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.

Clinical magnetic resonance imaging evaluation of glymphatic function.

The glymphatic system is a system of specialized perivascular spaces in the brain that facilitates removal of toxic waste solutes from the brain. Evaluation of glymphatic system function by means of magnetic resonance imaging (MRI) has thus far been largely focused on rodents because of the limitations of intrathecal delivery of gadolinium-based contrast agents to humans. This review discusses MRI methods that can be employed clinically for glymphatic-related measurements intended for early diagnosis, prevention, and the treatment of various neurological conditions. Although glymphatic system-based MRI research is in its early stages, recent studies have identified promising noninvasive MRI markers associated with glymphatic system alterations in neurological diseases. However, further optimization in data acquisition, validation, and modeling are needed to investigate the glymphatic system within the clinical setting.

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.

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.

Glymphatic transport is reduced in rats with spontaneous pituitary tumor.

Background and objective: Pituitary tumor in patients induces adverse alterations in the brain, accompanied by cognitive deficits. Dysfunction of glymphatic waste clearance results in accumulation of neurotoxic products within the brain, leading to cognitive impairment. However, the status of glymphatic function in the brain with pituitary tumor is unknown. Using magnetic resonance imaging (MRI) and an advanced mathematical modeling, we investigated the changes of glymphatic transport in the rats carrying spontaneous pituitary tumor. Methods: Rats (22-24 months, female, Wistar) with and without pituitary tumor (n = 7/per group) underwent the identical experimental protocol. MRI measurements, including T2-weighted imaging and dynamic 3D T1-weighted imaging with intracisternal administration of contrast agent, were performed on each animal. The contrast-induced enhancement in the circle of Willis and in the glymphatic influx nodes were observed on the dynamic images and verified with time-signal-curves (TSCs). Model-derived parameters of infusion rate and clearance rate that characterize the kinetics of glymphatic tracer transport were evaluated in multiple representative brain regions. Results: Our imaging data demonstrated a higher incidence of partially enhanced circle of Willis (86 vs. 14%; p < 0.033) and a lower incidence of enhancement in glymphatic influx nodes of pituitary (71 vs. 100%) and pineal (57 vs. 86%) recesses in the rats with pituitary tumor than in the rats with normal appearance of pituitary gland, indicating an intensification of impaired peri-vascular pathway and impeded glymphatic transport due to the presence of pituitary tumor. Consistently, our kinetic modeling and regional cerebral tissue quantification revealed significantly lower infusion and clearance rates in all examined regions in rats with spontaneous pituitary tumor than in non-tumor rats, representing a suppressed glymphatic transport in the brain with pituitary tumor. Conclusion: Our study demonstrates the compromised glymphatic transport in the rat brain with spontaneous pituitary tumor. The reduced efficiency in cerebral waste clearance increases the risk for neurodegeneration in the brain that may underlie the cognitive impairment commonly seen in patients with pituitary tumors.

Aging-Related Alterations of Glymphatic Transport in Rat: In vivo Magnetic Resonance Imaging and Kinetic Study.

Objective: Impaired glymphatic waste clearance function during brain aging leads to the accumulation of metabolic waste and neurotoxic proteins (e.g., amyloid-ß, tau) which contribute to neurological disorders. However, how the age-related glymphatic dysfunction exerts its effects on different cerebral regions and affects brain waste clearance remain unclear. Methods: We investigated alterations of glymphatic transport in the aged rat brain using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and advanced kinetic modeling. Healthy young (3-4 months) and aged (18-20 months) male rats (n = 12/group) underwent the identical MRI protocol, including T2-weighted imaging and 3D T1-weighted imaging with intracisternal administration of contrast agent (Gd-DTPA). Model-derived parameters of infusion rate and clearance rate, characterizing the kinetics of cerebrospinal fluid (CSF) tracer transport via the glymphatic system, were evaluated in multiple representative brain regions. Changes in the CSF-filled cerebral ventricles were measured using contrast-induced time signal curves (TSCs) in conjunction with structural imaging. Results: Compared to the young brain, an overall impairment of glymphatic transport function was detected in the aged brain, evidenced by the decrease in both infusion and clearance rates throughout the brain. Enlarged ventricles in parallel with reduced efficiency in CSF transport through the ventricular regions were present in the aged brain. While the age-related glymphatic dysfunction was widespread, our kinetic quantification demonstrated that its impact differed considerably among cerebral regions with the most severe effect found in olfactory bulb, indicating the heterogeneous and regional preferential alterations of glymphatic function. Conclusion: The robust suppression of glymphatic activity in the olfactory bulb, which serves as one of major efflux routes for brain waste clearance, may underlie, in part, age-related neurodegenerative diseases associated with neurotoxic substance accumulation. Our data provide new insight into the cerebral regional vulnerability to brain functional change with aging.

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.

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.

Cerebral endothelial cell-derived small extracellular vesicles enhance neurovascular function and neurological recovery in rat acute ischemic stroke models of mechanical thrombectomy and embolic stroke treatment with tPA.

Treatment of patients with cerebral large vessel occlusion with thrombectomy and tissue plasminogen activator (tPA) leads to incomplete reperfusion. Using rat models of embolic and transient middle cerebral artery occlusion (eMCAO and tMCAO), we investigated the effect on stroke outcomes of small extracellular vesicles (sEVs) derived from rat cerebral endothelial cells (CEC-sEVs) in combination with tPA (CEC-sEVs/tPA) as a treatment of eMCAO and tMCAO in rat. The effect of sEVs derived from clots acquired from patients who had undergone mechanical thrombectomy on healthy human CEC permeability was also evaluated. CEC-sEVs/tPA administered 4 h after eMCAO reduced infarct volume by ∼36%, increased recanalization of the occluded MCA, enhanced cerebral blood flow (CBF), and reduced blood-brain barrier (BBB) leakage. Treatment with CEC-sEVs given upon reperfusion after 2 h tMCAO significantly reduced infarct volume by ∼43%, and neurological outcomes were improved in both CEC-sEVs treated models. CEC-sEVs/tPA reduced a network of microRNAs (miRs) and proteins that mediate thrombosis, coagulation, and inflammation. Patient-clot derived sEVs increased CEC permeability, which was reduced by CEC-sEVs. CEC-sEV mediated suppression of a network of pro-thrombotic, -coagulant, and -inflammatory miRs and proteins likely contribute to therapeutic effects. Thus, CEC-sEVs have a therapeutic effect on acute ischemic stroke by reducing neurovascular damage.

MRI detection of impairment of glymphatic function in rat after mild traumatic brain injury.

We investigated the effect of mild traumatic brain injury (mTBI) on the glymphatic pathway using contrast-enhanced magnetic resonance imaging (CE-MRI) and quantified with kinetic parameters obtained from an advanced two-compartment model. mTBI was induced in male Wistar rats using a closed head impact. Animals with and without mTBI (n = 7/group) underwent the identical MRI protocol 10-weeks post-injury, including T2-weighted imaging and 3D T1-weighted imaging with intra-cisterna magna injection of contrast agent (Gd-DTPA). The parameters of infusion rate, clearance rate and clearance time constant, characterizing the kinetic features of glymphatic tracer transport in a living brain, were quantified in multiple brain tissue regions. In the majority of examined regions, our quantification demonstrated significantly reduced infusion and clearance rates, and significantly increased clearance time constant in the mTBI animals compared to the healthy controls. These data indicate that mTBI induces chronic changes in influx and efflux of contrast agent and glymphatic pathway dysfunction. While the reduced efficiency of glymphatic function after mTBI was apparent in brain, regional evaluation revealed heterogeneous glymphatic effects of the mTBI in different anatomical regions. The suppression of glymphatic function, rather than the presence of focal lesions, indicates a persistent injury of the brain after mTBI. Thus, dynamic CE-MRI in conjunction with advanced kinetic analysis may offer a useful methodology for an objective assessment and confirmatory diagnosis of mTBI.

Magnetic Resonance Imaging and Modeling of the Glymphatic System.

The glymphatic system is a newly discovered waste drainage pathway in the brain; it plays an important role in many neurological diseases. Ongoing research utilizing various cerebrospinal fluid tracer infusions, either directly or indirectly into the brain parenchyma, is investigating clearance pathways by using distinct imaging techniques. In the present review, we discuss the role of the glymphatic system in various neurological diseases and efflux pathways of brain waste clearance based on current evidence and controversies. We mainly focus on new magnetic resonance imaging (MRI) modeling techniques, along with traditional computational modeling, for a better understanding of the glymphatic system function. Future sophisticated modeling techniques hold the potential to generate quantitative maps for glymphatic system parameters that could contribute to the diagnosis, monitoring, and prognosis of neurological diseases. The non-invasive nature of MRI may provide a safe and effective way to translate glymphatic system measurements from bench-to-bedside.

Differences between normal and diabetic brains in middle-aged rats by MRI.

Normal aging is a risk factor for metabolic disorders such as diabetes, and diabetes is also a recognized cause of accelerated aging. Being able to distinguish changes caused by normal aging from those caused by diabetes, would provide insight into how the aging brain interacts with diabetes. Eight types of MRI metric maps (magnetization relaxation time constants of T1 and T2, cerebral blood flow, cerebrovascular permeability, mean diffusivity, diffusion fractional anisotropy, mean diffusion kurtosis and diffusion directional entropy) were generated for all rats from the three groups of normal young, healthy and 1.5-month diabetic middle-aged rats under investigation. Measurements of multiple MRI indices of cerebral white and gray matter from animals of the three groups provide complementary results and insight into differences between healthy and diabetic white / gray matter in the mid-aged rats. Our data indicate that MRI may distinguish between the normal and diabetes in mid-aged rat brains by measuring either T1 and T2 of gray matter, or fractional anisotropy of white matter and gray matter. Therefore, MRI can distinguish changes of cerebral tissue due to the normal aging from diabetic aging, which may lead to be able to better understand how diabetes accelerates aging in normal brain.

Diffuse white matter response in trauma-injured brain to bone marrow stromal cell treatment detected by diffusional kurtosis imaging.

Diffuse white matter (WM) response to traumatic brain injury (TBI) and transplantation of human bone marrow stromal cells (hMSCs) after the injury were non-invasively and dynamically investigated. Male Wistar rats (300-350 g) subjected to TBI were intravenously injected with 1 ml of saline (n = 10) or with hMSCs in suspension (∼3 × 106 hMSCs, n = 10) 1-week post-TBI. MRI measurements of T2-weighted imaging and diffusional kurtosis imaging (DKI) were acquired on all animals at multiple time points up to 3-months post-injury. Functional outcome was assessed using the Morris water maze test. DKI-derived metrics of fractional anisotropy (FA), axonal water fraction (AWF) and radial kurtosis (RK) longitudinally reveal an evolving pattern of structural alteration post-TBI occurring in the brain region remote from primary impact site. The progressive structural change is characterized by gradual disruption of WM integrity at an early stage (weeks post-TBI), followed by spontaneous recovery at a later stage (months post-TBI). Transplantation of hMSCs post-TBI promotes this structural plasticity as indicated by significantly increased FA and AWF in conjunction with substantially elevated RK at the later stage. Our long-term imaging data demonstrate that hMSC therapy leads to modified temporal profiles of these metrics, inducing an earlier presence of enhanced structural remodeling, which may contribute to improved functional recovery.

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.

Noninvasive measurement of renal blood flow by magnetic resonance imaging in rats.

Renal blood flow (RBF) provides important information regarding renal physiology and nephropathies. Arterial spin labeling-magnetic resonance imaging (ASL-MRI) is a noninvasive method of measuring blood flow without exogenous contrast media. However, low signal-to-noise ratio and respiratory motion artifacts are challenges for RBF measurements in small animals. Our objective was to evaluate the feasibility and reproducibility of RBF measurements by ASL-MRI using respiratory-gating and navigator correction methods to reduce motion artifacts. ASL-MRI images were obtained from the kidneys of Sprague-Dawley (SD) rats on a 7-Tesla Varian MRI system with a spin-echo imaging sequence. After 4 days, the study was repeated to evaluate its reproducibility. RBF was also measured in animals under unilateral nephrectomy and in renal artery stenosis (RST) to evaluate the sensitivity in high and low RBF models, respectively. RBF was also evaluated in Dahl salt-sensitive (SS) rats and spontaneous hypertensive rats (SHR). In SD rats, the cortical RBFs (cRBF) were 305 ± 59 and 271.8 ± 39 ml·min-1·100 g tissue-1 in the right and left kidneys, respectively. Retest analysis revealed no differences ( P = 0.2). The test-retest reliability coefficient was 92 ± 5%. The cRBFs before and after the nephrectomy were 296.8 ± 30 and 428.2 ± 45 ml·min-1·100 g tissue-1 ( P = 0.02), respectively. The kidneys with RST exhibited a cRBF decrease compared with sham animals (86 ± 17.6 vs. 198 ± 33.7 ml·min-1·100 g tissue-1; P < 0.01). The cRBFs in SD, Dahl-SS, and SHR rats were not different ( P = 0.35). We conclude that ASL-MRI performed with navigator correction and respiratory gating is a feasible and reliable noninvasive method for measuring RBF in rats.

Chronic global analysis of vascular permeability and cerebral blood flow after bone marrow stromal cell treatment of traumatic brain injury in the rat: A long-term MRI study.

Vascular permeability and hemodynamic alteration in response to the transplantation of human bone marrow stromal cells (hMSCs) after traumatic brain injury (TBI) were longitudinally investigated in non directly injured and normal-appearing cerebral tissue using magnetic resonance imaging (MRI). Male Wistar rats (300-350g, n=30) subjected to controlled cortical impact TBI were intravenously injected with 1ml of saline (at 6-h or 1-week post-injury, n=5/group) or with hMSCs in suspension (∼3×106 hMSCs, at 6-h or 1-week post-injury, n=10/group). MRI measurements of T2-weighted imaging, cerebral blood flow (CBF) and blood-to-brain transfer constant (Ki) of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA), and neurological behavioral estimates were performed on all animals at multiple time points up to 3-months post-injury. Our long-term imaging data show that blood-brain barrier (BBB) breakdown and hemodynamic disruption after TBI, as revealed by Ki and CBF, respectively, affect both hemispheres of the brain in a diffuse manner. Our data reveal a sensitive vascular permeability and hemodynamic reaction in response to the time-dependent transplantation of hMSCs. A more rapid reduction of Ki following cell treatment is associated with a higher level of CBF in the injured brain, and acute (6h) cell administration leads to enhanced therapeutic effects on both the recovery of vascular integrity and stabilization of cerebral perfusion compared to delayed (1w) cell engraftment. Our results indicate that cell-enhanced BBB reconstitution plays an important role in underlying the restoration of CBF in the injured brain, which in turn, contributes to the improvement of functional outcome.

Diffusion-Derived Magnetic Resonance Imaging Measures of Longitudinal Microstructural Remodeling Induced by Marrow Stromal Cell Therapy after Traumatic Brain Injury.

Using magnetic resonance imaging (MRI) and an animal model of traumatic brain injury (TBI), we investigated the capacity and sensitivity of diffusion-derived measures, fractional anisotropy (FA), and diffusion entropy, to longitudinally identify structural plasticity in the injured brain in response to the transplantation of human bone marrow stromal cells (hMSCs). Male Wistar rats (300-350g, n = 30) were subjected to controlled cortical impact TBI. At 6 h or 1 week post-injury, these rats were intravenously injected with 1 mL of saline (at 6 h or 1 week, n = 5/group) or with hMSCs in suspension (∼3 × 106 hMSCs, at 6 h or 1 week, n = 10/group). In vivo MRI measurements and sensorimotor function estimates were performed on all animals pre-injury, 1 day post-injury, and weekly for 3 weeks post-injury. Bielschowsky's silver and Luxol fast blue staining were used to reveal the axon and myelin status, respectively, with and without cell treatment after TBI. Based on image data and histological observation, regions of interest encompassing the structural alterations were made and the values of FA and entropy were monitored in these specific brain regions. Our data demonstrate that administration of hMSCs after TBI leads to enhanced white matter reorganization particularly along the boundary of contusional lesion, which can be identified by both FA and entropy. Compared with the therapy performed at 1 week post-TBI, cell intervention executed at 6 h expedites the brain remodeling process and results in an earlier functional recovery. Although FA and entropy present a similar capacity to dynamically detect the microstructural changes in the tissue regions with predominant orientation of fiber tracts, entropy exhibits a sensitivity superior to that of FA, in probing the structural alterations in the tissue areas with complex fiber patterns.

Impairment of the glymphatic system after diabetes.

The glymphatic system has recently been shown to clear brain extracellular solutes and abnormalities in glymphatic clearance system may contribute to both initiation and progression of neurological diseases. Despite that diabetes is known as a risk factor for vascular diseases, little is known how diabetes affects the glymphatic system. The current study is the first investigation of the effect of diabetes on the glymphatic system and the link between alteration of glymphatic clearance and cognitive impairment in Type-2 diabetes mellitus rats. MRI analysis revealed that clearance of cerebrospinal fluid contrast agent Gd-DTPA from the interstitial space was slowed by a factor of three in the hippocampus of Type-2 diabetes mellitus rats compared to the non-DM rats and confirmed by florescence imaging analysis. Cognitive deficits detected by behavioral tests were highly and inversely correlated to the retention of Gd-DTPA contrast and fluorescent tracer in the hippocampus of Type-2 diabetes mellitus rats. Type-2 diabetes mellitus suppresses clearance of interstitial fluid in the hippocampus and hypothalamus, suggesting that an impairment of the glymphatic system contributes to Type-2 diabetes mellitus-induced cognitive deficits. Whole brain MRI provides a sensitive, non-invasive tool to quantitatively evaluate cerebrospinal fluid and interstitial fluid exchange in Type-2 diabetes mellitus and possibly in other neurological disorders, with potential clinical application.