Inverse correlation between endothelin-1-induced peripheral microvascular vasoconstriction and blood pressure in glaucoma patients

• Background: The potent vasoconstrictor peptide endothelin-I has been shown to participate in the control of peripheral vascular tone and in the regulation of ocular perfusion. In glaucoma patients vasospasms and arterial hypotension have been identified as risk factors for the progression of glaucomatous damage, and the regulation of endothelin-1 release is disturbed in some of these patients. The aim of this study was to assess the relationship between resting blood pressure and cutaneous vascular responsiveness to endothelin-1 and phenylephrine in patients with glaucoma and in matched controls. • Methods: In 9 patients with primary open-angle glaucoma (POAG), 7 patient with normal tension glaucoma (NTG), and 16 age- and sex-matched controls, endothelin-1 and phenylephrine responses were assessed in the human forearm microcirculation using laser Doppler flowmetry during intra-arterial drug administration. Blood pressure was measured intra-arterially. • Results: In contrast to α1-adrenergic effects, endothelin-1 responses were inversely correlated to both systolic (r 2 = 0.27,P = 0.05) and diastolic (r 2 = 0.54,P = 0.001) blood pressure in glaucoma patients, whereas there was no such correlation in controls. Patients with lower blood pressure values were more sensitive to the vasoconstrictor effects of endothelin-1. Cutaneous responsiveness to endothelin-1 and phenylephrine was similar in glaucoma patients and in controls. • Conclusion: These results reveal that glaucoma patients appear to have peripheral microvascular abnormalities which are exhibited as altered responsiveness to endothelin-1. Thus, this study supports the hypothesis that endothelin-l-related microvascular dysfunction may be involved in the pathogenesis of glaucomatous damag

An acetylcholine alpha7 positive allosteric modulator rescues a schizophrenia-associated brain endophenotype in the 15q13.3 microdeletion, encompassing CHRNA7

The 15q13.3 microdeletion copy number variation is strongly associated with schizophrenia and epilepsy. The CHRNA7 gene, encoding nicotinic acetylcholine alpha 7 receptors (nAChA7Rs), is hypothesized to be one of the main genes in this deletion causing the neuropsychiatric phenotype. Here we used a recently developed 15q13.3 microdeletion mouse model to explore whether an established schizophrenia-associated connectivity phenotype is replicated in a murine model, and whether positive modulation of nAChA7 receptor might pharmacologically normalize the connectivity patterns. Resting-state fMRI data were acquired from male mice carrying a hemizygous 15q13.3 microdeletion (N=9) and from wild-type mice (N=9). To study the connectivity profile of 15q13.3 mice and test the effect of nAChA7 positive allosteric modulation, the 15q13.3 mice underwent two imaging sessions, one week apart, receiving a single intraperitoneal injection of either 15 mg/kg Lu AF58801 or saline. The control group comprised wild-type mice treated with saline. We performed seed-based functional connectivity analysis to delineate aberrant connectivity patterns associated with the deletion (15q13.3 mice (saline treatment) versus wild-type mice (saline treatment)) and their modulation by Lu AF58801 (15q13.3 mice (Lu AF58801 treatment) versus 15q13.3 mice (saline treatment)). Compared to wild-type mice, 15q13.3 mice evidenced a predominant hyperconnectivity pattern. The main effect of Lu AF58801 was a normalization of elevated functional connectivity between prefrontal and frontal, hippocampal, striatal, thalamic and auditory regions. The strongest effects were observed in brain regions expressing nAChA7Rs, namely hippocampus, cerebral cortex and thalamus. These effects may underlie the antiepileptic, pro-cognitive and auditory gating deficit-reversal effects of nAChA7R stimulation

A generalizable deep voxel-guided morphometry algorithm for the detection of subtle lesion dynamics in multiple sclerosis

IntroductionMultiple sclerosis (MS) is a chronic neurological disorder characterized by the progressive loss of myelin and axonal structures in the central nervous system. Accurate detection and monitoring of MS-related changes in brain structures are crucial for disease management and treatment evaluation. We propose a deep learning algorithm for creating Voxel-Guided Morphometry (VGM) maps from longitudinal MRI brain volumes for analyzing MS disease activity. Our approach focuses on developing a generalizable model that can effectively be applied to unseen datasets.MethodsLongitudinal MS patient high-resolution 3D T1-weighted follow-up imaging from three different MRI systems were analyzed. We employed a 3D residual U-Net architecture with attention mechanisms. The U-Net serves as the backbone, enabling spatial feature extraction from MRI volumes. Attention mechanisms are integrated to enhance the model's ability to capture relevant information and highlight salient regions. Furthermore, we incorporate image normalization by histogram matching and resampling techniques to improve the networks' ability to generalize to unseen datasets from different MRI systems across imaging centers. This ensures robust performance across diverse data sources.ResultsNumerous experiments were conducted using a dataset of 71 longitudinal MRI brain volumes of MS patients. Our approach demonstrated a significant improvement of 4.3% in mean absolute error (MAE) against the state-of-the-art (SOTA) method. Furthermore, the algorithm's generalizability was evaluated on two unseen datasets (n = 116) with an average improvement of 4.2% in MAE over the SOTA approach.DiscussionResults confirm that the proposed approach is fast and robust and has the potential for broader clinical applicability

Inherited and de novo SHANK2 variants associated with autism spectrum disorder impair neuronal morphogenesis and physiology

Mutations in the postsynaptic scaffolding gene SHANK2 have recently been identified in individuals with autism spectrum disorder (ASD) and intellectual disability. However, the cellular and physiological consequences of these mutations in neurons remain unknown. We have analyzed the functional impact caused by two inherited and one de novo SHANK2 mutations from ASD individuals (L1008_P1009dup, T1127M, R462X). Although all three variants affect spine volume and have smaller SHANK2 cluster sizes, T1127M additionally fails to rescue spine volume in Shank2 knock-down neurons. R462X is not able to rescue spine volume and dendritic branching and lacks postsynaptic clustering, indicating the most severe dysfunction. To demonstrate that R462X when expressed in mouse can be linked to physiological effects, we analyzed synaptic transmission and behavior. Principal neurons of mice expressing rAAV-transduced SHANK2-R462X present a specific, long-lasting reduction in miniature postsynaptic AMPA receptor currents. This dominant negative effect translates into dose-dependent altered cognitive behavior of SHANK2-R462X-expressing mice, with an impact on the penetrance of ASD

The modulation of auditory novelty processing by working memory load in school age children and adults: a combined behavioral and event-related potential study

<p>Abstract</p> <p>Background</p> <p>We investigated the processing of task-irrelevant and unexpected novel sounds and its modulation by working-memory load in children aged 9-10 and in adults. Environmental sounds (novels) were embedded amongst frequently presented standard sounds in an auditory-visual distraction paradigm. Each sound was followed by a visual target. In two conditions, participants evaluated the position of a visual stimulus (0-back, low load) or compared the position of the current stimulus with the one two trials before (2-back, high load). Processing of novel sounds were measured with reaction times, hit rates and the auditory event-related brain potentials (ERPs) Mismatch Negativity (MMN), P3a, Reorienting Negativity (RON) and visual P3b.</p> <p>Results</p> <p>In both memory load conditions novels impaired task performance in adults whereas they improved performance in children. Auditory ERPs reflect age-related differences in the time-window of the MMN as children showed a positive ERP deflection to novels whereas adults lack an MMN. The attention switch towards the task irrelevant novel (reflected by P3a) was comparable between the age groups. Adults showed more efficient reallocation of attention (reflected by RON) under load condition than children. Finally, the P3b elicited by the visual target stimuli was reduced in both age groups when the preceding sound was a novel.</p> <p>Conclusion</p> <p>Our results give new insights in the development of novelty processing as they (1) reveal that task-irrelevant novel sounds can result in contrary effects on the performance in a visual primary task in children and adults, (2) show a positive ERP deflection to novels rather than an MMN in children, and (3) reveal effects of auditory novels on visual target processing.</p

Progranulin Gene Variability and Plasma Levels in Bipolar Disorder and Schizophrenia

Basing on the assumption that frontotemporal lobar degeneration (FTLD), schizophrenia and bipolar disorder (BPD) might share common aetiological mechanisms, we analyzed genetic variation in the FTLD risk gene progranulin (GRN) in a German population of patients with schizophrenia (n = 271) or BPD (n = 237) as compared with 574 age-, gender- and ethnicity-matched controls. Furthermore, we measured plasma progranulin levels in 26 German BPD patients as well as in 61 Italian BPD patients and 29 matched controls

Multiple Sklerose Therapie Konsensus Gruppe (MSTKG): Positionspapier zur verlaufsmodifizierenden Therapie der Multiplen Sklerose 2021 (White Paper)

Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, Switzerland)