Different Brain Regions Are Infected with Fungi in Alzheimer’s Disease

http://www.nature.com/articles/srep15015

by wilder • 11 years ago

338 155 11 years ago

wilder• 11 years ago

"Different brain regions including external frontal cortex, cerebellar hemisphere, entorhinal cortex/hippocampus and choroid plexus contain fungal material, which is absent in brain tissue from control individuals. Analysis of brain sections from ten additional AD patients reveals that all are infected with fungi."

mschuster91• 11 years ago

Interesting. Does this mean that a treatment with fungicides may stop/prevent AD onset or progress?

msandford2• 11 years ago

Depends on which way the arrow of causality points. If AD makes the brain vulnerable to fungal infection, probably not. But if fungal infection causes AD, then it seems likely.

This might be a giant breakthrough, or it might be just a side effect. The uncertainty is not fun at all. But if the arrow points the right way, then yes it's possible that antifungals would be a big part of treatment.

x5n1• 11 years ago

In either case it makes a lot of sense to start dosing patients with anti-fungal medication and see if their symptoms improve. Usually you do not give fungicide to patients because it has a lot of side-effects but those drugs are readily available and easily prescribed.

sitkack2• 11 years ago

Given that there is a low incidence of AD in India, i'd suspect that fungal infection is partly a cause. It would be interesting to plot food spiceyness vs AD rates and spiceyness vs fungal infection rates in the world population.

moyix2• 11 years ago

The paper mentions in passing in the discussion section:

"Moreover, antifungal treatment in two patients diagnosed with AD reversed clinical symptoms [51,52]. The interpretation of these results was that perhaps these patients were misdiagnosed."

[51] Ala, T. A., Doss, R. C. & Sullivan, C. J. Reversible dementia: a case of cryptococcal meningitis masquerading as Alzheimer’s disease. J Alzheimers Dis 6, 503–508 (2004).

[52] Hoffmann, M., Muniz, J., Carroll, E. & De Villasante, J. Cryptococcal meningitis misdiagnosed as Alzheimer’s disease: complete neurological and cognitive recovery with treatment. J Alzheimers Dis 16, 517–520 (2009).

calinet63• 11 years ago

Wow. So there's a possibility that they were, in fact, diagnosed properly with Alzheimer's, and accidentally treated properly. Amazing.

smithkl42• 11 years ago

I know that toenail and fingernail fungus infections are very common (see, e.g., tons of late-night TV ads). Any chance that those kinds of infection could make their way into the brain?

xenadu02• 11 years ago

The article mentions infection of blood vessels so it seems likely that the fungi make their way into the brain from other sites.

Perhaps the fungi avoid the immune system by being very slow and relatively non-disruptive, and the reduced effectiveness of the immune system in old age allows it to take hold and spread.

chetanahuja3• 11 years ago

I wrote a comment in another subthread but basically that's not likely to happen anytime soon due to two factors. 1) currently available antifungals (for internal fungal infections) are not nearly as powerful and quick as we think of "regular" antibiotics to be even in the organs that get plenty of medicated-blood supply and 2) Blood-brain barrier means that it's hard to deliver any medications to the brain tissue (https://en.wikipedia.org/wiki/Blood%E2%80%93brain_barrier#Fu...)

rajacombinator2• 11 years ago

Wow sounds like a major breakthrough. How did they not notice this before?

stupidcar• 11 years ago

It took thirty years for the medical establishment to accept the hypothesis that the bacteria H. pylori was the cause of peptic ulcer disease, rather than excess stomach acid.

low_battery2• 11 years ago

Yeah, but that was in 1982.

CamperBob2• 11 years ago

They still haven't decided for sure if dietary cholesterol is bad for you, or salt for that matter.

The best minds of our generation are too busy selling ads to be bothered with trivial stuff like this.

rajacombinator2• 11 years ago

As someone busy working on selling ads, I can't tell whether I should appreciate or resent this comment...

msabalau• 11 years ago

Thanks for telling us how you think other people should be spending their lives. That's super valuable!

(For the record, work in healthcare, but no doubt am wasting my time saving the wrong lives.)

n0us2• 11 years ago

I wonder how many mental illnesses are the result of imbalances in foreign organic matter/microbes/fungi/dietary issues and not issues fundamental to the brain itself?

kawera2• 11 years ago

An old but interesting article and discussion related to your question:

http://www.theatlantic.com/magazine/print/1969/12/how-your-c...

https://news.ycombinator.com/item?id=3573694

Articles somehow related to the subject:

http://www.nature.com/news/the-tantalizing-links-between-gut...

http://universityofcalifornia.edu/news/do-gut-bacteria-rule-...

http://www.scientificamerican.com/article/gut-second-brain/

http://www.theverge.com/2013/8/21/4595712/gut-feelings-the-f...

http://newsroom.ucla.edu/portal/ucla/changing-gut-bacteria-t...

n0us2• 11 years ago

Thanks for all of the sources. I remember listening to a talk on NPR about the same subject a while back in my car but I couldn't find a link to it.

sitkack2• 11 years ago

Exactly, we have lots of instances of other parts of the body becoming infected but brain sicknesses I think go untreated probably because they are hard to detect and the brain is so resilient.

philipov2• 11 years ago

I think it's a combination of it being difficult/expensive to get inside the brain, limiting such exploration to only the most severe cases, and also a latent bias in western culture to buy into Mind-Body Duality. The idea that the Mind is separate from the Body is still prevalent, and has an insidious effect on many people's judgement: even people who are trained otherwise.

tim3337• 11 years ago

Schizophrenia is an interesting one showing a very high correlation with antibodies for a retrovirus called HERV-W which became part of the DNA of our pre-human ancestors about 60 million years ago and which has been passed down ever since.

http://discovermagazine.com/2010/jun/03-the-insanity-virus

zmmmmm3• 11 years ago

This seems like potentially an incredibly important breakthrough with a perplexingly weird title. Different brain regions? Different to what? From reading the study, the novelty is not about the "difference" of the brain regions, but the fact that fungal infection is found in AD patients at all. The controls had no infection, not different infections in their brains.

I'm curious if the title makes sense to people in the field or is this weird to them too?

soneca• 11 years ago

As a layman, i understood the title correctly I guess. That there were fungi not just on one spot, but different (ie several) regions.

zmmmmm3• 11 years ago

So, interpreting "different" as "multiple"? Seems unnecessary to use an ambiguous word. And then an ambiguous word that is not actually the main point of the study.

Myrmornis• 11 years ago

But that would be bad English. I wouldn't expect the Nature editors to let such bad English slip through in an important title, but I admit it is frustratingly common to see people not caring too much about that sort of thing.

I had the same concern as GP. I don't understand the title; the controls seem not to have fungi in their brain, which had always been my assumption about, for example, my brain.

dacompton• 11 years ago

There was recent speculation that alzheimer's was transmissible (prion thing). The transmissibility would make sense if it were actually the fungi causing the build up of the proteins and other damage.

rmtew• 11 years ago

From what I recall, the results in a study showed that the primary care giver of an alzheimer's patient was more likely to get alzheimer's themselves. The argument against transmissibility was that primary care givers tend to be related to the patient.. therefore the more likely reason for caregiver alzheimer's is genetics.

thawkins• 11 years ago

Or as primary care giver they are exposed to the same environmental factors the sufferer is exposed to, but are generaly younger so more resistant until later life.

niels_olson• 11 years ago

Hi, I do research using the same methods: immunohistochemistry. This was done with rabbit polyclonal antibodies. The key being polyclonal. We don't know what those antibodies are really staining. The difference, however, is intriguing.

moyix2• 11 years ago

Could you elaborate on what polyclonal means here? Does it mean that they might not have detected fungus after all, but some other thing that would activate the same antibodies?

dnautics• 11 years ago

Yeah, but that's true for monoclonals too, just a matter of degree.

A polyclonal antibody is an extraction of (usually rabbit) blood from an animal that has been insulted with the agent you'd like to detect. The extraction is enriched for antibodies. They are less reliable, because there could also be other antibodies in there. Even the antibodies that recognize what you're looking for could be a population of antibodies, each recognizing a different part (think the blind men and the elephant parable). Presumably, you have tested that a positive control of what you're trying to look for works.

A monoclonal is different. You insult a mouse with a sample of what you'd like to detect, and then resect the spleen, which contains b-cells, cells that produce the antibody. You then fuse the b-cells with a special strain of cancer cell that will immortalize the b-cell (these are called 'hybridomas'). After sorting one cell to a well, you then test to see if the cells in the well have produced an antibody that detects what you're looking for. Therefore, you can be confident that a monoclonal antibody contains only one antibody, that recognizes only one antigen.

You don't necessarily know what the antigen is that is recognized (that's called the epitope). The epitope could be, say, a piece of protein on the outside of the fungus or a different piece of protein on the outside of the fungus. It's even conceivable that even for a monoclonal there are side-reactions against things that are naturally in the sample.

And: Epitope retrieval techniques are really complicated. So figuring out exactly what epitope is recognized is not trivial.

modeless• 11 years ago

All of the Alzheimer's patients were 79 or older, while all of the control patients were younger than 79 except for one. More than half of the control patients were under 60. That doesn't seem like a very good control to me.

3327• 11 years ago

Perhaps but the discovery is still significant. Until now there was no such correlation with Alzeimher's and Fungi.

This has significant implications in terms of direction of future research.

dragonwriter• 11 years ago

Until now there was no such correlation with Alzeimher's and Fungi.

The point of the criticism seems to be that with an improper control group, there still isn't such a correlation, just a suggestion of a possibility of a correlation. But it might be a correlation between, e.g., age and fungal infection.

That's why, but for the variables under study, you want your control group to look as much like your experimental group as possible.

zeckalpha• 11 years ago

The improper control means that there is a just as strong of a correlation between age and fungi.

Uptrenda• 11 years ago

It's hard not to exaggerate the implications of this study if fungal infection does turn out to be the cause of AD given how huge this would be for humanity. Just off the top of my head I can say this disease has effected my family (1 set of grandparents effected by this disease so far) so I'd like for the conclusion to be correct.

I guess the next step would be testing the hypothesis with more people with AD to see if it holds up and then somehow getting approval to do drug trials (and I'm sure there will be no shortage of volunteers.) I can almost see a clamouring of families trying to get their hands on anti-fungal drugs in the future in the hope that it helps their loved ones but we simply won't know if this will help until there's more data.

Hoping for a break through. It's certainly not without precedent that we find something extremely simple / obvious that turns out to be the key. On a side note: it's interesting to think that the crack pots you see writing about candidas infections being the cause of numerous hard-to-treat illnesses -might- actually be right (in a sense.)

chetanahuja3• 11 years ago

The discovery, if corroborated by others, could indeed be huge but I'm afraid it wouldn't open up new treatment options anytime soon. Fungal infections inside the body are really really hard to treat in the first place. Add to that the blood-brain barrier which makes it very hard to treat any type of infection in the brain. https://en.wikipedia.org/wiki/Blood%E2%80%93brain_barrier#Fu...

Combination of these two factors sadly means that short of major breakthroughs in fungal antibiotic research or in drug delivery to the brain, Alzheimer is not likely to suddenly become more treatable even if the fungal infection theory proves to be true.

shostack• 11 years ago

Would the recent discovery of lymphatic tubes going into our brains[1] be a potential area of focus for potential treatment?

[1]https://news.ycombinator.com/item?id=9647253

kevinalexbrown2• 11 years ago

First, there are antifungal drugs that pass the BBB, with varying efficacy:

https://www.medicine.wisc.edu/sites/default/files/domfiles/i...

Second, antifungals have positively affected AD-like symptoms, though possibly through misdiagnosis.

melling• 11 years ago

Could you be more specific about the timeline? I remember when people said there was nothing that could ever be done for people with HIV. My guess is that if you know a precise cause, you'll have some basic treatments within a decade and an effective "cure" within two decades.

Retra• 11 years ago

According to your link, there is a possibility that some cases of Alzheimers are caused by a degraded blood-brain barrier, which might also allow for fungal infections to take hold more readily.

Nano2rad• 11 years ago

There is no need for drugs to cross blood-brain barrier. If antifungal treatment is effective, drugs can be delivered directly to brain although that may need new series of research.

andrewtian• 11 years ago

Coconut oil seems to have benefits in Alzheimer's patients [1]. It also has anti-fungal properties. Worth a look.

[1] http://www.alz.org/alzheimers_disease_alternative_treatments...

tim3337• 11 years ago

clamouring of families trying to get their hands on anti-fungal drugs in the future in the hope that it helps their loved ones but we simply won't know if this will help until there's more data.

It may not be so hard to get data - try anti-fungals and see if the patients get better. There are plenty of patients and the drugs could be tried in countries other than the US. It could be possible to get data in a few weeks rather than years of trials.

There seem to be about a dozen anti-fungals at the moment which could be tried. Presumably the best choice would depend on which fungi was involved. http://www.ncbi.nlm.nih.gov/pubmed/17381184

fernly• 11 years ago

try anti-fungals and see if the patients get better

I got the impression that the disease symptoms result not from the mere presence of the fungus, but from progressive damage over a long time. So, if you don't start to treat until there are symptoms, you could kill the fungus and at best, the person would not get worse. Which is not to be dismissed, but...

CCs• 11 years ago

If it turns out to be the cause too (maybe similar to cervical cancer), it's a huge discovery.

Asimov's book on science history is an interesting read, full with similar discoveries that were ignored for many years.

http://www.amazon.com/Far-Human-Eye-Could-See/dp/155817107X

bitL• 11 years ago

Is there any relation to the study that suggested AD is diabetes type 3? Insulin resistance + fungi?

carey• 11 years ago

Candida is a common opportunistic infection in diabetes type 2, so there's a few ways in which correlations could be observed. The fungal infection could be a symptom of the underlying "type 3" diabetetes; or the CNS fungal infections could be more common in diabetic or pre-diabetic people, leading to AD.

derefr• 11 years ago

Another recent discovery, that of the existence of a meningeal lymphatic system, makes this finding all the more interesting. As far as I know, fungus is in the set of foreign bodies that the adaptive immune system does the least about. Instead, the body mostly removes fungus by mechanical lymphatic clearance.

tim3337• 11 years ago

Therefore, 100% of the AD patients analysed thus far by our laboratory present fungal cells and fungal material in brain sections.
No fungal material was observed in brain tissue from ten control individuals, whereas fungal infection was clearly present in brains from ten additional AD patients.

So 100% correlation so far - pretty impressive results.

I wonder about my dad who has an unexplained Parkinson's like nervous deterioration.

nonbel7• 11 years ago

I bet if they double stain with anti-amyloid-Beta they will see the staining overlap. They just say they used "antibody raised against proteins obtained from C. glabrata, C. famata, C. albicans, P. betae and S. racemosum", so they don't even know (or want to say) what these antibodies react with...

Amyloids have generic secondary structure (can be created from any amino acid sequence under the right conditions) and yeast produce amyloids. They quite possibly raised antibodies towards yeast amyloids and then stained human amyloids. It is strange they do not report staining these brains for amyloid-Beta, it is an obvious thing to do.

jschwartzi• 11 years ago

Do the amyloid proteins you'd expect concentrate in similarly-shaped groupings? One claim is that the shape of the stains has fungal morphology. If Amyloid-beta concentrations can have fungal morphology then I would think that might strengthen your claim and weaken the paper's. I'm only an engineer though, so feel free to dismiss me as ignorant of your field. Either way I can see how these findings are not terribly interesting.

nonbel7• 11 years ago

"One claim is that the shape of the stains has fungal morphology. If Amyloid-beta concentrations can have fungal morphology then I would think that might strengthen your claim and weaken the paper's."

The evidence in the paper consists of a few representative pictures. I have never seen human brain stained for amyloid-beta, but if it stained at all I would bet lots of money that I could find at least one clump with "fungal morphology".

Also, ruling out the other explanations (such as they stained for amyloid) is not the audience's job, it is their job. They are the ones with access to the most detailed information, putting them in the best position to think about various explanations for what could be going on.

narrator• 11 years ago

Methylene Blue has shown promise as an alzheimer's treatment. It's a potent antifungal. It easily diffuses through the blood brain barrier. It also happens to be cheap and unpatentable.

dluan• 11 years ago

So, turns out there's many types of fungus that affect behavior, and there are even a few that create entirely new behaviors. One such example is ants, when infected by a type of fungus, will climb high and latch onto a branch by biting hard into it. This is so that the ant will get eaten by birds, which then complete the life cycle of that fungus.

There's not many well understood systems (the other well-studied one is toxoplasmosis and cats), but one researcher on Experiment, Charissa de Bekker, just released a new paper with findings from her project.

The results gave a first clue about the many genes that are involved in this manipulated biting behavior. For instance, that the fungus is likely producing LSD-like compounds and is secreting proteins that could affect serotonin and dopamine levels in the brain, as well as the ant’s ability to communicate through chemosignals with their nest mates. As well, in the paper, they release the entire transcriptome taken from the brains of these ants, giving other scientists a chance to use this as a model system and to begin to target which genes go on to influence behavior.

I was just talking to her about it this week, and so this news is very timely and a bit eerie. But very cool.

http://www.biomedcentral.com/content/pdf/s12864-015-1812-x.p...

thanatosmin3• 11 years ago

As a biomedical researcher, I'm confident in calling this sloppy science. There is no quantitation of staining differences across multiple fields (to demonstrate that the images aren't hand picked), no controls with the PCR study (or even showing the results besides one in the supplement), and no demonstration that the antibodies don't bind to amyloid. Extraordinary claims require extraordinary evidence, and this wouldn't even motivate me to perform a follow up study.

pcwalton• 11 years ago

I'm curious: how does something this obviously flawed get through peer review for Nature?

(I believe you that this is bad science.)

Edit: I answered my own question here: https://en.m.wikipedia.org/wiki/Scientific_Reports (Summary: It's not Nature; it's a "megajournal" affiliated with it with apparently much lower editorial standards.)

thanatosmin3• 11 years ago

It's hard to say--peer review isn't anything magical. Three experts read a paper and provide a recommendation to the journal editor. Ultimately, it's only the journal editor who decides whether to publish something. Unfortunately, the whole process is confidential, so in most of these cases it's not possible for most people to know what happened.

nextos• 11 years ago

Exactly. Scientific Reports (and Nature Communications) is sometimes used for papers that don't get into Nature or any of its siblings (Genetics, Methods, Protocols, Biotechnology).

dynomight3• 11 years ago

This may be sloppy science, but sometimes discoveries happen in very sloppy and unpredictable ways.

dynomight3• 11 years ago

Excuse me. Science only happens in precise and predictable ways.

thanatosmin3• 11 years ago

Definitely lots of exciting discoveries happen by accident--possibly most. But understanding what those discoveries actually are requires carefully designed experiments. In the absence of careful controls Occam's razor has to apply.

epalmer• 11 years ago

I'm not a scientist and defer to your judgement as to the quality of the research method. But if there is even a remote possibility of AD being caused by or someway associated with Fungus infections than I would hope someone does follow up research that is rock solid and not sloppy.

nonbel7• 11 years ago

Nature is not a good scientific journal. The good info will be found in highly specialized journals. The amount of BS in scientific journals is related to prestige like this:

x=seq(0,1,by=.01);

plot(x,dbeta(x,.5,.5), xlab="Prestige", ylab="BS")

TeMPOraL3• 11 years ago

For those without a R interpreter handy, Emacs to the rescue:

       ^
       |  |                                                                           |  
       |  |                                                                           |  
       |  |                                                                           |  
       |  |                                                                           |  
       |  \                                                                           /  
       |   |                                                                         |   
       |   \                                                                         /   
       |    |                                                                       |    
       |    \                                                                       /    
       |     \                                                                     /     
       |      \                                                                   /      
    B  |       \                                                                 /       
    S  |        \                                                               /        
       |         -\                                                           /-         
       |           \                                                         /           
       |            -\                                                     /-            
       |              -\                                                 /-              
       |                --\                                           /--                
       |                   --\                                     /--                   
       |                      ---\                             /---                      
       |                          -----\                 /-----                          
       |                                -----------------                                
       |                                                                                 
       +--------------------------------------------------------------------------------->
                                            Prestige

(Also an on-line R interpreter: http://www.r-fiddle.org/.)

sooheon2• 11 years ago

What package(s) did you use to create this?

dang2• 11 years ago

We detached this subthread from https://news.ycombinator.com/item?id=10403159 and marked it off-topic.

pmoriarty• 11 years ago

Are these fungi from Yuggoth?

captainill• 11 years ago

If you've ever taken antibiotics for an extended period and ended up with a fungal infection due to the loss commensal bacteria this is pretty intriguing. There is a lot of new literature proposing links between gut disruption and neurodegenerative disease.

mirimir• 11 years ago

Maybe antibiotics cause Alzheimer's.

ommunist• 11 years ago

This is extraordinary. It means antifungal drugs like Fluconazole can possibly prevent AD.

seesomesense3• 11 years ago

No, it means that a researcher doing fourth rate science has successfully trolled HN.

dang2• 11 years ago

Please stop posting unsubstantive comments to Hacker News.

seesomesense3• 11 years ago

Sounds like Bozo the Clown is now publishing articles in Nature.

One problem with biomedical research is the crackpots.

rwmj• 11 years ago

Are there other internal diseases caused by fungus? Obviously there are fungal skin infections, but it sounds strange that a fungus would be able to live inside the body.

carbocation2• 11 years ago

If Alzheimer's Disease (AD) is caused by fungal infection, why have antifungals (often given for people with invasive fungal disease) never cured an AD patient? AD is common enough that many of these people will have received antifungals for e.g. esophageal thrush or even fungemia.

Regarding the research, the data presented here are not convincing without larger scale replication with better controls and more standardized assays.

pohl• 11 years ago

Good question. Are anti fungal molecules small enough to cross the blood brain barrier easily?

tptacek• 11 years ago

Yes, a bunch of them, including fluconazole, which is a first-line treatment for common fungal infections.

tankenmate• 11 years ago

One possible reason I can think of is that the immune system in the brain is somewhat different from the rest of the body; not quite on par with say the mammary glands, testes, or eyes. Obviously I am not a doctor etc, anti biotics etc can have reduced effect in body parts that have reduced or modified immune responses; maybe anti fungals are similar?

carbocation2• 11 years ago

It is true that medication penetration of the blood-brain barrier and delivery to the brain is different from other organs (each organ has unique characteristics in this regard).

But we do treat people with CNS infections routinely, including CNS fungal infections.

tim3337• 11 years ago

I was thinking if this is real then there must have been past cases of people with Alzheimer’s having been given antifungals for other reasons and having gotten better. Googling randomly I came across one, sadly paywalled but from the abstract the guy had been diagnosed with Alzheimer's for three years, then they figured it was cryptococcal meningitis and gave antifungals and four months later he was normal.

The interpretation in the paper was it was a misdiagnosis rather than an Alzheimer's cure but you never know.

http://content.iospress.com/articles/journal-of-alzheimers-d...

Geeek• 11 years ago

Here you go http://www.docdroid.net/PBdotNO/contentserver.pdf.html

tim3337• 11 years ago

Thanks

erikreinertsen• 11 years ago

This article does NOT provide compelling evidence that fungi are the causative agent for AD. It merely reports correlative observations.

You may conclude that antifungal drugs could help patients with AD. You may also think that vaccination or some other mechanism of prevention could reduce the prevalence of AD. These conclusions are simply not supported by the data.

I am a biomedical data scientist, not a neuroimmunologist, so I asked a colleague in my MD/PhD program who has experience in the latter field. His thoughts:

"There are a number of concerning issues here:

1) They are using polyclonal antibodies. I don't think they addressed possibility of cross-reactivity. Comparing Alzheimer's disease vs control brain is like comparing apples and oranges. There can be very different inflammatory states between the two and yield different antigenic environments.

2) The possibility that neurofibrillary tangles or amyloid plaques are sticky and can non-specifically bind antibodies remains a possibility.

3) Only immunohistochemistry? Could have at least done some qPCR especially since they can grow these fungi for quantiation. The only other paper that observed fungus in CNS of AD patients is by the same group. The high possibility of artifact is has not been ruled out."

*edited grammatical typo

fasteo• 11 years ago

For what it's worth, the institution [1] behind this study is one of the most prestigious scientific institutions here in Spain.

[1] http://www.cbm.uam.es/

sea2summit• 11 years ago

I just moved out of a place I'd lived for 5 years that turned out to have black mold. I've had weird digestive issues and my immune system has gone to shit since living there but I wasn't aware of the mold problem and didn't know of the health problems it could cause. So this study is pretty terrifying; I should probably get tested.

Different Brain Regions Are Infected with Fungi in Alzheimer’s Disease

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