The enteric nervous system in PD: gateway, bystander victim, or source of solutions

Abstract

Apart from the characteristic and progressive motor- and movement-related problems, Parkinson's disease (PD) patients also suffer from several non-motor symptoms, including gastrointestinal dysfunction. The fact that the enteric nervous system (ENS) controls motility and that one of the typical PD hallmarks, α-synuclein-positive deposits, has also been found in the intestinal wall have rendered the ENS and the gut a popular subject of study in the context of PD. The possibility that these deposits could serve as an early biomarker is obviously of tremendous medical benefit but also the idea that the gut may possibly be a gateway via which the disease is initiated and progressively makes its way via the peripheral nerves to the central nervous system has increased the interest in the ENS-PD link. Furthermore, the fact that gastrointestinal symptoms are present in PD suggests that the ENS might be affected as well. However, despite a large body of literature on the topic, the actual role or the magnitude of involvement of the ENS in PD remains elusive. The multitudes of experimental approaches and animal models have complicated the interpretation of results and the outcome of different studies does not necessarily align well. In this review, we chose to highlight some elements of interest and some items of confusion, particularly those where research should be focusing. We also list a number of open questions in the field that could serve as a guideline for future, preferably concerted research.

Brain-First versus Gut-First Parkinson’s Disease: A Hypothesis

“…Of these cases, 94.3% displayed markedly reduced presynaptic functional tone of the cardiac sympathetic nerves compared to study-specific healthy control subjects. The cardiac sympathetic innervation imaged with 123 I-MIBG scintigraphy (top row) and the nigrostriatal dopamine storage capacity image by 18 F-DOPA PET (bottom row) in a healthy control (left column), a patient with idiopathic RBD (iRBD; middle), and a de novo H&Y stage I PD patient without RBD (right). Note that the iRBD patient shows severely reduced sympathetic cardiac innervation but almost normal striatal dopaminergic storage capacity.…”

“…Several studies have investigated the nigrostriatal dopamine system of idiopathic RBD using 123 I-FP-CIT SPECT (reviewed in [31]) and 18 F-FDOPA PET scans [26]. In summary, this literature finds that a large fraction of idiopathic RBD cases, often more than 50% in each study, still have nigrostriatal dopamine innervation within normal limits.…”

“…Nevertheless, the "periphery-first" hypothesis is still considered controversial and has been the subject of a large number of recent reviews [12][13][14][15][16][17][18]. This particular scientific discussion often takes a dichotomous format, i.e., evidence is examined to support that PD always originates in the PNS, or alternatively, that the pathology in all cases is initiated in the central nervous system (CNS).…”

“…This particular scientific discussion often takes a dichotomous format, i.e., evidence is examined to support that PD always originates in the PNS, or alternatively, that the pathology in all cases is initiated in the central nervous system (CNS). Rarely has it been considered that both of these scenarios could be true [2,18,19].…”

Special issue “Parkinson’s disease”

“…Despite the ongoing interest in the PD community in the role of the enteric nervous system (ENS) in the possible pathogenesis and/or progression of PD, the authors Shannon and Vanden Berghe (2018) believe that (too) many issues remain unclear or contradictory. Even if it could be shown that Lewy pathology in the ENS is a biomarker of PD, how solid is the available evidence that it influences the disease (e.g., gastrointestinal dysmotility or delayed transit) there or elsewhere in humans?…”