Fluids and Barriers of the CNS最新文献

Background: According to our previous findings, the integrity of the blood-brain barrier (BBB) is affected by tobacco smoke (TSe) and electronic cigarette (ECe) exposure, and metformin (MF) can counter these detrimental effects. It is unknown, therefore, if MF protects against neuronal dysfunction after BBB damage caused by either TSe or ECe alone or combined exposure (TSe and ECe) in stroke cases. Additionally, MF's ability to enter the ischemic brain during ischemic stroke is unknown. The purpose of this effort is to address these questions.

Methods: A well-established bEnd3/astrocyte co-culture in vitro BBB model was utilized to conduct permeability studies. Normoxia and hypoxia using oxygen-glucose deprivation (OGD) conditions were used to mimic the in vitro stroke conditions. Western blot (WB) and immunofluorescence analysis were performed for relevant molecular targets. Additionally, mitochondrial dysfunction was assessed using Seahorse Mito-stress analysis using primary neurons. Also, tMCAO was performed in C57BL/6 J mice to create ischemic injury. To quantify MF in the mouse brain, a highly sensitive LC-MS/MS technique was used.

Results: According to our findings, a decrease in transendothelial electric resistance (TEER) values and increased permeability coefficient (PC) for sodium fluorescein were observed in the OGD/R condition alone or when combined with TSe, ECe, or mixed exposure compared to the control group. MF pretreatment, however, protected the BBB from losing barrier properties by increasing the TEER and decreasing PC values. Altered expression of tight junction (TJ) proteins was observed following TSe and ECe exposure paired with OGD compared to the control and OGD alone. However, MF was capable of offsetting the majority of these adverse effects by differentially upregulating ZO-1, occludin, and claudin-5 expression. Altered neuronal mitochondrial dynamics and decreased OCR were observed after OGD alone or in combination with TSe or ECe, however, MF pretreatment significantly increased several indices of mitochondrial functions, especially basal respiration, ATP production, and non-mitochondrial O₂ consumption.

Conclusion: Our findings demonstrate that MF pretreatment could be an effective countermeasure following OGD exposure in conjunction with TSe and ECe exposure, which is often linked to the deterioration of the BBB and possibly mitochondrial function.

Background: Neurofluid flow dynamics are frequently studied from asynchronous blood and CSF flow measurements from real-time imaging using separate phase contrast (PC) MRI scans. Asynchronous measures can be influenced by changes in heart rate, respiration, and other physiological processes, obfuscating neurofluids assessment. Here we present an approach for synchronous measures of neurofluids using simultaneous real-time 2D PC MRI and investigated the effects of different breathing patterns on synchronous and asynchronous blood and CSF flow in a group of healthy participants.

Methods: Interleaved dual-velocity encoding 2D PC MRI with retrospective real-time reconstruction was utilized for synchronous neurofluid measures during free breathing, paced breathing and breath holds. Data were collected on a clinical 3.0T scanner at the level of C1/C2 vertebrae in 10 participants. From real-time images, flow rates repeated measures, and cardiac and respiratory flow power were assessed using Bland-Altman, power spectral analyses, and breathing pattern group differences. Neurofluids coupling from cross-correlation between arterial and venous blood and CSF flow signals were quantified from synchronous and asynchronous measures. Real-time images were re-binned to the cardiac cycle and compared to high-temporal resolution cardiac-resolved images in terms of flow rate, pulsatility index, and stroke volume.

Results: Flow repeatability was highest in free breathing scans and in arteries and spinal canal compared to veins from Bland-Altman and repeatability coefficients. Significant differences were measured in cardiac and respiratory flow power across breathing patterns in various vessel segments and spinal canal (P ≤ 0.006). Synchronous blood and CSF cardiac coupling were significantly higher than asynchronous results in all vessels (P = 0.002). For example, free breathing synchronous cardiac couplings ranged from [0.81, 0.93], compared to asynchronous range [0.49, 0.53]. Synchronous cardiac coupling showed significant differences across breathing patterns in most vessels (P = 0.002). Comparison between real-time cardiac re-binned images and high-temporal resolution cardiac-resolved images showed high correlations for flow rate and spinal canal stroke volume (ρ ≥ 0.95) and lower for pulsatility index (ρ = [0.45, 0.88]).

Conclusions: Breathing patterns induced significant responses across neurofluids including in flow rates, flow power, and coupling parameters. Higher cross-correlation among synchronous measures support benefits over asynchronous measures for neurofluids coupling characterization.

Cerebral small vessel disease (CSVD) encompasses diffuse brain lesions arising from structural injury to small vessels, and is closely associated with chronic hypoperfusion and blood-brain barrier (BBB) dysfunction. Its insidious onset and heterogeneous clinical manifestations render elucidation of its pathogenesis and development of targeted interventions of paramount clinical importance. Transforming growth factorβ (TGFβ), a pivotal regulator of vascular homeostasis, exerts bidirectional effects within the neurovascular unit (NVU) during CSVD: under physiological conditions, TGFβ maintains barrier integrity by modulating endothelial tight junction proteins and pericyte adhesion; under pathological stress, dysregulated TGFβ signaling induces endothelial dysfunction, pericyte degeneration and neuroinflammation, thereby promoting white-matter injury. Precise, spatiotemporal modulation of TGFβ pathways therefore represents a promising avenue for stage-specific, molecularly targeted therapy in CSVD.

Background: The white matter damage inducing the reemergence of grasp reflexes and their potential lateralization remains unstudied. Idiopathic normal pressure hydrocephalus (iNPH), a subcortical dementia, is an ideal model for these investigations. We aim to understand the contributions of white matter to the inhibition of grasp reflexes in patients with iNPH.

Methods: A total of 48 patients (mean age at admission: 77.8 ± 5.2 years; 56% male) with probable iNPH were retrospectively enrolled in this study. The intensity of grasp reflexes was assessed using a four-category classification. A voxel-based morphometric analysis of the fractional anisotropy (FA) maps was conducted to identify responsible regions related to the grasp reflex. The white matter fibers passing through these regions were tracked using fiber-tracking data from fifty age-/sex-matched healthy subjects from the Lifespan Human Connectome Project Aging Study. Fibers with an inter-subject overlap rate > 50% were defined as reliable tracts for further discussion.

Results: Positive grasp reflex was identified in 60% (29/48) of probable iNPH cases. The voxel-based multiple regression analysis revealed that the reflex intensity scores were negatively correlated with FA values in the right frontal subcortical white matter near the anterior horn of the right lateral ventricle. The white matter fibers project through this structure mainly to the posterior parts of the right superior, middle, and inferior frontal gyri; the bilateral presupplementary motor areas; the right dorsal anterior cingulate cortex; the ventral lateral nuclei of the bilateral thalami; the pulvinar inferior nucleus of the right thalamus; the lateral part of the right putamen; and the right subthalamic nucleus.

Conclusion: The inhibition of grasp reflexes is achieved via a right-lateralized prefrontal cortex-basal ganglia-thalamocortical 'stopping' network.

A Comment to our recent paper that described a budget for brain metabolic water production claimed that all ATP produced by oxidation of glucose is consumed by hydrolysis, and that the net calculated production of metabolic water is equal to that obtained by combustion of glucose. However, ATP is synthesized and consumed by enzymatic reactions that do not involve water in the mechanism. Not all ATP consumed is hydrolyzed.

A recent paper suggests that the water originating from the ATP production coupled to aerobic glucose oxidation causes more than a 6 fold increase in the production of metabolic water, compared with the standard textbook description of the oxidation process. However, the authors seem to have forgotten that the simultaneous processes of ATP utilization takes up the same amount of water, which was liberated during the ATP synthesis. Thus, at steady state, there is no net increase in the production of metabolic water.