Fluorine-19 Magnetic Resonance at 21.1 Tesla to Detect Brain Inflammation
Sonia Waiczies1, Jens T. Rosenberg2, Christian Prinz1, Ludger Starke1, Jason M. Millward1, Paula Ramos Delgado1, Andreas Pohlmann1, Andre Kuehne3, Helmar Waiczies3, and Thoralf Niendorf1,4

1Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrueck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany, 2The National High Magnetic Field Laboratory, Florida State University, Tallahassee, FL, United States, 3MRI TOOLs GmbH, Berlin, Germany, 4Experimental and Clinical Research Center (ECRC), a joint cooperation between the Charité Medical Faculty and the Max Delbrueck Center, Berlin, Germany


Detection of brain inflammation by fluorine-19 (19F) MRI was studied for the first time at 21.1 T (NHMFL, Tallahassee, FL). Studies on phantoms showed an SNR gain of 2.1 at 21.1 T, when compared to 9.4 T. A dependency between 19F-MR relaxation and magnetic field strength (B0) was demonstrated. A T1 reduction and higher SNR per unit time counterbalanced the T2 shortening-induced loss in 19F MR signal when performing high spatially-resolved MRI of post mortem experimental autoimmune encephalomyelitis (EAE) mouse samples at 21.1 T. 19F-signals, not seen at 9.4 T, were revealed in both mouse brain and draining lymph nodes.


Neuroinflammation can be monitored with 19F MRI using 19F-nanoparticles (NPs) that label immune cells in vivo. The migration of these cells into the brain can then be studied in EAE,1,2 a model of multiple sclerosis.3 Although the absence of background signal is an advantage, the low abundance of 19F nuclei in vivo poses a major challenge for MR detection in neuroinflammation. An increase in B0 from 9.4 to 21.1 T would result in a theoretical 5-fold increase in the received MR signal. This is the main driving force for using higher B0. However, the theoretical SNR gain is reduced with increasing frequencies due to increases in noise from sample and coil losses (e.g. SNR$$$\propto$$$B01.75 for solenoidal coils).4,5 Recognizing these opportunities and challenges, we investigated the influence of 21.1 T on 19F relaxation times and SNR gain, compared to 9.4 T.


Experiments were carried out on the 21.1 T vertical bore MR system (1H: f=900 MHz, 19F: f=844.9 MHz) of the National High Magnetic Field Laboratory (NHMFL) using a 19F/1H birdcage coil (linear, LP, 8 rungs, lengthcoil=54.5mm, Øinner=33mm, lengthshield=64mm, Øshield=53mm). On the 9.4 T small animal MR system (1H: f=400 MHz, 19F: f=376 MHz, Bruker BioSpin, Ettlingen, Germany) a similar coil was used (linear, HP, 12 rungs, lengthcoil=50mm, Øinner=35mm, lengthshield = 80mm, Øshield= 57mm). Electromagnetic field simulations at the same absorbed power were used to determine B1 fields for both coils.6 Relaxation time and SNR measurements: Four NMR tubes were filled with 19F-NPs prepared from perfluoro-15-crown-5-ether (60mM, 120mM, 600mM, 1200mM PFCE (Fluorochem))7 and submerged in a 50ml tube containing 4.5g/L NaCl. Parametric mapping was performed on axial slices (FOV=[30x30]mm², matrix=96x96, slice=10mm). RARE sequence for T1-mapping: 15xTRs=25-8000ms, TE=9.24ms, NEX=36 (9.4 T: TA=5h42m46s; 21.1 T: TA=4h7m19s). MSME protocol for T2-mapping: TR=4000ms, 150xTEs=7-1050ms (9.4 T: NEX=64, TA=6h49m36s; 21.1 T: NEX=36, TA=3h50m24s). SNR was calculated8 on axial 2D-RARE images (TR=4000ms, TE=9.1ms, ETL=4, FOV=[30x30]mm², matrix=128x126, slices=1-10mm, NEX=1, TA=17m4s). Animal experiments were carried out in accordance with local animal welfare protocols: EAE was induced in SJL/J mice,2 PFCE NPs were administered daily for five days2 after which mouse tissue was prepared for ex vivo MRI.2 3D-RARE brain 19F MRI: TR=800ms, TE=4.9ms, FOV=[30x20x20]mm³, NEX=256 (high-resolution: matrix=195x130x130, ETL=33, TA= 7h30m33s; medium-resolution: matrix=135x90x90, ETL=23, TA=5h14m1s; low-resolution: matrix=90x60x60, ETL=15, TA=3h24m46s). FLASH brain 1H MRI: TR=150ms, TE=7.5ms, FOV=[30x20x20]mm³, matrix=600x400x400, NEX=2, TA=3h20m.


Both T1 and T2 values for PFCE NPs were influenced by B0. Similar to other nuclei, the transverse spin-spin relaxation was decreased at 21.1 T (Figure 1A). Contrary to 1H, where T1 values increase with B0,9 the T1 of the PFCE NPs decreased by nearly 50% at 21.1 T (Figure 1B). The PFCE concentration did not influence T1 and T2 values (Table 1). For SNR measurements, slice thickness was varied for all PFCE concentrations. SNR was obtained as a function of the number of 19F atoms per voxel (Figure 2). An SNR gain of 2.1 was calculated at 21.1 T versus 9.4 T. The EM simulations revealed a 1.8-fold decrease in the B1 field at 21.1 T, when compared to 9.4 T: the maximum SNR gain is expected to be 2.8 (5/1.8), assuming total sample noise dominance and a lossless receive chain. High resolved MRI of EAE mice at 21.1 T revealed a greater level of detail of the immune cell migration in the inflamed brain and draining lymph nodes (Figure 3).


We demonstrate the feasibility of 19F MRI at 21.1 T for detecting inflammation in the brain and adjacent lymphatic system with high spatial definition. The decline in T1 with increasing B0 is consistent with previous studies.10,11 This suggests that at higher B0, data acquisition can be better accelerated. The decline in T2 at higher B0 hampers the expected increase in 19F MR signal at 21.1 T. The difference in the experimental SNR gain (2.1) and the maximum expected SNR gain (2.8) could be explained by coil and receive chain losses as well as preamplifier noise variations between both setups.


For a swift translation into application, high spatially-resolved 19F MRI was performed on EAE post mortem tissue to determine the feasibility of improved spatial definition of inflammatory cell location. This will allow us to study neuroinflammation with greater detail in future in vivo studies.


Part of this work was performed at the US National High Magnetic Field Laboratory, which is supported by the State of Florida and the National Science Foundation Cooperative Agreement No. DMR-1157490. The authors wish to thank Dr. William Brey and his team at the National High Magnetic Field Laboratory for valuable input and discussions on coil selection and design. The NHMFL User Collaborations Grant Program also provided travel funding to SW and HW.


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Fig. 1. Relaxation time parameters for 19F nanoparticles (1200mM PFCE) at 21.1 T and 9.4 T magnetic field strengths. (A) T2 relaxation at 21.1 T (T2=195ms) was shorter than T2 relaxation at 9.4 T (T2=503ms) (B) T1 relaxation at 21.1 T (T1=441ms) was shorter than T1 relaxation at 9.4 T (T1=913ms). T1 and T2-maps were generated using a RARE protocol with 15 TRs (T1 mapping) and an MSME protocol with 150 TEs (T2 mapping). The averaged intensities over the slice for all image series of both mapping protocols were then fitted to the T1 and T2 relaxation equations using Matlab.

Fig. 2. Plot of signal-to-noise ratio (SNR) versus 19F atoms per voxel at 21.1 T and 9.4 T magnetic field strengths. SNR was calculated from axial 2D-RARE images of four NMR tubes (60mM, 120mM, 600mM, 1200mM) with varying slice thicknesses (1.0 to 10mm). SNR was calculated by dividing signal from magnitude images by background standard deviation, and corrected to compensate for the non-Gaussian Rician distribution. A linear fit was determined for both 21.1 T (y=4e-19x, R²=0.9983) and 9.4 T (y=2e-19x, R²=0.9996).

Fig. 3. 19F MR image of an ex vivo EAE mouse brain acquired at 21.1 T and at different spatial resolutions. 19F MR images were acquired using a 3D-RARE sequence acquired at three different spatial resolutions: (A) high: matrix=195x130x130, 153µm³ (B) medium: matrix=135x90x90, 222µm³ (C) low: matrix=90x60x60, 333µm³. 19F MR images (shown in red) were scaled to units of SNR (pseudocolor scale), thresholded at SNR=3.5, and overlayed onto the FLASH 1H anatomical MR images (shown in grayscale). For all three spatial resolutions both horizontal (upper panel) and coronal (lower panel) views of the EAE mouse brain are shown.

Table 1. PFCE concentration in the 19F nanoparticles does not influence T1 and T2 values. Both T1 and T2 values for PFCE NPs were influenced by magnetic field strength but neither value was influenced by changes in the 19F amount at either magnetic field strength.

Proc. Intl. Soc. Mag. Reson. Med. 26 (2018)