43 ms·

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

338 points by wilder 11y ago

wilder 11y 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."
niels_olson 11y 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.
- moyix 11y 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 11y 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.
    - nonbel 11y ago
      >"you can be confident that a monoclonal antibody contains only one antibody, that recognizes only one antigen" Not sure if you really meant that since it is kind of contradicted by some later statements, but all antibodies are promiscuous. Thinking you can map one antibody to one epitope is extremely dangerous. It is a matter of quantity (affinity/avidity), not quality.
      - twic 11y ago
        Exactly. When i did immunocytochemistry, i had more confidence in polyclonals than monoclonals. If you get a strong signal with a polyclonal, then you know that many different antibodies are all binding the same thing, so it's very likely it's your protein. If you get a strong signal with a monoclonal, that's just one antibody - so it might be your protein, or it might be some other protein that, by chance, your antibody happens to bind tightly.
    - twic 11y ago
      It might be worth explaining a bit more about how antibodies are made. There are these cells called B lymphocytes, whose job is to produce antibodies. When they form, they randomise parts of the antibody genes: https://en.wikipedia.org/wiki/V%28D%29J_recombination https://en.wikipedia.org/wiki/V%28D%29J_recombination As a result, every B lymphocyte makes one particular antibody that is different to every other B lymphocyte, and which recognises a different molecular pattern to every other B lymphocyte. There's a process in their development which weeds out cells which recognises patterns in your own body, leaving a population of cells which (hopefully) recognise every possible pattern which is not part of your own body. B lymphocytes then wander round the body, looking for stuff which binds to their antibody; if they find it, they know it must be an invader, and they raise the alarm, triggering an immune response (subject to checks and balances from other parts of the immune system). As part of that, the cell which raised the alarm will proliferate, making millions of cells producing identical antibodies, which bind to the invader and mark it for destruction by other cells of the immune system. If an invader has more than one molecular pattern (which it will - every patch on the surface of a protein is a pattern, and a bacterium will have all sorts of proteins and other things on its surface), then a corresponding number of B lymphocytes should recognise it, and proliferate in response. So, if you insult a rabbit with your protein, you will activate all the B lymphocytes which recognise patterns on it. If you purify antibodies from its bloodstream, you will get antibodies recognising all those patterns - and any other antibodies which happen to be in the bloodstream at the time. If you isolate a single B lymphocyte its bloodstream, make it immortal, culture it, and purify the antibodies from that, you will get a single kind of antibody, recognising a single molecular pattern. In software terms, a monoclonal is a bit like detecting spam by grepping for a single spam-specific word, and a polyclonal is a bit like doing an n-gram comparison with a corpus of known spam.
  - deleted 11y ago
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mschuster91 11y ago
Interesting. Does this mean that a treatment with fungicides may stop/prevent AD onset or progress?
- msandford 11y 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 11y 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.
    - msandford 11y ago
      It's worth a try, especially if they're pretty far advanced. Doctors have the whole "first do no harm" thing that makes prescribing stuff randomly on hope not really an option. Now if patients start clamoring for it that's another story. But until it's shown that antifungal medicine does more good than harm (who knows, maybe killing all the fungus somehow leaves a void that bacteria could come fill) it's probably best not to do so widely.
    - pygy_ 11y ago
      Not sure why you got downvoted. It would have to be done in double blind trials vs placebo, but it would be a great way to test the causal link between fungi and symptoms. You'd have to make sure the fungicides cross the blood brain barrier in patients.
      - 11y ago
rajacombinator 11y ago
Wow sounds like a major breakthrough. How did they not notice this before?
- stupidcar 11y 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_battery 11y ago
    Yeah, but that was in 1982.
    - deleted 11y ago
      [deleted]
    - nickff 11y ago
      Are you implying that doctors have become more accepting of theories which challenge the status quo? Do you have any reason to believe things have gotten better? Doctors still seem to prescribe blood pressure medication and low-salt diets to people with hypertension, depite the overwhelming number of studies which show that neither prescription has any impact on mortality rates. It doesn't look like they are particularly evidence-driven or self-aware as a profession.
      - falsedan 11y ago
        Doctors are selected and trained to memorize insane amounts of facts, and how to match symptoms to facts. Updating those facts is hard since they're stored when the brain is young and still great at learning (there are refresher courses doctors are required to attend to keep their accreditation, but they lean heavily towards learning new facts, not changing existing ones).
        nickff 11y ago
n0us 11y 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?
- kawera 11y ago
  An old but interesting article and discussion related to your question: http://www.theatlantic.com/magazine/print/1969/12/how-your-cat-is-making-you-crazy/8873/ http://www.theatlantic.com/magazine/print/1969/12/how-your-c... https://news.ycombinator.com/item?id=3573694 https://news.ycombinator.com/item?id=3573694 Articles somehow related to the subject: http://www.nature.com/news/the-tantalizing-links-between-gut-microbes-and-the-brain-1.18557 http://www.nature.com/news/the-tantalizing-links-between-gut... http://universityofcalifornia.edu/news/do-gut-bacteria-rule-our-minds http://universityofcalifornia.edu/news/do-gut-bacteria-rule-... http://www.scientificamerican.com/article/gut-second-brain/ http://www.scientificamerican.com/article/gut-second-brain/ http://www.theverge.com/2013/8/21/4595712/gut-feelings-the-future-of-psychiatry-may-be-inside-your-stomach http://www.theverge.com/2013/8/21/4595712/gut-feelings-the-f... http://newsroom.ucla.edu/portal/ucla/changing-gut-bacteria-through-245617.aspx http://newsroom.ucla.edu/portal/ucla/changing-gut-bacteria-t...
  - n0us 11y 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.
    - kawera 11y ago
      Maybe this: http://www.npr.org/sections/health-shots/2012/07/02/156142214/a-parasite-carried-by-cats-could-hurt-humans-sanity http://www.npr.org/sections/health-shots/2012/07/02/15614221...
- sitkack 11y 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.
zmmmmm 11y 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 11y 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.
  - zmmmmm 11y 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.
    - nonbel 11y ago
      They meant multiple, the authors are from Spain. I'm not sure why an editor wouldn't try to alter the title though, perhaps they are also not native english speakers.
  - Myrmornis 11y 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.
    - zmmmmm 11y ago
      After reflecting I am wondering if this is a result of the natural tendency of scientists to avoid any hint of overstating their work. Were the fungal infections all in the same region or by the same fungus it'd be absolutely shocking. It'd be a "cold fusion" level revolution for the field - and a "cold fusion" level embarrassment for them if they are wrong. So they are extremely keen to put up front that the picture is not nearly so clear as that. There is also a tendency when scientists are extremely confident they have found something incredibly important to understate it. I always think of the Watson and Crick "It has not escaped our notice ..." statement in this context. This is all based on guesswork though, so that's why I'm curious about what people in the field think.
dacompton 11y 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 11y 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 11y 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.
modeless 11y 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 11y 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 11y 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.
    - philipov 11y ago
      A general correlation between age and fungal infection might be even more significant, since that suggests a path to reduce the effects of aging in general. Either way, a follow-up study to remove those control flaws and hone in on the cause would be necessary.
    - nickff 11y ago
      Even with an improper control group, the fungi-Alzheimer's correlation still exists. There may be another factor which is causing the correlation (a so-called 'dreaded third thing'), and the correlation may not indicate causation, but the correlation still exists.
    - deleted 11y ago
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    - 11y ago
Uptrenda 11y 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.)
- chetanahuja 11y 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#Function 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 11y 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 https://news.ycombinator.com/item?id=9647253
    - gus_massa 11y ago
CCs 11y 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 http://www.amazon.com/Far-Human-Eye-Could-See/dp/155817107X
bitL 11y ago
Is there any relation to the study that suggested AD is diabetes type 3? Insulin resistance + fungi?
- carey 11y 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 11y 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.
tim333 11y 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.
nonbel 11y 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 11y 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.
  - nonbel 11y 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.
deleted 11y ago
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narrator 11y 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 11y 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.pdf http://www.biomedcentral.com/content/pdf/s12864-015-1812-x.p...
thanatosmin 11y 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 11y 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 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.)
  - thanatosmin 11y 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 11y 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).
    - adrianN 11y ago
      Can confirm. Had a paper rejected by Nature with the suggestion to send it to Scientific Reports instead. Scientific Reports accepted it.
- dynomight 11y ago
nonbel 11y 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")
- TeMPOraL 11y 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/. http://www.r-fiddle.org/.)
pmoriarty 11y ago
Are these fungi from Yuggoth?
captainill 11y 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 11y ago
  Maybe antibiotics cause Alzheimer's.
ommunist 11y ago
This is extraordinary. It means antifungal drugs like Fluconazole can possibly prevent AD.
- seesomesense 11y ago
  No, it means that a researcher doing fourth rate science has successfully trolled HN.
  - dang 11y ago
    Please stop posting unsubstantive comments to Hacker News.
deleted 11y ago
[deleted]
seesomesense 11y ago
Sounds like Bozo the Clown is now publishing articles in Nature. One problem with biomedical research is the crackpots.
rwmj 11y 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.
carbocation 11y 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 11y ago
  Good question. Are anti fungal molecules small enough to cross the blood brain barrier easily?
  - tptacek 11y ago
    Yes, a bunch of them, including fluconazole, which is a first-line treatment for common fungal infections.
- tankenmate 11y 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?
  - carbocation 11y 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.
tim333 11y 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-disease/jad00985 http://content.iospress.com/articles/journal-of-alzheimers-d...
- Geeek 11y ago
  Here you go http://www.docdroid.net/PBdotNO/contentserver.pdf.html http://www.docdroid.net/PBdotNO/contentserver.pdf.html
  - tim333 11y ago
    Thanks
erikreinertsen 11y 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 11y 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/ http://www.cbm.uam.es/
sea2summit 11y 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.

338 points by wilder 11y 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."

niels_olson 11y 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.

moyix 11y 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 11y 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.
  - nonbel 11y ago
    >"you can be confident that a monoclonal antibody contains only one antibody, that recognizes only one antigen" Not sure if you really meant that since it is kind of contradicted by some later statements, but all antibodies are promiscuous. Thinking you can map one antibody to one epitope is extremely dangerous. It is a matter of quantity (affinity/avidity), not quality.
    - twic 11y ago
      Exactly. When i did immunocytochemistry, i had more confidence in polyclonals than monoclonals. If you get a strong signal with a polyclonal, then you know that many different antibodies are all binding the same thing, so it's very likely it's your protein. If you get a strong signal with a monoclonal, that's just one antibody - so it might be your protein, or it might be some other protein that, by chance, your antibody happens to bind tightly.
  - twic 11y ago
    It might be worth explaining a bit more about how antibodies are made. There are these cells called B lymphocytes, whose job is to produce antibodies. When they form, they randomise parts of the antibody genes: https://en.wikipedia.org/wiki/V%28D%29J_recombination https://en.wikipedia.org/wiki/V%28D%29J_recombination As a result, every B lymphocyte makes one particular antibody that is different to every other B lymphocyte, and which recognises a different molecular pattern to every other B lymphocyte. There's a process in their development which weeds out cells which recognises patterns in your own body, leaving a population of cells which (hopefully) recognise every possible pattern which is not part of your own body. B lymphocytes then wander round the body, looking for stuff which binds to their antibody; if they find it, they know it must be an invader, and they raise the alarm, triggering an immune response (subject to checks and balances from other parts of the immune system). As part of that, the cell which raised the alarm will proliferate, making millions of cells producing identical antibodies, which bind to the invader and mark it for destruction by other cells of the immune system. If an invader has more than one molecular pattern (which it will - every patch on the surface of a protein is a pattern, and a bacterium will have all sorts of proteins and other things on its surface), then a corresponding number of B lymphocytes should recognise it, and proliferate in response. So, if you insult a rabbit with your protein, you will activate all the B lymphocytes which recognise patterns on it. If you purify antibodies from its bloodstream, you will get antibodies recognising all those patterns - and any other antibodies which happen to be in the bloodstream at the time. If you isolate a single B lymphocyte its bloodstream, make it immortal, culture it, and purify the antibodies from that, you will get a single kind of antibody, recognising a single molecular pattern. In software terms, a monoclonal is a bit like detecting spam by grepping for a single spam-specific word, and a polyclonal is a bit like doing an n-gram comparison with a corpus of known spam.
- deleted 11y ago
  [deleted]

mschuster91 11y ago

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

msandford 11y 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 11y 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.
  - msandford 11y ago
    It's worth a try, especially if they're pretty far advanced. Doctors have the whole "first do no harm" thing that makes prescribing stuff randomly on hope not really an option. Now if patients start clamoring for it that's another story. But until it's shown that antifungal medicine does more good than harm (who knows, maybe killing all the fungus somehow leaves a void that bacteria could come fill) it's probably best not to do so widely.
  - pygy_ 11y ago
    Not sure why you got downvoted. It would have to be done in double blind trials vs placebo, but it would be a great way to test the causal link between fungi and symptoms. You'd have to make sure the fungicides cross the blood brain barrier in patients.
    - 11y ago

rajacombinator 11y ago

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

stupidcar 11y 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_battery 11y ago
  Yeah, but that was in 1982.
  - deleted 11y ago
    [deleted]
  - nickff 11y ago
    Are you implying that doctors have become more accepting of theories which challenge the status quo? Do you have any reason to believe things have gotten better? Doctors still seem to prescribe blood pressure medication and low-salt diets to people with hypertension, depite the overwhelming number of studies which show that neither prescription has any impact on mortality rates. It doesn't look like they are particularly evidence-driven or self-aware as a profession.
    - falsedan 11y ago
      Doctors are selected and trained to memorize insane amounts of facts, and how to match symptoms to facts. Updating those facts is hard since they're stored when the brain is young and still great at learning (there are refresher courses doctors are required to attend to keep their accreditation, but they lean heavily towards learning new facts, not changing existing ones).
      - nickff 11y ago

n0us 11y 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?

kawera 11y ago
An old but interesting article and discussion related to your question: http://www.theatlantic.com/magazine/print/1969/12/how-your-cat-is-making-you-crazy/8873/ http://www.theatlantic.com/magazine/print/1969/12/how-your-c... https://news.ycombinator.com/item?id=3573694 https://news.ycombinator.com/item?id=3573694 Articles somehow related to the subject: http://www.nature.com/news/the-tantalizing-links-between-gut-microbes-and-the-brain-1.18557 http://www.nature.com/news/the-tantalizing-links-between-gut... http://universityofcalifornia.edu/news/do-gut-bacteria-rule-our-minds http://universityofcalifornia.edu/news/do-gut-bacteria-rule-... http://www.scientificamerican.com/article/gut-second-brain/ http://www.scientificamerican.com/article/gut-second-brain/ http://www.theverge.com/2013/8/21/4595712/gut-feelings-the-future-of-psychiatry-may-be-inside-your-stomach http://www.theverge.com/2013/8/21/4595712/gut-feelings-the-f... http://newsroom.ucla.edu/portal/ucla/changing-gut-bacteria-through-245617.aspx http://newsroom.ucla.edu/portal/ucla/changing-gut-bacteria-t...
- n0us 11y 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.
  - kawera 11y ago
    Maybe this: http://www.npr.org/sections/health-shots/2012/07/02/156142214/a-parasite-carried-by-cats-could-hurt-humans-sanity http://www.npr.org/sections/health-shots/2012/07/02/15614221...
sitkack 11y 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.

zmmmmm 11y 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 11y 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.
- zmmmmm 11y 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.
  - nonbel 11y ago
    They meant multiple, the authors are from Spain. I'm not sure why an editor wouldn't try to alter the title though, perhaps they are also not native english speakers.
- Myrmornis 11y 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.
  - zmmmmm 11y ago
    After reflecting I am wondering if this is a result of the natural tendency of scientists to avoid any hint of overstating their work. Were the fungal infections all in the same region or by the same fungus it'd be absolutely shocking. It'd be a "cold fusion" level revolution for the field - and a "cold fusion" level embarrassment for them if they are wrong. So they are extremely keen to put up front that the picture is not nearly so clear as that. There is also a tendency when scientists are extremely confident they have found something incredibly important to understate it. I always think of the Watson and Crick "It has not escaped our notice ..." statement in this context. This is all based on guesswork though, so that's why I'm curious about what people in the field think.

dacompton 11y 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 11y 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 11y 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.

modeless 11y 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 11y 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 11y 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.
  - philipov 11y ago
    A general correlation between age and fungal infection might be even more significant, since that suggests a path to reduce the effects of aging in general. Either way, a follow-up study to remove those control flaws and hone in on the cause would be necessary.
  - nickff 11y ago
    Even with an improper control group, the fungi-Alzheimer's correlation still exists. There may be another factor which is causing the correlation (a so-called 'dreaded third thing'), and the correlation may not indicate causation, but the correlation still exists.
  - deleted 11y ago
    [deleted]
  - 11y ago

Uptrenda 11y 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.)

chetanahuja 11y 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#Function 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 11y 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 https://news.ycombinator.com/item?id=9647253
  - gus_massa 11y ago

CCs 11y 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 http://www.amazon.com/Far-Human-Eye-Could-See/dp/155817107X

bitL 11y ago

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

carey 11y 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 11y 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.

tim333 11y 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.

nonbel 11y 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 11y 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.
- nonbel 11y 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.

deleted 11y ago

[deleted]

narrator 11y 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 11y 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.pdf http://www.biomedcentral.com/content/pdf/s12864-015-1812-x.p...

thanatosmin 11y 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 11y 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 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.)
- thanatosmin 11y 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 11y 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).
  - adrianN 11y ago
    Can confirm. Had a paper rejected by Nature with the suggestion to send it to Scientific Reports instead. Scientific Reports accepted it.
dynomight 11y ago

nonbel 11y 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")

TeMPOraL 11y 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/. http://www.r-fiddle.org/.)

pmoriarty 11y ago

Are these fungi from Yuggoth?

captainill 11y 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 11y ago
Maybe antibiotics cause Alzheimer's.

ommunist 11y ago

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

seesomesense 11y ago
No, it means that a researcher doing fourth rate science has successfully trolled HN.
- dang 11y ago
  Please stop posting unsubstantive comments to Hacker News.

deleted 11y ago

[deleted]

seesomesense 11y ago

Sounds like Bozo the Clown is now publishing articles in Nature. One problem with biomedical research is the crackpots.

rwmj 11y 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.

carbocation 11y 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 11y ago
Good question. Are anti fungal molecules small enough to cross the blood brain barrier easily?
- tptacek 11y ago
  Yes, a bunch of them, including fluconazole, which is a first-line treatment for common fungal infections.
tankenmate 11y 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?
- carbocation 11y 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.

tim333 11y 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-disease/jad00985 http://content.iospress.com/articles/journal-of-alzheimers-d...

Geeek 11y ago
Here you go http://www.docdroid.net/PBdotNO/contentserver.pdf.html http://www.docdroid.net/PBdotNO/contentserver.pdf.html
- tim333 11y ago
  Thanks

erikreinertsen 11y 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 11y 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/ http://www.cbm.uam.es/

sea2summit 11y 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.