Tuesday, August 9, 2011

12 Paper: Alzheimer's disease - a neurospirochetosis.

Miklossy has recently published a work on a probable causal relationship with infection with spirochetes in the brain and Alzheimer's disease which has many people talking. Here's the abstract:

Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria.
Judith Miklossy
Journal of Neuroinflammation 2011, 8:90 doi:10.1186/1742-2094-8-90
Published: 4 August 2011

Abstract (provisional)

It is established that chronic spirochetal infection can cause slowly progressive dementia, brain atrophy and amyloid deposition in late neurosyphilis. Recently it has been suggested that various types of spirochetes, in an analogous way to Treponema pallidum, could cause dementia and may be involved in the pathogenesis of Alzheimer's disease (AD). Here, we review all data available in the literature on the detection of spirochetes in AD and critically analyze the association and causal relationship between spirochetes and AD following established criteria of Koch and Hill.

The results show a statistically significant association between spirochetes and AD (P = 1.5 x 10-17, OR = 20, 95% CI = 8-60, N = 247). When neutral techniques recognizing all types of spirochetes were used, or the highly prevalent periodontal pathogen Treponemas were analyzed, spirochetes were observed in the brain in more than 90% of AD cases. Borrelia burgdorferi was detected in the brain in 25.3% of AD cases analyzed and was 13 times more frequent in AD compared to controls.

Periodontal pathogen Treponemas (T. pectinovorum, T. amylovorum, T. lecithinolyticum, T. maltophilum, T. medium, T. socranskii) and Borrelia burgdorferi were detected using species specific PCR and antibodies. Importantly, co-infection with several spirochetes occurs in AD.

The pathological and biological hallmarks of AD were reproduced in vitro. The analysis of reviewed data following Koch's and Hill's postulates shows a probable causal relationship between neurospirochetosis and AD.

Persisting inflammation and amyloid deposition initiated and sustained by chronic spirochetal infection form together with the various hypotheses suggested to play a role in the pathogenesis of AD a comprehensive entity.

As suggested by Hill, once the probability of a causal relationship is established prompt action is needed. Support and attention should be given to this field of AD research. Spirochetal infection occurs years or decades before the manifestation of dementia. As adequate antibiotic and anti-inflammatory therapies are available, as in syphilis, one might prevent and eradicate dementia.


Comments:

These are my preliminary comments, I may come back at some point to revise them.

This paper is one in a long line of research by Dr. Miklossy on the relationship between infection and Alzheimer's disease, with a much earlier similar work being "Alzheimer's disease - a spirochetosis?"

Those of you who were interested in reading the paper on which this abstract was based may also find the following full text of interest:

The Alzheimer's Disease-Associated Amyloid β-Protein Is an Antimicrobial Peptide
Stephanie J. Soscia, James E. Kirby, Kevin J. Washicosky, Stephanie M. Tucker, Martin Ingelsson, Bradley Hyman, Mark A. Burton, Lee E. Goldstein, Scott Duong, Rudolph E. Tanzi, Robert D. Moir.
Source link: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0009505

And there are examples of other papers not by Dr. Miklossy in a similar vein which may be of interest:
http://www.ncbi.nlm.nih.gov/pubmed/19560105
http://www.ncbi.nlm.nih.gov/pubmed/19958038

I realize that a number of Lyme disease patients - especially those with persisting neurological symptoms - are probably reading the abstract and feeling somewhat nervous about their future potential for developing Alzheimer's disease. However, I want to point out a few pieces of information from the paper itself which highlight two important items:

1) That we don't know exactly what causes Alzheimer's disease yet and

2) That in the samples studied, the majority of Alzheimer patients' brains of those sampled which were infected did not contain Borrelia burgdorferi spirochetes.

Before everyone reading along rests easy, though, you might want to take note that the analysis states that in those samples studied, there is a strong statistical correlation with the presence of other spirochetal bacteria in the brains of patients with Alzheimer's disease.

Graph showing that Alzheimer disease patient
samples contained more oral spirochetes and B.
burgdorferi compared to control groups.
Miklossy's meta-analysis points out that the majority of those brains sampled and studied show evidence of infection, mostly by non-syphilitic Treponema. Other studies point out that C. pneumoniae and Herpes Simplex Virus Type 1 (HSV-1, oral herpes - cold sores - which many people get) are also associated with Alzheimer's disease.

Yet while many are infected with such virus, most people do not go on to develop Alzheimer's disease. Why is that? Is one specific kind of pathogen the precursor that leads to beta amyloid plaques?

This said, spirochetes - especially periodontal ones, but also Borrelia burgdorferi - may play a role in the development of Alzheimer's disease.

Miklossy states in her paper:
"When considering all studies (Table 1, Fig. 1) detecting all types of spirochetes and their specific species, their frequency was 8 times higher in the brain in AD (90/131= 68.7%) compared to controls (6/71 = 8.45 %).The difference is statistically significant (P = 1.7 x 10-17; OR = 23; 95% CI = 9-71, N = 202). The association remains strongly significant when the 12 cases with mild AD-type changes (P = 1.5 x 10-19, OR = 26, 95% CI = 10-80, N = 214) or those cases where spirochetes were analyzed in the blood were also included (P = 1.5 x 10-17, OR = 20, 95% CI = 8-60, N = 247)."

Those are some crazy P values.

I am still looking at those studies which are referred to in Table 1, Figure 1 of Miklossy's recent paper: of the Bb studies, 3 are small scale studies by MacDonald, some by Miklossy, and then a few by others. I think more sample studies would be good... I also want to read up on their methods more.

It should be noted that 8 out of 10 of the spirochetal studies in the top half of the table are by Miklossy, and only 2 by McLaughlin. And there is only one specific periodontal spirochetal study mentioned by Riviere et al, 2002... Is anyone else doing research in this area?

But I digress...

Once Miklossy outlined the statistical analysis of the studies and the correlation between the presence of pathogens in the brain and Alzheimer's disease, she continued with an outline of how the pathogenesis of spirochetal infection leads to the development of specific immunological responses and reactions within the brain. This part is the most difficult to summarize, but the intention is to show how similar the unfolding pathogenesis of spirochetal brain infections is to the development of Alzheimer's disease.

Later on, Miklossy shows how to apply Koch's Postulates and Hill's Postulates to the studies conducted, though there isn't a full cycle of re-infection or true xenodiagnosis done from the samples extracted. This is something I would like to see in a new study.

The notable part of the conclusion, for me, is this part:
"Spirochetes are able to escape destruction by the host immune reactions and establish chronic infection and sustained inflammation. In vivo studies with long exposure times will be necessary to efficiently study the sequence of events and the cellular mechanisms involved in spirochete induced AD-type host reactions and Aβ-plaque, “tangle” and “granulovacuolar” formation. The characterization of all types of spirochetes and co-infecting bacteria and viruses is needed, in order to develop serological tests for the early detection of infection. The pathological process is thought to begin long before the diagnosis of dementia is made therefore, an appropriate targeted treatment should start early in order to prevent dementia."
The basic message to take from this paper if you are a Lyme disease patient is that last sentence there:

"The pathological process is thought to begin long before the diagnosis of dementia is made. Therefore, an appropriate targeted treatment should start early in order to prevent dementia."

Regardless of the significance of the findings, early diagnosis and treatment of tickborne infections is paramount to reduce the risk of future problems. Something we all already knew.

My general thought about this meta-analysis is that more studies are needed and a larger collection of samples taken from Alzheimer disease patients need to be analyzed using similar means and methods. I think there is more that needs to be known about the relationship between any pathogenic invasion and the development of Alzheimer's disease.

12 comments:

  1. CO,

    I admit this is a bit "off the wall", however I'm increasingly convinced that dementia and other neurodegenerative disorders are likely a multi-factorial end result of predisposition and triggers rather than a single "cause and effect" state of affairs. Genetic predisposition and environmental factors (including lifestyle choices, infections, and others) may all contribute to dementia.

    The role of glutamate in dementia and neuropsychiatric disorders continues to be studied extensively, and the medication Namenda (memantine) is described here:
    http://www.nia.nih.gov/Alzheimers/Publications/medicationsfs.htm

    Wikipedia describes other potential (and currently investigationals uses) for memantine because of its effect on glutamate. Here is the long list:

    Memantine is also being tested for generalized anxiety disorder, epilepsy, opioid dependence, systemic lupus erythematosus, depression, obsessive compulsive disorder, Tourette Syndrome, problem gambling, attention-deficit hyperactivity disorder (ADHD),[7] glaucoma, tinnitus, neuropathic pain including Complex Regional Pain Syndrome,[8] pervasive developmental disorders, HIV associated dementia,[9] nystagmus,[10] multiple sclerosis[11], autism[12] and migraine.[13]

    (end Wiki quote)

    The following caught my attention today -- partly because it's relatively new and also because JA Carroll has also studied the proteomics of Lyme disease and syphilis -- both of which have been raised as possible infections that may contribute to Alzheimer's disease):

    http://www.ncbi.nlm.nih.gov/pubmed/21766339

    Glia. 2011 Jul 15. doi: 10.1002/glia.21215. [Epub ahead of print]

    Increased excitatory amino acid transport into murine prion protein knockout astrocytes cultured in vitro.

    Pathmajeyan MS, Patel SA, Carroll JA, Seib T, Striebel JF, Bridges RJ, Chesebro B.

    Source

    Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, NIAID, National Institute of Health, Hamilton, Montana; Center for Structural and Functional Neuroscience, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, Montana; Division of Biological Sciences, University of Montana, Missoula, Montana.

    Abstract

    Prion protein (PrP) is expressed on a wide variety of cells and plays an important role in the pathogenesis of transmissible spongiform encephalopathies. However, its normal function remains unclear. Mice that do not express PrP exhibit deficits in spatial memory and abnormalities in excitatory neurotransmission suggestive that PrP may function in the glutamatergic synapse. Here, we show that transport of D-aspartate, a nonmetabolized L-glutamate analog, through excitatory amino acid transporters (EAATs) was faster in astrocytes from PrP knockout (PrPKO) mice than in astrocytes from C57BL/10SnJ wild-type (WT) mice. Experiments using EAAT subtype-specific inhibitors demonstrated that in both WT and PrPKO astrocytes, the majority of transport was mediated by EAAT1. Furthermore, PrPKO astrocytes were more effective than WT astrocytes at alleviating L-glutamate-mediated excitotoxic damage in both WT and PrPKO neuronal cultures. Thus, in this in vitro model, PrPKO astrocytes exerted a functional influence on neuronal survival and may therefore influence regulation of glutamatergic neurotransmission in vivo. © 2011 Wiley-Liss, Inc.

    Copyright © 2011 Wiley-Liss, Inc.

    PMID: 21766339 [PubMed - as supplied by publisher]

    ReplyDelete
  2. Rita,

    I return to my original statement, pretty much:

    1) That we don't know exactly what causes Alzheimer's disease yet and

    2) That in the samples studied, the majority of Alzheimer patients' brains of those sampled which were infected did not contain Borrelia burgdorferi spirochetes.

    I think it's possible that infection can be part of the precursor or a cascade effect that gets the ball rolling towards AD - but the question remains: Why do plenty of people have Bb or HSV-1 or any of a number of infections who do not develop AD?

    The old science maxim applies: Correlation is not causation.

    Miklossy has been working in this area for years, and states herself that: "In vivo studies with long exposure times will be necessary to efficiently study the sequence of events and the cellular mechanisms involved in spirochete induced AD-type host reactions and Aβ-plaque, “tangle” and “granulovacuolar” formation." I think she recognizes that infection may play a role but she also sees that more research is needed to provide stronger evidence for her hypothesis.

    ReplyDelete
  3. Here's a hypothesis:

    Some other process or processes are making it more likely for the person who develops AD to be open to brain infections in general. Genetic disposition, something opens up the blood-brain barrier, and/or a chink in the immune system armor has gone awry, letting common oral bacteria pass barriers and go to immune privileged sites when it normally wouldn't.

    On the other hand, someone with HSV-1 already has a latent virus living in neural ganglia (or other ganglia) - quite possibly from early childhood. (I remember several kids in first grade sporting their first cold sores.) I think it's possible that the odds of developing AD may be an additive issue - that is, once you have HSV-1 and certain genetic background, maybe it is more likely that additional infections to the CNS will trigger the process for AD.

    Don't know. Just speculating.

    ReplyDelete
  4. CO,

    You've pretty much summed up my theory that it requires a genetic and/or immunologic vulnerability and some sort of trigger (whether infection, exposure to a noxious substance or even a traumatic injury) that allows the blood-brain barrier to be compromised in most cases. There are without a doubt pathogens (like those responsible for meningitis) that target the brain, and there may be especially virulent strains of Bb that behave in the same fashion. I consider the "noxious substance" umbrella to cover everything from certain foods to chemicals to vaccine adjuvants (in a vulnerable subset of people). In a similar vein, why do some oral microbes travel through the bloodstream without causing harm while some people end up with endocarditis? Is it just by pure chance or are some people immunologically or otherwise more vulnerable?

    I've been saving this (lol), but please take a look if you have time and interest because Dr. Hadjivissiliou's work has provided important clues to many people who have suffered from neurological problems as a result of gluten sensitivity. His article starts on page 8, and here's a brief description (in bold):

    In his article, Marios Hadjivassiliou introduces us to the idea of Primary
    Autoimuune Cerebellar Ataxia (PACA) – a disorder characterised by a slowly progressive cerebellar syndrome, typically beginning later in life often in association with other autoimmune disorders. He brings the evidence together in favour of this theory from a range of sources.


    http://www.acnr.co.uk/JF10/ACNRJF10_web.pdf

    You may notice there's a book review on page 32 of the pdf above having to do with Lyme disease. For those who may not fully appreciate the implications, I suppose this part (in bold) seems perfectly reasonable:

    What should be done in case of persistent symptoms after adequate antibiotic treatment for Lyme disease? (this latter question is a most vexing problem and assuming the diagnosis of Lyme is correct and there is no active infection, repeated courses of antibiotics are not recommended but emotional support and symptomatic treatment is indicated)

    There's something about MS, autoimmunity and T-cells that I wanted to share with you as well, but I'll try to wait until that might be more appropriate. I may even post it on CanLyme tomorrow (after I get some sleep).

    ReplyDelete
  5. The above link does not work, Rita. So I am relinking it here for others to view:

    http://www.acnr.co.uk/JF10/ACNRJF10_web.pdf

    ReplyDelete
  6. I have the pdf of Anti-Borrelia burgdorferi antibody profile in post-Lyme disease syndrome. Chandra A et al. Clin Vaccine Immunol. (2011)
    (PMID 21411605). This is different than the vlsE paper or the anti-neural paper. It's about antibodies detected by the standard Western blot but with all bands reported. Am I right that you haven't discussed this one? Please email me at loakley55@gmail.com if you'd like a copy, or like to discuss it. Here's the abstract:

    Abstract

    Patients with post-Lyme disease syndrome (PLDS) report persistent symptoms of pain, fatigue, and/or concentration and memory disturbances despite antibiotic treatment for Lyme borreliosis. The etiopathogenesis of these symptoms remains unknown and no effective therapies have been identified. We sought to examine the antiborrelia antibody profile in affected patients with the aim of finding clues to the mechanism of the syndrome and its relationship to the original spirochetal infection. Serum specimens from 54 borrelia-seropositive PLDS patients were examined for antibodies to Borrelia burgdorferi proteins p18, p25, p28, p30, p31, p34, p39, p41, p45, p58, p66, p93, and VlsE by automated immunoblotting and software-assisted band analysis. The presence of serum antibodies to the 31-kDa band was further investigated by examination of reactivity against purified recombinant OspA protein. Control specimens included sera from 14 borrelia-seropositive individuals with a history of early localized or disseminated Lyme disease who were symptom free (post-Lyme healthy group), as well as 20 healthy individuals without serologic evidence or history of Lyme disease. In comparison to the post-Lyme healthy group, higher frequencies of antibodies to p28 (P < 0.05), p30 (P < 0.05), p31 (P < 0.0001), and p34 (P < 0.05) proteins were found in the PLDS group. Assessment of antibody reactivity to recombinant OspA confirmed the presence of elevated levels in PLDS patients (P < 0.005). The described antiborrelia antibody profile in PLDS offers clues about the course of the antecedent infection in affected patients, which may be useful for understanding the pathogenic mechanism of the disease.

    ReplyDelete
  7. Rita,

    You said, "There are without a doubt pathogens (like those responsible for meningitis) that target the brain, and there may be especially virulent strains of Bb that behave in the same fashion."

    The pathogens responsible for meningitis...N. meningitidis can leave toxins in the brain which contribute to the infection's effect (endotoxin).
    If the person doesn't have antibodies to it or a complement deficiency, then the infection is severe and the outcome bleak. Two other bacteria along with N. meningitidis are responsible for about 80% of all bacterial meningitis cases.

    There are strains of Bb which disseminate more quickly through the blood than others. There are also ones which are more neurotropic than others, but being more neurotropic doesn't necessarily mean more virulent.

    One interesting thing I read is that some strains of Bb are more likely to result in a negative blood culture test than others. In the paper "Borrelia burgdorferi predicts the capacity for hematogenous dissemination during early Lyme disease", it's stated that in samples of Lyme disease patients studied, there were three general RST (ribosomal RNA intergenic spacer type) genotypes for Borrelia burgdorferi. Of those who had RST 1, it was generally the most invasive and most readily detected in skin and blood culture samples. If, however, a patient had RST 3, it was generally less detectable by blood and skin cultures.

    Is there a silver lining there? The main one is that if you have RST 3, it's supposedly less likely to disseminate quickly unless you have one specific OspC genotype for it - Type I. (There are letter assignments for marking virulence for each of these types, with A being the most virulent form.)

    You said, "I consider the "noxious substance" umbrella to cover everything from certain foods to chemicals to vaccine adjuvants (in a vulnerable subset of people)."

    I think that the mechanisms underlying these responses are still poorly understood, although research has been uncovering more especially in regards to our guts and immunological responses, and conditions like Celiac disease. I've posted a number of articles and papers on the immune systems in our guts in the Friday Four columns.

    In the future we may be able to determine what triggers a response or which people are more likely to develop a response as we move into an era of individualized medicine. Right now, this area of study is in the beginning stages, but I definitely think it's where things are headed and what is needed to avoid drug reactions, negative immunological reactions, and ensure people use medicines which actually work for them because they are more closely tailor-made to their individual profile.

    You said, "In a similar vein, why do some oral microbes travel through the bloodstream without causing harm while some people end up with endocarditis? Is it just by pure chance or are some people immunologically or otherwise more vulnerable?

    Good questions. I know that like other bacteria, some microbes are pathogenic and some aren't. N. meningitidis causes meningitis, but there are types of Neisseria which live in your body all the time and don't cause any problems and some people's nasopharyngeal areas are colonized by N. meningitidis and it doesn't give them any issues at all. Those who do not have antibodies to N. meningitidis do have a problem with them, though, and can be infected by these asymptomatic carriers.

    People who develop endocarditis tend to have some sort of vulnerability that makes them more likely to get it - congenital heart defects, artificial heart valves, and mitral valve prolapse seem to make infection more likely, along with general immunocompromised states or immune suppression. Why it happens to people without these issues? I'm not sure.

    ReplyDelete
  8. Rita wrote:

    You may notice there's a book review on page 32 of the pdf above having to do with Lyme disease. For those who may not fully appreciate the implications, I suppose this part (in bold) seems perfectly reasonable:

    What should be done in case of persistent symptoms after adequate antibiotic treatment for Lyme disease? (this latter question is a most vexing problem and assuming the diagnosis of Lyme is correct and there is no active infection, repeated courses of antibiotics are not recommended but emotional support and symptomatic treatment is indicated)


    This is pretty much the standard message being given and promoted by the IDSA guidelines for Lyme disease patients who have symptoms after initial antibiotic treatment. At least on the face of it, this statement isn't as harsh and dismissive as the "aches and pains of daily living" statement that was given. This one sounds more caring. The problem is though - and anyone can see it, especially a patient: being caring is better than not being caring, but what really helps is effective treatment that improves our symptoms if not cures us entirely.

    Part of my issue with the entire autoimmune hypothesis is that it is just a hypothesis. One of a few out there for persisting symptoms. Until it's a proven solid theory, there isn't much to go on.

    Those who support the autoimmune hypothesis may advocate for immunosuppressive drugs, like steroids - but if their hypothesis is wrong or at least wrong for a sizeable portion of patients who are affected - then if a persisting infection is in fact present they will be worsening those patients' condition rather than improving it.

    Those who support an immune dysregulation hypothesis (which I think there is something to it for at least part of the picture) also have to be careful of advocating immunomodulatory treatment, if one is to look at the Finnish study on mice (see this post I made back in February about Yrjanainen et al's study) and see the outcome there:

    "TNF is a pro-inflammatory cytokine which, when blocked, typically results in a reduction in clinical inflammation; for this reason, such treatment is used for patients with rheumatoid arthritis. To the surprise of the authors, viable spirochetes were recovered in these PCR- and culture-negative mice after TNF blocking treatment was given. Also interesting is that anti-TNF treatment did not result in the expected finding of a reduction of joint swelling."

    I'm not sure what to make of this, other than it seems immunomodulatory treatment is something one also needs to be careful about. How this applies to human patients, I'm not certain.

    And of course, those who support the persistent infection hypothesis also have their work cut out for them because they have to show that not only do longer-term antibiotic treatments work - they have to provide evidence that Bb is still present in the human host.

    Which at this point is very difficult, because it's hard to find in the blood and CSF of patients the longer they are infected. Researchers have been able to find it in human brains and in animals, but after the subjects are dead and their tissues are ground up and tested by PCR.

    We haven't found an easy way to do this on still-living human hosts, which is why so many early Lyme disease skin biopsies and such are taken to examine the early stage of infection. It's just far easier to study the early stage, which is problematic because those who go on to suffer more symptoms either hit the late stage of infection without treatment or inadequate treatment (my hypothesis).

    ReplyDelete
  9. Loakley,

    Thank you for your offer. I'll email you separately. Just know that I can be reached at CampOther */at/* gmail. I don't post the email address on the site and try to avoid mentioning it much to avoid spambots and spider harvesting of my email address.

    ReplyDelete
  10. Possible retraction for this statement:

    "If, however, a patient had RST 3, it was generally less detectable by blood and skin cultures."

    I'm not sure about this - it may just be fewer people contract OspC RST 3 Bb infections so fewer people test positive for it. In other words, wait until I confirm this before passing it on - or read the original paper yourself to confirm findings.

    ReplyDelete
  11. Revisiting this post 3 months later, and I wanted to make a note of this:

    "TNF is a pro-inflammatory cytokine which, when blocked, typically results in a reduction in clinical inflammation; for this reason, such treatment is used for patients with rheumatoid arthritis. To the surprise of the authors, viable spirochetes were recovered in these PCR- and culture-negative mice after TNF blocking treatment was given. Also interesting is that anti-TNF treatment did not result in the expected finding of a reduction of joint swelling."

    Old comment from me: I'm not sure what to make of this, other than it seems immunomodulatory treatment is something one also needs to be careful about. How this applies to human patients, I'm not certain.

    New comment from me: There is another way to look at this. If someone injected post-treatment Lyme disease patients with anti-TNF treatment and their symptoms did NOT improve, could this be an indication they are still infected? Could this form the basis for some sort of test?

    Why would anti-TNF treatment NOT work to reduce inflammation and swelling in someone who is currently infected with Bb? Perhaps that's the best question here of my three.

    ReplyDelete

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