Pathways of Gadomer-17 Elimination From Cerebrospinal Fluid After Intraventricular Infusion or Injection Into the Cisterna Magna—Ultra-High-Field Magnetic Resonance Imaging Investigation A.H. Müller, P. Fries, M. Laschke, G. Schneider, A. Bücker, K. Fassbender, and Y. Decker. andreas.h.mueller@gmail.com.
Read how the NanoJet Stereotaxic Syringe Header was used in this study.
Purpose: The aim of this study was to elucidate pathways of cerebrospinal fluid (CSF) circulation and outflow, with focus on potential routes and mechanisms of gadolinium-based contrast agent (GBCA) uptake. Methods and Materials: Two experiments were conducted in mice under general anesthesia. First, we injected GBCA into the cisterna magna and performed dynamic magnetic resonance imaging of the head during a 50-minute time frame (n = 5). Second, we infused GBCA after intraventricular cannulation and performed dynamic whole-body magnetic resonance imaging with a greater than 100-minute time frame (n = 5). We used Gadomer-17 (GM17, 25 mM; NanoPET Pharma GmbH, Germany) as contrast agent applied with a NanoJet syringe (Chemyx, USA) injecting 5 μL at 1 μL/min (first group) or 6 μL at 0.1 μL/min (second group). Images were acquired with high-resolution T1-weighted 3D-FLASH sequences on a 9.4-Tanimal scanner (Bruker, Germany). Reconstruction and analysis were performed with Horos v2.0.1 (Horos Project).
Results: In animals injected into the cisterna magna, GM17 outflow occurs via nerve roots and the cribriform plates, subsequently following peripheral lymph vessels to submaxillary and deep cervical lymph nodes. In animals infused into the first ventricle, additional GM17 outflow into the subarachnoidal space of the spine, the central canal, peripheral lymph vessels, and sacral and iliac lymph nodes is observed. In these whole-body imaging experiments profound excretion into the urinary bladder is detectable from 30 minutes after complete intraventricular infusion of contrast medium. Distribution of GM17 to the cerebrum could not be detected. During the short time frame experiments, no GM17 transfer from the cisterna magna to the ventricles was detected as well.
Discussion: Results suggest that GM17 is eliminated from CSF in accordance with animal experiments demonstrating strong elimination of GBCA administrated intravenously, when mimicking sleep conditions by narcosis. However, this effect has also been described as a result of drastic reduction of CSF flow through the brain during general anesthesia. Mechanisms underlying CSF clearance are to date not fully understood. In particular, this holds true considering the connection between CSF circulation and the glymphatic pathway. In our investigation, transport of GM17 from the CSF into neocortical perivascular space and through the brain parenchyma could not be demonstrated. While this study in part supports preclinical and clinical studies on entry of GBCA into brain parenchyma, further investigations are needed to completely clarify underlying physiological principles.