Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases

Abstract

Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression. In combination with neuropathological biomarkers, in vivo locus coeruleus imaging could help to understand the contribution of locus coeruleus neurodegeneration to clinical and pathological manifestations in Alzheimer's disease, atypical neurodegenerative dementias and Parkinson's disease. Moreover, as the functional sensitivity of the noradrenergic system is likely to change with disease progression, in vivo measures of locus coeruleus integrity could provide new pathophysiological insights into cognitive and behavioural symptoms. Locus coeruleus imaging also holds the promise to stratify patients into clinical trials according to noradrenergic dysfunction. In this article, we present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases. We outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases.

Keywords: locus coeruleus (LC); magnetic resonance imaging (MRI); neurodegeneration; noradrenaline (NA) biomarker.

Figure 1

Overview of LC visibility using post-mortem and in vivo MRI. The LC can be imaged in post-mortem tissue using numerous MRI protocols [arrows indicate the LC, evident as dark spots in T₂* (A and G) and bright spots in T₁-weighted (E) and MT-weighted (F) scans] in addition to using histological techniques. (D) The LC is visible as dark spots in a post-mortem slice without any staining, due to neuromelanin deposits, which are thought to contribute to magnetic resonance visibility of the LC. (C) Myelination in the LC area. The LC and central pontine grey show very low myelination, but are surrounded by areas with very high and intermediate myelination (green areas), possibly also contributing to MR visibility of the LC. To image the LC in vivo, T₁-weighted (H, O and S) and MT-weighted (I–K) MRI protocols can be used (arrows indicate the LC, evident as bright spots in T₁-weighted and MT-weighted scans). Using these protocols, a decline in LC integrity in Alzheimer’s disease dementia (S) compared to healthy elderly adults (O) can be identified (Betts et al., 2019). To fine-tune these scan protocols further, it is necessary to understand the magnetic resonance contrast mechanisms that underlie LC visibility. (L–N and P–R) Quantitative maps which isolate different magnetic resonance contrast effects (R₁, MT and R₂* effects), show that LC visibility in T₁-weighted as well as MT-weighted scans in vivo is mostly due to R₁ effects (mean LC visibility across 22 healthy older adults extracted from line regions of interest; see inset on right for position of line regions of interest. Black dots indicate position of maximal signal intensity based on T₁-weighted maps. Peaks in signal intensity are apparent in R₁ and to some extent in R₂* maps (Hämmerer et al., 2018a)]. Sequence details/ stains: (A) 7 T T₂*-weighted (50 μm resolution) FLASH MRI image TE = 19 ms; (B) TH staining for LC neurons (dark); (C) Luxol fast blue staining for myelinated fibres in same slice (green); (D) Block face image after celloidin embedding (LC neurons dark); (E) 7 T T₁-weighted (0.2 × 0.2 × 2 mm) TSE image (TE/TR/TI = 11/3000/825 ms); (F) 7 T MT-weighted FLASH MRI image (TE/TR = 5.1/26 ms); (G) 7 T T₂*-weighted FLASH image (TE/TR = 21/30 ms) (Otaduy et al., unpublished results); (H) 3 T T₁-weighted (0.4 × 0.4 × 3 mm) FLASH image (TE/TR = 3.35–16.95/27) averaged across six repetitions; (I) 3 T MT-weighted (0.4 × 0.4 × 3 mm) FLASH image (TE/TR = 3.35–16.95/30.74); (J) 7 T MT-TFL image (0.4 × 0.4 × 0.5 mm); (K) 3 T MT-weighted (1.5 mm³) SPGR image (TE/TR = 5 ms/30 ms; (O and S) 3 T T₁-weighted (0.75 mm³) FLASH image (TE/TR = 5.56 ms/20 ms). Image in J is reproduced with permission from Priovoulos et al. (2018); O is reproduced with permission from Betts et al. (2017). TE/TR/TI = echo time/repetition time/inversion time.

Figure 2

Establishing LC imaging as a biomarker for noradrenergic dysfunction. LC imaging offers potential as a disease monitoring and stratification tool to predict the success of novel pharmacological ligands in clinical trials. To achieve this aim, it will be essential to validate in vivo LC MRI contrast with respect to the concentration of neuromelanin and density of noradrenergic neurons in post-mortem tissue. This will be important for developing a deeper understanding into how changes in LC MRI contrast both in vivo and in post-mortem tissue correlate with neuromelanin-bound metals in noradrenergic neurons and is influenced by the neuropathological characteristics of neurodegenerative diseases. In the clinic, longitudinal LC imaging may be combined with biomarkers (e.g. in CSF or molecular imaging) to assess how changes in LC MRI contrast may drive clinical and pathological manifestations of neurodegenerative diseases. Source of CSF image: Wikimedia Commons; molecular imaging figure is adapted from Palmqvist et al. (2017); LC integrity image (middle) adapted with permission from Betts et al. (2017); age effects on LC integrity image (right) reproduced with permission from Liu et al. (2019).