Recurring Gastrointestinal Infections Increase the Risk of Dementia

Background:Gastrointestinal infections cause significant health problems, including those affecting the immune, musculoskeletal, and nervous system, and are one of the leading causes for death worldwide. Recent findings suggest that microbiota of the gastrointestinal tract contribute to dementia.Objective:In this nested case-control study we investigated the role of common gastrointestinal infections on the subsequent risk of dementia.Methods:We used a longitudinal sample of 202,806 individuals from health claims data of the largest German health insurer and applied a nested case-control design with 23,354 initial dementia cases between 2006 and 2014 and 23,354 matched controls. We used conditional logistic regression to compute odds ratios (ORs) for dementia and corresponding 95%confidence intervals (CIs), adjusting for potential confounders.Results:The risk of dementia was increased in patients with recurring incidences of quarters with diagnosed gastrointestinal infections when compared to the unexposed population (one quarter: OR = 1.49, 95%CI = 1.40–1.58; two quarters: OR = 1.70, 95%CI = 1.51–1.91; three or more quarters: OR = 1.64, 95%CI = 1.40–1.93), adjusted for potential confounders.Conclusion:Our findings suggest that recurring gastrointestinal infections are associated with an increased risk of subsequent dementia

Body-first Parkinson’s disease and variant Creutzfeldt–Jakob disease – similar or different?

In several neurodegenerative disorders, proteins that typically exhibit an α-helical structure misfold into an amyloid conformation rich in β-sheet content. Through a self-templating mechanism, these amyloids are able to induce additional protein misfolding, facilitating their propagation throughout the central nervous system. This disease mechanism was originally identified for the prion protein (PrP), which misfolds into PrPSc in a number of disorders, including variant Creutzfeldt–Jakob disease (vCJD) and bovine spongiform encephalopathy (BSE). More recently, the prion mechanism of disease was expanded to include other proteins that rely on this self-templating mechanism to cause progressive degeneration, including α-synuclein misfolding in Parkinson’s disease (PD). Several studies now suggest that PD patients can be subcategorized based on where in the body misfolded α-synuclein originates, either the brain or the gut, similar to patients developing sporadic CJD or vCJD. In this review, we discuss the human and animal model data indicating that α-synuclein and PrPSc misfolding originates in the gut in body-first PD and vCJD, and summarize the data identifying the role of the autonomic nervous system in the gut-brain axis of both diseases

Bioluminescence Imaging of Neuroinflammation in a Mouse Model of Parkinson’s Disease

In Parkinson’s disease (PD) and related disorders pathological alpha-synuclein has been discussed to propagate via a prion-like mechanism in the CNS. The application of exogenous alpha-synuclein fibrils via injection to animal models of PD has been shown to be a useful method to study prion-like propagation of pathological alpha-synuclein and of transmission pathways that play a critical role in recapitulating characteristics of synucleinopathies. Using bigenic mice expressing mutant human alpha-synuclein in neurons and firefly luciferase in astrocytes we showed that transmission via the tongue and the peritoneum represent entrance points for pathological alpha-synuclein to invade the CNS. Here we present a method to quantify astrogliosis by bioluminescence imaging in an animal model of PD. This method allows noninvasive tracking of the neuroinflammatory process that often precedes neurological signs of disease and represents an alternative to behavioral or histological and biochemical analysis to detect disease

GI infections are associated with an increased risk of Parkinson’s disease

We have read with interest the recent publication of Perez-Pardo and colleagues1 reporting the role of the TLR4 in the gut–brain axis in Parkinson’s disease (PD). These findings prompted us to investigate the role of common GI infections (GIIs) in the pathogenesis of PD. In this prospective cohort study, we assessed the risk of PD in patients who previously suffered from GIIs compared with the control group not exposed to GIIs (table 1). At study entry (1 January 2005), the analysis sample from health claims data of the largest German health insurer consisted of2 28 485 individuals aged 50 years and older, which were followed for a mean time of 8.6 years (median=11.0 years; IQR=7.6 years). PD and GIIs were defined by ICD-10 codes as described in the supplementary material. Overall, 6195 individuals (2.7%) developed PD and 50 492 individuals (22.1%) were affected by any GII during the observation period between 2005 and 2015. The most frequent GIIs were those that caused infectious gastroenteritis and colitis of unspecified origin (IGCUs; 39 093 individuals, 17.1%), followed by viral intestinal infections (VIIs; 9328 individuals, 4.1%) and bacterial intestinal infections (BIIs; 9298 individuals, 4.1%). The cumulative incidence of PD was significantly higher among individuals with GIIs (p<0.001, online supplementary figure S1). Multivariable analyses (table 2) using Cox regression to compute HRs revealed an increased risk of PD in patients with GIIs when compared with the control group (HR=1.42; 95% CI 1.33 to 1.52). Subgroup analyses (table 2) revealed positive associations of GIIs for men (HR=1.48; 95% CI 1.34 to 1.63), women (HR=1.38; 95% CI 1.27 to 1.50), individuals aged 70 years or older (HR=1.25; 95% CI 1.04 to 1.49) and individuals with (HR=1.40; 95% CI 1.23 to 1.59) or without chronic obstructive pulmonary disease (HR=1.43; 95% CI 1.33 to 1.54). To solidify our results, we performed sensitivity analyses and found no remarkable changes compared with our primary analysis (online supplementary table S1). In a secondary analysis, where we considered GIIs separately (online supplementary table S2), BIIs (HR=1.30; 95% CI 1.12 to 1.50), VIIs (HR=1.31; 95% CI 1.14 to 1.50) and IGCUs (HR=1.34; 95% CI 1.24 to 1.44) were each associated with an increased risk of PD

Sporadic Use of Antibiotics in Older Adults and the Risk of Dementia: A Nested Case–Control Study Based on German Health Claims Data

Background: Antibiotics for systemic use may increase the risk of neurodegeneration, yet antibiotic therapy may be able to halt or mitigate an episode of neurodegenerative decline.Objective: To investigate the association of sporadic use of antibiotics and subsequent dementia risk (including Alzheimer's disease).Methods: We used data from the largest public health insurance fund in Germany, the Allgemeine Ortskrankenkasse (AOK). Each of the 35,072 dementia cases aged 60 years and older with a new dementia diagnosis during the observation period from 2006 to 2018 was matched with two control-patients by age, sex, and time since 2006. We ran conditional logistic regression models for dementia risk in terms of odds ratios (OR) as a function of antibiotic use for the entire antibiotic group and for each antibiotic subgroup. We controlled for comorbidities, need for long-term care, hospitalizations, and nursing home placement.Results: Antibiotic use was positively associated with dementia (OR = 1.18, 95% confidence interval (95% CI):1.14-1.22), which became negative after adjustment for comorbidities, at least one diagnosis of bacterial infection or disease, and covariates (OR = 0.93, 95% CI:0.90-0.96). Subgroups of antibiotics were also negatively associated with dementia after controlling for covariates: tetracyclines (OR = 0.94, 95% CI:0.90-0.98), beta-lactam antibacterials, penicillins (OR = 0.93, 95% CI:0.90-0.97), other beta-lactam antibacterials (OR = 0.92, 95% CI:0.88-0.95), macrolides, lincosamides, and streptogramins (OR = 0.88, 95% CI:0.85-0.92), and quinolone antibacterials (OR = 0.96, 95% CI:0.92-0.99).Conclusion: Our results suggest that there was a decreased likelihood of dementia for preceding antibiotic use. The benefits of antibiotics in reducing inflammation and thus the risk of dementia need to be carefully weighed against the increase in antibiotic resistance

Oral and intravenous transmission of α-synuclein fibrils to mice

Parkinson’s disease and related disorders are neuropathologically characterized by cellular deposits of misfolded and aggregated α-synuclein in the CNS. Disease-associated α-synuclein adopts a conformation that causes it to form oligomers and fibrils, which have reduced solubility, become hyperphosphorylated, and contribute to the spatiotemporal spreading of pathology in the CNS. The infectious properties of disease-associated α-synuclein, e.g., by which peripheral route and with which efficiency it can be transmitted, are not fully understood. Here, we investigated the potential of α-synuclein fibrils to induce neurological disease in TgM83+/− mice expressing the A53T mutant of human α-synuclein after oral or intravenous challenge and compared it to intraperitoneal and intracerebral challenge. Oral challenge with 50 µg of α-synuclein fibrils caused neurological disease in two out of eight mice in 220 days and 350 days, and challenge with 500 µg in four out of eight mice in 384 ± 131 days, respectively. Intravenous challenge with 50 µg of α-synuclein fibrils led to disease in 208 ± 20 days in 10 out of 10 mice and was in duration comparable to intraperitoneal challenge with 50 µg of α-synuclein fibrils, which caused disease in 10 out of 10 mice in 202 ± 35 days. Ten out of 10 mice that were each intracerebrally challenged with 10 µg or 50 µg of α-synuclein fibrils developed disease in 156 ± 20 days and 133 ± 4 days, respectively. The CNS of diseased mice displayed aggregates of sarkosyl-insoluble and phosphorylated α-synuclein, which colocalized with ubiquitin and p62 and were accompanied by gliosis indicative of neuroinflammation. In contrast, none of the control mice that were challenged with bovine serum albumin via the same routes developed any neurological disease or neuropathology. These findings are important, because they show that α-synuclein fibrils can neuroinvade the CNS after a single oral or intravenous challenge and cause neuropathology and disease

Neuroinvasion of α-Synuclein Prionoids after Intraperitoneal and Intraglossal Inoculation

α-Synuclein is a soluble, cellular protein that in a number of neurodegenerative diseases, including Parkinson's disease and multiple system atrophy, forms pathological deposits of protein aggregates. Because misfolded α-synuclein has some characteristics that resemble those of prions, we investigated its potential to induce disease after intraperitoneal or intraglossal challenge injection into bigenic Tg(M83(+/−):Gfap-luc(+/−)) mice, which express the A53T mutant of human α-synuclein and firefly luciferase. After a single intraperitoneal injection with α-synuclein fibrils, four of five mice developed paralysis and α-synuclein pathology in the central nervous system, with a median incubation time of 229 ± 17 days. Diseased mice accumulated aggregates of Sarkosyl-insoluble and phosphorylated α-synuclein in the brain and spinal cord, which colocalized with ubiquitin and p62 and were accompanied by gliosis. In contrast, only one of five mice developed α-synuclein pathology in the central nervous system after intraglossal injection with α-synuclein fibrils, after 285 days. These findings are novel and important because they show that, similar to prions, α-synuclein prionoids can neuroinvade the central nervous system after intraperitoneal or intraglossal injection and can cause neuropathology and disease. IMPORTANCE Synucleinopathies are neurodegenerative diseases that are characterized by the pathological presence of aggregated α-synuclein in cells of the nervous system. Previous studies have shown that α-synuclein aggregates made of recombinant protein or derived from brains of patients can spread in the central nervous system in a spatiotemporal manner when inoculated into the brains of animals and can induce pathology and neurologic disease, suggesting that misfolded α-synuclein can behave similarly to prions. Here we show that α-synuclein inoculation into the peritoneal cavity or the tongue in mice overexpressing α-synuclein causes neurodegeneration after neuroinvasion from the periphery, which further corroborates the prionoid character of misfolded α-synuclein