Direct imaging of glymphatic transport using H217O MRI.
Ontology highlight
ABSTRACT:
SUBMITTER: Alshuhri MS
PROVIDER: S-EPMC8262348 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The glymphatic system is a low resistance pathway, by which cerebrospinal fluid enters the brain parenchyma along perivascular spaces via AQP4 channels. It is hypothesised that the resulting convective flow of the interstitial fluid provides an efficient mechanism for the removal of waste toxins from the brain. Therefore, enhancing AQP4 function might protect against neurodegenerative diseases such as Alzheimer's disease (AD), in which the accumulation of harmful proteins and solutes is a hallmark feature. Here, we test the effect of a putative AQP4 facilitator, TGN-073, on glymphatic transport in a normal rat brain by employing different MRI techniques. Surgical procedures were undertaken to catheterise the cisterna magna, thereby enabling infusion of the MRI tracer. Followed by the intraperitoneal injection of either TGN-073, or the vehicle. Using a paramagnetic contrast agent (Gd-DTPA) as the MRI tracer, dynamic 3D T1 weighted imaging of the glymphatic system was undertaken over two hours. Further, the apparent diffusion coefficient was measured in different brain regions using diffusion-weighted imaging (DWI). While physiological parameters and arterial blood gas analysis were monitored continuously. We found that rats treated with TGN-073 showed the distribution of Gd-DTPA was more extensive and parenchymal uptake was higher compared with the vehicle group. Water diffusivity was increased in the brain of TGN-073 treated group, which indicates greater water flux. Also, MRI showed the glymphatic transport and distribution in the brain is naturally heterogeneous, which is consistent with previous studies. Our results indicate that compounds such as TGN-073 can improve glymphatic function in the brain. Since glymphatic impairment due to AQP4 dysfunction is potentially associated with several neurological disorders such as AD, dementia and traumatic brain injury, enhancing AQP4 functionality might be a promising therapeutic target.
| S-EPMC10016657 | biostudies-literature
Project description:Whether you are reading, running or sleeping, your brain and its fluid environment continuously interacts to distribute nutrients and clear metabolic waste. Yet, the precise mechanisms for solute transport within the human brain have remained hard to quantify using imaging techniques alone. From multi-modal human brain MRI data sets in sleeping and sleep-deprived subjects, we identify and quantify CSF tracer transport parameters using forward and inverse subject-specific computational modelling. Our findings support the notion that extracellular diffusion alone is not sufficient as a brain-wide tracer transport mechanism. Instead, we show that human MRI observations align well with transport by either by an effective diffusion coefficent 3.5[Formula: see text] that of extracellular diffusion in combination with local clearance rates corresponding to a tracer half-life of up to 5 h, or by extracellular diffusion augmented by advection with brain-wide average flow speeds on the order of 1-9 [Formula: see text]m/min. Reduced advection fully explains reduced tracer clearance after sleep-deprivation, supporting the role of sleep and sleep deprivation on human brain clearance.
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Project description:The glymphatic system has in previous studies been shown as fundamental to clearance of waste metabolites from the brain interstitial space, and is proposed to be instrumental in normal ageing and brain pathology such as Alzheimer's disease and brain trauma. Assessment of glymphatic function using magnetic resonance imaging with intrathecal contrast agent as a cerebrospinal fluid tracer has so far been limited to rodents. We aimed to image cerebrospinal fluid flow characteristics and glymphatic function in humans, and applied the methodology in a prospective study of 15 idiopathic normal pressure hydrocephalus patients (mean age 71.3 ± 8.1 years, three female and 12 male) and eight reference subjects (mean age 41.1 + 13.0 years, six female and two male) with suspected cerebrospinal fluid leakage (seven) and intracranial cyst (one). The imaging protocol included T1-weighted magnetic resonance imaging with equal sequence parameters before and at multiple time points through 24 h after intrathecal injection of the contrast agent gadobutrol at the lumbar level. All study subjects were kept in the supine position between examinations during the first day. Gadobutrol enhancement was measured at all imaging time points from regions of interest placed at predefined locations in brain parenchyma, the subarachnoid and intraventricular space, and inside the sagittal sinus. Parameters demonstrating gadobutrol enhancement and clearance in different locations were compared between idiopathic normal pressure hydrocephalus and reference subjects. A characteristic flow pattern in idiopathic normal hydrocephalus was ventricular reflux of gadobutrol from the subarachnoid space followed by transependymal gadobutrol migration. At the brain surfaces, gadobutrol propagated antegradely along large leptomeningeal arteries in all study subjects, and preceded glymphatic enhancement in adjacent brain tissue, indicating a pivotal role of intracranial pulsations for glymphatic function. In idiopathic normal pressure hydrocephalus, we found delayed enhancement (P < 0.05) and decreased clearance of gadobutrol (P < 0.05) at the Sylvian fissure. Parenchymal (glymphatic) enhancement peaked overnight in both study groups, possibly indicating a crucial role of sleep, and was larger in normal pressure hydrocephalus patients (P < 0.05 at inferior frontal gyrus). We interpret decreased gadobutrol clearance from the subarachnoid space, along with persisting enhancement in brain parenchyma, as signs of reduced glymphatic clearance in idiopathic normal hydrocephalus, and hypothesize that reduced glymphatic function is instrumental for dementia in this disease. The study shows promise for glymphatic magnetic resonance imaging as a method to assess human brain metabolic function and renders a potential for contrast enhanced brain extravascular space imaging.
| S-EPMC5841149 | biostudies-other
Project description:Background and purposeThere is growing evidence of leakage of gadolinium in an impaired blood-retina barrier. We investigated gadolinium enhancement in different eye compartments and correlated the enhancement with specific ophthalmologic diseases.Materials and methodsIn a prospective clinical study (ClinicalTrials.gov Identifier: NCT05035251), 95 patients (63 with and 32 without ophthalmologic disease) were examined before and after gadolinium administration (20 and 120 minutes) with heavily T2-weighted FLAIR. The cohort was divided according to the location of pathology into anterior and posterior eye compartment groups. Relative signal intensity increase in the anterior eye chamber, vitreous body with retina, optic nerve sheath, and the Meckel cave was analyzed and correlated with the final clinical diagnosis.ResultsIn patients with a disorder in the anterior eye compartment, significant signal intensity increases were found in the central anterior eye chamber (P 20 minutes = .000, P 120 minutes = .000), lateral anterior eye chamber (P 20 minutes = .001, P 120 minutes = .005), and vitreous body with retina (P 20 minutes = .02) compared with the control group. Patients with pathologies in the posterior eye compartment showed higher signal intensity levels in the central anterior eye compartment (P 20 minutes = .041) and vitreous body with retina (P 120 minutes = .006).ConclusionsIncreased gadolinium enhancement was found in the central and lateral anterior eye compartments and the vitreous body with retina in patients with anterior eye compartment disorders 20 and 120 minutes after contrast application, suggesting impairment of the blood-aqueous barrier. In patients with a disorder in the posterior eye compartment, pathologic enhancement indicated disruption of the blood-retinal barrier that allows gadolinium to diffuse into the vitreous body with retina from posterior to anterior, opposite to the known physiologic glymphatic pathway.
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2016-06-07 | GSE80683 | GEO
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Project description:The glymphatic system is a brain-wide clearance pathway; its impairment contributes to the accumulation of amyloid-?. Influx of cerebrospinal fluid (CSF) depends upon the expression and perivascular localization of the astroglial water channel aquaporin-4 (AQP4). Prompted by a recent failure to find an effect of Aqp4 knock-out (KO) on CSF and interstitial fluid (ISF) tracer transport, five groups re-examined the importance of AQP4 in glymphatic transport. We concur that CSF influx is higher in wild-type mice than in four different Aqp4 KO lines and in one line that lacks perivascular AQP4 (Snta1 KO). Meta-analysis of all studies demonstrated a significant decrease in tracer transport in KO mice and rats compared to controls. Meta-regression indicated that anesthesia, age, and tracer delivery explain the opposing results. We also report that intrastriatal injections suppress glymphatic function. This validates the role of AQP4 and shows that glymphatic studies must avoid the use of invasive procedures.
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Project description:To what extent does the subarachnoid cerebrospinal fluid (CSF) compartment communicate directly with the extravascular compartment of human brain tissue? Interconnection between the subarachnoid CSF compartment and brain perivascular spaces is reported in some animal studies, but with controversy, and in vivo CSF tracer studies in humans are lacking. In the present work, we examined the distribution of a CSF tracer in the human brain by MRI over a prolonged time span. For this, we included a reference cohort, representing close to healthy individuals, and a cohort of patients with dementia and anticipated compromise of CSF circulation (idiopathic normal pressure hydrocephalus). The MRI contrast agent gadobutrol, which is confined to the extravascular brain compartment by the intact blood-brain barrier, was used as a CSF tracer. Standardized T1-weighted MRI scans were performed before and after intrathecal gadobutrol at defined time points, including at 24 hours, 48 hours, and 4 weeks. All MRI scans were aligned and brain regions were segmented using FreeSurfer, and changes in normalized T1 signals over time were quantified as percentage change from baseline. The study provides in vivo evidence of access to all human brain subregions of a substance administered intrathecally. Clearance of the tracer substance was delayed in the dementia cohort. These observations translate previous findings in animal studies into humans and open new prospects concerning intrathecal treatment regimens, extravascular contrast-enhanced MRI, and assessment of brain clearance function.
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Project description: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.
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