Universität zu Köln

Knudsen, Karoline, Fedorova, Tatyana D., Hansen, Allan K., Sommerauer, Michael, Otto, Marit, Svendsen, Kristina B., Nahimi, Adjmal, Stokholm, Morten G., Pavese, Nicola ORCID: 0000-0002-6801-6194, Beier, Christoph P., Brooks, David J. and Borghammer, Per ORCID: 0000-0001-6391-8052 (2018). In-vivo staging of pathology in REM sleep behaviour disorder: a multimodality imaging case-control study. Lancet Neurol., 17 (7). S. 618 - 629. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1474-4465

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Abstract

Background Accumulating evidence suggests that a-synuclein aggregates-a defining pathology of Parkinson's disease-display cell-to-cell transmission. a-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 C-11-donepezil PET and CT to assess cholinergic (parasympathetic) gut innervation, I-123-metaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure integrity of pigmented neurons of the locus coeruleus, C-11-methylreboxetine (MeNER) PET to assess noradrenergic nerve terminals originating in the locus coeruleus, and F-18-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 C-11-donepezil uptake (-0.322, 95% CI-0.112 to -0.531; p=0.0020), I-123-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 F-18-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 C-11-donepezil (p=0.39), I-123-MIBG (p>0.99), neuromelanin-sensitive MRI (p=0.96), and C-11-MeNER (p=0.56). By contrast, 15 (71%) of 21 patients with idiopathic REM sleep behaviour disorder had (1)8F-DOPA Ki values within normal limits, whereas all patients with Parkinson's disease had significantly decreased F-18-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 a-synuclein pathology in Parkinson's disease initially targets peripheral autonomic nerves and then spreads rostrally to the brainstem. Copyright (c) 2018 Elsevier Ltd. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Knudsen, Karoline UNSPECIFIED UNSPECIFIED UNSPECIFIED Fedorova, Tatyana D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hansen, Allan K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sommerauer, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Otto, Marit UNSPECIFIED UNSPECIFIED UNSPECIFIED Svendsen, Kristina B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nahimi, Adjmal UNSPECIFIED UNSPECIFIED UNSPECIFIED Stokholm, Morten G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pavese, Nicola UNSPECIFIED orcid.org/0000-0002-6801-6194 UNSPECIFIED Beier, Christoph P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Brooks, David J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Borghammer, Per UNSPECIFIED orcid.org/0000-0001-6391-8052 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-180567
DOI:	10.1016/S1474-4422(18)30162-5
Journal or Publication Title:	Lancet Neurol.
Volume:	17
Number:	7
Page Range:	S. 618 - 629
Date:	2018
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1474-4465
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PARKINSON DISEASE PATIENTS; ALPHA-SYNUCLEIN PATHOLOGY; LEWY BODY DISEASE; COERULEUS/SUBCOERULEUS COMPLEX; NERVOUS-SYSTEM; HUMAN BRAIN; COHORT; PET; ACETYLCHOLINESTERASE; NEUROPATHOLOGY Multiple languages Clinical Neurology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/18056