Histoplasma capsulatum
 

As with so many of my posts, the staring point for this post is the paper by Willis et al. [1]. It contains, amongst other things, maps of the US, at a county-by-county level, showing the distribution of the incidence and prevalence of Parkinson's among Medicare beneficiaries. The data is age and ethnically normalized.

Incidence: http://www.ncbi.nlm.nih.gov/pmc/arti...395/figure/F2/

Prevalence: http://www.ncbi.nlm.nih.gov/pmc/arti...395/figure/F1/

To my eyes, the key feature of these maps is the under representation of Parkinson's in the west coast and Rocky Mountain states and an over representation in a band from the Texas coast north eastwards to the Canadian border. In particular, areas close to the Mississippi and Ohio rivers seem to have high incidence.

I've searched the internet for any form of data which has a similar distribution. (I don't have access to the raw PD data, so I've not been able to use statistical techniques. My approach has been to simply "eye-ball" the maps.)

I've posted on apparent correlations (which may or may not be causal) between PD and:
- surface ozone [2];
- atmospheric nitric oxide [2];
- air quality [3].

I've now extended my search to look for biological entities with similar distributions to PD. One that has jumped out is the fungus histoplasma capsulatum, which causes a disease called histoplasmosis.

The paper by Baddley et al. [4] shows the incidence of histoplasmosis in people over 65: http://www.ncbi.nlm.nih.gov/pmc/arti...071/figure/F1/

The correlation between PD and histoplasmosis is far from perfect. For instance South Dakota is high for histoplasmosis, but low for PD. Also, histoplasmosis is rare in areas further than 45 degrees from the equator, so it is unlikely to play a large role in PD in, for instance, the UK.

The symptoms of histoplasmosis are:
"Many people who are infected with the fungus do not show any symptoms. In areas of the world where the fungus is very common in the environment, many people may have been infected with Histoplasma capsulatum without having any symptoms. If symptoms occur, they usually start within 3 to 17 days after being exposed to the fungus.

In people who develop disease, the most common symptoms are similar to those of pneumonia, and include: fever, chest pains, and a dry or nonproductive cough. Some people may also experience joint pain. If the disease is not treated, it can disseminate (spread) from the lungs to other organs." [5]

Histoplasmosis can be chronic. It can affect the brain.

Wu-Hsieh et al. write [6]:
"Experimental infection of animals with Histoplasma capsulatum caused a massive macrophage infiltration into the spleen and induced the production of tumor necrosis factor alpha (TNF-alpha) locally."

Mogi et al. write [7]:
"Tumor necrosis factor-alpha (TNF-alpha), a glial-cell-related factor, was
measured for the first time in the brain (striatum) and cerebrospinal fluid
(CSF) from control and parkinsonian patients by a sensitive sandwich enzyme
immunoassay. The concentrations of TNF-alpha in the brain and CSF were
significantly higher in parkinsonian patients than those in controls. Since
TNF-alpha is an important signal transducer of the immune system with cytotoxic and stimulator properties, these results suggest that an immune response may occur in the nigrostriatal dopaminergic regions in Parkinson's disease and that TNF-alpha may be related, at least in part, to the neuronal degeneration."

Given the above evidence, albeit circumstantial, it seems to me that histoplasma capsulatum could possibly be a cause of some cases of Parkinson's. If so, anti-fungals might help some people.


References

[1] "Geographic and Ethnic Variation in Parkinson Disease: A Population-Based

Study of US Medicare Beneficiaries"
Allison Wright Willis, Bradley A. Evanoff, Min Lian, Susan R. Criswell, and Brad

A. Racette
Neuroepidemiology. 2010 April; 34(3); 143-151.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2865395/

[2] http://neurotalk.psychcentral.com/thread113014.html

[3] http://neurotalk.psychcentral.com/thread113014-2.html

[4] "Geographic distribution of endemic fungal infections among older persons,

United States"
Baddley JW, Winthrop KL, Patkar NM, Delzell E, Beukelman T, Xie F, et al.
Emerg Infect Dis. 2011 Sep
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3322071/

[5] http://www.cdc.gov/fungal/histoplasmosis/symptoms.html

[6] "Early activation of splenic macrophages by tumor necrosis factor alpha is
important in determining the outcome of experimental histoplasmosis in mice."
Wu-Hsieh et al.
Infect Immun 1992 Oct; 60(10);4230-4238
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC257457/

[7] "Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients."
Mogi M. et al.
Neurosci Lett, 1994 Jan 3; 165(1-2):208-210
http://www.ncbi.nlm.nih.gov/pubmed/8015728

John

John-

Good work. As a former land surveyor and GIS hobbyist there's nothing more I like than a good map :-) I have an attempt or two buried in the archives that pre date the datasets that you are working with that you might want to look for. One, in particular, is based on a state by state ranking based on sale of sinemet! But they didn't break down into counties even though they had the data! Amateurs! :-) One other that is back there somewhere is one where I tried to fit agricultural data as an overlay to PD. It is very primative but I did find one - alfalfa. <I am going to pass up the opportunity to make "Our Gang" jokes here> Alfalfa is an extremely dusty crop and god only knows what fungi inhabit it. Might be a lead for you there.

One problem, though, is that any single source hypothesis should produce more clusters among people in the same environment (i.e. everyone on a particular farm). The theory where one's immune system is first sensitized by a childhood infection which leads to a hypersensitivity to the bacterial toxin lipopolysaccharide (LPS) is a plausible one. It is especially so when one factors in the many things that trigger it. Even stress does it.

Finally, that reaction produces a dozen or so inflammatory chemicals in the brain, but the name that keeps popping up is, as you note, TNF-a.
-Rick

John,

This is just as viable as the research linking cyanobacteria "blooms" to ALS and most likely PD and AD. Further studies prove that people dying with PD or AD also had this bacteria present in the brain upon autopsy. Did you see the threads on it? Incidentally, the connection started with plugging in addresses of patients diagnosed with ALS into Google and finding that a statistically high number of them lived near a lake with this bacteria present. It is all quite interesting...I think you suggested we try to start our own similar data collection. Maybe in light of all this we should revisit the idea?

http://neurotalk.psychcentral.com/sh...=cyanobacteria

Laura

...amazing
 

you guys are amazing. i think you will fnd the information here

http://www.inchem.org/documents/kemi/kemi/ah2006_21.pdf

beneficial.

also, have you adjusted your maps to allow for the time that it takes for symptoms t occur after the insult has happened (perhaps 2 years)?

here is an excerpt from the above , very indepth document.

"

Fungal spore levels can be much higher at workplaces where the presence of
fungi is related to production and the contribution from natural outdoor levels is
usually negligible. Fungi are used in the food industry, e.g. for production of dairy
products, alcoholic beverages, bread, and soy sauce, in the biotechnological industry
for production of citric acid, antibiotics, and enzymes, and for composting
of plant debris and the organic fraction of domestic waste. Fungi can also be
produced as an end-product, e.g. baker’s yeast and mushrooms. Exposure levels
often exceed 10

Rick, thanks for pointing me at your data giving PD rates state by state.
http://neurotalk.psychcentral.com/thread149766.html
(Rick, have you got a reference for the data? I'd like to know the details.)

This allowed me to do some simple statistical analysis. The map by Baddley shows the incidence of histoplasmosis by shading each state in one of six bands. I did the stats in two ways:
- based on the number of the band, the correlation between histoplasmosis rates and PD rates is 0.36 (which implies that it accounts for 13% of the variance), significant, p<0.005;
- based on the value of the centre point of each band, the correlation is 0.31 (10% of the variance), significant, p<0.013.
This suggests to me that the connection between the two diseases is real, but not the whole story.

(By saying there is a connection, I am not implying causality.)

Laura, you're right we discussed running a survey of PwP to hold, amongst other things, geographical information. I still believe this would be very useful, but only if we got a substantial number of replies, at least 1000, say. But, given the experience of the Handedness Survey, which currently has had about 90 replies, I'm not optimistic.

Michael, I haven't adjusted for time: I don't have the data. But, still, it's a question worth asking. Your reference, mentions TNF-alpha in many places. Perhaps this suggests a solution to the problem I posed in my first post: how do we explain the fact that PD prevalence rates are similar in the UK, where histoplasmosis is rare? We have our own set of fungi. Perhaps TNF-alpha is the common denominator.

There are a few cases on the web of antifungals leading to a reduction of Parkinson's symptoms. See:
http://forum.parkinson.org/index.php...al-medication/
However, the connection may not be causal: sickness of any kind seems to make the symptoms of PD worse; so reducing the other sickness is likely to reduce the PD symptoms.

Wikipedia, http://en.wikipedia.org/wiki/Clioquinol
reports that clioquinol, an antifungal drug, has in animal studies reversed the progression of PD.

Has anyone on this forum had histoplasmosis?

Has anyone here used an antifungal? Did you notice any change in your PD symptoms?

John

data source
 

John-
I was working from a book by Dr. Lieberman titled "Shaking Up Parkinson's: Figfhting Like a Tiger, Thinking Like a Fox" page 125 has a bar graph showing each state's PD prevalence. It says that it was from data gathered by the National Parkinson's Foundation, seemingly from Big Pharma and showing Sinemet sales by individual stores. Some duckhead made the decision to combine that fine, detailed data into a statewide unit. However, the possibilities are great. If the orgs want to do something it seens as though this would be a good start.

This post adds indirect evidence that histoplasma capsulatum plays a role in the aetiology of PD. However, the case remains inconclusive.

Start with the maps by Willis et al. [1]

Parkinson's incidence: http://www.ncbi.nlm.nih.gov/pmc/arti...395/figure/F2/

Parkinson's prevalence: http://www.ncbi.nlm.nih.gov/pmc/arti...395/figure/F1/

Compare with the map by Rosahn showing the wintering areas of the European Starling [2]: http://icwdm.org/handbook/birds/EuropeanStarlings.asp

There appears to be a correlation between the maps.

Is there causality? Not directly, but possibly, as described before, via histoplasma capsulatum which grows in the birds' droppings [2], or by other pathogens in the faeces such as E. coli, salmonella, mycobacterium avium subsp paratuberculosis [3].

References

[1] "Geographic and Ethnic Variation in Parkinson Disease: A Population-Based Study of US Medicare Beneficiaries"
Allison Wright Willis, Bradley A. Evanoff, Min Lian, Susan R. Criswell, and Brad A. Racette
Neuroepidemiology. 2010 April; 34(3); 143-151.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2865395/

[2] http://icwdm.org/handbook/birds/EuropeanStarlings.asp

[3] "Escherichia coli, Salmonella, and Mycobacterium avium subsp. paratuberculosis in wild European starlings at a Kansas cattle feedlot."
Gaukler SM, Linz GM, Sherwood JS, Dyer NW, Bleier WJ, Wannemuehler YM, Nolan LK, Logue CM.
Avian Dis., 2009, Dec; 53(4);544-51
http://www.ncbi.nlm.nih.gov/pubmed/20095155

John

Hi John. The links on prevalence and incidence would not work for me.

I had pneumonia at 15 and tested positive for histoplasmosis at that time. My childhood home was central Illinois and I had worked as a camp lifeguard the summer before. I also drank well water on a farm as a child and had a head and neck injury in my 20s...

Canna,

I'm sorry the prevalence and incidence links don't work. I'll look into why they've stopped working, and repost. In the meantime you can get to the maps via the reference [1], scroll down and you'll find links to the maps.

Do you have any local knowledge of links between histoplasmosis and PD? For instance, what percentage of your PD support group have tested positive for histoplasmosis? Did you live near large flocks of starlings?

John

A few more details. Of special note is the possible danger of taking a TNF blocker.

more histoplasma => more TNF-alpha
"TNF-α is a key modulator of disease in both primary and secondary histoplasmosis" [1].

more TNF-alpha => more damage to the substantia niagra
"Chronic expression of low levels of tumor necrosis factor-alpha in the substantia nigra elicits progressive neurodegeneration" [2]

more damage to the substantia nigra => more progression of PD
"Parkinson's disease is a neurodegenerative disease characterized, in part, by the death of dopaminergic neurons in the pars compacta of the substantia nigra." [3]

more progression of PD => more TNF-alpha
"TNF and solTNFR1 levels are elevated in cerebrospinal fluid and tissues of PD patients as well as in postmortem PD brains with the highest TNF levels present in areas that have the greatest loss of dopaminergic neurons" [4]

more TNF-alpha => better defence to histoplasmosis
"FDA ALERT [9/4/2008]: FDA is notifying healthcare professionals that histoplasmosis and other invasive fungal infections are not consistently recognized in patients taking tumor necrosis factor-α blockers (TNF blockers), Cimzia (certolizumab pegol), Enbrel (etanercept), Humira (adalimumab), and Remicade (infliximab). This has resulted in delays in appropriate treatment, sometimes resulting in death." [5].

References:

[1] "Histoplasma Virulence and Host Responses"
Mircea Radu Mihu and Joshua Daniel Nosanchuk
International Journal of MicrobiologyVolume 2012 (2012), Article ID 268123, 5
pagesdoi:10.1155/2012/268123
http://www.hindawi.com/journals/ijmb/2012/268123/

[2] "Chronic expression of low levels of tumor necrosis factor-alpha in the substantia nigra elicits progressive neurodegeneration, delayed motor symptoms and microglia/macrophage activation."
De Lella Ezcurra AL, Chertoff M, Ferrari C, Graciarena M, Pitossi F.
www.ncbi.nlm.nih.gov/pubmed/19969084

[3] http://en.wikipedia.org/wiki/Substantia_nigra

[4] "TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease"
Melissa K McCoy and Malú G Tansey
Journal of Neuroinflammation 2008, 5:45
http://www.jneuroinflammation.com/content/5/1/45

[5]
http://www.fda.gov/drugs/drugsafety/.../ucm124185.htm

John

... and South America too.
 

There appears to be a connection between the distribution of histoplasma and the prevalence of PD in South America.

"Histoplasmosis is a cosmopolitan mycosis with areas of particularly high endemicity. In North America, the endemic regions are in the Midwestern and Southeastern of United States ... In Latin America, the most prevalent areas are in Venezuela, Ecuador, Brazil, Paraguay, Uruguay and Argentina ... (Fig. 2)." [1]

The figure shows endemic areas around the north and east coasts of South America and along the Amazon. All this detail would be very interesting if only we had detailed maps showing the distribution of PD within these countries. Unfortunately, we have, at best, national statistics. Most countries have zones within and without the endemic area. The exception is Uruguay which is entirely within the endemic area.

If histoplasma is a driver of PD, we would expect a higher prevalence of PD in those areas in which a higher proportion of the population are in the endemic area.

Parkinson's prevalence statistics are difficult to get, but many point to Uruguay as being a hot spot, e.g. a crude prevalence rate of 405 per 100,000 of population [2].

References

[1] "Diagnosis of histoplasmosis"
Allan Jefferson GuimarãesI,II; Joshua D. NosanchukII; Rosely Maria Zancopé-OliveiraI
Braz. J. Microbiol. vol.37 no.1 São Paulo Jan./Mar. 2006
http://www.scielo.br/scielo.php?pid=...pt=sci_arttext

[2] "The challenge of Parkinson's disease management in Africa"
Age and againg, vol 36.2, pp 122-127
C. L. Dotchin, O. Msuya and R. W. Walker
http://ageing.oxfordjournals.org/content/36/2/122.full

John

amazed at research from all of you
 

Thank you all for the research. I do not have PD but do have multipal auto immune problems. I always thought is was environmental. Mayo clinic suggested as much. I ate blueberrys off the bush in the 50's in Michigan. Fields were sprayed with DDT at the time and noone thought it could harm. Good book called "Silent Spring" I wish you all the best. ginnie:hug:

It's now three years after the previous post. There was bound to be a paper showing a possible link between histoplasma and PD, it's just one case and causality is unclear, but still interesting nevertheless.

Eid et al. report [1] a "case of Histoplasma capsulatum infection localized to the central nervous system (CNS). ... A 53-year-old woman ... presented with slowly progressive weakness in the lower extremities, new-onset numbness below the midthoracic area, urinary incontinence, and slurred speech. One year prior to presentation, she experienced left-sided transitory weakness involving the face and extremities. ... her brain imaging studies were unrevealing. She later developed tremor in the upper extremities and she was suspected to have central tremor or Parkinson’s disease."

They conclude:
"Histoplasmosis should be considered in the differential diagnosis of patients experiencing slowly progressive neurological deficit."

Reference:

[1] "Compartmentalized Histoplasma capsulatum Infection of the Central Nervous System"
Albert J. Eid, John D. Leever and Kathrin Husmann
Case Reports in Infectious Diseases Volume 2015 (2015), Article ID 581415
http://www.hindawi.com/journals/criid/2015/581415/

John

Two more years have passed.

The aetiology of Parkinson's is still unknown. In a number of posts that I've made in the past, in both this and other threads, I've used epidemiological data to suggest an association between fungal infection and PD.

In this paper [1] Berstad and Berstad present the hypothesis that "a causative agent in [PD] might be either a fungus or bacteria with fungus-like properties".

Reference:

[1] "Parkinson's disease; the hibernating spore hypothesis"
K. Berstad, J Berstad
Medical Hypotheses, July 2017
Parkinson’s disease; the hibernating spore hypothesis - ScienceDirect

John

Suddenly all my dots are connecting
 

I was just diagnosed with chronic histoplasmosis that has caused total blindness, ive apparently had it over ten years and never knew cause no doctor could care enough. Everything you said rang true. Chest pain, bowel and abdominal pain, joint pain, brain problems, all of it. It's crazy how when you finally get the diagnosis everything just starts making sense. Thank you for sharing, now i know im not alone in all this.