Locus Coeruleus Integrity from 7T MRI Relates to Apathy and Cognition in Parkinson’s Disease and Progressive Supranuclear Palsy

Abstract

Background and ObjectivesThe loss of noradrenergic neurons in the locus coeruleus (LC) contributes to various cognitive and neuropsychiatric symptoms in Parkinson’s disease (PD) and progressive supranuclear palsy (PSP). The spatial precision of in vivo LC imaging is improved using a magnetisation transfer sequence combined with ultra-high field 7T MRI. This study aimed to test the sensitivity of LC imaging in PD and PSP, to characterise the spatial pattern of LC atrophy in patients, and its relationship to cognition and apathy.MethodsThis cross-sectional observational study recruited patients with idiopathic PD, probable PSP-Richardson’s syndrome and age-matched healthy controls (HC) via specialist clinics and volunteer registries. All participants underwent clinical assessments for cognition and apathy, and high-resolution (0.08 mm3) LC scans. To quantify LC integrity, the contrast-to-noise ratio (CNR) relative to a pons reference region was calculated and extracted using a probabilistic atlas. Subregional mean CNRs were summarised to test group differences and to correlate LC integrity with apathy and cognition scores. LC clusters were identified to confirm the spatial pattern of the effect (threshold free cluster enhancement, 10000 permutations, p<0.05, corrected for family-wise error).ResultsTwenty-five patients with PD, 14 with PSP and 24 controls with completed dataset were included in the study. Patients with PSP were more impaired on global cognition and apathy scores, compared to controls and PD. Clusters with reduced contrast were observed in the caudal LC for both PD and PSP patients relative to controls (HC>PD, right caudal LC, 37 voxels; HC>PSP, bilateral caudal LC, 206 voxels). PSP and PD patients showed similar levels of LC degeneration, but this was more extensive in PSP. Across both disease groups, LC integrity was associated with cognitive performance (MoCA: F(1,37)=5.339, p=0.027, bilateral LC, 200 voxels; ACE-R: F(1,37)=4.297, p=0.045, left LC, 70 voxels) and apathy (Apathy Scale: F(1,37)=4.335, p=0.044, left LC, 99 voxels).DiscussionWe confirm the sensitivity of 7T LC imaging to detect sub-regional LC changes in PD and PSP. The relationship between LC integrity and non-motor symptoms highlights the potential for noradrenergic therapeutic strategies to ameliorate cognitive and behavioural features of PD and PSP.

Prefrontal cortical connectivity mediates locus coeruleus noradrenergic regulation of inhibitory control in older adults

“…The locus coeruleus signal was extracted through a probabilistic atlas-based segmentation, which provides unbiased estimation, with superior accuracy and reliability compared to the manual segmentation approaches (Chen et al, 2014;Langley, Huddleston, Liu, & Hu, 2016;Ye et al, 2021). These features are preferable when using 3T MRI images, where the manual segmentation approach may be unreliable due to the relatively low signal-to-noise ratio.…”

“…By exploiting the accumulation of iron-rich neuromelanin, magnetization-transfer (MT) sensitive magnetic resonance imaging sequences can be used to assess the integrity of the locus coeruleus (Liu et al 2019;Ye et al, 2020; but see also Watanabe et al, 2019). Such studies have associated locus coeruleus integrity with diverse cognitive function in health (Liu et al, 2020) and disease Holland, Robbins, & Rowe, 2021;O'Callaghan et al, 2021;Ye et al, 2021).…”

“…Our study has four main advances with respect to an earlier analysis of the Cam-CAN cohort (Liu et al, 2020). First, we use an atlas-based segmentation of the locus coeruleus, which provides unbiased estimation, with good accuracy and reliability compared to manual and semi-automatic segmentation approaches (Ye et al, 2021). Second, we focus on middle-aged and older healthy adults, because neuromelanin accumulates with age (Zecca, Youdim, Riederer, Connor, & Crichton, 2004) and in younger participants the locus coeruleus neurons may not yet be sufficiently pigmented to allow reliable inference on structural integrity by MT weighted MRI.…”

Prefrontal Cortical Connectivity Mediates Locus Coeruleus Noradrenergic Regulation of Inhibitory Control in Older Adults

“…This is because of the greater neuromelanin based contrast with age (Zecca et al, 2004). The locus coeruleus signal was extracted through a probabilistic atlas-based segmentation, which provides unbiased estimation, with superior accuracy and reliability compared to the manual segmentation approaches (Chen et al, 2014;Langley et al, 2016;Ye et al, 2021). These features are preferable when using 3T MRI images, where the manual segmentation approach may be unreliable due to the relatively low signal-to-noise ratio.…”

“…Our study has four main advances with respect to an earlier analysis of the Cam-CAN cohort (Liu et al, 2020). First, we use an atlas-based segmentation of the locus coeruleus, which provides unbiased estimation, with good accuracy and reliability compared to manual and semiautomatic segmentation approaches (Ye et al, 2021). Second, we focus on middle-aged and older healthy adults, because neuromelanin accumulates with age (Zecca, et al, 2004) and in younger participants the locus coeruleus neurons may not yet be sufficiently pigmented to allow reliable inference on structural integrity by MT weighted MRI.…”