The locus coeruleus shows a spatial pattern of structural disintegration in Parkinson’s disease

Abstract

Background Parkinson's disease (PD) leads to a loss of neuromelanin positive, noradrenergic neurons in the locus coeruleus (LC) which has been implicated in non-motor dysfunction. "Neuromelanin sensitive" magnetic resonance imaging (MRI) has emerged as a promising tool for mapping the structural integrity of LC in vivo. Objectives To identify spatial patterns of structural LC disintegration in PD and regions in the LC where structural disintegration is associated with specific non-motor dysfunctions. Methods 42 patients with PD and 24 age-matched healthy volunteers underwent ultra-high field MRI of the LC using a "neuromelanin sensitive" magnetization transfer weighted (MTw) sequence. The contrast-to-noise ratio of the MTw signal (CNRMTw) served as an estimate of structural integrity, slice- and voxel-wise analyses of CNRMTw were performed to map the spatial pattern of structural disintegration, complemented by Principal Component Analysis (PCA). We also tested for correlations between CNRMTw and the severity of non-motor symptoms. Results Mean CNRMTw of LC was reduced in patients relative to controls. The attenuation of CNRMTw was not uniformly expressed in LC, but confined to the middle and caudal LC. CNRMTw attenuation in caudal LC scaled with the orthostatic drop in systolic blood pressure and apathy ratings. PCA identified a bilaterally expressed component that was more weakly expressed in patients. This component was characterized by a gradual change in CNRMTw along the rostro-caudal and dorso-ventral axes of the nucleus. The individual expression score of this component reflected the overall severity of non-motor symptoms. Conclusion PD related structural disintegration of LC mainly affects its caudal part and may determine the individual expression of specific non-motor symptoms such as orthostatic dysregulation or apathy.

Locus Coeruleus Integrity from 7 T MRI Relates to Apathy and Cognition in Parkinsonian Disorders

“…The main group‐wise effect of PD and PSP on the LC was most apparent in the caudal subregion. This rostrocaudal gradient has been noted in some neuropathological studies of PD, 27 although not all, 28 and is in keeping with more recent in vivo LC imaging showing a prominence of caudal changes in PD 29,30 . In contrast, Alzheimer's disease, Down's syndrome, 28 and healthy aging 31 have been associated with greater cell loss from the rostral LC.…”

“…This rostrocaudal gradient has been noted in some neuropathological studies of PD, 27 although not all, 28 and is in keeping with more recent in vivo LC imaging showing a prominence of caudal changes in PD. 29,30 In contrast, Alzheimer's disease, Down's syndrome, 28 and healthy aging 31 have been associated with greater cell loss from the rostral LC. The caudal subregion may be especially vulnerable as it lies adjacent to the fourth ventricle, exposed to environmental insults from the cerebrospinal fluid.…”

Application of Neuromelanin MR Imaging in Parkinson Disease

“…A recent study investigated the association of LC structural changes with nonmotor clinical symptomatology in PD and found that there is a spatially heterogeneous degeneration of LC among PD patients. There was an association between regional structural degeneration and individual expressions of PD nonmotor symptoms (such as orthostatic dysregulation or apathy) 43 . Another group found a significant positive correlation between LC NM contrast and the extent of motor improvement after levodopa administration 45 .…”

“…While the vast majority of NM imaging studies in PD patients have been conducted using 3 T MRI scanners, recent developments and applications using 7 T have been able to show NM contrast in the SN and in the LC using high‐resolution imaging 43,54,60,61 . There is no clinical study that directly compares the diagnostic performance of NM loss in the SN using 3 T and 7 T scanners on the same patient population.…”

“…With increased imaging SNR, 7 T has the potential to provide a much better depiction of the rod‐like LC structure 54 . Using 7 T NM‐MRI, it is possible to investigate the spatial heterogeneity of LC contrast 43 and regional NM loss in the LC, 60 which are thought to be related to nonmotor symptoms in PD patients.…”