Image Credit:Shutterstock/Andrii Vodolazhskyi
Magnetic resonance imaging (MRI) provides visual insight into different parts of the body for the identification, diagnosis, and monitoring of disease. Some research, however, is using MRI to see the molecular makeup of the brain, particularly to identify changes in the brain tissue. These insights may offer additional information about the progression of certain aging-related brain diseases, including Alzheimer’s disease.
The MRI technique readily differentiates and can assist in characterizing large cell assemblies from surrounding tissue, such as in the central nervous system of vertebrates where neuronal cell bodies are typically assembled as either nuclei or cellular layers.
Differentiation of large cell assemblies by MRI is made possible due to the exhibition of T1 and T2 relaxation times in intracellular water protons. These are often smaller than bulk water protons found in the extracellular space while larger than intra- and extracellularly located water protons that form an interaction with lipid bilayers.
In a study published in Nature, researchers from Germany selectively studied cell assemblies with the MRI technique using water proton signals associated with intracellular paramagnetic ions. The researchers performed this action by saturating lipid-associated water protons as well as extracellular free water protons by direct on-resonance irradiation.
Researchers Perform First In Vivo MRI Study of Hippocampal and A2 Cell Assemblies
The first part of the study consisted of an MRI of the human brain and spinal cord, performed at 3T resolution. In addition, the researchers calculated signal intensity in gradient-echo MRI of the brain in vivo, which is only found to originate from water protons.
A mouse model, consisting of 32 mice, was also included in this study. A total of 24 mice were tested for optimizing magnetization transfer. In this mouse model, the investigators used an MRI unit from Bruker Biospin (Bruker Biospin MRI GmbH) to monitor the respiratory movement of the abdomen as well as rectal temperature.
Additionally, MRI measurements at 2.35T were taken using a 4.7/400 mm magnet that was equipped with 200 mT m-1 gradients also supplied by Bruker. Prior to treatment with kainic acid or placebo, as well as 4 days after administration of either, an MRI was performed. Following the second MRI examination, the mice were transcardially perfused with a 10% solution of neutral phosphate-buffered formalin.
In a mouse brain MRI evaluation of signal intensities, the researchers also used Bruker’s ParaVision 5.0 for obtaining anatomically defined cross-sections by multiplanar reconstructions. The ParaVision system is MRI software that allows researchers to perform acquisition of multi-dimensional MRI/magnetic resonance spectroscopy data, reconstruction, analysis, and visualization in preclinical imaging research. German animal protection laws governed all animal experiments following approval and review by an institutional review board.
Image Production Relies on Saturation of Extracellular Free Water Protons
The investigators found that magnetization-transfer MRI of the brain offers proton-density contrast while saturating extracellular free water protons. The white matter demonstrated a downward deviation due to its lower concentration of paramagnetic ions and strong interaction with water protons. Also, they found that the average regional R1 of gray matter structures correlated linearly with their corresponding water content.
An MRI technique using signals from water protons was capable of visualizing cell assemblies in the hippocampal formation that were not shown in human participants in vivo. The technique, however, did delineate noradrenergic neuron groups in the brainstem, such as the locus coeruleus in both humans and mice in vivo.
The noradrenergic neurons are involved in the production of the neuromodulator, subsequently responsible for releasing it from axonal terminals that spread throughout the brain. Ultimately, they are then assembled in the brainstem as A1 to A7 cell groups. According to the researchers, their reduced magnetization-transfer ratios in combination with their prolonged relaxation times versus other gray matter suggest that the high signal intensity source is not the presence of T1-shortening molecules but is predominantly due to their high-water content.
The study investigators concluded that the production of image contrast primarily relies on the saturation of both lipid-associated water protons as well as extracellular free water protons. Ultimately, this results in the preservation of the water proton signals associated with intracellular paramagnetic ions. Signal intensity of the image, they concluded, is mostly due to the density of the intracellular water protons associated with the paramagnetic ions, which is generally not impacted by endogenous paramagnetic ion concentrations in the body.
The main clinical domain application of water diffusion MRI has been historically neurological disease, particularly in acute brain ischemia. In terms of the clinical implications related to this study, the researchers suggest that MRI of and hippocampal cell assemblies may play an important role in translational biomedical research of neurodegenerative diseases in both animals and humans. Given the reduction in the numbers of locus coeruleus neurons and the correlating noradrenalin shortage in the brain that is associated with aging, dementia, Aβ plaque load, and Alzheimer’s disease progression.
- Watanabe T, Wang X, Tan Z, Frahm J. Magnetic resonance imaging of brain cell water. Sci Rep. 2019;9(1):5084.
- Le Bihan D. Diffusion MRI: what water tells us about the brain. EMBO Mol Med. 2014 May;6(5):569-573.
- Bruke. ParaVision 360. https://www.bruker.com/products/mr/preclinical-mri/paravision-360.html. Accessed March 1, 2020.