by Elena Moro
For January 2019, we have selected: Killinger BA, Madaj Z, Sikora JW, et al. The vermiform appendix impacts the risk of developing Parkinson’s disease. Sci Transl Med 2018,10:1-15.
It is now acknowledged that the pathological process of Parkinson’s disease (PD) starts many years before the onset of motor signs. The dual-hit hypothesis stands on the beginning of the pathology from the olfactory system or from the gut. Several environmental factors would act on a genetically predisposed background to promote the pathogenic aggregation of the alpha-synuclein protein, a protein present in central and peripheral neurons. The pathogenic alpha-synuclein would then slowly spread from neuron to neuron as a prion-like mechanism. Recently, two reports suggested that the amount of alpha-synuclein was especially high in the appendix from both healthy subjects and PD patients (Gray, PMID: 24352892; Stokholm, PMID: 27015771).
In this paper, the authors investigated the role of the vermiform appendix in the pathophysiology of PD. They used both an epidemiological and a laboratory approach.
First, they collected and analyzed data coming from two different databases: a) the nationwide administrative Swedish National Patient Registry (SNPR), containing more than 1.6 million individuals with up to 52-year follow-up; b) the Parkinson’s Progression Markers Initiative (PPMI), including 849 well characterized de novo PD patients.
From the SNPR analyses, they found 551,647 individuals who had undergone appendectomy. In these subjects, the risk to develop PD was significantly lower (19.3%) compared to controls without appendectomy. PD incidence was 1.60 per 100,000 person-years (95% CI, 1.46-1-75) versus 1.98 (95% CI, 1.87-2.10), respectively. Cumulative PD prevalence was also lower by 16.9% in people with appendectomy compared to controls (95% CI, 9.3-24.4; p<0.0001). The age at PD diagnosis appeared to be 1.6 years later in subjects who had appendectomy ³20 years prior compared to cases without appendectomy (95% CI, -0.09-3.34; p<0.03). Moreover, subjects with appendectomy and living in rural areas had 25.4% decreased risk of PD.
From the PPMI analyses, 54 patients (6.4%) had previous history of appendectomy. In those patients with appendectomy 30 years before diagnosis, age of PD onset was significantly delayed by 3.6 years (95% CI, 1.03-6.13, p<0.03).
Secondly, the authors examined appendix tissue coming from 48 healthy individuals. In the immunochemistry study, the authors found abundant proteinase K-resistant alpha-synuclein aggregated in the mucosa, submucosal plexus, myenteric plexus, and nerve fibers in almost all subjects. Compared to PD appendix and substantia nigra samples, there was plenty of similar oligomers and truncated alpha-synuclein similar to what seen in Lewy bodies pathology. In a further experiment, they were able to induce aggregation of alpha-synuclein coming from healthy subjects’ appendix.
“Taken all together, these results suggest a role of the appendix in PD pathogenesis. The appendix could host pathogenic forms of alpha-synuclein that could be activated by specific factors during the life of the individual”, says Prof. Connie Marras, Edmond J Safra Program in Parkinson’s Disease, UHN, Toronto, Canada. “It is compelling that similar results have been found in complementary datasets. The associations are small in magnitude, indicating that the appendix would explain a small part of the etiologic puzzle of Parkinson’s disease. Nonetheless this may be an important clue.”
“These results further support the assumption that GI inflammation might be involved in the development of PD,” says Prof. Pascal Derkinderen, Division of Neurology, CHU of Nantes, France. “Elevated levels of pro-inflammatory cytokines and fecal markers of inflammation have been reported in PD patients (Devos, PMID: 23017648; Schwiertz, PMID: 29454662) and recent findings demonstrated epidemiological, genetic and biochemical links between PD and inflammatory bowel diseases (Villumsen, PMID: 29785965; Hui, PMID: 29321258; Prigent, PMID: 30506319). In addition, Killinger and colleagues found that the appendix from both healthy subjects and PD patients contained truncated and aggregated forms of alpha-synuclein, which likely represent pathological forms of the protein. This is an interesting and intriguing finding. However, before suggesting that the appendix might be the starting point for PD, further studies are needed to compare alpha-synuclein post-translational modifications between the vermiform appendix and other GI tract segments such as ileum and colon.”
The other nominees for the January 2019 Paper of the Month are:
- Rutten-Jacobs LCA, Larsson SC, Malik R, et al. Genetic risk, incident stroke, and the benefits of adhering to a healthy lifestyle: cohort study of 306,473 UK Biobank participants. BMJ 2018;363:k4168 | doi: 10.1136/bmj.k4168. In this large cohort study, the authors assessed the risk for a first stroke related to a polygenic risk score for stroke of 90 single nucleotide polymorphism, and adherence to a healthy lifestyle (non-smoker, healthy diet, mass index <30kg/m2, and regular physical exercise). During a follow-up of about 7 years, the risk of incident stroke was 35% and 66% higher in people with genetic predisposition and with unfavorable lifestyle, respectively.
- Krag M, Marker S, Perner A, et al., for the SUP-ICU trial group. Pantoprazole in patients at risk for gastrointestinal bleeding in the ICU. N Engl J Med Oct 24, 2018;doi: 10.1056/NEJMoa1714919. The efficacy of pantoprazole in preventing gastric stress ulceration was assessed in this multicenter study involving patients admitted to the ICU for an acute condition, and at risk for gastrointestinal bleeding. A total of 3298 patients were randomized to received 40 mg IV of pantoprazole vs. placebo. Mortality at 90 days and clinically relevant events did not differ between pantoprazole and placebo.
Prof. Elena More is Editor in Chief of EAN Pages and treasurer of EAN as well as Director of the Movement Disorders Center at the Centre Hospital Universitaire (CHU) of Grenoble, France and the Associate Director of the CHU Department of Psychiatry, Neurology and Rehabilitation.