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In vivo staging of pathology in REM Sleep Behaviour Disorder – a multi-modality imaging case-control study

Lookup NU author(s): Professor Nicola PaveseORCiD, Professor David BrooksORCiD



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Background. Accumulating evidence suggests that a-synuclein aggregates, a defining pathology of Parkinson’s disease (PD), display cell-to-cell transmission. The initial a-synuclein aggregation may start in autonomic nerve terminals years prior to appearance of motor symptoms, and subsequently spread via autonomic nerves to the spinal cord and brainstem. If this hypothesis is correct, patients with idiopathic REM sleep behaviour disorder (iRBD), a prodromal phenotype of PD with RBD and dementia with Lewy bodies, could display a pattern of pathology where the peripheral autonomic nervous system and locus coeruleus (LC) are affected ahead of the nigrostriatal dopamine system. We aimed to investigate function of sympathetic, parasympathetic, noradrenergic, and dopaminergic innervation in iRBD patients using multi-modality imaging. Methods. In this clinically prospective, case-control study, polysomnography-confirmed iRBD subjects without clinical signs of parkinsonism or dementia were recruited via advertisement and sleep clinics in Denmark. We used 11C-donepezil PET/CT to assess their cholinergic activity (parasympathetic) in the gut, 123I-MIBG scintigraphy to measure cardiac sympathetic function, neuromelanin-sensitive MRI to measure density of pigmented neurons of the LC, 11C-MeNER PET to assess noradrenergic transporter availability in terminals originating from the LC, and 18F-DOPA PET to assess nigrostriatal dopamine storage capacity. For each imaging modality, findings for iRBD subjects were compared to those of controls without neurological disorders or cognitive impairment and to symptomatic PD patients. Imaging data were interrogated with one-way ANOVAs corrected for multiple comparisons. Findings. Twenty two iRBD patients were consecutively included between June 2016 and Dec 2017. Compared to healthy controls, the iRBD patients showed significant decreases in colonic 11C-donepezil uptake (-0·322 (CI-0·112; -0·531); p=0·0020), 123I-MIBG heart-mediastinum ratios (-0·508 (CI:-0·353; -0·664); p<0·0001), neuromelanin-MRI LC/pons ratios (-0·059 (CI:-0·019; -0·099); p=0·0028), 11C-MeNER binding potential in the left thalamus (-0·080 (CI:-0·010; -0·150) p=0·023), and putaminal 18F-DOPA Ki (-0·0023 (CI:-0·0009; -0·0037); p=0·0013). The iRBD and PD groups had similar gut 11C-donepezil (p=0·39), heart 123I-MIBG (p>0·99), neuromelanin-MRI (P=0·96), and brain 11C-MeNER signals (P=0·66). In contrast, while 71% of iRBD cases had normal putamen 18F-FDOPA Ki values, this was significantly reduced in all the PD patients (iRBD vs. PD: p<0·0001). Interpretation. Patients with iRBD displayed similar peripheral dysfunction to symptomatic PD in their sympathetic and parasympathetic nervous systems, and a similar loss of pigmented cells of the LC. In contrast to PD, 71% of iRBD cases had normal putaminal dopaminergic storage capacity. As iRBD can progress to PD with RBD or DLB, the peripheral dysfunction present in the absence of dopamine terminal damage supports the hypothesis that a-synuclein pathology in PD targets peripheral autonomic nerves ahead of involving nigral cells in the midbrain.

Publication metadata

Author(s): Knudsen K, Fedorova TD, Hansen AK, Sommerauer M, Otto M, Svendsen KB, Nahimi A, Stokholm MG, Pavese N, Beier CP, Brooks DJ, Borghammer P

Publication type: Article

Publication status: Published

Journal: Lancet Neurology

Year: 2018

Volume: 17

Issue: 7

Pages: 618-628

Print publication date: 01/07/2018

Online publication date: 01/06/2018

Acceptance date: 17/04/2018

Date deposited: 17/04/2018

ISSN (print): 1474-4422

ISSN (electronic): 1474-4465

Publisher: The Lancet Publishing Group


DOI: 10.1016/S1474-4422(18)30162-5


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