Colonic inflammation in Parkinson's disease.

Lewy pathology affects the gastrointestinal tract in Parkinson's disease (PD) and data from recent genetic studies suggest a link between PD and gut inflammation. We therefore undertook the present survey to investigate whether gastrointestinal inflammation occurs in PD patients. Nineteen PD patients and 14 age-matched healthy controls were included. For each PD patients, neurological and gastrointestinal symptoms were assessed using the Unified Parkinson's Disease Rating Scale part III and the Rome III questionnaire, respectively and cumulative lifetime dose of L-dopa was calculated. Four biopsies were taken from the ascending colon during the course of a total colonoscopy in controls and PD patients. The mRNA expression levels of pro-inflammatory cytokines (tumor necrosis factor alpha, interferon gamma, interleukin-6 and interleukin-1 beta) and glial marker (Glial fibrillary acidic protein, Sox-10 and S100-beta) were analyzed using real-time PCR in two-pooled biopsies. Immunohistochemical analysis was performed on the two remaining biopsies using antibodies against phosphorylated alpha-synuclein to detect Lewy pathology. The mRNA expression levels of pro-inflammatory cytokines as well as of two glial markers (Glial fibrillary acidic protein and Sox-10) were significantly elevated in the ascending colon of PD patients with respect to controls. The levels of tumor necrosis factor alpha, interferon gamma, interleukin-6, interleukin-1 beta and Sox-10 were negatively correlated with disease duration. By contrast, no correlations were found between the levels of pro-inflammatory cytokines or glial markers and disease severity, gastrointestinal symptoms or cumulative lifetime dose of L-dopa. There was no significant difference in the expression of pro-inflammatory cytokines or glial marker between patients with and without enteric Lewy pathology. Our findings provide evidence that enteric inflammation occurs in PD and further reinforce the role of peripheral inflammation in the initiation and/or the progression of the disease.

Analysis of colonic alpha-synuclein pathology in multiple system atrophy.

Routine colonic biopsies allow the detection of alpha-synuclein aggregates in the enteric nervous system (ENS) in living Parkinson's disease (PD) patients. Whether the ENS is affected by alpha-synuclein pathology in multiple system atrophy (MSA) has not been studied yet. The aim of the present research was therefore to analyze colonic biopsies in MSA for the presence of alpha-synuclein pathology. Six MSA and 9 PD patients were included. Four biopsies, taken from the descending colon during the course of a rectosigmoidscopy were microdissected, and analyzed by immunohistochemistry using antibodies against phosphorylated alpha-synuclein and neurofilaments NF 200 kDa. Aggregates of alpha-synuclein were detected in one out of 6 MSA patients and in 5 out of 9 PD patients. This demonstrates that, despite being less frequent than in PD, alpha-synuclein deposits can be observed in the ENS in MSA.

[Autonomic nervous system as a source of biomarkers in Parkinson's disease]. / Système nerveux autonome : une source de biomarqueurs dans la maladie de Parkinson.

No validated biomarker is yet available for Parkinson's disease (PD). Clinical PD symptoms include dopa-responsive motor symptoms and dopa-resistant non motor symptoms. Some of the non motor symptoms begin during the premotor stage, like constipation, hyposmia or REM-sleep disorders. Dementia, gait disorders and dysarthria occur in later stages of the disease. PD pathology extends well beyond the substantia nigra. It affects autonomic and non autonomic nuclei in the brainstem and in the medulla, the olfactory bulb and the peripheral autonomic nervous system. Alpha-synuclein aggregates, called Lewy bodies and Lewy neurites, are detectable in these structures at early stages. The study of the enteric nervous system (ENS) displays the Lewy pathology in living patients through the digestive biopsies. Minor salivary glands analysis could be a good marker as well, but this needs confirmation. An anatomopathologic PD biomarker would be interesting at different stages of PD: for the positive diagnosis, to follow the progression and to develop neuroprotective treatments.

A comparison between rectal and colonic biopsies to detect Lewy pathology in Parkinson's disease.

We have shown that routine biopsies of the ascending colon obtained at colonoscopy allow the detection of Lewy neurites (LN) in the enteric nervous system (ENS) of Parkinson's disease (PD) patients. Although colonoscopy is a relatively safe procedure, it requires colon preparation and anesthesia. The present study was therefore undertaken to evaluate whether descending colon and rectal biopsies that are obtainable by rectosigmoidoscopy allow the detection of Lewy pathology in the ENS. A total of 9 controls and 26 PD patients were included and analyzed. Two biopsies were taken from the ascending, descending colon and rectum during the course of a total colonoscopy. Immunohistochemical analysis was performed using antibodies against phosphorylated alpha-synuclein to detect LN and neurofilaments 200 kDa to label the neuronal structures. Biopsies from ascending, descending colon and rectum were morphologically comparable. LN were detected in the biopsies of ascending colon in 17 PD patients (65%), of descending colon in 11 patients (42%) and of rectum in only 6 patients (23%). No LN were seen in control biopsies. Our results show that Lewy pathology follows a rostrocaudal distribution in the colon and rectum of PD patients. Therefore, rectal biopsies have substantially lower sensitivity than ascending colon biopsies to detect Lewy pathology in the gut.

Colonic neuropathology is independent of olfactory dysfunction in Parkinson's disease.

Olfactory dysfunction (OD) and constipation are two frequent and early non-motor features of Parkinson's disease (PD). Colonic PD neuropathology, the putative cause of constipation, can be analyzed and quantified using routine colonic biopsies and parallels disease severity. The present study was aimed at investigating whether the severity of neuropathology in the colon in PD is related to OD. Twenty-six PD patients were included. Colonic neuropathology, i.e., the density of Lewy pathology and the number of submucosal neurons, was unrelated to OD as assessed using the University of Pennsylvania Smell Identification. This suggests that unlike colonic Lewy pathology, OD is unrelated to disease severity.

Biopsable neural tissues: toward new biomarkers for Parkinson's disease?

Biomarkers for Parkinson's disease (PD) are mainly intended for the early diagnosis of the disease and to monitor its progression, two aspects insufficiently covered by clinical evaluation. In the last 20 years, the search for biomarkers has been supported by technological advances in the fields of molecular genetics and neuroimaging. Nevertheless, no fully validated biomarker is yet available, and there is still a need for biomarkers that will complement those already available. Development of biomarkers for PD has been hampered by the fact that the core pathology lies in the brainstem, hidden from direct study in living patients. In this context, the recent observations that clearly demonstrated the presence of PD pathology in peripheral neural tissues provide new opportunities to develop original histopathological markers of the disease. Some of these peripheral tissues, especially the enteric nervous system, by being assessable using routine biopsies, could represent a window to assess in vivo the neuropathological processes occurring in PD.