Magnetic resonance imaging of noradrenergic neurons

• Published in: Brain Structure and Function Vol. 224; no. 4; pp. 1609 - 1625
• Main Authors: Watanabe, Takashi, Tan, Zhengguo, Wang, Xiaoqing, Martinez-Hernandez, Ana, Frahm, Jens
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.05.2019; Springer Nature B.V
• Subjects: Alzheimer's disease; Arousal; Attention; Biomedical and Life Sciences; Biomedicine; Brain stem; Cell Biology; Cortex (frontal); Dopamine; Dopamine β-monooxygenase; Hemoglobin; Hydroxylase; Hypercapnia; Hyperoxia; Hypoxia; Ions; Locus coeruleus; Magnetic resonance imaging; Magnetic resonance spectroscopy; Manganese; N-Acetylaspartate; Neurodegeneration; Neuroimaging; Neurology; Neurons; Neurosciences; NMR; Norepinephrine; Nuclear magnetic resonance; Original; Original Article; Protons; Rodents; Solitary tract nucleus; Substantia grisea; Transgenic mice; Magnetization transfer; Nucleus tractus solitarius; Alzheimer’s disease; Neuromelanin; Dorsal motor vagus nucleus; Locus coeruleus
• ISSN: 1863-2653; 1863-2661; 1863-2661; 0340-2061
• DOI: 10.1007/s00429-019-01858-0

Noradrenaline is a neurotransmitter involved in general arousal, selective attention, memory, inflammation, and neurodegeneration. The purpose of this work was to delineate noradrenergic neurons in vivo by T 1 -weighted MRI with magnetization transfer (MT). In the brainstem of human and mice, MRI identified the locus coeruleus, dorsal motor vagus nucleus, and nucleus tractus solitarius. Given (1) the long T 1 and low magnetization transfer ratio for the noradrenergic cell groups compared to other gray matter, (2) significant correlation between MT MRI signal intensity and proton density, and (3) no correlation between magnetization transfer ratio (or R 1 ) and iron, copper, or manganese in human brain, the high MRI signal of the noradrenergic neurons must be attributed to abundant water protons interacting with any T 1 -shortening paramagnetic ions in active cells rather than to specific T 1 -shortening molecules. The absence of a high MRI signal from the locus coeruleus of Ear2(−/−) mice lacking noradrenergic neurons confirms that cell bodies of noradrenergic neurons are the source of the bright MRI appearance. The observation of this high signal in DBH(−/−) mice, in 3-week-old mice, and in mice under hyperoxia/hypercapnia/hypoxia together with the general absence of neuromelanin (NM) in noradrenergic neurons of young rodents further excludes that it is due to NM, dopamine β-hydroxylase, their binding to paramagnetic ions, blood inflow, or hemoglobin. Instead, these findings indicate a high density of water protons whose T 1 is shortened by paramagnetic ions as the relevant source of the high MRI signal. In the brain of APP/PS1/Ear2(−/−) mice, a transgenic model of Alzheimer’s disease, MRI detected noradrenergic neuron loss in the locus coeruleus. Proton magnetic resonance spectroscopy revealed that a 60–75% reduction of noradrenaline is responsible for a reduction of N -acetylaspartate and glutamate in the hippocampus as well as for a shortening of the water proton T 2 in the frontal cortex. These results suggest that a concurrent shortage of noradrenaline in Alzheimer’s disease accelerates pathologic processes such as inflammation and neuron loss.