targeting the necessary elements such as causative organism, patient immune status, type of cancer, choosing evidence-based treatment modalities, and to improve the outcome of the disease in an already exasperating condition called cancer.

Development of a new AgriSeq 4K mid-density SNP genotyping panel and its utility in pearl millet breeding.

Pearl millet is a crucial nutrient-rich staple food in Asia and Africa and adapted to the climate of semi-arid topics. Since the genomic resources in pearl millet are very limited, we have developed a brand-new mid-density 4K SNP panel and demonstrated its utility in genetic studies. A set of 4K SNPs were mined from 925 whole-genome sequences through a comprehensive in-silico pipeline. Three hundred and seventy-three genetically diverse pearl millet inbreds were genotyped using the newly-developed 4K SNPs through the AgriSeq Targeted Genotyping by Sequencing technology. The 4K SNPs were uniformly distributed across the pearl millet genome and showed considerable polymorphism information content (0.23), genetic diversity (0.29), expected heterozygosity (0.29), and observed heterozygosity (0.03). The SNP panel successfully differentiated the accessions into two major groups, namely B and R lines, through genetic diversity, PCA, and structure models as per their pedigree. The linkage disequilibrium (LD) analysis showed Chr3 had higher LD regions while Chr1 and Chr2 had more low LD regions. The genetic divergence between the B- and R-line populations was 13%, and within the sub-population variability was 87%. In this experiment, we have mined 4K SNPs and optimized the genotyping protocol through AgriSeq technology for routine use, which is cost-effective, fast, and highly reproducible. The newly developed 4K mid-density SNP panel will be useful in genomics and molecular breeding experiments such as assessing the genetic diversity, trait mapping, backcross breeding, and genomic selection in pearl millet.

Circulating Donor Heart Exosome Profiling Enables Noninvasive Detection of Antibody-mediated Rejection.

BACKGROUND: Endomyocardial biopsy remains the gold standard for distinguishing types of immunologic injury-acute versus antibody-mediated rejection (AMR). Exosomes are tissue-specific extracellular microvesicles released by many cell types, including transplanted heart. Circulating transplant heart exosomes express donor-specific human leukocyte antigen (HLA) I molecules. As AMR is mediated by antibodies to donor HLAs, we proposed that complement deposition that occurs with AMR at tissue level would also occur on circulating donor heart exosomes. METHODS: Plasma exosomes in 4 patients were isolated by column chromatography and ultracentrifugation. Donor heart exosomes were purified using anti-donor HLA I antibody beads and complement C4d protein expression was assessed in this subset as marker for AMR. RESULTS: Three patients had no rejection episodes. Circulating donor heart exosomes showed troponin protein and mRNA expression at all follow-up time points. One patient developed AMR on day 14 endomyocardial biopsy that was treated with rituximab, IVIG/plasmapheresis. Time-specific detection of C4d protein was seen in donor heart exosome subset in this patient, which resolved with treatment. C4d was not seen in other 3 patients' donor exosomes. CONCLUSIONS: Anti-donor HLA I specificity enables characterization of circulating donor heart exosomes in the clinical setting. Further characterization may open the window to noninvasively diagnose rejection type, such as AMR.

Syncytiotrophoblast extracellular microvesicle profiles in maternal circulation for noninvasive diagnosis of preeclampsia.

Preeclampsia is the most common placental pathology in pregnant females, with increased morbidity and mortality incurred on the mother and the fetus. There is a need for improved biomarkers for diagnosis and monitoring of this condition. Placental syncytiotrophoblasts at the maternal-fetal interface release nanoparticles, including extracellular microvesicles, into the maternal blood during pregnancy. Syncytiotrophoblast extracellular microvesicles (STEVs) are being studied for their diagnostic potential and for their potential physiologic role in preeclampsia. We hypothesized that STEV profiles in maternal circulation would be altered under conditions of preeclampsia compared to normal pregnancy. Extracellular vesicles (EVs) released by BeWo cells in vitro showed high expression of syncytin-1, but no plac1 expression, demonstrating that trophoblast cell EVs express syncytin-1 on their surface. Placental alkaline phosphatase also showed high expression on BeWo EVs, but due to concern for cross reactivity to highly prevalent isoforms of intestinal and bone alkaline phosphatase, we utilized syncytin-1 as a marker for STEVs. In vivo, syncytin-1 protein expression was confirmed in maternal plasma EVs from Control and Preeclampsia subjects by Western blot, and overall, lower expression was noted in samples from patients with preeclampsia (n = 8). By nanoparticle analysis, EV profiles from Control and Preeclampsia groups showed similar total plasma EV quantities (p = 0.313) and size distribution (p = 0.415), but STEV quantitative signal, marked by syncytin-1 specific EVs, was significantly decreased in the Preeclampsia group (p = 2.8 × 10-11). Receiver operating characteristic curve demonstrated that STEV signal threshold cut-off of <0.316 was 95.2% sensitive and 95.6% specific for diagnosis of preeclampsia in this cohort (area under curve = 0.975 ± 0.020). In conclusion, we report that the syncytin-1 expressing EV profiles in maternal plasma might serve as a placental tissue specific biomarker for preeclampsia.

Clinical Utility of a Hand-Held Scanner for Breast Cancer Early Detection and Patient Triage.

PURPOSE: Globally, breast cancer represents the most common cause of cancer death among women. Early cancer diagnosis is difficult in low- and middle-income countries, most of which are unable to support population-based mammographic screening. Triage on the basis of clinical breast examination (CBE) alone can be difficult to implement. In contrast, piezo-electric palpation (intelligent Breast Exam [iBE]) may improve triage because it is portable, low cost, has a short learning curve, and provides electronic documentation for additional diagnostic workup. We compared iBE and CBE performance in a screening patient cohort from a Western mammography center. METHODS: Women presenting for screening or diagnostic workup were enrolled and underwent iBE then CBE, followed by mammography. Mammography was classified as negative (BI-RADS 1 or 2) or positive (BI-RADS 3, 4, or 5). Measures of accuracy and κ score were calculated. RESULTS: Between April 2015 and May 2017, 516 women were enrolled. Of these patients, 486 completed iBE, CBE, and mammography. There were 101 positive iBE results, 66 positive CBE results, and 35 positive mammograms. iBE and CBE demonstrated moderate agreement on categorization (κ = 0.53), but minimal agreement with mammography (κ = 0.08). iBE had a specificity of 80.3% and a negative predictive value of 94%. In this cohort, only five of 486 patients had a malignancy; iBE and CBE identified three of these five. The two cancers missed by both modalities were small-a 3-mm retro-areolar and a 1-cm axillary tail. CONCLUSION: iBE performs comparably to CBE as a triage tool. Only minimal cancers detected through mammographic screening were missed on iBE. Ultimately, our data suggest that iBE and CBE can synergize as triage tools to significantly reduce the numbers of patients who need additional diagnostic imaging in resource-limited areas.

Noninvasive diagnosis of recurrent autoimmune type 1 diabetes after islet cell transplantation.

Islet cell transplantation is curative therapy for patients with complicated autoimmune type 1 diabetes (T1D). We report the diagnostic potential of circulating transplant islet-specific exosomes to noninvasively distinguish pancreatic ß cell injury secondary to recurrent autoimmunity vs immunologic rejection. A T1D patient with hypoglycemic unawareness underwent islet transplantation and maintained normoglycemia until posttransplant day 1098 before requiring exogenous insulin. Plasma analysis showed decreased donor islet exosome quantities on day 1001, before hyperglycemia onset. This drop in islet exosome quantity signified islet injury, but did not distinguish injury type. However, analysis of purified transplant islet exosome cargoes showed decrease in insulin-containing exosomes, but not glucagon-containing exosomes, indicating selective destruction of transplanted ß cells secondary to recurrent T1D autoimmunity. Furthermore, donor islet exosome cargo analysis showed time-specific increase in islet autoantigen, glutamic acid decarboxylase 65 (GAD65), implicated in T1D autoimmunity. Time-matched analysis of plasma transplant islet exosomes in 3 control subjects undergoing islet cell transplantation failed to show changes in islet exosome quantities or intraexosomal cargo expression of insulin, glucagon, and GAD65. This is the first report of noninvasive diagnosis of recurrent autoimmunity after islet cell transplantation, suggesting that transplant tissue exosome platform may serve as a biomarker in islet transplant diagnostics.

Donor tissue-specific exosome profiling enables noninvasive monitoring of acute rejection in mouse allogeneic heart transplantation.

OBJECTIVE: In heart transplantation, there is a critical need for development of biomarkers to noninvasively monitor cardiac allografts for immunologic rejection or injury. Exosomes are tissue-specific nanovesicles released into circulation by many cell types. Their profiles are dynamic, reflecting conditional changes imposed on their tissue counterparts. We proposed that a transplanted heart releases donor-specific exosomes into the recipient's circulation that are conditionally altered during immunologic rejection. We investigated this novel concept in a rodent heterotopic heart transplantation model. MATERIALS AND METHODS: Full major histocompatibility mismatch (BALB/c [H2-Kd] into C57BL/6 [H2-Kb]) heterotopic heart transplantation was performed in 2 study arms: Rejection (n = 64) and Maintenance (n = 28). In the Rejection arm, immunocompetent recipients fully rejected the donor heart, whereas in the Maintenance arm, immunodeficient recipients (C57BL/6 PrkdcSCID) accepted the allograft. Recipient plasma exosomes were isolated and a donor heart-specific exosome signal was characterized on the nanoparticle detector for time-specific profile changes using anti-H2-Kd antibody quantum dot. RESULTS: In the Maintenance arm, allografts were viable throughout follow-up of 30 days, with histology confirming absence of rejection or injury. Time course analysis (days 1, 2, 3, 4, 5, 7, 9, 11, 15, and 30) showed that total plasma exosome concentration (P = .157) and donor heart exosome signal (P = .538) was similar between time points. In the Rejection arm, allografts were universally rejected (median, day 11). Total plasma exosome quantity and size distribution were similar between follow-up time points (P = .278). Donor heart exosome signals peaked on day 1, but significantly decreased by day 2 (P = 2 × 10-4) and day 3 (P = 3.3 × 10-6), when histology showed grade 0R rejection. The receiver operating characteristic curve for a binary separation of the 2 study arms (Maintenance vs Rejection) demonstrated that a donor heart exosome signal threshold < 0.3146 was 91.4% sensitive and 95.8% specific for diagnosis of early acute rejection. CONCLUSIONS: Transplant heart exosome profiling enables noninvasive monitoring of early acute rejection with high accuracy. Translation of this concept to clinical settings might enable development of a novel biomarker platform for allograft monitoring in transplantation diagnostics.

Ex Vivo Lung Perfusion Model to Study Pulmonary Tissue Extracellular Microvesicle Profiles.

BACKGROUND: Extracellular microvesicles (EVs) are being increasingly studied for their diagnostic potential. We investigated the feasibility of studying the kinetics and tissue-specific profiles of pulmonary EVs in the context of ex vivo lung perfusion (EVLP) used for salvaging marginal lungs for transplantation. METHODS: Perfusate from six marginal donor lungs placed on EVLP was collected at the following time points: 0, 10, and 60 minutes after and after perfusate exchange with Steen Solution; 120 and 180 minutes. Three lungs were successfully recovered for transplantation (transplant group), and three were not recoverable (nontransplant group). Perfusate EVs were isolated using methods of size exclusion chromatography, ultrafiltration, and ultracentrifugation. EVs were analyzed on NanoSight nanoparticle detector for quantity, size distribution, and surface expression of pulmonary tissue-specific markers. EV cargoes were profiled using mass spectrometry, reverse transcription polymerase chain reaction (RT-PCR), and Western blot analysis. RESULTS: Time course analysis showed EV presence by 10-minute time point. EV median size was smaller in the transplant group (165 nm versus 212 nm, p = 0.04). EV cargo analysis on Western blot analysis, RT-PCR, and NanoSight showed contribution from monocytes (CD14), endothelium (platelet endothelial cell adhesion molecule 1), and pulmonary parenchyma (epithelial cell adhesion molecule) into the perfusate total EV pool. Mass spectrometry showed differences in the EV protein cargoes of the transplant group versus the nontransplant group. CONCLUSIONS: EVLP system provides a platform to understand the kinetics of pulmonary EVs in an isolated fashion. Donor lung recovery may be associated with changes in EV size distribution and proteomic profiles. Pulmonary tissue-specific EV profiling using the EVLP system may provide insights into EV contribution to pulmonary pathologic processes.

Tissue-specific exosome biomarkers for noninvasively monitoring immunologic rejection of transplanted tissue.

In transplantation, there is a critical need for noninvasive biomarker platforms for monitoring immunologic rejection. We hypothesized that transplanted tissues release donor-specific exosomes into recipient circulation and that the quantitation and profiling of donor intra-exosomal cargoes may constitute a biomarker platform for monitoring rejection. Here, we have tested this hypothesis in a human-into-mouse xenogeneic islet transplant model and validated the concept in clinical settings of islet and renal transplantation. In the xenogeneic model, we quantified islet transplant exosomes in recipient blood over long-term follow-up using anti-HLA antibody, which was detectable only in xenoislet recipients of human islets. Transplant islet exosomes were purified using anti-HLA antibody-conjugated beads, and their cargoes contained the islet endocrine hormone markers insulin, glucagon, and somatostatin. Rejection led to a marked decrease in transplant islet exosome signal along with distinct changes in exosomal microRNA and proteomic profiles prior to appearance of hyperglycemia. In the clinical settings of islet and renal transplantation, donor exosomes with respective tissue specificity for islet ß cells and renal epithelial cells were reliably characterized in recipient plasma over follow-up periods of up to 5 years. Collectively, these findings demonstrate the biomarker potential of transplant exosome characterization for providing a noninvasive window into the conditional state of transplant tissue.

Characterization of viscosupplementation formulations using chemical exchange saturation transfer (ViscoCEST).

BACKGROUND: Osteoarthritis (OA) is characterized by progressive loss of cartilage in joints, and is a major cause of pain and disability, and imposes significant health care expense. New therapies are being developed to treat the symptomatic effect of OA, one of which is intra-articular injection of viscosupplementations of different forms of hyaluronic acid (HA). The current study evaluates the chemical exchange saturation transfer (CEST) effect from two popular viscosupplementations [Hylan gf-20 (Synvisc) and hyaluronan (Orthovisc)] by targeting the exchangeable hydroxyl protons present on these molecules (ViscoCEST). METHODS: ViscoCEST imaging from two viscosupplementations (Synvisc and Orthovisc) was performed on a 7T Siemens whole body MRI scanner. ViscoCEST images were collected with different combination of saturation pulse power and saturation duration. Z spectra were acquired at B1rms of 3.6 µT and 1 s saturation duration by varying the frequency from -4 to +4 ppm in step size of 0.1 ppm. Field inhomogeneity (B0) and radiofrequency (B1) maps were also acquired to correct ViscoCEST contrast map for any inhomogeneity. RESULTS: Both viscosupplementations showed broad CEST effect (ViscoCEST), which peaked ~0.8 ppm from down field of water resonance. Orthovisc showed 20 % higher ViscoCEST contrast than Synvisc suggestive of more HA component in Orthovisc. Increased ViscoCEST contrast was observed from both viscosupplementations with increase in B1rms and saturation pulse duration. CONCLUSION: ViscoCEST has a potential to image the spatial distribution of viscosupplements in vivo in patients' intra-articular space as well as temporal variation in their spatial distribution.

In vivo measurement of glutamate loss is associated with synapse loss in a mouse model of tauopathy.

Glutamate is the primary excitatory neurotransmitter in the brain, and is implicated in neurodegenerative diseases such as Alzheimer's disease (AD) and several other tauopathies. The current method for measuring glutamate in vivo is proton magnetic resonance spectroscopy ((1)H MRS), although it has poor spatial resolution and weak sensitivity to glutamate changes. In this study, we sought to measure the effect of tau pathology on glutamate levels throughout the brain of a mouse model of tauopathy using a novel magnetic resonance imaging (MRI) technique. We employed glutamate chemical exchange saturation transfer (GluCEST) imaging, which has been previously validated as a complimentary method for measuring glutamate levels with several important advantages over conventional (1)H MRS. We hypothesized that the regional changes in glutamate levels would correlate with histological measurements of pathology including pathological tau, synapse and neuron loss. Imaging and spectroscopy were carried out on tau transgenic mice with the P301S mutation (PS19, n=9) and their wild-type littermates (WT, n=8), followed by immunohistochemistry of their brain tissue. GluCEST imaging resolution allowed for sub-hippocampal analysis of glutamate. Glutamate was significantly decreased by 29% in the CA sub-region of the PS19 hippocampus, and by 15% in the thalamus, where synapse loss was also measured. Glutamate levels and synapse density remained high in the dentate gyrus sub-region of the hippocampus, where neurogenesis is known to occur. The further development of GluCEST imaging for preclinical applications will be valuable, as therapies are being tested in mouse models of tauopathy.

Imaging of glutamate neurotransmitter alterations in Alzheimer's disease.

Glutamate (Glu) is a major excitatory neurotransmitter in the brain and has been shown to decrease in the early stages of Alzheimer's disease (AD). Using a glutamate chemical (amine) exchange saturation transfer (GluCEST) method, we imaged the change in [Glu] in the APP-PS1 transgenic mouse model of AD at high spatial resolution. Compared with wild-type controls, AD mice exhibited a notable reduction in GluCEST contrast (~30%) in all areas of the brain. The change in [Glu] was further validated through (1) H MRS. A positive correlation was observed between GluCEST contrast and (1) H MRS-measured Glu/total creatine ratio. This method potentially provides a novel noninvasive biomarker for the diagnosis of the disease in preclinical stages and enables the development of disease-modifying therapies for AD.