Karoline Knudsen1, Tatyana D Fedorova1, Allan K Hansen1, Michael Sommerauer2, Marit Otto3, Kristina B Svendsen4, Adjmal Nahimi1, Morten G Stokholm1, Nicola Pavese5, Christoph P Beier6, David J Brooks5, Per Borghammer7. 1. Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark. 2. Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark; Department of Neurology, University Hospital Cologne, Cologne, Germany. 3. Department of Clinical Neurophysiology, Aarhus University Hospital, Aarhus, Denmark; Department of Neurology, Aarhus University Hospital, Aarhus, Denmark. 4. Department of Neurology, Aarhus University Hospital, Aarhus, Denmark. 5. Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark; Division of Neuroscience, Department of Medicine, Imperial College London, London, UK; Division of Neuroscience, Newcastle University, Newcastle, UK. 6. Southern University of Denmark, Department of Neurology, Odense, Denmark. 7. Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark. Electronic address: perborgh@rm.dk.
Abstract
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.
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 colonic11C-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.
Authors: Zachary D Wallen; Mary Appah; Marissa N Dean; Cheryl L Sesler; Stewart A Factor; Eric Molho; Cyrus P Zabetian; David G Standaert; Haydeh Payami Journal: NPJ Parkinsons Dis Date: 2020-06-12
Authors: Yves Dauvilliers; Carlos H Schenck; Ronald B Postuma; Alex Iranzo; Pierre-Herve Luppi; Giuseppe Plazzi; Jacques Montplaisir; Bradley Boeve Journal: Nat Rev Dis Primers Date: 2018-08-30 Impact factor: 52.329
Authors: Bryan A Killinger; Zachary Madaj; Jacek W Sikora; Nolwen Rey; Alec J Haas; Yamini Vepa; Daniel Lindqvist; Honglei Chen; Paul M Thomas; Patrik Brundin; Lena Brundin; Viviane Labrie Journal: Sci Transl Med Date: 2018-10-31 Impact factor: 17.956