Gastrointestinal involvement in Parkinson's disease: the horse or the cart

The past two decades have witnessed an explosion in the recognition that Parkinson’s disease (PD) is not only a motor disorder, but also is characterized by an array of features that have little or nothing to do with motor function, such as abnormalities of sensation, behavioural changes, sleep disorders, fatigue and autonomic dysfunction. Among the features of autonomic dysfunction, gastrointestinal (GI) dysfunction has been most widely studied and involvement, including the presence of alpha-synuclein and Lewy bodies, has been described within the enteric nervous system at all levels of the GI tract (Pfeiffer 2011, Heetun & Quigley 2012). Non-motor features of PD, including GI dysfunction, not only are common in PD, they also can develop prior to the appearance of the classic motor features. This is especially true for one of the GI features, constipation, which may be evident even decades prior to the emergence of motor dysfunction (Abbott et al. 2001). The early appearance of GI involvement in PD has been demonstrated pathologically by Braak et al. (2006), who suggested that PD actually may originate not in the brain but in the enteric nervous system and spread from there via the vagus nerve to reach the central nervous system, then spreading from the dorsal motor nucleus of the vagus upward in the brainstem in a caudal–rostral direction, eventually reaching the substantia nigra (SN), at which time the motor features of PD finally appear. Building on this, others have suggested that this gradual spread of synuclein pathology may be driven by a prion-like process (Olanow & Prusiner 2009, Olanow & Brundin 2013). In their very interesting and provocative report, however, Zheng et al. (2014) suggest and provide evidence for an alternate scenario for the development of GI dysfunction, specifically gastroparesis, in PD. Utilizing the 6-OHDA lesion rat model, they report that dopaminergic neuronal loss in the SN results in impaired gastric motility and delayed gastric emptying. They also demonstrate that this is accompanied by increased dopamine content and over-expression of D2 dopamine receptors within the stomach and that subdiaphragmatic vagotomy prevents these changes. They suggest that the early appearance of clinical GI dysfunction, specifically gastroparesis, in PD prior to the development of motor dysfunction may be explained by their observation that GI dysmotility was evident in 6-OHDA rats demonstrating only a 45% reduction in tyrosine hydroxylase protein expression in the SN and a 26% reduction in dopamine content in the SN, whereas a loss of dopamine neurons in the SN of greater than 70% is necessary before the classic motor features of PD emerge. However, it should be noted that others have suggested that a loss of only slightly more than 40% of dopamine neurons is necessary for motor features to develop (Bezard et al. 2001). The ability of vagotomy to prevent the development of gastroparesis in the 6-OHDA rats also supports the suggestion of Zheng et al. that GI dysfunction in PD may be mediated from the central nervous system via the vagus to the enteric nervous system, rather than originating within the enteric nervous system. The report of Zheng et al. raises a number of intriguing questions. Just how might loss of dopaminergic neurons in the SN produce dysfunction in vagal pathways? In a very recent report by some of the same authors, also utilizing the 6-OHDA rat model, no direct projections were identified between the SN and the dorsal vagus complex, but both reduced cholinergic expression and increased dopaminergic expression were documented in the dorsal motor nucleus of the vagus (Wang et al. 2014). Indirect regulation through either the lateral hypothalamus or the locus ceruleus (or through both) was suggested. The proposal by Zheng et al. that over-expression of D2 receptors within the stomach might be responsible for the development of impaired gastric motility also raises some clinical questions with regard to the treatment of PD. Do dopaminergic drugs play any role in potentiating or aggravating gastroparesis in patients with PD? If so, does this result in more inconsistent delivery of levodopa to its absorptive sites in the small intestine and, thus, magnify the risk of developing motor fluctuations and dyskinesia? Would employment of a drug such as domperidone, by accelerating gastric emptying, reduce the risk of developing motor fluctuations or ameliorate motor fluctuations once they have developed? The report by Zheng et al. adds interesting and important information regarding the possible genesis of GI dysfunction in the setting of PD, but the question of which comes first – which is the horse and which is the cart: enteric nervous system involvement or central nervous system involvement – remains and consideration of the potential role for GI hormones such as ghrelin in the process adds further complexity to the conundrum