Unraveling the contributions to the neuromelanin-MRI contrast

Abstract

The Locus Coeruleus (LC) and the Substantia Nigra (SN) are small brainstem nuclei that change with aging and may be involved in the development of various neurodegenerative and psychiatric diseases. Magnetization Transfer (MT) MRI has been shown to facilitate LC and the SN visualization, and the observed contrast is assumed to be related to neuromelanin accumulation. Imaging these nuclei may have predictive value for the progression of various diseases, but interpretation of previous studies is hindered by the fact that the precise biological source of the contrast remains unclear, though several hypotheses have been put forward. To inform clinical studies on the possible biological interpretation of the LC- and SN contrast, we examined an agar-based phantom containing samples of natural Sepia melanin and synthetic Cys-Dopa-Melanin and compared this to the in vivo human LC and SN. T1 and T2* maps, MT spectra and relaxation times of the phantom, the LC and the SN were measured, and a two-pool MT model was fitted. Additionally, Bloch simulations and a transient MT experiment were conducted to confirm the findings. Overall, our results indicate that Neuromelanin-MRI contrast in the LC likely results from a lower macromolecular fraction, thus facilitating interpretation of results in clinical populations. We further demonstrate that in older individuals T1 lengthening occurs in the LC.

Age differences in diffusivity in the locus coeruleus and its ascending noradrenergic tract

“…While LC-MRI contrast has been validated to correlate with the location of neuromelanin ( Keren et al, 2015 ), it is not yet entirely clear what factors contribute to currently employed LC-MRI contrast measures. Current hypotheses include presence of macromolecules ( Priovoulos et al, 2020 ), density of water protons ( Watanabe et al, 2019 ), and the relative proportion of macromolecular protons to free water protons ( Trujillo et al, 2019 ).…”

Associations between locus coeruleus integrity and nocturnal awakenings in the context of Alzheimer’s disease plasma biomarkers: a 7T MRI study

“…All participants underwent high-resolution imaging of the brainstem on a 7T Magnetom Siemens scanner (Siemens Healthineers, Erlangen, Germany) using a magnetization transfer-weighted turbo flash (MT-TFL) sequence particularly sensitive to LC-related contrast [ 18 , 19 ], with a field-of-view placed perpendicular to the pons and covering the area between the inferior colliculus and the inferior border of the pons. Importantly, the LC-related MRI signal obtained with this sequence has been established to reflect LC neuronal and fiber projection density [ 20 ].…”

Substantia nigra ferric overload and neuromelanin loss in Parkinson’s disease measured with 7T MRI

“…Magnetization transfer imaging shows specificity to the dopaminergic neurons of the SNpc but its biological relationship with neuromelanin is still elusive (76)(77)(78) as a contrast-to-noise measurement is only semi-quantitative. In order to better quantify nonexchangeable protons attached to macromolecules like neuromelanin, kinetic model parameters describing magnetization dynamics via a two-pool model could be used (79,80).…”