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A colonic biomarker of Parkinson's disease?

In the present issue of Movement Disorders, Shannon et al. present two articles suggesting that alphasynuclein accumulation in colonic neurons might be a biomarker of Parkinson’s disease (PD). In the first study, they examined colonic biopsies obtained from untreated PD patients and controls who underwent flexible sigmoidoscopy, a 5to 10-minute office-based procedure that does not require sedation or preparation. They observed alpha-synuclein pathology in submucosal nerve fibers in 9 of 9 PD subjects, but in none of 23 healthy controls or 23 subjects with inflammatory bowel disease (IBD). In the second report, they describe similar alpha-synuclein pathology in 3 PD patients who had undergone colonic biopsy 2 to 5 years before the diagnosis of PD and the onset of clinical features. Interestingly, alpha-synuclein accumulations were localized to the neurites and perikarya of submucosal neurons that also stained for substance P. Although interest has historically focused on pathology in dopamine neurons of the SNc, it is evident that in PD patients, Lewy pathology is much more widespread, involving cholinergic neurons of the nucleus basalis of Meynert, norepinephrine neurons of the locus coeruleus, and serotonin neurons of the raphe as well as neurons of the olfactory system, cerebral hemisphere, spinal cord, and peripheral autonomic nervous system. Specifically, with respect to the GI system, postmortem studies have demonstrated alpha-synuclein pathology in neurons of Meisner’s and Auerbach’s plexuses. Alpha-synuclein– positive neurites have also been detected during life in a gastric biopsy obtained from a PD patient undergoing catheter insertion for a duodopa procedure, as well as in biopsy of neurons in the ascending and descending colon obtained at the time of routine colonoscopy. Lewy pathology could also be detected in tissue obtained with rectal biopsy, but with a much lower yield, perhaps reflecting observations suggesting that Lewy pathology is more pronounced in the upper gastrointestinal (GI) tract. The present reports extend on these observations, noting that alpha-synuclein accumulation in colonic neurons can be detected in PD patients in biopsies obtained from the distal sigmoid colon using a simple, minimally invasive, readily available, and inexpensive sigmoidoscopy procedure. Of particular interest is the finding that alpha-synuclein pathology was detected in the colon of PD patients years before they went on to develop the classical motor features of the disease. Braak et al. reported that in the brain, Lewy pathology is first observed in the dorsal motor nucleus (DMN), and that this occurs before involvement of SNc dopamine neurons. In this regard it is noteworthy that nerve fibers originating in DMN also stain for substance P as was observed in these patients. Because DMN fibers provide innervation to the gut, they hypothesized that PD could theoretically originate in GI terminals. In support of this concept, the prospective longitudinal Honolulu Heart Study demonstrated that constipation was associated with a significantly increased risk of developing PD. The observations of Shannon et al. are consistent with the hypothesis that GI pathology represents an early form of PD that precedes the development of the more-classical motor features of the disease. It is intriguing to speculate on what the finding of alpha-synuclein accumulation in GI neurons preceding the onset of the classical clinical manifestatons of the disease might tell us about causation. For one thing, it suggests that protein accumulation and the disease process might indeed begin in the GI tract. Earlier reports suggested a possible association between PD and gastric or duodenal ulcer disease, possibly resulting from Helicobacter pylori infection, but this theory has not been substantiated. Furthermore, in the present study, alphasynuclein accumulation was not observed in patients with IBD nor was there a correlation with the expression of 3-nitrotyrosine, a marker of oxidative/excitotoxic stress. These findings argue against local inflammation or oxidative stress in the GI tract being a causative factor. Braak et al. raise the possibility that PD may originate in the gut, based on his findings that Lewy pathology in the brain first affects the DMN, which provides axons that innervate the upper GI system. They point out that axons from the submucosal plexus -