Desulfovibrio bacteria enhance alpha-synuclein aggregation in a Caenorhabditis elegans model of Parkinson's disease.

Introduction: The aggregation of the neuronal protein alpha-synuclein (alpha-syn) is a key feature in the pathology of Parkinson's disease (PD). Alpha-syn aggregation has been suggested to be induced in the gut cells by pathogenic gut microbes such as Desulfovibrio bacteria, which has been shown to be associated with PD. This study aimed to investigate whether Desulfovibrio bacteria induce alpha-syn aggregation. Methods: Fecal samples of ten PD patients and their healthy spouses were collected for molecular detection of Desulfovibrio species, followed by bacterial isolation. Isolated Desulfovibrio strains were used as diets to feed Caenorhabditis elegans nematodes which overexpress human alpha-syn fused with yellow fluorescence protein. Curli-producing Escherichia coli MC4100, which has been shown to facilitate alpha-syn aggregation in animal models, was used as a control bacterial strain, and E. coli LSR11, incapable of producing curli, was used as another control strain. The head sections of the worms were imaged using confocal microscopy. We also performed survival assay to determine the effect of Desulfovibrio bacteria on the survival of the nematodes. Results and Discussion: Statistical analysis revealed that worms fed Desulfovibrio bacteria from PD patients harbored significantly more (P<0.001, Kruskal-Wallis and Mann-Whitney U test) and larger alpha-syn aggregates (P<0.001) than worms fed Desulfovibrio bacteria from healthy individuals or worms fed E. coli strains. In addition, during similar follow-up time, worms fed Desulfovibrio strains from PD patients died in significantly higher quantities than worms fed E. coli LSR11 bacteria (P<0.01). These results suggest that Desulfovibrio bacteria contribute to PD development by inducing alpha-syn aggregation.

Hydrogen Sulfide Produced by Gut Bacteria May Induce Parkinson's Disease.

Several bacterial species can generate hydrogen sulfide (H2S). Study evidence favors the view that the microbiome of the colon harbors increased amounts of H2S producing bacteria in Parkinson's disease. Additionally, H2S can easily penetrate cell membranes and enter the cell interior. In the cells, excessive amounts of H2S can potentially release cytochrome c protein from the mitochondria, increase the iron content of the cytosolic iron pool, and increase the amount of reactive oxygen species. These events can lead to the formation of alpha-synuclein oligomers and fibrils in cells containing the alpha-synuclein protein. In addition, bacterially produced H2S can interfere with the body urate metabolism and affect the blood erythrocytes and lymphocytes. Gut bacteria responsible for increased H2S production, especially the mucus-associated species of the bacterial genera belonging to the Desulfovibrionaceae and Enterobacteriaceae families, are likely play a role in the pathogenesis of Parkinson's disease. Special attention should be devoted to changes not only in the colonic but also in the duodenal microbiome composition with regard to the pathogenesis of Parkinson's disease. Influenza infections may increase the risk of Parkinson's disease by causing the overgrowth of H2S-producing bacteria both in the colon and duodenum.

Desulfovibrio Bacteria Are Associated With Parkinson's Disease.

Parkinson's disease (PD) is the most prevalent movement disorder known and predominantly affects the elderly. It is a progressive neurodegenerative disease wherein α-synuclein, a neuronal protein, aggregates to form toxic structures in nerve cells. The cause of Parkinson's disease (PD) remains unknown. Intestinal dysfunction and changes in the gut microbiota, common symptoms of PD, are evidently linked to the pathogenesis of PD. Although a multitude of studies have investigated microbial etiologies of PD, the microbial role in disease progression remains unclear. Here, we show that Gram-negative sulfate-reducing bacteria of the genus Desulfovibrio may play a potential role in the development of PD. Conventional and quantitative real-time PCR analysis of feces from twenty PD patients and twenty healthy controls revealed that all PD patients harbored Desulfovibrio bacteria in their gut microbiota and these bacteria were present at higher levels in PD patients than in healthy controls. Additionally, the concentration of Desulfovibrio species correlated with the severity of PD. Desulfovibrio bacteria produce hydrogen sulfide and lipopolysaccharide, and several strains synthesize magnetite, all of which likely induce the oligomerization and aggregation of α-synuclein protein. The substances originating from Desulfovibrio bacteria likely take part in pathogenesis of PD. These findings may open new avenues for the treatment of PD and the identification of people at risk for developing PD.

Magnetic Nanoparticles in Human Cervical Skin.

Magnetic iron oxide nanoparticles, magnetite/maghemite, have been identified in human tissues, including the brain, meninges, heart, liver, and spleen. As these nanoparticles may play a role in the pathogenesis of neurodegenerative diseases, a pilot study explored the occurrence of these particles in the cervical (neck) skin of 10 patients with Parkinson's disease and 10 healthy controls. Magnetometry and transmission electron microscopy analyses revealed magnetite/maghemite nanoparticles in the skin samples of every study participant. Regarding magnetite/maghemite concentrations of the single-domain particles, no significant between-group difference was emerged. In low-temperature magnetic measurement, a magnetic anomaly at ~50 K was evident mainly in the dermal samples of the Parkinson group. This anomaly was larger than the effect related to the magnetic ordering of molecular oxygen. The temperature range of the anomaly, and the size-range of magnetite/maghemite, both refute the idea of magnetic ordering of any iron phase other than magnetite. We propose that the explanation for the finding is interaction between clusters of superparamagnetic and single-domain-sized nanoparticles. The source and significance of these particles remains speculative.

Altered N100-potential associates with working memory impairment in Parkinson's disease.

The diagnosis of cognitive impairment and dementia often occurring with Parkinson's disease (PD) is still based on the clinical picture and neuropsychological examination. Ancillary methods to detect cognitive decline in these patients are, therefore, needed. Alterations in the latencies and amplitudes of evoked response potential (ERP) components N100 and P200 have been described in PD. Due to limited number of studies their relation to cognitive deficits in PD remains obscure. The present study was designed to examine if alterations in the N100- and P200-potentials associate with neuropsychological impairment in PD. EEG-ERP was conducted to 18 PD patients and 24 healthy controls. The patients underwent a thorough neuropsychological evaluation. The controls were screened for cognitive impairment with Consortium to Establish Alzheimer's disease (CERAD)-testing and a normal result were required to be included in the study. The N100-latency was prolonged in the patients compared to the controls (p = 0.05). In the patients, the N100 latency correlated significantly with a visual working memory task (p = 0.01). Also N100 latency was prolonged and N100 amplitude habituation diminished in the patients achieving poorly in this task. We conclude that prolonged N100-latency and diminished amplitude habituation associate with visual working memory impairment in PD.

Gut microbiota are related to Parkinson's disease and clinical phenotype.

In the course of Parkinson's disease (PD), the enteric nervous system (ENS) and parasympathetic nerves are amongst the structures earliest and most frequently affected by alpha-synuclein pathology. Accordingly, gastrointestinal dysfunction, in particular constipation, is an important non-motor symptom in PD and often precedes the onset of motor symptoms by years. Recent research has shown that intestinal microbiota interact with the autonomic and central nervous system via diverse pathways including the ENS and vagal nerve. The gut microbiome in PD has not been previously investigated. We compared the fecal microbiomes of 72 PD patients and 72 control subjects by pyrosequencing the V1-V3 regions of the bacterial 16S ribosomal RNA gene. Associations between clinical parameters and microbiota were analyzed using generalized linear models, taking into account potential confounders. On average, the abundance of Prevotellaceae in feces of PD patients was reduced by 77.6% as compared with controls. Relative abundance of Prevotellaceae of 6.5% or less had 86.1% sensitivity and 38.9% specificity for PD. A logistic regression classifier based on the abundance of four bacterial families and the severity of constipation identified PD patients with 66.7% sensitivity and 90.3% specificity. The relative abundance of Enterobacteriaceae was positively associated with the severity of postural instability and gait difficulty. These findings suggest that the intestinal microbiome is altered in PD and is related to motor phenotype. Further studies are warranted to elucidate the temporal and causal relationships between gut microbiota and PD and the suitability of the microbiome as a biomarker.

Uric acid and cognition in Parkinson's disease: a follow-up study.

Cognitive changes are common in Parkinson's disease (PD). Low plasma uric acid (UA) level is associated with risk of PD and predicts faster progression of motor symptoms in established disease. Whether UA levels predict cognitive changes has not been studied. In a crossectional study, our group has previously shown an association of plasma and urine UA levels with cognition in PD. The aim of the present controlled longitudinal study was to examine the evolution of cognitive changes and the prognostic value of the UA levels on cognition in the previously reported PD-patient cohort. Of the original 40 patients, 31 were available for follow-up after three years. Both plasma and daily urine UA levels were measured, nutrition was evaluated using 4-day dietary recall diary and cognition was assessed by a thorough neuropsychological examination including computerized tasks with Cognispeed©. The plasma and urine UA levels of the patients remained stable during the follow-up. At the same time, the rate of cognitive decline was unexpectedly slow. A statistically significant deterioration was noted in verbal fluency (p=0.04) and in Cognispeed©'s vigilance task (p=0.0001). In forward linear regression analysis only the baseline daily urine UA level contributed to verbal fluency (p=0.01), picture completion (p=0.001), block design (p=0.006), vigilance (p=0.006), subtraction (p=0.01) and statement verification (p=0.04) tasks. The implications of the study results are discussed.

Uric acid associates with cognition in Parkinson's disease.

Cognitive dysfunction is common in Parkinson's disease (PD). Low plasma uric acid level is a risk factor for PD but its association with cognitive impairment in PD has not been previously studied. In the present study urine uric acid level as well as plasma uric acid- and homocysteine levels were measured in 40 patients with PD. Comprehensive neuropsychological tests including computerized tasks were performed on all. Both low plasma and low urine uric acid levels associated with decreased neuropsychological performance. In multiple linear regression low urine uric acid level predicted worse performance in the Picture completion subtest of the Wechsler Adult Intelligence Scale-Revised (WAIS-R) (p=0.003) and in the Rule shift cards test of the Behavioral Assessment of the Dysexecutive Syndrome (BADS) (p=0.04). Low plasma uric acid level predicted worse performance both in the Picture completion (p=0.02) and Similarities subtest of the WAIS-R (p=0.02). Reaction time and the time spent on cognitive processing in the Statement verification task were inversely correlated with the uric acid levels (p=0.0001). There was no correlation between the homocysteine level and neuropsychological performance. Instead, the plasma uric acid and homocysteine levels correlated significantly and their possible association in PD is discussed.

Low plasma uric acid level in Parkinson's disease.

Earlier studies suggest that low plasma uric acid level is a risk factor for Parkinson's disease (PD), and that uric acid associates with iron-binding proteins. We therefore decided to examine plasma uric acid levels and markers of peripheral iron metabolism in PD patients and healthy controls. For the study, 40 patients with PD and 29 controls underwent clinical screening, laboratory testing, and body mass index (BMI) measurement. The average consumption of different foodstuffs and dairy products was estimated. Plasma uric acid level was significantly lower in the patients than in the controls. There were no significant differences in the levels of plasma iron parameters, but plasma uric acid correlated strongly with serum ferritin both in the patient and the control group. The BMI was slightly lower in the patients compared with the controls despite equal daily calorie consumption. Plasma uric acid level is low in patients with PD, which may have implications for both the disease pathogenesis and treatment recommendations.