Histologic validation of locus coeruleus MRI contrast in post-mortem tissue

Abstract

The locus coeruleus (LC) noradrenergic system regulates arousal and modulates attention through its extensive projections across the brain. LC dysfunction has been implicated in a broad range of neurodevelopmental, neurodegenerative and psychiatric disorders, as well as in the cognitive changes observed during normal aging. Magnetic resonance imaging (MRI) has been used to characterize the human LC (elevated contrast relative to surrounding structures), but there is limited understanding of the factors underlying putative LC contrast that are critical to successful biomarker development and confidence in localizing nucleus LC. We used ultra-high-field 7 T magnetic resonance imaging (MRI) to acquire T1-weighted microscopy resolution images (78 μm in-plane resolution) of the LC from post-mortem tissue samples. Histological analyses were performed to characterize the distribution of tyrosine hydroxylase (TH) and neuromelanin in the scanned tissue, which allowed for direct comparison with MR microscopy images. Our results indicate that LC-MRI contrast corresponds to the location of neuromelanin cells in LC; these also correspond to norepinephrine neurons. Thus, neuromelanin appears to serve as a natural contrast agent for nucleus LC that can be used to localize nucleus LC and may have the potential to characterize neurodegenerative disease.

Neuromelanin marks the spot: identifying a locus coeruleus biomarker of cognitive reserve in healthy aging

“…Combined with our current finding of reduced PT signal intensity with age, we conclude that age-related changes in LC CNR should be interpreted with caution. Nonetheless, fast spin-echo MRI remains a highly effective method for localizing and quantifying neuromelanin-containing LC neurons in vivo (Keren et al, 2009, 2015). …”

The Locus Coeruleus: Essential for Maintaining Cognitive Function and the Aging Brain

“…With the use of magnetic resonance imaging sequences optimized to detect neuromelanin, the LC can now be reliably located (Fig. 1B; [26, 30, 31]). Among older adults, greater signal contrast in the LC is associated with higher verbal knowledge [26], whereas lower signal intensity is associated with mild cognitive impairment and Alzheimer’s disease [27].…”

A Neural Model of Mind Wandering

“…Recently, the first in vivo anatomical map of the human LC in standard space was created [55] using a T1-TSE sequence [54] that exploited the increased contrast that the presence of neuromelanin in the LC offers. This method was later validated with post-mortem scans and histology ( [56], see Figure I). …”