Brain-first versus body-first Parkinson’s disease: a multimodal imaging case-control study

Abstract

Parkinson’s disease is characterized by the presence of abnormal, intraneuronal α-synuclein aggregates, which may propagate from cell-to-cell in a prion-like manner. However, it remains uncertain where the initial α-synuclein aggregates originate. We have hypothesized that Parkinson’s disease comprises two subtypes. A brain-first (top-down) type, where α-synuclein 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 hypothesized that isolated REM sleep behaviour disorder (iRBD) is a prodromal phenotype for the body-first type. Using multimodal imaging, we tested the hypothesis by quantifying neuronal dysfunction in structures corresponding to Braak stages I, II and III involvement in three distinct patient groups. We included 37 consecutive de novo patients with Parkinson’s disease into this case-control PET study. Patients with Parkinson’s disease were divided into 24 RBD-negative (PDRBD−) and 13 RBD-positive cases (PDRBD+) and a comparator group of 22 iRBD patients. We used 11C-donepezil PET/CT to assess cholinergic (parasympathetic) innervation, 123I-metaiodobenzylguanidine (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 times were 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. 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 ratio 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). The combined iRBD and PDRBD+ patient data were compatible with a body-first trajectory, characterized by initial loss of cardiac MIBG signal and 11C-colonic donepezil signal followed by loss of putaminal FDOPA uptake. In contrast, the PDRBD− data were compatible with a brain-first trajectory, characterized by primary loss of putaminal FDOPA uptake 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 Parkinson’s disease.

A Prodromal Brain‐Clinical Pattern of Cognition in Synucleinopathies

“…The iRBD‐related deformation pattern is in line with pathological studies in PD with dementia reporting higher amount of alpha‐synuclein pathology in the subcortical, limbic, and neocortical regions, 47 and with the basal ganglia showing abnormal morphology, 5 reduced dopamine binding, 48 and abnormal functional connectivity in iRBD 49 . In terms of the progression of imaging markers in PD, which has been proposed to fall into 2 major subtypes based on the spread of alpha‐synuclein, 50 patients with iRBD have been suggested to belong to a more caudal‐to‐rostral subtype of pathology propagation like that described by Braak 51,52 . However, in this study, we show that some regions rostral to the midbrain also undergo changes in iRBD, suggesting that changes also occur in supratentorial brain areas before a severe dopamine depletion has occurred in patients 53 .…”

“…49 In terms of the progression of imaging markers in PD, which has been proposed to fall into 2 major subtypes based on the spread of alpha-synuclein, 50 patients with iRBD have been suggested to belong to a more caudal-to-rostral subtype of pathology propagation like that described by Braak. 51,52 However, in this study, we show that some regions rostral to the midbrain also undergo changes in iRBD, suggesting that changes also occur in supratentorial brain areas before a severe dopamine depletion has occurred in patients. 53 The nature of these changes, whether they originate from local pathogenous effects and/or occur downstream from changes in more caudal regions, remains to be understood.…”

Gastrointestinal Dysfunction in Parkinson’s Disease

“…Likewise, loss of cardiac sympathetic innervation and colonic acetylcholinesterase in RBD cases have been shown to be comparable to that of diagnosed PD patients, although the dopaminergic system in the RBD cases was still intact [ 44 ]. Consequently, it has been proposed that RBD represents a prodromal biomarker of a gastrointestinal, body-first onset of PD [ 45 ].…”

“…The robustness of colonic volumetric measures was also utilized in a study comparing newly diagnosed PD patients. Here, a highly significant increase in colonic volume was detected in PD patients with RBD when comparing to PD patients without RBD [ 45 ].…”

Overexpression of human alpha-Synuclein leads to dysregulated microbiome/metabolites with ageing in a rat model of Parkinson disease

“…GIT dysfunction (in particular constipation) is observed in approximately 80% PD patients (sporadic and familial forms) before the occurrence of motor symptoms 14,15 . Recent patient study indicating two subtypes of PD, (1) brain-to-gut and (2) gut-to-brain with respect to α-Syn pathology, thus, clarifies the issue with different potentially conflicting earlier report in the PD field 16 .…”