Unraveling the contributions to the neuromelanin-MRI contrast

Nikos Priovoulos,Heidi I L Jacobs,Stan C J Van Boxel,Frans R J Verhey,Kamil Uludag,Dimo Ivanov,Benedikt A Poser

doi:10.1007/s00429-020-02153-z

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.

Highlights

The Locus Coeruleus (LC) and the Substantia Nigra (SN) are small, neuromelanin (NM)-rich gray matter nuclei in the brainstem that show alterations in several neurodegenerative and psychiatric diseases, such as Parkinson’s and Alzheimer’s (AD) disease or depressive disorder
The regression was performed for the frequency offset in which maximum Magnetization Transfer (MT) contrast between LC/SN and gray matter has been observed in vivo before (Priovoulos et al 2018; Trujillo et al 2015)
MT and Turbo Spin Echo (TSE) signal in the LC and the SN, the socalled NM-MRI, has been related to the presence of NE and DA neurons or NM macromolecules (Cassidy et al 2019; Keren et al 2015; Kitao et al 2013), while signal differences in these regions are commonly observed in aging and neurodegenerative diseases compared to young people (Clewett et al 2016; Hämmerer et al 2018; Liu et al 2018; Takahashi et al 2015)

Summary

Introduction

The Locus Coeruleus (LC) and the Substantia Nigra (SN) are small, neuromelanin (NM)-rich gray matter nuclei in the brainstem that show alterations in several neurodegenerative and psychiatric diseases, such as Parkinson’s and Alzheimer’s (AD) disease or depressive disorder 2011; Busch et al 1997; Liu et al 2017; Marcyniuk et al 1986; Sara 2009). Because of their critical modulating role in cognition and behavior, as well as being part of the pathophysiology of several neurodegenerative diseases, there is an increasing interest in imaging the LC and the SN with the so-called NM-MRI, and understanding the biological correlates of the MRI contrast observed (a search in Pubmed for NM-MRI provides 160 hits, as of 07–08–2020). Prior work has reported MRI signal differences in the LC between younger and older individuals and between clinically healthy older individuals and patients with AD, Parkinson’s disease,

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