Parkinson's disease

Mayo Clinic overview

Clustering of Parkinson disease: shared cause or coincidence?

BACKGROUND: The spatial and temporal pattern of excessive disease occurrence, termed clustering, may provide clues about the underlying etiology.

OBJECTIVE: To report the occurrence of 3 clusters of Parkinson disease (PD) in Canada.

DESIGN AND PATIENTS: We determined the population groups containing the clusters, geographical limits, and duration of exposure to the specific environments. We tested whether there was an excessive presence of Parkinson disease by calculating the probability of the observed cases occurring under the null hypothesis that the disease developed independently and at random in cluster subjects. Results of genetic testing for mutations in the alpha-synuclein, parkin, tau genes, and spinocerebellar ataxia genes (SCA2 and SCA3) were negative.

RESULTS: The probabilities of random occurrence (P values) in the 3 clusters were P = 7.9 x 10 (-7)for cluster 1, P = 2.6 x 10 (-7)for cluster 2, and P = 1.5 x 10 (-7)for cluster 3.

CONCLUSIONS: Our findings indicate an important role for environmental causation in Parkinson disease. A possible role exists for environmental factors such as viral infection and toxins in the light of current evidence. ¹⁾

Colonoscopy or flexible sigmoidoscopy may be used to predict Parkinson's ^{2) 3) 4)}

OBJECTIVE:An inflammationThe complex biological response of vascular tissues to harmful stimuli such as pathogens or damaged cells. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue.-driven model of PD has been proposed based on the endotoxin lipopolysaccaride (LPS), a potential source of inflammation in the gastrointestinal system linked to neurotoxicity. Systemic exposure to bacterial endotoxin (LPS) can be determined by measuring plasma LPS binding protein (LBP). We aimed to evaluate whether lipopolysaccharide binding protein (LBP) can be used to distinguish PD subjects from control subjects and to assess whether LBP levels correlate with PD disease severity.

CONCLUSIONS: Our data suggests that LBP is one GI biomarker related to LPS induced neurotoxicity. However, there was significant variability in LBP levels within the PD and control groups, limiting its utility as a stand-alone biomarker. Pal et al Front Neurosci. 2015 Sep 1 ⁵⁾

Strong epidemiologic evidence suggests that smokers and coffee drinkers have a lower risk of Parkinson's disease (PD). The explanation for this finding is still unknown, and the discussion has focused on two main hypotheses.

We propose an alternative third hypothesis, in which both cigarette and coffee consumption change the composition of the microbiotaThe bacterial community which causes chronic diseases - one which almost certainly includes multiple species and bacterial forms. in the gut in a way that mitigates intestinal inflammation. Derkinderen et al Mov Disord. 2014 Jul 29 ⁶⁾

Nature Reviews Neuroscience 10, 393 (June 2009) | doi:10.1038/nrn2650

Neurodegenerative disease: NURR1 puts a dampener on inflammation

Katherine Whalley

The nuclear receptorIntracellular receptor proteins that bind to hydrophobic signal molecules (such as steroid and thyroid hormones) or intracellular metabolites and are thus activated to bind to specific DNA sequences which affects transcription. NURR1 (also known as NR4A2) has an essential role in the development and maintenance of dopaminergic neurons, and mutations in this protein cause a familial form of Parkinson's disease (PD). Now, a study from Saijo et al. suggests a previously unknown function of NURR1 in microglia and astrocytes in protecting dopaminergic neurons from inflammation-induced death.

Growing evidence suggests that inflammatory processes contribute to neuropathology in PD. For example, experimentally infusing inflammatory substances such as lipopolysaccharide (LPS) into the brain can replicate some of the pathology of PD. In macrophages, NURR1 expression can be induced by LPS, prompting the authors to investigate the influence of NURR1 on the effects of LPS in the CNS. They found that injecting lentiviruses encoding short hairpin RNAs against NURR1 (shNURR1) into the substantia nigra of mice significantly accelerated and augmented the loss of dopaminergic neurons in this region in response to LPS, suggesting that NURR1 can protect neurons from LPS-induced cell death.

Next the authors investigated the mechanisms and cell types involved in NURR1's protective effects. Expressing shNURR1 in cultured microglia or astrocytes increased their production of inflammatory mediators, such as tumour necrosis factor- and inducible nitric oxide synthase, in response to LPS. The conditioned media taken from shNURR1 microglia cultures was highly toxic to cultured dopaminergic neurons. Moreover, when the media was sequentially used to culture shNURR1-treated microglia and then shNURR1-treated astrocytes, its toxicity for dopaminergic neurons was increased further, indicating that NURR1 inhibits the production of toxic inflammatory factors in both microglia and astrocytes.

In subsequent experiments, the authors dissected the mechanism by which NURR1 influences the expression of inflammatory genes in astrocytes and microglia. They revealed that NURR1 represses the transcription of these genes by interacting with the transcription factor complex nuclear factor-B–p65 on the gene promoter, a process known as transrepression. This interaction was shown to rely on both the sumoylation of NURR1 and the phosphorylation of p65 by glycogen synthase kinase 3. Furthermore, the authors showed that the co-repressor COREST, together with the chromatin-modifying enzymes that it recruits (histone methyltransferase G9a, lysine-specific demethylase and histone deacetylase 1), is required for NURR1-mediated transrepression. The interaction between NURR1 and COREST required the activity of Nemo-like kinase.

This study describes a previously unknown role for NURR1 in suppressing potentially neurotoxic inflammatory gene expression in microglia and astrocytes and suggests that the loss of this ability might contribute to some forms of PD. The transrepression pathway uncovered may provide further clues to the cause of PD pathology as well as potential therapeutic targets.

Helicobacter. 2005 Aug;10(4):276-87. Role of chronic infection and inflammation in the gastrointestinal tract in the etiology and pathogenesis of idiopathic parkinsonism. Part 2: response of facets of clinical idiopathic parkinsonism to Helicobacter pylori eradication. A randomized, double-blind, placebo-controlled efficacy study. Bjarnason IT, Charlett A, Dobbs RJ, Dobbs SM, Ibrahim MA, Kerwin RW, Mahler RF, Oxlade NL, Peterson DW, Plant JM, Price AB, Weller C. ⁷⁾

Section of Neuropharmacology, Institute of Psychiatry, London, UK. Erratum in:

Helicobacter. 2005 Oct;10(5):557. Bjarnason, Inguar T [corrected to Bjarnason, Ingvar T]. Abstract

BACKGROUND: Links between etiology/pathogenesis of neuropsychiatric disease and infection are increasingly recognized. AIM: Proof-of-principle that infection contributes to idiopathic parkinsonism.

METHODS: Randomized, double-blind, placebo-controlled efficacy study of proven Helicobacter pylori eradication on the time course of facets of parkinsonism. Intervention was 1 week's triple eradication therapy/placebos. Routine deblinding at 1 year (those still infected received open-active), with follow-up to 5 years post-eradication. Primary outcome was mean stride length at free-walking speed, sample size 56 for a difference, active vs. placebo, of 3/4 (between-subject standard deviation). Recruitment of subjects with idiopathic parkinsonism and H. pylori infection was stopped at 31, because of marked deterioration with eradication failure. Interim analysis was made in the 20 who had reached deblinding, seven of whom were receiving antiparkinsonian medication (long-t(1/2), evenly spaced) which remained unchanged.

RESULTS: Improvement in stride-length, on active (n = 9) vs. placebo (11), exceeded size of effect on which the sample size was calculated when analyzed on intention-to-treat basis (p = .02), and on protocol analysis of six weekly assessments, including (p = .02) and excluding (p = .05) those on antiparkinsonian medication. Active eradication (blind or open) failed in 4/20, in whom B-lymphocyte count was lower. Their mean time course was: for stride-length, -243 (95% CI -427, -60) vs. 45 (-10, 100) mm/year in the remainder (p = .001); for the ratio, torque to extend to flex relaxed arm, 349 (146, 718) vs. 58 (27, 96)%/ year (p < .001); and for independently rated, visual-analog scale of stance-walk videos (worst-best per individual identical with 0-100 mm), -64 vs. -3 mm from anterior and -50 vs. 11 lateral (p = .004 and .02).

CONCLUSIONS: Interim analysis points to a direct or surrogate (not necessarily unique) role of a particular infection in the pathogenesis of parkinsonism. With eradication failure, bolus release of antigen from killed bacteria could aggravate an effect of ongoing infection.

Bacteria may cause Parkinson’s disease

Results and conclusions: Infection of late middle-aged mice with a particular strain of the bacteria Helicobacter pylori results in development of Parkinson’s disease symptoms (abnormal movement and brain chemistry) after 3-5 months. Feeding mice with extracts of killed H. pylori also induces these changes, indicating that a substance found in the bacteria is absorbed by the body and damages certain brain cells. Since H. pylori strains differ in their ability to cause inflammation and Parkinson’s disease, we suspect that bacterial factors and/or chronic inflammation also affect susceptibility to Parkinson’s disease. Our findings suggest that H. pylori infection could play a significant role in development of Parkinson’s disease in humans.

“Unfortunately, this study also revealed a strong cautionary note. Antibiotic treatment does not always cure H. pylori infection. 20% of patients receiving antibiotics remained infected with H. pylori, and these patients deteriorated more rapidly than those who were not treated at all. Therefore, a physician wishing to treat a Parkinson’s disease patient for H. pylori infection faces a Russian roulette; there is an 80% chance that the patient will benefit from H. pylori treatment, but a 20% chance that the patient will become more debilitated.”

Ulcer bacteria may contribute to development of Parkinson's disease

https://www.eurekalert.org/pub_releases/2011-05/asfm-ubm051811.php

NEW ORLEANS, LA – May 22, 2011 – The stomach bacteria responsible for ulcers could also play a role in the development of Parkinson's disease according to research presented today at the 111th General Meeting of the American Society for Microbiology.

“Infection of late middle-aged mice with a particular strain of the bacteria Helicobacter pylori results in development of Parkinson's disease symptoms after 3-5 months,” says Traci Testerman of Louisiana State University Health Sciences Center, Shreveport, who presented the research. “Our findings suggest that H. pylori infection could play a signficant role in the development of Parkinson's disease in humans.”

Physicians have noted a correlation between stomach ulcers and Parkinson's disease as far back as the 1960s, before it was even known that H. pylori was the cause of ulcers. More recently, a number of studies found that people with Parkinson's disease were more likely to be infected with the bacterium, and that Parkinson's patients who were treated and cured of infection showed slight improvement compared to controls that continued to deteriorate.

In Guam, a study of why some populations had a high risk of developing a Parkinson's-like disease discovered that a specific compound in cycad seeds eaten by these populations was neurotoxic. The compound, which resembles a cholesterol with an attached sugar group, is almost identical to a compound produced by H. pylori.

Testerman and her colleagues developed an animal model to more effectively understand the role of H. pylori and its modified cholesterol in Parkinson's disease. They infected young and aged mice with three different strains of the bacteria and monitored their locomotor activity and dopamine levels in the brain. Mice infected with one of the strains showed significant reductions in both.

“The results were far more dramatic in aged mice than in young mice, demonstrating that normal aging increases susceptibility to Parkinsonian changes in mice, as is seen in humans,” says Testerman.

In order to determine whether the modified cholesterol or other substances could be responsible for Parkinson's disease development, they fed aged mice with H. pylori extracts. The mice did not become infected but developed the same symptoms as those infected with the bacteria, suggesting that the modified cholesterol or some other product contained within the bacteria contribute to disease development.

“Our mouse model demonstrates a direct effect of H. pylori infection on the development of Parkinson's disease. The observation that not all H. pylori strains are equally able to cause symptoms will allow us to investigate bacterial factors and/or immune response to H. pylori infection that increase the risk for Parkinson's disease,” says Testerman.

Studies in the Role of chronic infection and inflammation in the gastrointestinal tract in the etiology and pathogenesis of idiopathic parkinsonism. Dobbs RJ1, Dobbs SM, Weller C, Bjarnason IT, Oxlade NL, Charlett A et al

AIM: To consider the candidature of Helicobacter in parkinsonism with cachexia. ⁸⁾

AIM: Proof-of-principle that infection contributes to idiopathic parkinsonism. ⁹⁾

AIM: To explore the cross-sectional fit of parkinsonism as an extra-alimentary consequence of Helicobacter pylori, using the serum antibody profile. ¹⁰⁾

Abstract: We challenge the concept of idiopathic parkinsonism (IP) as inevitably progressive neurodegeneration ^{11) 12)}

Med Hypotheses. 2010 May;74(5):895-7. Epub 2009 Dec 3.

Microbial endocrinology as a basis for improved L-DOPA bioavailability in Parkinson's patients treated for Helicobacter pylori.

Lyte M.

Department of Pharmacy Practice, School of Pharmacy, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA. mark.lyte@ttuhsc.edu

Abstract

Antibiotic therapy to eradicate Helicobacter pylori, the causative agent of gastric and duodenal ulcers, has been suggested to improve L-DOPA bioavailability in Parkinson's and thereby improve patient symptomology. To date, there has been no proven mechanism to explain the purported benefit of treatment of H. pylori in the management of Parkinson's disease. I propose the hypothesis, and provide initial data, that the mechanism of action is due to direct utilization of L-DOPA by H. pylori to maintain its ecological niche within the gastrointestinal tract. In support of this hypothesis, data is presented which demonstrates for the first time the ability of L-DOPA to influence the in vitroA technique of performing a given procedure in a controlled environment outside of a living organism - usually a laboratory. growth of H. pylori in an iron-restricted minimal medium. H. pylori utilization of L-DOPA for its own growth requirement reduces the amount of per orally administered L-DOPA that would be available to the patient for the treatment of Parkinson's disease-related pathology. Neuroendocrine-mediated interactions with bacteria represent the emerging interdisciplinary field of microbial endocrinology. Thus, microbial endocrinology provides for a mechanism between L-DOPA and H. pylori with which to explain the purported benefit of H. pylori-directed antibiotic therapy to improve L-DOPA bioavailability in Parkinson's patients and thereby improve drug therapy management. Further, if other bacterial species within the gastrointestinal tract depend on the availability of L-DOPA or other similar neuroendocrine-based drugs for their survival, then the efficacy of such neuroendocrine-based drugs not restricted solely for the management of parkinsonian symptomology may also be adversely affected and may therefore justify the use of an antibiotic regimen to eradicate them. ¹³⁾

I am a Parkinson's patient and on the MP since Sept 2008. I am currently halfway phase 3. The results in summary: The progression of the disease has not stopped (maybe slowed down?).

I know one other person on the MP who thinks he has Parkinson's. He is also in phase 3 but not reporting on an MP site. I am reporting as EpoxyJan since Oct.2009 on the study site here.

EpoxyJan, MarshallProtocol.com

Towards this end, we used a published dataset to analyse bacteriophage composition and determine the phage/bacteria ratio in faecal samples from drug-naive PD patients and healthy participants. Our analyses revealed significant alterations in the representation of certain bacteriophages in the phagobiota of PD patients. ¹⁴⁾

In 1919, it was first recognized that loss of pigmentation in the substantia nigra of the midbrain is a feature ¹⁵⁾

The implication of tyrosine hydroxylase (TH), the enzyme that catalyzes the formation of L-3,4-dihydroxyphenylalanine, in the pathogenesis of PD at different levels makes it a promising candidate for developing efficient treatment based on correcting or bypassing the enzyme deficiency. ¹⁶⁾

Parkinson's Another Look