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Lookup NU author(s): Professor Nicola PaveseORCiD, Professor David BrooksORCiD
This is the authors' accepted manuscript of an article that has been published in its final definitive form by Oxford University Press , 2020.
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Background. Parkinson’s disease (PD) is characterised by the presence of abnormal, intraneuronal a-synuclein (a-syn) aggregates, which may propagate from cell-to-cell in a prion-like manner. However, it remains uncertain where the initial a-syn aggregates originate. We have hypothesised that PD comprises two subtypes. A brain-first (top-down) type, where a-syn pathology initially arises in the brain with secondary spreading to the peripheral autonomic nervous system; and a body-first (bottom-up) type, where the pathology originates in the enteric or peripheral autonomic nervous system and then spreads to the brain. We also hypothesised that isolated REM sleep behaviour disorder (iRBD) is a prodromal phenotype for the body-first type. Using multi-modal imaging, we tested the hypothesis by quantifying neuronal dysfunction in structures corresponding to Braak stage I, II, and III involvement in three distinct patient groups. Methods. Between August 2018 and January 2020, we included 37 consecutive denovo PD patients into this case-control PET study. PD patients were divided into 24 RBD-negative (PDRBD- ) and 13 RBD-positive cases (PDRBD+) and a comparator group of 22 iRBD patients. We used 11Cdonepezil PET/CT to assess cholinergic (parasympathetic) innervation, 123Imetaiodobenzylguanidine (MIBG) scintigraphy to measure cardiac sympathetic innervation, neuromelanin-sensitive MRI to measure the integrity of locus coeruleus pigmented neurons, and 18F-dihydroxyphenylalanine (FDOPA) PET to assess putaminal dopamine storage capacity. Colon volume and transit time was assessed with CT scans and radiopaque markers. Imaging data from the three groups were interrogated with ANOVA and Kruskal-Wallis tests corrected for multiple comparisons. Findings. The PDRBD- and PDRBD+ groups showed similar marked reductions in putaminal FDOPA specific uptake, whereas two-thirds of iRBD patients had normal scans (p<10-13, ANOVA). When compared to the PDRBD- patients, the PDRBD+ and iRBD patients showed reduced mean MIBG heart:mediastinum ratios (p<10-5, ANOVA) and colon 11C-donepezil standard uptake values (p=0.008, ANOVA). The PDRBD+ group trended towards a reduced mean MRI locus coeruleus:pons ratios compared to PDRBD- (p=0.07, t-test). In comparison to the other groups, the PDRBD+ group also had enlarged colon volumes (p<0.001, ANOVA) and delayed colonic transit times (p=0.01, Kruskal-Wallis). On x-y plots, the FDOPA and MIBG uptake showed two distinct trajectories - iRBD and PDRBD+ forming one cluster and PDRBD- another cluster. Interpretation. The combined iRBD and PDRBD+ patient data were compatible with an initial loss of cardiac MIBG signal and 11C-colonic donepezil signal followed by loss of putaminal FDOPA signal. In contrast, the PDRBD- data were compatible with a brain-first trajectory, characterised by primary loss of putaminal FDOPA signal followed by a secondary loss of cardiac MIBG signal and 11C-donepezil signal. These findings support the existence of brain-first and body-first subtypes of PD.
Author(s): Horsager J, Andersen KB, Knudsen K, Skjærbæk C, Fedorova TD, Okkels N, Schaeffer E, Bonkat SK, Geday J, Otto M, Sommerauer M, Danielsen EH, Bech E, Kraft J, Munk OL, Hansen SD, Pavese N, Göder R, Brooks DJ, Berg D, Borghammer P
Publication type: Article
Publication status: Published
Journal: Brain
Year: 2020
Volume: 143
Issue: 10
Pages: 3077-3088
Print publication date: 01/10/2020
Online publication date: 24/08/2020
Acceptance date: 15/06/2020
Date deposited: 15/06/2020
ISSN (print): 0006-8950
ISSN (electronic): 1460-2156
Publisher: Oxford University Press
URL: https://doi.org/10.1093/brain/awaa238
DOI: 10.1093/brain/awaa238
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