Velocity of cerebrospinal fluid in the aqueduct measured by phase-contrast MRI in rat.

Cerebrospinal fluid (CSF) circulation plays a key role in cerebral waste clearance via the glymphatic system. Although CSF flow velocity is an essential component of CSF dynamics, it has not been sufficiently characterized, and particularly, in studies of the glymphatic system in rat. To investigate the relationship between the flow velocity of CSF in the brain aqueduct and the glymphatic waste clearance rate, using phase-contrast MRI we performed the first measurements of CSF velocity in rats. Phase-contrast MRI was performed using a 7 T system to map mean velocity of CSF flow in the aqueduct in rat brain. The effects of age (3 months old versus 18 months old), gender, strain (Wistar, RNU, Dark Agouti), anesthetic agents (isoflurane versus dexmedetomidine), and neurodegenerative disorder (Alzheimer' disease in Fischer TgF344-AD rats, males and females) on CSF velocity were investigated in eight independent groups of rats (12 rats per group). Our results demonstrated that quantitative velocities of CSF flow in the aqueduct averaged 5.16 ± 0.86 mm/s in healthy young adult male Wistar rats. CSF flow velocity in the aqueduct was not altered by rat gender, strain, and the employed anesthetic agents in all rats, also age in the female rats. However, aged (18 months) Wistar male rats exhibited significantly reduced the CSF flow velocity in the aqueduct (4.31 ± 1.08 mm/s). In addition, Alzheimer's disease further reduced the CSF flow velocity in the aqueduct of male and female rats.

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.

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.