Similar α‐Synuclein staining in the colon mucosa in patients with Parkinson's disease and controls

Antunes, Laurent; Frasquilho, Sónia; Ostaszewski, Marek; Weber, Jean-Marie; Longhino, Laura; Antony, Paul; Baumuratov, Aidos; Buttini, Manuel; Shannon, Kathleen M.; Balling, Rudi; Diederich, Nico J.

doi:10.1002/mds.26702

Cited by 50 publications

(31 citation statements)

References 21 publications

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“…The deposition of α-syn within the colon can help to distinguish PD patients from controls [10–13]. Nevertheless, when assessed with conventional immunohistochemistry, its diagnostic value as a biomarker has not been finally confirmed as α-syn staining in colonic mucosa was likewise found in PD patients and controls [14], which not necessarily refutes the concept of an intestinal origin of PD pathogenesis. Thus, additional yet unidentified factors beyond α-syn must be involved in the presumed PD disease process.…”

Section: Introductionmentioning

confidence: 99%

Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naïve Parkinson’s disease patients

et al. 2017

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BackgroundParkinson’s disease (PD) presently is conceptualized as a protein aggregation disease in which pathology involves both the enteric and the central nervous system, possibly spreading from one to another via the vagus nerves. As gastrointestinal dysfunction often precedes or parallels motor symptoms, the enteric system with its vast diversity of microorganisms may be involved in PD pathogenesis. Alterations in the enteric microbial taxonomic level of L-DOPA-naïve PD patients might also serve as a biomarker.MethodsWe performed metagenomic shotgun analyses and compared the fecal microbiomes of 31 early stage, L-DOPA-naïve PD patients to 28 age-matched controls.ResultsWe found increased Verrucomicrobiaceae (Akkermansia muciniphila) and unclassified Firmicutes, whereas Prevotellaceae (Prevotella copri) and Erysipelotrichaceae (Eubacterium biforme) were markedly lowered in PD samples. The observed differences could reliably separate PD from control with a ROC-AUC of 0.84. Functional analyses of the metagenomes revealed differences in microbiota metabolism in PD involving the ẞ-glucuronate and tryptophan metabolism. While the abundances of prophages and plasmids did not differ between PD and controls, total virus abundance was decreased in PD participants. Based on our analyses, the intake of either a MAO inhibitor, amantadine, or a dopamine agonist (which in summary relates to 90% of PD patients) had no overall influence on taxa abundance or microbial functions.ConclusionsOur data revealed differences of colonic microbiota and of microbiota metabolism between PD patients and controls at an unprecedented detail not achievable through 16S sequencing. The findings point to a yet unappreciated aspect of PD, possibly involving the intestinal barrier function and immune function in PD patients. The influence of the parkinsonian medication should be further investigated in the future in larger cohorts.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0428-y) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naïve Parkinson’s disease patients

et al. 2017

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“…The gastrointestinal tract is the most studied in vivo tissue for α-syn aggregates to date. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] Previous autopsy-based studies reported relatively high prevalence of abnormal α-syn deposits in the gastrointestinal tract among peripheral tissues. 3 Within the gastrointestinal tract, abnormal α-syn deposits have been shown to be concentrated on the Meissner's submucosal plexus and Auerbach's myenteric plexus, 3,48 and there is a rostrocaudal gradient in terms of the severity of α-syn deposition with the esophagus being most severely involved.…”

Section: Discussionmentioning

confidence: 99%

Value of in vivo α‐synuclein deposits in Parkinson's disease: A systematic review and meta‐analysis

et al. 2019

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Previous studies that have investigated the potential of in vivo abnormal α‐synuclein deposits as a pathological biomarker for PD included few participants and reported different diagnostic accuracies. Here, we aimed to confirm the diagnostic value of in vivo α‐synuclein deposits in PD through a systematic review and meta‐analysis, with special emphasis on determining the tissue most suitable for examination and assessing whether anti‐native α‐synuclein or anti‐phosphorylated α‐synuclein antibodies should be used. Databases were searched on December 30, 2018. We finally included 41 case‐control studies that examined in vivo tissue samples using anti‐native α‐synuclein or anti‐phosphorylated α‐synuclein antibody in PD patients and controls. Using a univariate random‐effects model, pooled sensitivity and specificity (95% confidence interval) of anti‐native α‐synuclein antibody were 0.54 (0.49‐0.60) and 0.72 (0.68‐0.76) for the gastrointestinal tract and 0.76 (0.60‐0.89) and 0.60 (0.43‐0.74) for the skin. Pooled sensitivity and specificity (95% confidence interval) of anti‐phosphorylated α‐synuclein antibody were 0.43 (0.37‐0.48) and 0.82 (0.78‐0.86) for the gastrointestinal tract, 0.76 (0.69‐0.82) and 1.00 (0.98‐1.00) for the skin, 0.42 (0.26‐0.59) and 0.94 (0.84‐0.99) for the minor salivary glands, and 0.66 (0.51‐0.79) and 0.96 (0.86‐1.00) for the submandibular glands. Although ubiquitous heterogeneity between the included studies should be noted when interpreting our results, our analyses demonstrated the following: (1) in vivo α‐synuclein immunoreactivity has the potential as a pathological biomarker for PD; (2) anti‐phosphorylated α‐synuclein antibody consistently has higher specificity than anti‐native α‐synuclein antibody; and (3) skin biopsy examination using anti‐phosphorylated α‐synuclein antibody has the best diagnostic accuracy, although feasibility remains an important issue. © 2019 International Parkinson and Movement Disorder Society

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“…Improved quantification of aSyn staining could also benefit sensitivity and specificity. To date, studies have mostly used qualitative assessment of sections to define pathology, and only a few studies have attempted quantification with semiquantitative grading scales to measure the severity of staining [14,20,39]. Virtual microscopy and whole-slide imaging could allow a more robust quantitative analysis of enteric aSyn and potentially facilitate definition of reliable cut-off scores to distinguish PD patients from controls.…”

Section: Discussionmentioning

confidence: 99%

Detection of alpha‐synuclein conformational variants from gastro‐intestinal biopsy tissue as a potential biomarker for Parkinson's disease

Ruffmann

Bengoa-Vergniory

Poggiolini

et al. 2018

Neuropathology Appl Neurobio

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AimsGastrointestinal (GI) α‐synuclein (aSyn) detection as a potential biomarker of Parkinson's disease (PD) is challenged by conflicting results of recent studies. To increase sensitivity and specificity, we applied three techniques to detect different conformations of aSyn in GI biopsies obtained from a longitudinal, clinically well‐characterized cohort of PD patients and healthy controls (HC).MethodsWith immunohistochemistry (IHC), we used antibodies reactive for total, phosphorylated and oligomeric aSyn; with aSyn proximity ligation assay (AS‐PLA), we targeted oligomeric aSyn species specifically; and with paraffin‐embedded tissue blot (AS‐PET‐blot) we aimed to detect fibrillary, synaptic aSyn.ResultsA total of 163 tissue blocks were collected from 51 PD patients (113 blocks) and 21 HC (50 blocks). In 31 PD patients, biopsies were taken before the PD diagnosis (Prodromal); while in 20 PD patients biopsies were obtained after diagnosis (Manifest). The majority of tissues blocks were from large intestine (62%), followed by small intestine (21%), stomach (10%) and oesophagus (7%). With IHC, four staining patterns were detected (neuritic, ganglionic, epithelial and cellular), while two distinct staining patterns were detected both with AS‐PLA (cellular and diffuse signal) and with AS‐PET‐blot (aSyn‐localized and pericrypt signal). The level of agreement between different techniques was low and no single technique or staining pattern reliably distinguished PD patients (Prodromal or Manifest) from HC.ConclusionsOur study suggests that detection of aSyn conformational variants currently considered pathological is not adequate for the diagnosis or prediction of PD. Future studies utilizing novel ultrasensitive amyloid aggregation assays may increase sensitivity and specificity.

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Similar α‐Synuclein staining in the colon mucosa in patients with Parkinson's disease and controls

Cited by 50 publications

References 21 publications

Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naïve Parkinson’s disease patients

Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naïve Parkinson’s disease patients

Value of in vivo α‐synuclein deposits in Parkinson's disease: A systematic review and meta‐analysis

Detection of alpha‐synuclein conformational variants from gastro‐intestinal biopsy tissue as a potential biomarker for Parkinson's disease

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