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Background: Accumulating evidence suggests that α-synuclein aggregates-a defining pathology of Parkinson's disease-display cell-to-cell transmission. α-synuclein aggregation is hypothesised to start in autonomic nerve terminals years before the appearance of motor symptoms, and subsequently spread via autonomic nerves to the spinal cord and brainstem. To assess this hypothesis, we investigated sympathetic, parasympathetic, noradrenergic, and dopaminergic innervation in patients with idiopathic rapid eye movement (REM) sleep behaviour disorder, a prodromal phenotype of Parkinson's disease.Methods: In this prospective, case-control study, we recruited patients with idiopathic REM sleep behaviour disorder, confirmed by polysomnography, without clinical signs of parkinsonism or dementia, via advertisement and through sleep clinics in Denmark. We used 11C-donepezil PET and CT to assess cholinergic (parasympathetic) gut innervation, 123I-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure integrity of pigmented neurons of the locus coeruleus, 11C-methylreboxetine (MeNER) PET to assess noradrenergic nerve terminals originating in the locus coeruleus, and 18F-dihydroxyphenylalanine (DOPA) PET to assess nigrostriatal dopamine storage capacity. For each imaging modality, we compared patients with idiopathic REM sleep behaviour disorder with previously published reference data of controls without neurological disorders or cognitive impairment and with symptomatic patients with Parkinson's disease. We assessed imaging data using one-way ANOVA corrected for multiple comparisons.Findings: Between June 3, 2016, and Dec 19, 2017, we recruited 22 consecutive patients with idiopathic REM sleep behaviour disorder to the study. Compared with controls, patients with idiopathic REM sleep behaviour disorder had decreased colonic 11C-donepezil uptake (-0·322, 95% CI -0·112 to -0·531; p=0·0020), 123I-MIBG heart:mediastinum ratio (-0·508, -0·353 to -0·664; p<0·0001), neuromelanin-sensitive MRI locus coeruleus:pons ratio (-0·059, -0·019 to -0·099; p=0·0028), and putaminal 18F-DOPA uptake (Ki; -0·0023, -0·0009 to -0·0037; p=0·0013). No between-group differences were detected between idiopathic REM sleep behaviour disorder and Parkinson's disease groups with respect to 11C-donepezil (p=0·39), 123I-MIBG (p>0·99), neuromelanin-sensitive MRI (p=0·96), and 11C-MeNER (p=0·56). By contrast, 15 (71%) of 21 patients with idiopathic REM sleep behaviour disorder had 18F-DOPA Ki values within normal limits, whereas all patients with Parkinson's disease had significantly decreased 18F-DOPA Ki values when compared with patients with idiopathic REM sleep behaviour disorder (p<0·0001).Interpretation: Patients with idiopathic REM sleep behaviour disorder had fully developed pathology in the peripheral autonomic nervous system and the locus coeruleus, equal to that in diagnosed Parkinson's disease. These patients also showed noradrenergic thalamic denervation, but most had normal putaminal dopaminergic storage capacity. This caudorostral gradient of dysfunction supports the hypothesis that α-synuclein pathology in Parkinson's disease initially targets peripheral autonomic nerves and then spreads rostrally to the brainstem.Funding: Lundbeck Foundation, Jascha Foundation, and the Swiss National Foundation. [ABSTRACT FROM AUTHOR]

Background: The 3D‐Transit electromagnet tracking system (Motilis Medica, SA, Lausanne, Switzerland) is an emerging tool for the ambulatory assessment of gastrointestinal (GI) transit and motility. Using this tool, we aimed to derive normative values for region‐specific colonic and GI transit times and to assess the influence of age, gender, and body mass index (BMI). Methods: Regional and total colonic transit times (CTT), gastric emptying (GET), small intestinal (SITT), and whole gut (WGTT) transit times were extracted from 111 healthy volunteers from the United Kingdom and Denmark (58 female; median age: 40 years [range: 21‐88]). The effects of age, gender, and BMI were assessed using standard statistical methods. Key Results: The ascending, transverse, descending, and rectosigmoid colon transit times accounted for 32%, 34%, 17%, and 17% of total CTT in females, and 33%, 25%, 14%, and 28% of total CTT in males. CTT and WGTT were seen to cluster at intervals separated by approximately 24 hours, providing further evidence of the non‐continuous nature of these measurements. Increasing age was associated with longer CTT (P =.021), WGTT (P <.001) ascending (P =.004), transverse (P <.001), and total right (P <.001) colon transit times, but shorter rectosigmoid (P =.004) transit time. Female gender was significantly associated with longer transverse (P =.049) and descending (P <.001) colon transit times, but shorter rectosigmoid (P <.001) transit time. Increasing BMI was significantly associated with shorter WGTT (P =.012). Conclusions and Inferences: For the first time, normative reference values for region‐specific colonic transit have been presented. Age, gender, and BMI were seen to have an effect on transit times. [ABSTRACT FROM AUTHOR]