Histoplasma capsulatum Posted NeuroTalk, 23rd May, 2012, http://neurotalk.psychcentral.com/thread170268.html -------------------------------------------------------------------------------- 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 ================================================================================================= Posted 26th May 2012 ------------------------------------------------------------------------------------------------- X, thanks for pointing me at data giving PD rates state by state. 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.) Y, 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 ================================================================================================ Posted 3rd August 2012 ------------------------------------------------------------------------------------------------ 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 =============================================================================================== Posted 15th August 2012 ------------------------------------------------------------------------------------------------ A few more details. Of special note is the possible danger of taking a TNF blocker. more histoplasma => more TNF-alpha "TNF-a 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-a 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 ============================================================================================== Posted 17th August 2012 ... 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