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Does Sporadic Parkinson's Disease Begin in the Enteric Nervous System?

Although the cause(s) of sporadic Parkinson's disease are still unknown, recent studies indicate the disease-related destruction is highly specific and involves a few nerve cell types within the human nervous system. A retrospective  cross-sectional post-mortem staging procedure published by the Frankfurt-based group in 2003 proposes the pathological process in the brain begins in the brainstem dorsal motor nucleus of the vagal nerve and not in the substantia nigra of the midbrain. From the brainstorm, the pathological process appears to progress in a predictable manner. The vulnerable neurons have long axons and the involved brain regions are, anatomically speaking, closely interconnected. Thus, physical contacts between susceptible nerve cell types may play a central pathogenic role. These initial findings prompted us to ask whether Parkinson's disease begins outside of the central nervous system. Our project aims to test whether the enteric nervous system is hit first in sporadic PD.

Project Description: 
This project entails screening, dissection and light microscopic study of a large number of autopsy cases (45> years of age) to determine if the pathological process begins in the enteric (gastrointestinal) nervous system of the foregut. Early disease-related lesions have been described previously in nerve cell plexuses of the esophagus, gastric cardia, fundus, and pylorus regions. Unconventionally thick (100 micrometer) tissue sections will be used with immunocytochemistry and is a unique feature of our laboratory, having originally been developed by the PI especially to meet the demands of studying the human brain in serial sections.

Relevance to Diagnosis/Treatment of Parkinson's Disease: 
If cases are found showing Parkinson's disease-related lesions in the foregut in the absence of such pathology in the brain, this knowledge would be invaluable to clinicians in their search for all of the non-parkinsonian features of PD, particularly when they occur prior to parkinsonism.

Anticipated Outcome: 
The pathologically changed cell processes of the enteric plexuses lie close to the epithelial lining of the gut, i.e., the body's innermost environment. From there, the disease process could reach the brain via the vagal nerve and ascend through the basal mid- and forebrain until it reaches the cerebral cortex. This study could provide new insights into the pathogenesis and progression of PD.

Final Outcome

This pilot study included examination of brain and stomach tissues from 150 autopsy cases. Of these, the brains of 120 cases (80%) showed no alpha-synuclein pathology. The remaining 30 cases (20%) demonstrated PD-associated alpha-synuclein at varying stages of disease progression. No cases were found where the absence of brain alpha-synuclein was accompanied by detectable alpha-synuclein in the nerve cell plexuses of the stomach.

Only one case out of 14 at PD stage 1 showed the presence of subtle alpha-synuclein in the gastric plexuses. Of the cases at PD stage 2, two of three individuals had very mild lesions in the stomach; of those at PD stage 3, two of three showed mild gastric lesions. By contrast, most individuals at PD stage 4 (four of five) displayed a moderate alpha-synuclein burden in the gastric plexuses, and all of those at PD stage 5 (five of five) had severe to very severe gastric lesions.

These initial results indicate that the stomach is almost certainly not the first region within the enteric nervous system (ENS) to become involved in PD, although the size of that organ makes it difficult to be certain that a negative finding really represents the absence of any alpha-synuclein whatsoever. The project has since been expanded to include additional autopsy cases where previously unexamined portions of the ENS, as well as peripheral nerves and autonomic ganglia, are being studied. The investigators’ focus has shifted to whether the peripheral sympathetic or parasympathetic nervous system becomes involved prior to the central nervous system. At least one 2009 publication in the journal Movement Disorders points to this possibility (Miki et al.).

Results of this project were published in the journals Advances in Anatomy, Embryology and Cell Biology, Acta Neuropathologica and Lancet Neurology.


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