Wednesday, 4 July 2018

Neurology Conference | Parkinson's disease | Intestine | Research Topics | Neurology 2018 | Call For Papers |

Parkinson's disease |  Intestine | Research Topics  | Neurology 2018 

When we think of Parkinson's disease we typically associate it with its motor complications (difficulty initiating movement, stiffness, tremor, instability in posture). These symptoms are caused by the death of dopamine-producing neurons, located in a region of the brain called the substantia nigra. The gradual death of these neurons occurs over the course of several years. When patients have movement difficulties, it is estimated that more than 60% of their dopaminergic neurons have been irreversibly affected.

In the early stages of the disease, other types of complications have been observed, including constipation and gastrointestinal disorders. Constipation is one of the most common non-motor symptoms of the disease. It was documented for more than 200 years by James Parkinson in the first report of the disease. In 2010, researchers from the National Institute of Neurology and Neurosurgery in Mexico City reported that 30% of Parkinson's patients studied suffer from gastrointestinal disorders.

In recent years, various investigations have linked Parkinson's Disease with an alleged origin in the intestine. This is due to the findings of a possible transmission of the intestine to the brain. Here I will present the main mechanisms that are proposed to explain this relationship between these parts of the body.

1. Transmission of the intestine to the brain

In 2003, Heiko Braak and colleagues published extensive research that analyzed brain tissue from 168 samples of cases diagnosed with Parkinson's disease, cases with indications of the disease and individuals without neurological disorders. The objective was to compare the lesions in the samples and establish a pattern of Parkinson's progression. One of the key lesions in the disease is the toxic buildup of a protein called alpha-synuclein in affected neurons. They found in the patients studied the accumulation of alpha-synuclein in a part of the vagus nerve, which is responsible for intestinal functions. Braak suggested a new mechanism combining his observations with other reports of defective alpha-synuclein in the intestinal tract of Parkinson's patients. It was speculatively suggested that the disease was following a progression similar to that of a "pathogen" and that the entry route could be the intestine. Although this work continues to be a benchmark for Parkinson's research, many other studies have shown that not all patients follow the stages of progression suggested by Braak et al. There are reports of up to 50% of patients studied that do not agree with the pathological signs described in the Braak stage system (Kalaitzakis, 2008).

Currently an "unknown pathogen" is not the first line of research as the origin of the disease. Environmental factors that use the vagus nerve as a transport route have also been suggested as possible initiators or catalysts. But there are still questions about this mechanism of propagation of Parkinson's disease, such as Why is the distribution of alpha-synuclein accumulations so variable once they reach the brain of patients? o Why would alpha-synuclein begin to accumulate defectively in the intestine in the first place? Till the date,

2. The intestinal flora and its possible role in the disease

Different research groups have studied the changes in intestinal flora in patients with Parkinson's. For example, some groups have described a greater abundance of bacterial families in Parkinson's patients than in people without the disease.  

Other groups have associated the presence of certain bacteria with worsening of symptoms in patients. Some groups began to observe that the intestinal flora of Parkinson's patients with motor complications has more abundance of some types of bacteria, compared with patients who do not develop those specific symptoms. It was also reported that patients with Parkinson's who suffer gastrointestinal infections caused by the bacterium Helicobacter pylori present more serious motor symptoms. Recently, a research group led by Sarkis Mazmanian showed that metabolites produced by certain bacteria can worsen the motor symptoms and brain pathology of model mice of this disease.
Changes in bacterial flora have also been associated with specific drugs that are used to treat patients (Scheperjans, 2015). However, it is still unclear if the prevalence of certain bacteria can influence the metabolism of drugs and affect the regulation of motor symptoms.

Although all these investigations present a relation between intestinal flora and Parkinson's disease, the evidence is very limited to issue conclusions about the relevance of treatments that involve the intestinal flora for the disease. These studies have not made clear whether changes in the intestinal flora are a cause or consequence of Parkinson's disease. Therefore, the relationship between certain types of bacteria in the intestinal flora and the processing of medications administered to patients should be properly investigated before proposing the intestinal flora as a target for treatment.

3. Inflammation, key process for a new model

In recent years, a model of disease progression that involves inflammation in the intestine has become more important. This model tries to combine evidence of reports of patients with intestinal inflammation, associations of Parkinson's disease with other intestinal diseases and the implication of important agents for Parkinson's disease with immunological processes in our body. A greater probability (28%) of developing Parkinson's disease was reported in a considerable number of patients with inflammatory bowel diseases. One of these diseases is Crohn's disease, an intestinal disorder related to Parkinson's disease due to a gene ( LRRK2 ) associated with these two diseases, which has a role in the regulation of inflammatory processes.

Do you remember alpha-synuclein? now more studies relate it to processes of immune response and inflammation. Increased inflammatory activity may increase alpha-synuclein levels in the intestine and in the brain. It has also been observed that alpha-synuclein stimulates inflammatory responses by promoting a cycle that further complicates the disease and would help the spread to other organs and tissues.

The model now suggested indicates that an external factor could trigger an immune response of chronic inflammation, which, when not regulated by the organism, would affect the intestinal flora and the production of proteins such as alpha-synuclein. The accumulation of defective alpha-synuclein would spread from the intestine to the brain through the vagus nerve and from there it would affect different neurons, including those that produce dopamine, to give rise to Parkinson's disease.

Although this model combines Braak's observations with recent findings about the disease, it still does not conclude whether intestinal complications are a cause or consequence of the disease. It is known that the intestinal symptoms of the disease precede the motor, but this does not indicate that the cause of the disease is in the intestine. Nor does it explain why a proportion of patients do not present intestinal disorders, nor does it resolve the aforementioned inconsistencies of the Braak system. In addition, this new model does not exclude the possible existence of an external factor that would cause intestinal inflammation, so in this case the intestinal anomalies would not represent the true origin.

All these studies begin to give more indications of the different faults in the organism that occur in Parkinson's disease. As mentioned above, it is possible that Parkinson's disease has different origins, which explains the different symptoms and patterns of progression in each of the patients. This also agrees with the difficulties that exist to establish an effective treatment for this disease, since each patient develops differently.

Chris Isaac
Neurology 2018 

July 4, 2018 by Melissa Leija Salazar

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