The glucocorticoid receptor as a master regulator of the Müller cell response to diabetic conditions in mice.

Diabetic retinopathy (DR) is considered a primarily microvascular complication of diabetes. Müller glia cells are at the centre of the retinal neurovascular unit and play a critical role in DR. We therefore investigated Müller cell-specific signalling pathways that are altered in DR to identify novel targets for gene therapy. Using a multi-omics approach on purified Müller cells from diabetic db/db mice, we found the mRNA and protein expression of the glucocorticoid receptor (GR) to be significantly decreased, while its target gene cluster was down-regulated. Further, oPOSSUM TF analysis and ATAC- sequencing identified the GR as a master regulator of Müller cell response to diabetic conditions. Cortisol not only increased GR phosphorylation. It also induced changes in the expression of known GR target genes in retinal explants. Finally, retinal functionality was improved by AAV-mediated overexpression of GR in Müller cells. Our study demonstrates an important role of the glial GR in DR and implies that therapeutic approaches targeting this signalling pathway should be aimed at increasing GR expression rather than the addition of more ligand.

Cerebral Microhemorrhage at MRI in Mild Cognitive Impairment and Early Alzheimer Disease: Association with Tau and Amyloid ß at PET Imaging.

Background Growing evidence indicates an association between cerebral microhemorrhages (MHs) and amyloid ß accumulation in Alzheimer disease (AD), but to the knowledge of the authors the association with tau burden is unknown. Purpose To investigate the association between cerebral MH load and tau pathologic structure measured in healthy older individuals and individuals along the AD spectrum, stratified by using the A (amyloid ß)/T (tau)/N (neurodegeneration) biomarker classification system. Materials and methods In this prospective cohort study, participants from the AD Neuroimaging Initiative were included (healthy control participants, participants with mild cognitive impairment, and participants with AD dementia; data from October 2005 to January 2019). T2*-weighted gradient-echo MRI was performed to quantify MH, fluorine 18 (18F) flortaucipir (AV-1451) PET was performed to quantify tau, and 18F-florbetaben/18F- florbetapir (AV45) PET was performed to quantify amyloid ß to study associations of MH with regional and global tau and amyloid ß load. Associations with cerebrospinal fluid (CSF) biomarkers (amyloid ß1-42, total tau, phosphorylated tau 181) were also assessed. Analysis of covariance and Spearman rank correlation test for cross-sectional analysis and Wilcoxon signed rank test for longitudinal analyses were used, controlling for multiple comparisons (Bonferroni significance threshold, P < .008). Results Evaluated were 343 participants (mean age, 75 years ± 7; 186 women), including 205 participants who were A-TN- (mean age, 73 years ± 7; 115 women), 80 participants who were A+TN- (mean age, 76 years ± 7; 38 women), and 58 participants who were A+TN+ (mean age, 77 ± 8; 34 women). MH count was associated with global (Spearman ρ = 0.27; P = .004) and frontal (ρ = 0.27; P = .005) amyloid ß load and global tau load (ρ = 0.31; P = .001). In a longitudinal analysis, MH count increased significantly over approximately 5 years in the entire cohort (T-1, 81 [range, 0-6 participants]; T0, 214 [range, 0-58 participants]; P < .001), in A+TN+ (T-1, 20 [range, 0-5 participants]; T0, 119 [range, 1-58 participants]; P < .001), A+TN- (T-1, 31 [range, 0-6 participants]; T0, 43 [range, 0-8 participants]; P = .03), and A-TN- (T-1, 30 [range, 0-4 participants]; T0, 52 [range, 0-6 participants]; P = .007). A higher MH count was associated with higher future global (ρ = 0.29; P = .008) and parietal (ρ = 0.31; P = .005) amyloid ß and parietal tau load (ρ = 0.31; P = .005). Conclusion Cerebral microhemorrhage load is associated spatially with tau accumulation, both cross-sectionally and longitudinally. © RSNA, 2020 Online supplemental material is available for this article.

The role of Müller cell glucocorticoid signaling in diabetic retinopathy.

Diabetic retinopathy (DR) is a sight-threatening complication associated with the highly prevalent diabetes disorder. Both the microvascular damage and neurodegeneration detected in the retina caused by chronic hyperglycemia have brought special attention to Müller cells, the major macroglia of the retina that are responsible for retinal homeostasis. Given the role of glucocorticoid signaling in anti-inflammatory responses and the almost exclusive expression of glucocorticoid receptors (GRs) in retinal Müller cells, administration of corticosteroid agonists as a potential treatment option has been widely studied. Although these approaches have been moderately efficacious in treating or de-escalating DR pathomechanisms, there are various side effects and gaps of knowledge with regard to introducing exogenous glucocorticoids to the diseased retina. In this paper, we provide a review of the literature concerning the available evidence for the role of Müller cell glucocorticoid signaling in DR and we discuss previously investigated approaches in modulating this system as possible treatment options. Furthermore, we propose a novel alternative to the available choices of treatment by using gene therapy as a tool to regulate the expression of GR in retinal Müller cells. Upregulating GR expression allows for induced glucocorticoid signaling with more enduring effects compared to injection of agonists. Hence, repetitive injections would no longer be required. Lastly, side effects of glucocorticoid therapy such as glucocorticoid resistance of GR following chronic exposure to excess ligands or agonists can be avoided.

Code Stroke Postendoscopy: A Case of Pneumocephalus From a Spinal-Esophageal Fistula.

Esophageal fistula to the respiratory tract and mediastinum is a well-described complication from esophageal malignancies. Spinal-esophageal fistula (SEF) on the other hand is a much rarer complication that has only been reported in few instances. Here, we report a unique case of fatal spinal-esophageal fistula with an associated pneumocephalus in an 83-year-old woman with metastatic esophageal squamous cell carcinoma.

Delayed Topographical and Refractive Changes Following Corneal Cross-Linking for Keratoconus.

Background: The aim of this study was to analyze the long-term topographic and refractive outcomes of corneal cross-linking (CXL) in keratoconus. Methods: We used a retrospective observational study of patients with keratoconus who underwent CXL with a minimum follow-up of 5 years. Patients' refractive and topography data (corrected distance visual acuity, sphere, cylinder, average and maximum keratometry, and corneal aberrations) were collected. Results: A total of 112 patients/150 eyes (mean age: 33.2 ± 10.7 years; range: 13−61) were included. The mean follow-up was 5.87 ± 1.35 years (range: 5−10). At the last follow-up visit, an improvement in CDVA, spherical and cylindrical refraction, average and steepest keratometry, and corneal aberrations were observed (p < 0.05), with the exception of trefoil. At the last visit, 49 (34.8%) and 31 (22.0%) eyes had an improvement beyond 1D in their spherical and cylindrical power, respectively, and 43 (28.7%) eyes had a flattening of their steepest keratometry. Progressive improvement over time was observed for spherical refraction; max and mean-K; as well as corneal RMS, total, high, coma, and spherical aberrations (p < 0.05). More severe disease at the baseline correlated with an improvement in corneal aberrations over time. Conclusions: In addition to a progressive improvement in refractive and keratometric indices, corneal aberrations also demonstrate a steady decline with long-term follow-up after CXL, which was more pronounced in more severe patients.

The impact of endurance training and table soccer on brain metabolites in schizophrenia.

Higher glutamate and glutamine (together: Glx) and lower N-acetyl-aspartate (NAA) levels were reported in schizophrenia. Endurance training normalizes NAA in the hippocampus, but its effects on other metabolites in the brain and the relationship of metabolites to clinical symptoms remain unknown. For 12 weeks, 20 schizophrenia inpatients (14 men, 6 women) and 23 healthy controls (16 men, 7 women) performed endurance training and a control group of 21 schizophrenia inpatients (15 men, 6 women) played table soccer. A computer-assisted cognitive performance training program was introduced after 6 weeks. We assessed cognitive performance, psychopathological symptoms, and everyday functioning at baseline and after 6 and 12 weeks and performed single voxel magnetic resonance spectroscopy of the hippocampus, left dorsolateral prefrontal cortex (DLPFC), and thalamus. We quantified NAA, Glx, total creatine (tCr), calculated NAA/tCr and Glx/tCr and correlated these ratios with physical fitness, clinical and neurocognitive scores, and everyday functioning. At baseline, in both schizophrenia groups NAA/tCr was lower in the left DLPFC and left hippocampus and Glx/tCr was lower in the hippocampus than in the healthy controls. After 6 weeks, NAA/tCr increased in the left DLPFC in both schizophrenia groups. Brain metabolites did not change significantly in the hippocampus or thalamus, but the correlation between NAA/tCr and Glx/tCr normalized in the left DLPFC. Global Assessment of Functioning improvements correlated with NAA/tCr changes in the left DLPFC. In our study, endurance training and table soccer induced normalization of brain metabolite ratios in the brain circuitry associated with neuronal and synaptic elements, including metabolites of the glutamatergic system.

Predicting Response to Repetitive Transcranial Magnetic Stimulation in Patients With Schizophrenia Using Structural Magnetic Resonance Imaging: A Multisite Machine Learning Analysis.

Background: The variability of responses to plasticity-inducing repetitive transcranial magnetic stimulation (rTMS) challenges its successful application in psychiatric care. No objective means currently exists to individually predict the patients' response to rTMS. Methods: We used machine learning to develop and validate such tools using the pre-treatment structural Magnetic Resonance Images (sMRI) of 92 patients with schizophrenia enrolled in the multisite RESIS trial (http://clinicaltrials.gov, NCT00783120): patients were randomized to either active (N = 45) or sham (N = 47) 10-Hz rTMS applied to the left dorsolateral prefrontal cortex 5 days per week for 21 days. The prediction target was nonresponse vs response defined by a ≥20% pre-post Positive and Negative Syndrome Scale (PANSS) negative score reduction. Results: Our models predicted this endpoint with a cross-validated balanced accuracy (BAC) of 85% (nonresponse/response: 79%/90%) in patients receiving active rTMS, but only with 51% (48%/55%) in the sham-treated sample. Leave-site-out cross-validation demonstrated cross-site generalizability of the active rTMS predictor despite smaller training samples (BAC: 71%). The predictive pre-treatment pattern involved gray matter density reductions in prefrontal, insular, medio-temporal, and cerebellar cortices, and increments in parietal and thalamic structures. The low BAC of 58% produced by the active rTMS predictor in sham-treated patients, as well as its poor performance in predicting positive symptom courses supported the therapeutic specificity of this brain pattern. Conclusions: Individual responses to active rTMS in patients with predominant negative schizophrenia may be accurately predicted using structural neuromarkers. Further multisite studies are needed to externally validate the proposed treatment stratifier and develop more personalized and biologically informed rTMS interventions.