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Locus coeruleus degeneration is associated with disorganized functional topology in Parkinson’s disease
Cheng Zhou1, Tao Guo1, Jingjing Wu1, Xueqin Bai1, Xiaojun Guan1, and Minming Zhang1
1Zhejiang University, Hangzhou, China

Synopsis

A major emphasis has been placed on the symptom related brain alterations caused by dopamine deficiency, the brain organization underlying the norepinephrine deficiency is largely unknown. We used the neuromelanin sensitive-magnetic resonance imaging for evaluating the degeneration of LC, and using graph theory-based network analysis for characterizing the brain functional topology in 94 PD patients and 68 healthy controls.Relationships between LC degeneration, network disruption and cognitive/motor manifestations in PD patients were assessed.An independent PD subgroup with MRI scanning before and after levodopa administration was enrolled to clarify whether LC degeneration related network disruption were independent of dopamine deficiency.

Objective

Locus coeruleus (LC) degeneration is recognized as a critical hallmark of Parkinson's disease (PD). However, whether LC degeneration contribute to cognitive/motor manifestations through modulating brain functional organization remains unknown, though recent studies reported that LC-norepinephrine have crucial effects on brain functional organization.

Methods

Ninety-four PD patients and 68 healthy controls (HC) were enrolled. LC integrity was measured using the contrast-to-noise ratio of LC (CNRLC) calculated from neuromelanin sensitive magnetic resonance imaging. Graph theory-based network analysis was used to characterize the functional organization (degree centrally, nodal efficiency). Relationships between LC degeneration, network disruption and cognitive/motor manifestations in PD patients were assessed. Mediation analysis was conducted to test whether network disruption was a mediator between LC degeneration and cognitive/motor impairments. An independent PD subgroup (n = 35) with MRI scanning before and after levodopa administration was enrolled to clarify whether those LC degeneration related network attributes were independent of dopamine deficiency.

Results

We found significant LC degeneration in PD group (Figure 1). Extensive network disruption in cognitive and motor related cortex were found in PD patients, which is consist with previous knowledge of widespread functional disorganization and have an incremental value (Figure 2). CNRLC was positively correlated with Montreal Cognitive Assessment (MoCA) score (Figure 3A) and the nodal efficiency of several cognitive related regions (Figure 3B). Decreased nodal efficiency in superior temporal gyrus was a mediator between LC degeneration and cognitive impairment in PD patients (Figure 3C, D). And we demonstrated that network attributes of frontal and motor cortex were normalized by levodopa administration while decreased nodal efficiency of superior temporal gyrus (mediator) could not be modulated (Figure 4).

Conclusion

Our findings suggested that LC degeneration was a key pathway for PD cognitive decline through associating with the disorganized functional topology.

Acknowledgements

We thank all patients with Parkinson’s disease patients and healthy controls who participated in this study.

References

1. Betts MJ, Kirilina E, Otaduy MCG, et al. Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases. Brain 2019;142:2558-2571.

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Figures

Figure 1. Comparison of CNRLC between the HC and PD groups. (A) Signal intensity measurements of the LC (two small red circles) and pontine (a big red circles) from a HC; (B) and (C) The location of LC in continuous layers (red arrow); (D) Significantly decreased CNRLC was found in PD group when compared with HC group. CNRLC: Contrast-to-noise ratio of the locus coeruleus; HC: Healthy control; PD: Parkinson's disease; L: Left; ***: P < 0.001.

Figure 2. The differences of network attributes between HC and PD groups. HC: Healthy controls; PD: Parkinson’s disease; DC: Degree centrality; NE: Nodal efficiency; L: Left; R: Right; SFG: Superior Frontal Gyrus; PoG: Postcentral Gyrus; CG: Cingulate Gyrus; FMG: Middle Frontal Gyrus; PrG: Precentral Gyrus; PCL: Paracentral Lobule; FuG: Fusiform Gyrus; IPL: Inferior Parietal Lobule; PoG: Postcentral Gyrus; INS: Insular Gyrus; Cun: Cuneus; OcG: Occipital Gyrus; STG: Superior Temporal Gyrus. Green / Orange means HC > PD.

Figure 3. Correlation analysis among CNRLC, network attributes, and MoCA score in PD group. (A) CNRLC was significantly correlated with MoCA score in PD group; (B) CNRLC was significantly correlated with the network attributes of cognitive and motor related regions in PD group; (C) Network attributes of two cognitive related regions were associated with MoCA score in PD group; (D) Mediation analysis showed that damaged NE of STG was a mediator between LC degeneration and cognitive decline.

Figure 4. The difference of network attributes among HC group, PD group, and PDsub group. (A) Compared with HC , PDsub group showed decreased DC and NE during OFF state. (B) No difference was found between PD group and PDsub group during OFF state, which means a good consistent between the two groups; (C) Significantly increased DC and NE of frontal and sensorimotor related nodes (SFG and PrG) was detected after levodopa administration. No difference was found in NE of cognitive related nodes (STG and INS) between OFF state and ON state within PDsub group.

Proc. Intl. Soc. Mag. Reson. Med. 29 (2021)
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