Abstract
Background Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and nonmotor impairments, including constipation. Lewy bodies and neurites, the pathological hallmarks of PD, are found in the enteric nervous system (ENS) as well as the central nervous system. Constipation is a well-documented premotor symptom in PD, and recent reports have demonstrated Lewy pathology in gastrointestinal (GI) tissues of PD patients prior to the onset of motor symptoms. Objective In the present study, we assessed Lewy pathology in the GI tracts of seven PD patients who had undergone a gastrectomy, gastric polypectomy, or colonic polypectomy prior to the onset of motor symptoms in order to assess whether the presence of pathological αSyn in the ENS could be a predictor for PD. Methods GI tissue samples were collected from control patients and patients with premotor PD. Immunohistochemistry was performed using primary antibodies against α-synuclein (αSyn) and phosphorylated αSyn (pαSyn), after which Lewy pathology in each sample was assessed. Results In all control and premotor PD patients, accumulation of αSyn was observed in the myenteric plexus in both the stomach and colon. In 82% (18/22) of control patients, mild-to-moderate accumulation of αSyn was observed in the submucosal plexus. However, there was no deposition of pαSyn in the ENS of control patients. In patients with premotor PD, abundant accumulation of αSyn was observed in the myenteric plexus, similar to control patients. On the other hand, pαSyn-positive aggregates were also observed in the nerve fibers in the muscularis propria in all examined patients with premotor PD (100%, 3/3), while the deposition of pαSyn in the submucosal plexus was only observed in one patient (14%, 1/7). Conclusion Our results suggest that the detection of pαSyn, but not αSyn, especially in the muscularis propria of GI tracts, could be a sensitive prodromal biomarker for PD.
Highlights
Parkinson’s disease (PD), one of the most prevalent neurodegenerative disorders, is characterized by the progressive degeneration of the dopaminergic nigrostriatal system, which is responsible for the core motor symptoms including tremor at rest, bradykinesia, and rigidity [1, 2], and by the involvement of many other neuronal systems and organs affected by different nonmotor deficiencies, including olfactory dysfunction, cardiac involvement, and REM sleep behavior disorder [3]
Besides the central nervous system, Lewy pathology is observed within the sympathetic and parasympathetic ganglia [11], adrenal glands [12], enteric nervous system (ENS) [13,14,15,16], and cutaneous nerves [17]. e clinical diagnosis of PD depends on the appearance of cardinal motor symptoms, which are signs that do not appear before the loss of an estimated 70–80% of striatal dopamine [2, 18]
We demonstrated the accumulation of pathological αSyn in the muscularis propria of GI tracts in all examined premotor PD patients, it was observed in the submucosa of only 14% of premotor PD cases. e accumulation of αSyn, which exists ubiquitously in the nervous system [25], was visible in the GI muscularis propria in both control and premotor PD groups
Summary
Parkinson’s disease (PD), one of the most prevalent neurodegenerative disorders, is characterized by the progressive degeneration of the dopaminergic nigrostriatal system, which is responsible for the core motor symptoms including tremor at rest, bradykinesia, and rigidity [1, 2], and by the involvement of many other neuronal systems and organs affected by different nonmotor deficiencies, including olfactory dysfunction, cardiac involvement, and REM (rapid eye movement) sleep behavior disorder [3]. Postmortem studies of incidental Lewy body disease suggest that αSyn pathology may begin in tissues of the gastrointestinal (GI) tract, salivary gland, and olfactory system [14, 15, 21, 22]. Constipation is a well-documented premotor symptom in PD, and recent reports have demonstrated Lewy pathology in gastrointestinal (GI) tissues of PD patients prior to the onset of motor symptoms. We assessed Lewy pathology in the GI tracts of seven PD patients who had undergone a gastrectomy, gastric polypectomy, or colonic polypectomy prior to the onset of motor symptoms in order to assess whether the presence of pathological αSyn in the ENS could be a predictor for PD. Our results suggest that the detection of pαSyn, but not αSyn, especially in the muscularis propria of GI tracts, could be a sensitive prodromal biomarker for PD
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