Modeling idiopathic PD as a complex illness - infections

[aspergerian]

Subgroup analysis seems important, even necessary for progress in halting PD progression.

Recently, Hikoi posted ~17 minute video:

healthunlocked.com/parkinso...

Today or yesterday, p-oui posted:

healthunlocked.com/parkinso...

healthunlocked.com/parkinso...

See also [not a complete list of co-factors that may be etiologically significant in one or more subgroups of PwP]:

The association between infectious burden and Parkinson's disease: A case-control study.

Parkinsonism Relat Disord 2015 Aug;21(8):877-81.

ncbi.nlm.nih.gov/pubmed/260...

"IB [infectious burden] consisting of CMV, EBV, HSV-1, B. burgdorferi, C. pneumoniae and

H. pylori is associated with PD. This study supports the role of

infection in the etiology of PD."

Exposure to bacterial endotoxin generates a distinct strain of α-synuclein fibril.

Sci Rep 2016 Aug 4;6:30891.

ncbi.nlm.nih.gov/pubmed/274...

"These results suggest that amyloid fibrils with self-renewable

structures cause distinct types of proteinopathies despite the identical

primary structure and that exposure to exogenous pathogens may

contribute to the diversity of synucleinopathies."

Small intestinal bacterial overgrowth in Parkinson's disease.

Parkinsonism Relat Disord 2014 May;20(5):535-40.

ncbi.nlm.nih.gov/pubmed/246...

"This is the largest study to date on SIBO in PD. SIBO was detected in

one quarter of patients, including patients recently diagnosed with the

disease. SIBO was not associated with worse gastrointestinal symptoms,

but independently predicted worse motor function."

Modelling idiopathic Parkinson disease as a complex illness can inform incidence rate in healthy adults: the PR EDIGT score.

Eur J Neurosci 2017 Jan;45(1):175-191.

ncbi.nlm.nih.gov/pubmed/278...

Dare we hope that researchers crunching data for 5 Repurposed Drugs will be aware of Complex PD models that include subgroups.

healthunlocked.com/parkinso...

[johntPM]

The subgroup we should work with is the individual. Apart from some implied placebo effect, if a treatment works for me, it works for me regardless of whether or not it works for you.

The non-commercial reason for using large sample sizes in clinical trials is to get statistical significance. To measure significance in a n=1 trial we must test differently: we need to run high-frequency tests (daily, every second etc.)

To illustrate this, for a n=1 trial, suppose we have a baseline, T=0, result of 100, and an end point, T=100, result of 200. The results have increased, but we can't measure statistical significance. We may have just got lucky with the timing of the tests.

But, if we test daily and find that performance increases every day, 100, 101, 102, ... 200, we have enough data to measure significance.

John

[aspergerian in reply to johntPM]

JohnTPM,

I agree that N=1 data are important. Nonetheless, if N=1000 was included in experimental design for treatment X so as to increase statistical significance,

with 500 Pwp receiving X and 500 Pwp receiving placebo, such a study is likely to belittle or discredit a subgroup of (eg) 23 who responded favorably to X.

If PD is comprised of subgroups reflecting different disease processes and or reflecting different combinations and/o timings of co-factors having potentially etiologic significance, then research design that includes looking for small groups of responders within the larger N may be instructive.

Defining subgroups by symptoms present and symptoms absent would augment findings of responder (small) subgroups in otherwise larger studies.

The link Hikoi provided expresses this point well.

healthunlocked.com/parkinso...

[Hikoi]

Well aspergerian I am hopeful. I was diagnosed nearly 10 years ago and i heard this thinking not long after that so it isnt entirely new. I dont know that it has translated into research design but there is a movement to include pwp in the whole research process, including design. Indeed i remember a heated exchange on it!

healthunlocked.com/parkinso...

There is some off topic posts in the thread but you may find it interesting.

[Astra7]

Has anyone been to a gastroenterologist in relation to PD? My friend has suggested that a sample should be taken to determine where the inflammation is in the gut and hence what is needed to shift it ( and hence magically cure us all!).

Do people on this site feel they have had poor stomach health? Surely we would have had some symptoms and would know?

[Ruffinglgo in reply to Astra7]

I will ask my primary physician to test for H pylori. Yes stomach issues are a persistent complaint. We drink well water in tobacco country.

[aspergerian in reply to Ruffinglgo]

H pylori may not be the only significant factor within the GI tract. SIBO too.

"Infection with H. pylori is common. About two-thirds of the world’s

population has it in their bodies. For most people, it doesn’t cause

ulcers or any other symptoms. If you do have problems, there are

medicines that can kill the germs and help sores heal.Infection with H.

pylori is common. About two-thirds of the world’s population has it in

their bodies. For most people, it doesn’t cause ulcers or any other

symptoms. If you do have problems, there are medicines that can kill the

germs and help sores heal."

webmd.com/digestive-disorde...

See also:

The gut-brain axis: is intestinal inflammation a silent driver of Parkinson's disease pathogenesis?

NPJ Parkinsons Dis 2017 Jan 11;3:3.

ncbi.nlm.nih.gov/pubmed/286...

The gut-brain axis in Parkinson's disease: Possibilities for food-based therapies.

Eur J Pharmacol 2017 May 23. pii: S0014-2999(17)30373-4.

ncbi.nlm.nih.gov/pubmed/285...

Intestinal Dysbiosis and Lowered Serum Lipopolysaccharide-Binding Protein in Parkinson's Disease.

PLoS One 2015 Nov 5;10(11):e0142164.

ncbi.nlm.nih.gov/pubmed/265...

Small intestinal bacterial overgrowth in Parkinson's disease.

Parkinsonism Relat Disord 2014 May;20(5):535-40.

ncbi.nlm.nih.gov/pubmed/246....

Inflammatory dysregulation of blood monocytes in Parkinson's disease patients.

Acta Neuropathol 2014 Nov;128(5):651-63.

ncbi.nlm.nih.gov/pubmed/252...

LPS-induced proNGF synthesis and release in the N9 and BV2 microglial

cells: a new pathway underling microglial toxicity in neuroinflammation.

PLoS One 2013 Sep 9;8(9):e73768.

ncbi.nlm.nih.gov/pubmed/240...

Potential of the cannabinoid CB(2) receptor as a pharmacological target against inflammation in Parkinson's disease.

Prog Neuropsychopharmacol Biol Psychiatry 2016 Jan 4;64:200-8.

ncbi.nlm.nih.gov/pubmed/258...

Studies of lipopolysaccharide effects on the induction of α-synuclein pathology by exogenous fibrils in transgenic mice.

Mol Neurodegener 2015 Jul 30;10:32.

ncbi.nlm.nih.gov/pubmed/262...

Physiological, pathological, and therapeutic implications of

zonulin-mediated intestinal barrier modulation: living life on the edge

of the wall.

Fasano A: Am J Pathol 2008 Nov;173(5):1243-52.

ncbi.nlm.nih.gov/pubmed/188...

Intestinal permeability and its regulation by zonulin: diagnostic and therapeutic implications.

Fasano A: Clin Gastroenterol Hepatol 2012 Oct;10(10):1096-100.

ncbi.nlm.nih.gov/pubmed/229...

Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer.

Fasano A: Physiol Rev 2011 Jan;91(1):151-75.

ncbi.nlm.nih.gov/pubmed/212...

[Ruffinglgo in reply to aspergerian]

Thank you for researching this important topic. I will settle down to read with interest.

[seamus60680 in reply to Astra7]

I've had gastro problems for twenty years. ...urticaria/skin welts on light contact - taking a shirt off for example, results in serious neck rash but only for ten minutes. I suspect an abnormality in my stomach/gut has allowed toxins in to my bloodstream over many years...combined with exceptional stress too much sugar and alcohol. The cause of my pd I suspect. Plan to rebalance gut with plenty of water/vigorous exercise. ...no meds, I'll want to give my body a chance, albiet perhaps a slim one, to fix itself! ......just about to cost me job and car tho

[Opt8]

I sometimes wonder if I have a virus from the numerous viruses in my lifetime like a left over viruses in my system that will not leave my body ever. Sometimes I have flu like symptoms that reoccur that start with intestinal upset then canker sores in mouth for s3veral days. Then leaves my body for a few weeks only to return at another day. I have wondered about perhaps a viral connection to pd. I too think there maybe multiple causes also more complicated then researchers have Initially thought. My grandfather had pd with tremors. I have non tremoring with 3xtreme stiffness along with other pd symptoms. Being helped with cl and azilect. Thankful for all the research with dedicated Scientists to help unlock some answers.

[aspergerian in reply to Opt8]

Opt8,

Thank you for sharing. You might find something of interest among the citations in:

healthunlocked.com/parkinso...

[aspergerian in reply to aspergerian]

Oct8,

Here's a study of viral latency. The focus is MS, but there may be relevance for some PD subgroups.

Hidden herpes virus may play key role in MS, other brain disorders.

sciencedaily.com/releases/2...

Expression of the Human Herpesvirus 6A Latency-Associated Transcript U94A Disrupts Human Oligodendrocyte Progenitor Migration.

Scientific Reports, 2017; 7 (1).

nature.com/articles/s41598-...

[aspergerian in reply to Opt8]

Oct8,

Here's a study of viral latency. The focus is MS, but there may be relevance for some PD subgroups.

Hidden herpes virus may play key role in MS, other brain disorders.

sciencedaily.com/releases/2...

Expression of the Human Herpesvirus 6A Latency-Associated Transcript U94A Disrupts Human Oligodendrocyte Progenitor Migration.

Scientific Reports, 2017; 7 (1).

nature.com/articles/s41598-...

[aspergerian in reply to aspergerian]

Opt8,

Lai et al 2017 found an enhanced risk of PD among elderly people

with herpes zoster. See also, Welsby 2006, for differences between

US and UK. Perhaps VZV may be an etiologically significant co-factor in a small subgroup of individuals who develop PD.

Herpes zoster correlates with increased

risk of Parkinson's disease in older people: A

population-based cohort study in Taiwan.

Lai SW, et al.

Medicine (Baltimore) 2017 Feb;96(7):e6075.

ncbi.nlm.nih.gov/pmc/articl...

Chickenpox, chickenpox vaccination, and

shingles.

Welsby PD.

Postgrad Med J 2006 May;82(967):351-2.

ncbi.nlm.nih.gov/pmc/articl...