Single Versus Multi-channel Dispersion Analysis of Ultrasonic Guided Waves Propagating in Long Bones.

Ultrasonic guided wave techniques have been applied to characterize cortical bone for osteoporosis assessment. Compared with the current gold-standard X-ray-based diagnostic methods, ultrasound-based techniques pose some advantages such as compactness, low cost, lack of ionizing radiation, and their ability to detect the mechanical properties of the cortex. Axial transmission technique with a source-receiver offset is employed to acquire the ultrasound data. The dispersion characteristics of the guided waves in bones are normally analyzed in the transformed domains using the dispersion curves. The transformed domain can be time-frequency map using a single channel or wavenumber-frequency (or phase velocity-frequency) map with multi-channels. In terms of acquisition effort, the first method is more cost- and time-effective than the latter. However, it remains unclear whether single-channel dispersion analysis can provide as much quantitative guided-wave information as the multi-channel analysis. The objective of this study is to compare the two methods using numerically simulated and ex vivo data of a simple bovine bone plate and explore their advantages and disadvantages. Both single- and multi-channel signal processing approaches are implemented using sparsity-constrained optimization algorithms to reinforce the focusing power. While the single-channel data acquisition and processing are much faster than those of the multi-channel, modal identification and analysis of the multi-channel data are straightforward and more convincing.

Epigenetic Mechanisms Underlying Adult Post Stroke Neurogenesis.

Stroke remains the leading cause of adult disability. Post-stroke neurogenesis contributes to functional recovery. As an intrinsic neurorestorative process, it is important to elucidate the molecular mechanism underlying stroke-induced neurogenesis and to develop therapies designed specifically to augment neurogenesis. Epigenetic mechanisms include DNA methylation, histone modification and its mediation by microRNAs and long-non-coding RNAs. In this review, we highlight how epigenetic factors including DNA methylation, histone modification, microRNAs and long-non-coding RNAs mediate stroke-induced neurogenesis including neural stem cell self-renewal and cell fate determination. We also summarize therapies targeting these mechanisms in the treatment of stroke.

Modeling glymphatic system of the brain using MRI.

The glymphatic system is functional waste clearance path from the brain parenchyma through dynamic exchange of cerebrospinal fluid (CSF) with interstitial fluid (ISF). Impairment of glymphatic waste clearance is involved in the development of neurodegenerative conditions. Despite many recent studies investigating the glymphatic system, few studies have tried to use a mathematical model to describe this system, quantitatively. In this study, we aim to model the glymphatic system from the kinetics of Gd-DTPA tracer measured using MRI in order to: 1) map the glymphatic system path, 2) derive kinetic parameters of the glymphatic system, and 3) provide quantitative maps of the structure and function of this system. In the proposed model, the brain is clustered to similar regions with respect to the profile of contrast agent (CA) density measured by MRI. Then, each region is described as a two-compartment kinetic model 'derived from' or 'clears to' its neighbors with local input function. We thus fit our model to the local cerebral regions rather than to the averaged time signal curve (TSC) of the whole brain. The estimated parameters showed distinctive differences between diabetes mellitus (DM) and control rats. The results suggest that in a typical DM brain the CSF bulk speed in the para-vasculature network is low. In addition, the resulting maps indicate that there may be increased binding and decreased absorbing of large molecules in a diabetic compared with a non-diabetic brain. The important contribution of this work was to fit the model to the local regions rather than to the averaged time signal curve (TSC) of the whole brain. This enabled us to derive quantitative maps of the glymphatic system from MRI.

MRI investigation of glymphatic responses to Gd-DTPA infusion rates.

The glymphatic system is a newly identified waste clearance pathway in brain discovered and investigated predominately using in vivo two-photon confocal microscopy. Magnetic resonance imaging (MRI), in contrast to two-photon confocal microscopy, provides dynamic and real-time pictures of the glymphatic system in whole brain. We employ MRI to investigate the response of the glymphatic system to the rate of infusion of Gd-DTPA (magnevist). Wistar rats were subjected to a surgery of inserting a tube into the cisterna magna for infusion during MRI. Three infusion rates were chosen for 20 min infusions of diluted magnevist into the cerebrospinal fluid (CSF) of rat brain. Glymphatic response was imaged using dynamic MRI 3D measurement for 5 hr. Robust correlations were found in all ventricles between the peak intensities of image enhancement and infusion rates, with additional correlations between the peak times of MRI image enhancement and infusion rates in the fourth ventricle. An infusion rate of 2.92 µL/min induced an evident accumulation of tracer in the fourth ventricle near the cisterna magna. In hippocampal tissue, image enhancements exhibited low correlation with the infusion rates. However, an infusion rate of 1.67 µL/min provided a high image enhancement, but less tracer accumulation near the cisterna magna. Contrast-enhanced MRI provides a suitable tool for investigating image contrast infusion rate response of the glymphatic system in rat brain. Considering both T1 and T2* effects in response to the infused magnevist into CSF, the infusion rate of 1.67 µL/min appears suitable for MRI study of the glymphatic system in rat.

ABCA1/ApoE/HDL Pathway Mediates GW3965-Induced Neurorestoration After Stroke.

BACKGROUND AND PURPOSE: ATP-binding cassette transporter A1 (ABCA1) is a major reverse cholesterol transporter and plays critical role in the formation of brain high-density lipoprotein (HDL) cholesterol. Apolipoprotein E (ApoE) is the most abundant apolipoprotein and transports cholesterol into cells in brain. ABCA1 and ApoE are upregulated by liver-X receptors. Activation of liver-X receptors has neurorestorative benefit for stroke. The current study investigates whether ABCA1/ApoE/HDL pathway mediates GW3965, a synthetic dual liver-X receptor agonist, induced neurorestoration after stroke. METHODS: Middle-aged male specific brain ABCA1-deficient (ABCA1-B/-B) and floxed-control (ABCA1fl/fl) mice were subjected to distal middle-cerebral artery occlusion (dMCAo) and gavaged with saline or GW3965 (10 mg/kg) or intracerebral infusion of artificial cerebrospinal fluid or human plasma HDL3 in ABCA1-B/-B stroke mice, starting 24 hours after dMCAo and daily until euthanization 14 days after dMCAo. RESULTS: No differences in the blood level of total cholesterol and triglyceride and lesion volume were found among the groups. Compared with ABCA1fl/fl ischemic mice, ABCA1-B/-B ischemic mice exhibited impairment functional outcome and decreased ABCA1/ApoE expression and decreased gray/white matter densities in the ischemic boundary zone 14 days after dMCAo. GW3965 treatment of ABCA1fl/fl ischemic mice led to increased brain ABCA1/ApoE expression, concomitantly to increased blood HDL, gray/white matter densities and oligodendrocyte progenitor cell numbers in the ischemic boundary zone, as well as improved functional outcome 14 days after dMCAo. GW3965 treatment had negligible beneficial effects in ABCA1-B/-B ischemic mice. However, intracerebral infusion of human plasma HDL3 significantly attenuated ABCA1-B/-B-induced deficits. In vitro, GW3965 treatment (5 µM) increased ABCA1/synaptophysin level and neurite/axonal outgrowth in primary cortical neurons derived from ABCA1fl/fl embryos, but not in neurons derived from ABCA1-B/-B embryos. HDL treatment (80 µg/mL) attenuated the reduction of neurite/axonal outgrowth in neurons derived from ABCA1-B/-B embryos. CONCLUSIONS: ABCA1/ApoE/HDL pathway, at least partially, contributes to GW3965-induced neurorestoration after stroke.

Effect of inserting charged peptide at NH(2)-terminal on N-type inactivation of Kv1.4 channel.

Rapid inactivation of voltage-gated potassium channel plays an important role in shaping the electrical signaling in neurons and other excitable cells. N-type ("ball and chain") inactivation, as the most extensively studied inactivation model, is assumed to be the inactivation mechanism of Kv1.4 channel. The inactivation ball inactivates the channel by interacting with the hydrophobic wall of inner pore and occluding it. Recently, we have proved that the electrostatic interaction between two charged segments in the NH(2)-termainal plays an important role through promoting the inactivation process of the Kv1.4 channel. This study investigates the effect of inserting negatively or positively charged short peptides at NH(2)-terminal on the inactivation of Kv1.4 channel. The results that inserting negatively-charged peptide (either myc or D-peptide) at different sites of NH(2)-terminal, deceleraes inactivation process of Kv1.4 channel to a different extent with inserting site changing and that the mutant Kv1.4-D50 exhibits a more slower inactivation rate than Kv1.4-K50 further identified the role of electrostatic interactions in the "ball and chain" inactivation mechanism.

The Glymphatic Response to the Development of Type 2 Diabetes.

The glymphatic system has recently been shown to be important in neurological diseases, including diabetes. However, little is known about how the progressive onset of diabetes affects the glymphatic system. The aim of this study is to investigate the glymphatic system response to the progressive onset of diabetes in a rat model of type 2 diabetic mellitus. Male Wistar rats (n = 45) with and without diabetes were evaluated using MRI glymphatic tracer kinetics, functional tests, and brain tissue immunohistochemistry. Our data demonstrated that the contrast agent clearance impairment gradually progressed with the diabetic duration. The MRI data showed that an impairment in contrast clearance occurred prior to the cognitive deficits detected using functional tests and permitted the detection of an early DM stage compared to the immuno-histopathology and cognitive tests. Additionally, the quantitative MRI markers of brain waste clearance demonstrated region-dependent sensitivity in glymphatic impairment. The improved sensitivity of MRI markers in the olfactory bulb and the whole brain at an early DM stage may be attributed to the important role of the olfactory bulb in the parenchymal efflux pathway. MRI can provide sensitive quantitative markers of glymphatic impairment during the progression of DM and can be used as a valuable tool for the early diagnosis of DM with a potential for clinical application.

Treatment of vascular dementia in female rats with AV-001, an Angiopoietin-1 mimetic peptide, improves cognitive function.

Background: Vascular dementia (VaD) is a complex neurodegenerative disorder. We previously found that treatment of VaD in middle-aged male rats subjected to multiple microinfarction (MMI) with AV-001, a Tie2 receptor agonist, significantly improves cognitive function. Age and sex affect the development and response of VaD to therapeutic intervention. Thus, the present study investigated the therapeutic effect of AV-001 on VaD in aged female rats subjected to MMI. Methods: Female 18-month-old Wistar rats were subjected to MMI by injecting either 1,000 (low dose, LD-MMI) or 6,000 (high dose, HD-MMI) cholesterol crystals of size 70-100 µm into the right internal carotid artery. AV-001 (1 µg/Kg, i.p.) was administered once daily after MMI for 1 month, with treatment initiated 1 day after MMI. A battery of behavioral tests to examine sensorimotor and cognitive functions was performed at 21-28 days after MMI. All rats were sacrificed at 1 month after MMI. Results: Aged female rats subjected to LD-MMI exhibit severe neurological deficits, memory impairment, and significant white matter (WM) and oligodendrogenesis injury in the corpus callosum compared with control rats. HD-MMI in aged female rats induces significant anxiety- and depression-like behaviors, which were not detected in LD-MMI aged female rats. Also, HD-MMI induces significantly increased WM injury compared to LD-MMI. AV-001 treatment of LD-MMI and HD-MMI increases oligodendrogenesis, myelin and axon density in the corpus callosum and striatal WM bundles, promotes WM integrity and attenuates neurological and cognitive deficits. Additionally, both LD-MMI and HD-MMI rats exhibit a significant increase, while AV-001 significantly decreases the levels of inflammatory factors in the cerebrospinal fluid (CSF). Conclusion: MMI reduces oligodendrogenesis, and induces demyelination, axonal injury and WM injury, and causes memory impairment, while HD-MMI induces increased WM injury and further depression-like behaviors compared to LD-MMI rats. AV-001 has a therapeutic effect on aged female rats with MMI by reducing WM damage and improving neuro-cognitive outcomes.

The Association between Glymphatic System and Perivascular Macrophages in Brain Waste Clearance.

The glymphatic system suggests the convective bulk flow of cerebrospinal fluid (CSF) through perivascular spaces and the interstitial spaces of the brain parenchyma for the rapid removal of toxic waste solutes from the brain. However, the presence of convective bulk flow within the brain interstitial spaces is still under debate. We first addressed this argument to determine the involvement of the glymphatic system in brain waste clearance utilizing contrast-enhanced 3D T1-weighted imaging (T1WI), diffusion tensor imaging (DTI), and confocal microscopy imaging. Furthermore, perivascular macrophages (PVMs), which are immune cells located within perivascular spaces, have not been thoroughly explored for their association with the glymphatic system. Therefore, we investigated tracer uptake by PVMs in the perivascular spaces of both the arteries/arterioles and veins/venules and the potential association of PVMs in assisting the glymphatic system for interstitial waste clearance. Our findings demonstrated that both convective bulk flow and diffusion are responsible for the clearance of interstitial waste solutes from the brain parenchyma. Furthermore, our results suggested that PVMs may play an important function in glymphatic system-mediated interstitial waste clearance. The glymphatic system and PVMs could be targeted to enhance interstitial waste clearance in patients with waste-associated neurological conditions and aging.

Therapeutic effects of CD133 + Exosomes on liver function after stroke in type 2 diabetic mice.

Background and purpose: Non-alcoholic fatty liver disease (NAFLD) is known to adversely affect stroke recovery. However, few studies investigate how stroke elicits liver dysfunction, particularly, how stroke in type 2 diabetes mellitus (T2DM) exacerbates progression of NAFLD. In this study, we test whether exosomes harvested from human umbilical cord blood (HUCBC) derived CD133 + cells (CD133 + Exo) improves neuro-cognitive outcome as well as reduces liver dysfunction in T2DM female mice. Methods: Female, adult non-DM and T2DM mice subjected to stroke presence or absence were considered. T2DM-stroke mice were randomly assigned to receive PBS or Exosome treatment group. CD133 + Exo (20 µg/200 µl PBS, i.v.) was administered once at 3 days after stroke. Evaluation of neurological (mNSS, adhesive removal test) and cognitive function [novel object recognition (NOR) test, odor test] was performed. Mice were sacrificed at 28 days after stroke and brain, liver, and serum were harvested. Results: Stroke induces severe and significant short-term and long-term neurological and cognitive deficits which were worse in T2DM mice compared to non-DM mice. CD133 + Exo treatment of T2DM-stroke mice significantly improved neurological function and cognitive outcome indicated by improved discrimination index in the NOR and odor tests compared to control T2DM-stroke mice. CD133 + Exo treatment of T2DM stroke significantly increased vascular and white matter/axon remodeling in the ischemic brain compared to T2DM-stroke mice. However, there were no differences in the lesion volume between non-DM stroke, T2DM-stroke and CD133 + Exo treated T2DM-stroke mice. In T2DM mice, stroke induced earlier and higher TLR4, NLRP3, and cytokine expression (SAA, IL1ß, IL6, TNFα) in the liver compared to heart and kidney, as measured by Western blot. T2DM-stroke mice exhibited worse NAFLD progression with increased liver steatosis, hepatocellular ballooning, fibrosis, serum ALT activity, and higher NAFLD Activity Score compared to T2DM mice and non-DM-stroke mice, while CD133 + Exo treatment significantly attenuated the progression of NAFLD in T2DM stroke mice. Conclusion: Treatment of female T2DM-stroke mice with CD133 + Exo significantly reduces the progression of NAFLD/NASH and improves neurological and cognitive function compared to control T2DM-stroke mice.

Imaging glymphatic response to glioblastoma.

BACKGROUND: The glymphatic system actively exchanges cerebrospinal fluid (CSF) and interstitial fluid (ISF) to eliminate toxic interstitial waste solutes from the brain parenchyma. Impairment of the glymphatic system has been linked to several neurological conditions. Glioblastoma, also known as Glioblastoma multiforme (GBM) is a highly aggressive form of malignant brain cancer within the glioma category. However, the impact of GBM on the functioning of the glymphatic system has not been investigated. Using dynamic contrast-enhanced magnetic resonance imaging (CE-MRI) and advanced kinetic modeling, we examined the changes in the glymphatic system in rats with GBM. METHODS: Dynamic 3D contrast-enhanced T1-weighted imaging (T1WI) with intra-cisterna magna (ICM) infusion of paramagnetic Gd-DTPA contrast agent was used for MRI glymphatic measurements in both GBM-induced and control rats. Glymphatic flow in the whole brain and the olfactory bulb was analyzed using model-derived parameters of arrival time, infusion rate, clearance rate, and residual that describe the dynamics of CSF tracer over time. RESULTS: 3D dynamic T1WI data identified reduced glymphatic influx and clearance, indicating an impaired glymphatic system due to GBM. Kinetic modeling and quantitative analyses consistently indicated significantly reduced infusion rate, clearance rate, and increased residual of CSF tracer in GBM rats compared to control rats, suggesting restricted glymphatic flow in the brain with GBM. In addition, our results identified compromised perineural pathway along the optic nerves in GBM rats. CONCLUSIONS: Our study demonstrates the presence of GBM-impaired glymphatic response in the rat brain and impaired perineural pathway along the optic nerves. Reduced glymphatic waste clearance may lead to the accumulation of toxic waste solutes and pro-inflammatory signaling molecules which may affect the progression of the GBM.

The Association between Glymphatic System and Perivascular Macrophages in Brain Waste Clearance.

The glymphatic system suggests the convective bulk flow of cerebrospinal fluid (CSF) through perivascular spaces and the interstitial spaces of the brain parenchyma for the rapid removal of toxic waste solutes from the brain. However, the presence of convective bulk flow within the brain interstitial spaces is still under debate. We first addressed this argument to determine the involvement of the glymphatic system in brain waste clearance utilizing contrast-enhanced 3D T1-weighted imaging (T1WI), diffusion tensor imaging (DTI), and confocal microscopy imaging. Furthermore, perivascular macrophages (PVMs), which are immune cells located within perivascular spaces, have not been thoroughly explored for their association with the glymphatic system. Therefore, we investigated tracer uptake by PVMs in the perivascular spaces of both the arteries/arterioles and veins/venules and the potential association of PVMs in assisting the glymphatic system for interstitial waste clearance. Our findings demonstrated that both convective bulk flow and diffusion are responsible for the clearance of interstitial waste solutes from the brain parenchyma. Furthermore, our results suggested that PVMs play an important function in glymphatic system-mediated interstitial waste clearance. The glymphatic system and PVMs could be targeted to enhance interstitial waste clearance in patients with waste-associated neurological conditions and aging.

Adipose-derived exosomal miR-421 targets CBX7 and promotes metastatic potential in ovarian cancer cells.

Background: Chromobox protein homolog 7 (CBX7), a member of the Polycomb repressor complex, is a potent epigenetic regulator and gene silencer. Our group has previously reported that CBX7 functions as a tumor suppressor in ovarian cancer cells and its loss accelerated formation of carcinomatosis and drove tumor progression in an ovarian cancer mouse model. The goal of this study is to identify specific signaling pathways in the ovarian tumor microenvironment that down-regulate CBX7. Given that adipocytes are an integral component of the peritoneal cavity and the ovarian tumor microenvironment, we hypothesize that the adipose microenvironment is an important regulator of CBX7 expression. Results: Using conditioned media from human omental explants, we found that adipose-derived exosomes mediate CBX7 downregulation and enhance migratory potential of human ovarian cancer cells. Further, we identified adipose-derived exosomal miR-421 as a novel regulator of CBX7 expression and the main effector that downregulates CBX7. Conclusion: In this study, we identified miR-421 as a specific signaling pathway in the ovarian tumor microenvironment that can downregulate CBX7 to induce epigenetic change in OC cells, which can drive disease progression. These findings suggest that targeting exosomal miR-421 may curtail ovarian cancer progression.

Adipose-derived exosomal miR-421 targets CBX7 and promotes metastatic potential in ovarian cancer cells.

BACKGROUND: Chromobox protein homolog 7 (CBX7), a member of the Polycomb repressor complex, is a potent epigenetic regulator and gene silencer. Our group has previously reported that CBX7 functions as a tumor suppressor in ovarian cancer cells and its loss accelerated formation of carcinomatosis and drove tumor progression in an ovarian cancer mouse model. The goal of this study is to identify specific signaling pathways in the ovarian tumor microenvironment that down-regulate CBX7. Given that adipocytes are an integral component of the peritoneal cavity and the ovarian tumor microenvironment, we hypothesize that the adipose microenvironment is an important regulator of CBX7 expression. RESULTS: Using conditioned media from human omental explants, we found that adipose-derived exosomes mediate CBX7 downregulation and enhance migratory potential of human ovarian cancer cells. Further, we identified adipose-derived exosomal miR-421 as a novel regulator of CBX7 expression and the main effector that downregulates CBX7. CONCLUSION: In this study, we identified miR-421 as a specific signaling pathway in the ovarian tumor microenvironment that can downregulate CBX7 to induce epigenetic change in OC cells, which can drive disease progression. These findings suggest that targeting exosomal miR-421 may curtail ovarian cancer progression.

An activated protein C analog with reduced anticoagulant activity extends the therapeutic window of tissue plasminogen activator for ischemic stroke in rodents.

BACKGROUND AND PURPOSE: Tissue plasminogen activator (tPA) is the only approved therapy for acute ischemic stroke. However, tPA has a brief therapeutic window. Its side effects include intracerebral bleeding and neurotoxicity. Therefore, a combination therapy with tPA and agents that can extend the therapeutic window of tPA and/or counteract its side effects are warranted. Here, we studied whether 3K3A-APC, a neuroprotective analog of activated protein C with reduced anticoagulant activity, can enhance the therapeutic effects of tPA in models of ischemic stroke in rodents. METHODS: Human recombinant tPA (10 mg/kg), alone or in combination with human recombinant 3K3A-APC (2 mg/kg), was administered intravenously 4 hours after proximal or distal transient middle cerebral artery occlusion in mice and embolic stroke in rats. The 3K3A-APC was additionally administered for 3 to 4 consecutive days after stroke. The neuropathological and neurological analyses were performed at 1 to 7 days after stroke. RESULTS: In all models, tPA alone had no effects on the infarct volume or behavior (ie, neurological score, foot-fault, forelimb asymmetry, adhesive removal) compared with vehicle. The tPA and 3K3A-APC combination therapy reduced the infarct volume 24 hours and 7 days after proximal or distal transient middle cerebral artery occlusion in mice and 7 days after embolic stroke in rats by 65%, 63%, and 52%, respectively, significantly (P<0.05) improved behavior and eliminated tPA-induced intracerebral microhemorrhages. CONCLUSIONS: The 3K3A-APC extends the therapeutic window of tPA for ischemic stroke in rodents. Therefore, this combination therapy also should be considered for treating stroke in humans.

Case-control study on the association between qi-stagnation and insomnia.

OBJECTIVE: To investigate the relationship between insomnia and qi-stagnation by using the international standardized measurement of sleep quality and the Traditional Chinese Medicine (TCM) Constitution Scales. METHODS: A survey by means of the TCM Constitution Scales, the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and the Deep Sleep Scale (DSS) in 169 participants aged between 16 and 80 years old was conducted. Comparison was made to examine the sleep quality and insomnia symptoms in the qi-stagnation group and other-constitution group. RESULTS: Univariate analysis found that the qi-stagnation group had a significantly increased risk of difficulty in falling asleep (OR=3.012, and 95% CI 1.310 to 6.923 for PSQI; OR=3.016, and 95% CI 1.358 to 6.709 for DSS) and early waking (OR=3.545, and 95% CI 1.229 to 10.232 for PSQI; OR=2.742, and 95% CI 1.072 to 7.014 for DSS), while the other-constitution group had a significant risk of dreaminess (OR=2.419, and 95% CI 1.154 to 5.072 for PSQI; OR=2.561, and 95% CI 1.116 to 5.880 for DSS). A dose-effect relationship existed between insomnia symptoms and qi-stagnation. Qi-stagnation significantly increased the risk of difficulty in falling asleep and early waking. CONCLUSION: This case-control study revealed that there is a statistically significant association between qi-stagnation and insomnia. Based on this study, we recommend that further research should be conducted for the rehabilitative care and cure of insomnia from the perspective of TCM constitution.

Insight into the Contact Impedance between the Electrode and the Skin Surface for Electrophysical Recordings.

To obtain a performance improved dry electrode for bioelectrical activity detection is still a challenge, which is mainly due to the poor fundamental understanding on the impedance of the electrode-skin interface. Herein, the impedance between the electrode and the skin interface of three types of electrodes, which are the wet electrode, semidry electrode, and dry electrode, is investigated with electrochemical impedance spectroscopy combined with the spectra fitting technique. The parameters of performance duration, potential, and frequency associated with the impedance are explored for these three types of electrodes. The overall impedance is roughly constant within the performance duration and the potential applied in this study. Along with the frequency decreases, the impedance of the dry electrode reduces faster and is more complicated compared with the other two types of electrodes. Moreover, the results computed with the equivalent circuits show that the charge transfer resistance is additionally present compared to the wet and semidry electrodes. This large and additional charge transfer resistance may explain its relatively poorer electrophysiological properties.

MRI Metrics of Cerebral Endothelial Cell-Derived Exosomes for the Treatment of Cognitive Dysfunction Induced in Aging Rats Subjected to Type 2 Diabetes.

Ongoing neurovascular dysfunction contributes to type 2 diabetes mellitus (T2DM)-induced cognitive deficits. However, it is not known whether early post onset of T2DM interventions may reduce evolving neurovascular dysfunction and thereby lead to diminution of T2DM-induced cognitive deficits. Using multiple MRI metrics, we evaluated neurovascular changes in T2DM rats treated with exosomes derived from cerebral endothelial cells (CEC-Exos). Two months after induction of T2DM in middle-aged male rats by administration of streptozotocin nicotinamide, rats were randomly treated with CEC-Exos twice weekly or saline for 4 consecutive weeks (n = 10/group). MRI measurements were performed at the end of the treatment, which included cerebral blood flow (CBF), contrast-enhanced T1-weighted imaging, and relaxation time constants T1 and T2. MRI analysis showed that compared with controls, the CEC-Exo-treated T2DM rats exhibited significant elevation of T2 and CBF in white matter and significant augmentation of T1 and reduction of blood-brain barrier permeability in gray matter. In the hippocampus, CEC-Exo treatment significantly increased T1 and CBF. Furthermore, CEC-Exo treatment significantly reduced T2DM-induced cognitive deficits measured by the Morris water maze and odor recognition tests. Collectively, our corresponding MRI data demonstrate that treatment of T2DM rats with CEC-Exos robustly reduced neurovascular dysfunction in gray and white matter and the hippocampus.

Longitudinal magnetic resonance imaging of sildenafil treatment of embolic stroke in aged rats.

BACKGROUND AND PURPOSE: Sildenafil provides restorative therapeutic benefits in the treatment of experimental stroke. The majority of experimental studies on treatment of stroke have been performed in young animals; however, stroke is primarily a disease of the aged. Thus, using MRI, we evaluated the effects of sildenafil treatment of embolic stroke in aged animals. METHODS: Aged male Wistar rats (18 months) were subjected to embolic stroke and treated daily with saline (n=10) or with sildenafil (n=10) initiated at 24 hours and subsequently for 7 days after onset of ischemia. MRI measurements were performed at 24 hours and weekly to 6 weeks after embolization. RESULTS: MRI and histological measurements demonstrated that sildenafil treatment of aged rats significantly enhanced angiogenesis and axonal remodeling after stroke compared to saline-treated aged rats. Local cerebral blood flow in the angiogenic area was elevated and expansion of the ipsilateral ventricle and, consequently, brain atrophy was significantly reduced in the sildenafil-treated rats. CONCLUSIONS: Treatment of embolic stroke in aged rats with sildenafil significantly augments angiogenesis and axonal remodeling, which increased local blood flow and reduced expansion of the ipsilateral ventricle 6 weeks after stroke compared to control aged rats. MRI can be used to investigate brain repair after stroke in aged rats.

Waste Clearance in the Brain.

Waste clearance (WC) is an essential process for brain homeostasis, which is required for the proper and healthy functioning of all cerebrovascular and parenchymal brain cells. This review features our current understanding of brain WC, both within and external to the brain parenchyma. We describe the interplay of the blood-brain barrier (BBB), interstitial fluid (ISF), and perivascular spaces within the brain parenchyma for brain WC directly into the blood and/or cerebrospinal fluid (CSF). We also discuss the relevant role of the CSF and its exit routes in mediating WC. Recent discoveries of the glymphatic system and meningeal lymphatic vessels, and their relevance to brain WC are highlighted. Controversies related to brain WC research and potential future directions are presented.