Tuesday, August 1, 2017

Is Mouth Bacteria Causing Dementia?

In the 1897 fictional book War of the Worlds, H.G. Wells kills off the invading Martians and their gigantic robotic machines, by microbial infection. Two hundred years later we are just now appreciating the power of this microbial world.  We have been resisting studying how bacteria influence our behavior, including our mental health, in favor of the obvious low hanging fruit: a malfunction. Areas of study include the gut, but the best way to study bacteria is to look at it as it gets into our system through our mouth. [1]
In 2017 Kenji Takeuchi, with Kyushu University, Fukuoka, Japan and his colleagues reported that people in their 60s, who lost their teeth were more likely to get dementia five years later. And there was a dose effect, with fewer teeth the higher the rate of dementia, peaking at nearly twice as high. Only when older people completely had no teeth did this rate of dementia drop slightly.
What was interesting was that the same result was not found for vascular dementia—when dementia is caused by lack of blood supply to the brain. Having fewer teeth promoted dementia through something other than a problem with blood supply to the brain—the main cause of dementia.  Could this be the elusive cause of Alzheimer’s disease?
In a comprehensive review of periodontal disease and its relation to aging, the Brazilian Eder Abreu Huttner and Eduardo Hebling and their colleagues reported that although aging alone does not cause periodontal disease, aging does increase the risk by having less resilience, fostering conditions promoting the disease, and having a biological reaction that is more damaging than for younger people.
Controlling for other effects is difficult. For example Kenji Takeuchi also reported that teeth loss was related to having less than 10 years formal education.. After age, lack of formal education by itself remains the best predictor of dementia. Education has a protective function, perhaps delaying rather than eliminating dementia. Related to education is also income.  
In 2008 Nora Donaldson with King’s College London, and her colleagues reported data on 3,817 participants in the UK and found that social economic status had direct influence on the number of good teeth participants had. Richer people made better use of preventive care and also independently had better teeth. There is also a genetic component to teeth loss. With the main contender for dementia being the apolipoprotein E epsilon 4 gene we also find that this gene is also related to teeth loss. All of these factors can moderate and mediate the susceptibility to teeth loss.
Then in 2006 Margaret Gatz with the University of Southern California and her colleagues addressed these factors by using a Swedish study of identical twins. By controlling for most of these social and genetic factors, the authors report that the twin who had tooth loss before age 35 was 5.5 times more likely to develop Alzheimer’s disease. Tooth loss is directly involved in Alzheimer’s disease. We also observe that  centenarians—those that have lived to a 100 years and older—and their offspring have slight but significantly better oral health than their respective peers when they were in their early 60s.
Tooth loss can be caused by many factors, but the main contender seems to be periodontal disease. Periodontal disease is caused by bacteria that initially forms a sticky “plaque” which if not removed by brushing can harden and form “tartar” that attacks the gum causing “gingivitis” and eventually infects the tooth and bone as ”periodontitis.” The association of periodontal disease with dementia has been reported in many studies. In one recent 2017 review Yago Leira Feijóo and his colleagues with the University of Santiago de Compostela, Spain concluded that those with severe forms of periodontal disease are nearly three times more likely of getting dementia.
The cause of periodontal disease is primarily bacteria. But the story is more nuanced.  There are some 400 bacterial species populating the mouth in symbiosis with some viruses and maybe even fungi. A concoction that is also capable of invading the brain.  Although we still do not know how they get there. [2] It could be that the effect on the brain is indirect. Angela Kamer with the NYU College of Dentistry, and her colleagues proposes that it is likely that this mouth cocktail causes an inflammatory reaction throughout the body that also affects the brain.[3] But the brain also has traces of these microbes.
It is surprising to learn that the brain can be infected with the same microbial world that H.G. Wells wrote about 200 years ago. But unlike the story, in reality these microbes are killing humans instead of Martians. Autopsy studies find bacteria, fungi, viruses and a host of other microbial infections in our brain, especially among people that die with dementia. In 2011 Judith Miklossy confirmed these associations when she found that in four out of five autopsied brains of Alzheimer's patient there were spirochetal bacteria that originate in the mouth. [4]
In some cases these infections can be activated—both the rate of infection and the response—when the immune system is compromised through stress or other unknown mechanisms. This initial infection can cause inflammation in the brain and it is this inflammation that attacks the brain from inside. Ruth Utzhaki and her colleagues, in a 2016 review, came up with incontrovertible evidence that Alzheimer’s disease has a microbial component. Although always present, the authors report that this microbial world is woken up by an iron imbalance in the brain. An iron rich brain causes microbes to flourish, causing a reaction. There might be many such tipping points—that awaken this sleeping and toxic world—among older adults.
In fact the hallmarks of Alzheimer’s disease—plaques and tangles—are observed in mice and in cell culture after an infection with herpes simplex virus or bacteria. These plaques and tangles have been found to have anti-microbial function against multiple bacteria, yeast and viruses. In response to a microbial world that exists around and within us. The World Health Organization estimates that 3.7 billion people under age 50 have the non-sexually transmitted herpes simplex virus infection globally. Around a third to half of all adults in developed countries have periodontal disease. So bacteria and viruses are already present, the issue is how does bacteria, in particular, invade and damage our brain.
Bacterial infection is not simple. With periodontal disease, bacterial infection is dependent on the presence of the infection together with the susceptibility of the individual, including a direct genetic susceptibility. However age seems to be the main reason why we become more susceptible to these infections. With greater susceptibility and immune deficiency, older adults are more likely to suffer bacterial infection that results in periodontal disease that promoted dementia. And this is bi-directional, as memory lapses, dental care is further ignored, increasing the continual onslaught of infection in the brain.  A central aspect of this theory is that there is a multiplying effect with the infection causing an initial inflammatory reaction in the brain, making it susceptible to more infection. [5]
Since the plaques and tangles are in fact not dead cells as presumed, but very much alive, the idea that the plaques and tangles—characteristic features of Alzheimer’s disease—are protecting the brain seems plausible. Despite the success of drugs eliminating these plaques and tangles there has been no improvement in cognition. As a result there is now enough evidence to accept that the plaques and tangles are a reaction to lesions in the brain rather than what Alois Alzheimer initially proposed as the disease itself. They are brain scabs caused by a brain lesion. Bacterial infection is such one of many such lesions that the brain has to contend with on a daily basis. Bacteria that enters the mouth and is cultivated through periodontal disease is an important sources of infection.
Overall these studies indicate that it is biologically feasible for oral bacteria to go through the bloodstream, reach the brain and either initiate or promote existing lesions and cause an inflammatory response. The brain reacts by protecting itself through inflammation and surrounding the toxic substance with plaques and tangles. If this inflammation mechanism is the cause of dementia then perhaps simple medication can lower the inflammation in the brain.
Jeffrey Rich with the Sentara Cardiovascular Research Institute, Norfolk, Virginia; USA and his colleagues conducted a follow-up study looking at the use of non-steroidal anti-inflammatory drugs (NSAIDs)—include aspirin, ibuprofen, naproxen, COX-2 inhibitors, and other medications They found that the group using the NSAIDs had slower progression of the disease a year after initiating treatment. Although in a much later study, when they performed autopsies on these same patients, the authors reported that some had vascular dementia as well as Alzheimer’s disease (which diffuses the effect of inflammation on Alzheimer’s disease). However the results are still positive. In a review of the literature, the Dutch William van Gool and his colleagues make the argument that the body is maintaining a balance, that not all inflammation is bad, that some of the benefits of these medication might have nothing to do with inflammation and that the timing is important and they might only work at the early stages of the disease.
It seems that we are still on the periphery, searching for answers to a complex disease, in a piecemeal fashion, without coordination. Perhaps we are reaching our own tipping point in science and will have to admit that the body is a supraorganism. [6] The appreciation that other organisms live in harmony with and within us is a finely tuned symphony that aging has a way of disrupting.
© USA Copyrighted 2017 Mario D. Garrett  
This blog was initiated by a discussion with Peter Kraus.
___________________________________
[1]
It has long been known that there is a direct effect of oral bacteria such as Porphyromonas gingivalis and Streptococcus sanguis on induction of platelet activation and aggregation, which in turn contributes to heart disease such as atheroma formation and thrombosis. See earlier blog
https://www.psychologytoday.com/blog/iage/201305/aging-teeth
Also studies have consistently shown that mothers with significant periodontal disease had a 7.5 fold increase in the risk of having a preterm, low birth weight baby.
There is also a relationship between periodontal disease and diabetes, with improved metabolic control seen in poorly controlled diabetics following periodontal therapy.
The periodontal bacterium P. gingivalis has also been linked to rheumatoid arthritis through the enzyme peptidylarginine deiminase.
[2]
Among periodontal bacteria, species such as A. actinomycetemcomitans, P. gingivalis, T. denticola and F. nucleatum are capable of invading the brain. 
[3]
This reaction involves; cytokines—substances, such as interferon, interleukin, and growth factors, that are secreted by certain cells of the immune system and have an effect on other cells; and C-reactive protein (CRP)—substance produced by the liver that increases in the presence of inflammation in the body. CRP increases up to 1000 folds in acute inflammatory diseases. These cytokines and CRP stimulate glial cells to produce amyloid-β 1-42 peptide (Aβ42) and hyperphosphorylated tau protein (P-Tau).
[4]
But there is also an indication that the infection can also come from outside infection such as Lyme bacteria.
https://www.psychologytoday.com/blog/iage/201705/the-coming-pandemic-lyme-dementia
[5]
Characterized by the production of high levels of inflammatory mediators such as IL-1, IL-6, IL-17 and TNF-α, and low levels of anti-inflammatory molecules such as IL-10
[6]
We are becoming Gods
https://www.psychologytoday.com/blog/iage/201511/we-are-becoming-gods
Geography of Aging and the Illusion of Self
https://www.psychologytoday.com/blog/iage/201505/geography-aging-and-the-illusion-self

References
Donaldson, A. N., Everitt, B., Newton, T., Steele, J., Sherriff, M., & Bower, E. (2008). The effects of social class and dental attendance on oral health. Journal of Dental Research, 87(1), 60-64.

Gatz, M., Mortimer, J. A., Fratiglioni, L., Johansson, B., Berg, S., Reynolds, C. A., & Pedersen, N. L. (2006). Potentially modifiable risk factors for dementia in identical twins. Alzheimer's & Dementia, 2(2), 110-117.

Itzhaki, R. F., Lathe, R., Balin, B. J., Ball, M. J., Bearer, E. L., Braak, H., ... & Del Tredici, K. (2016). Microbes and Alzheimer's disease. Journal of Alzheimer's disease: JAD, 51(4), 979.

Kamer, A. R., Dasanayake, A. P., Craig, R. G., Glodzik-Sobanska, L., Bry, M., & De Leon, M. J. (2008). Alzheimer's disease and peripheral infections: the possible contribution from periodontal infections, model and hypothesis. Journal of Alzheimer's Disease, 13(4), 437-449.

Leira, Y., Dom’nguez, C., Seoane, J., Seoane-Romero, J., P’as-Peleteiro, J. M., Takkouche, B., ... & Aldrey, J. M. (2017). Is Periodontal Disease Associated with Alzheimer's Disease A Systematic Review with Meta-Analysis. Neuroepidemiology, 48(1-2), 21-31.

Miklossy, J. (2011). Alzheimer's disease-a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria. Journal of neuroinflammation, 8(1), 90.

Rich, J. B., Rasmusson, D. X., Folstein, M. F., Carson, K. A., Kawas, C., & Brandt, J. (1995). Nonsteroidal anti-inflammatory drugs in Alzheimer's disease. Neurology, 45(1), 51-55.

Ridley RM, Baker HF, Windle CP, Cummings RM. Very long term studies of the seeding of beta-amyloidosis in primates. J Neural Transm. 2006;113:1243-1251
Sochocka, M., Sobczy_ski, M., Sender-Janeczek, A., Zwoli_ska, K., Bachowicz, O., Tomczyk, T., ... & Leszek, J. (2017). Association between periodontal health status and cognitive abilities. The role of cytokine profile and systemic inflammation. Current Alzheimer research.

Stein, P. S., Scheff, S., & Dawson, D. R. (2006). Alzheimer’s disease and periodontal disease: mechanisms underlying a potential bidirectional relationship. Grand Rounds Oral-Sys Med, 1(3), 14-24.

Takeuchi, K., Ohara, T., Furuta, M., Takeshita, T., Shibata, Y., Hata, J., ... & Ninomiya, T. (2017). Tooth Loss and Risk of Dementia in the Community: the Hisayama Study. Journal of the American Geriatrics