Healthy Mouth, Healthy Brain: Exploring the Connection Between Periodontitis and Neurodegenerative Disease
This clandestine condition is periodontal disease. The data from the Centers for Disease Control and Prevention indicate that almost half (42%) of adults 30 and older in the United States are affected by some form of periodontal disease1. Recent studies have also assessed the relationship between periodontitis and neurodegenerative diseases (ND), such as Alzheimer’s Disease (AD).
While it was previously thought that the brain was immune-privileged, inflammation in the brain has been discovered in neurodegenerative diseases such as AD, HIV dementia, and Parkinson’s Dis-ease7. There also appears to be a consensus in the research that this inflammation occurs in response to the primary etiology of the ND, rather than be the initial cause of the ND. In the case of Alzheimer’s disease, evidence supports that the primary etiology is the aggregation of amyloid-Beta (AB) plaques and neurofibrillary tangles of the protein tau in the prefrontal cortex and limbic system. Then, microglia in the brain act in a similar fashion to the way macrophages work in the rest of the body, inciting the inflammatory response to these aggregates. Microglia are capable of phagocytosis as well as secretion of several pro-inflammatory cytokines when activated, such as Il-1, Il-6, and TNF-a, to name a few. These particular cytokines play an active role in several chronic inflammatory diseases, including periodontitis. It is also suspected that this resulting inflammation in the brain can contribute as much to the neuro-degenerative effects as the primary etiology itself. This is something we also see with periodontitis, in that the inflammatory response itself, rather than the oral bacteria, is what leads to attachment loss. A natural next research target for the dental community is to define the role of periodontal inflammation in the manifestation and progression of neurodegenerative diseases like AD.
Several studies have determined a positive association between periodontal disease and dementia, but confounding factors such as age make the exact relationship difficult to delineate. A systematic review by Nadin et al in the European Journal of Epidemiology calculated the relative risk of dementia in individuals with periodontal disease to be 1.382. In another recent study published in Neurology, patients with periodontitis and missing teeth were found to have hippocampal atrophy (the part of the brain associated with memory and significantly affected by AD) when compared to periodontally healthy peers3. When this study considered age, participants with mild gum disease had the equivalent of one-year hippocampal atrophy per missing tooth. High serum levels of periodontitis-causing P. gingivalis bacteria have also been associated with impaired delayed recall memory in older adults4. However, these results are somewhat contradicted by another study that did not find an association be-tween increased levels of P. gingivalis se-rum antibodies and AD mortality after 21 years5. Another prospective cohort study also found no association between dementia and deep probing depth, finding similar rates of development of dementia in those with and without deep probing depths over 7 years6. While the evidence is mixed, many studies indicate a positive relationship between dementia and periodontal disease.
To showcase the potential importance of inflammation in Alzheimer’s Disease, one may look to the study of “high pathology controls”, individuals who have AB plaques but do not exhibit symptoms of dementia. A major difference between these individuals and those with diagnosed AD dementia is the absence of inflammation and lack of microglial activation in the high pathology controls. In the Journal of Periodontology, Gil-Montoya, and colleagues published a case-control study evaluating patients with cognitive impairment against cognitively healthy individuals of similar age for the presence of periodontitis and venous blood levels of AB. Higher blood levels of AB were significantly associated with the presence of periodontitis and were significantly higher in individuals with periodontal disease. The authors concluded that “periodontitis may be a modulating variable of the association between amyloid plaques and cognitive impairment”8. Perhaps, periodontal inflammation plays a role in the overall inflammatory response to these plaques, which eventually leads to the characteristic dementia of AD.
A more direct relationship between periodontal disease bacteria and AD has also been established. This research is possibly of the greatest importance because, unlike the association studies and their issues with confounding factors, it allows us to gain an understanding of the mechanism by which one disease entity may lead to the other. As previously mentioned, P gingivalis (Pg) is a cornerstone pathogen in the development of periodontal disease. P gingivalis makes proteases called “gingipains” that contribute to its virulence. Gingipains aid in multispecies colonization of periodontal disease sites, allow Pg to infiltrate tissue, and help Pg evade the host immune system9. Pg DNA and gingipains have been discovered in autopsy specimens from the brains and CSF of individuals with AD10. Gingipains also tend to be more prevalent in memory-associated regions of the brain such as the hippocampus, in individuals with AD. Taking this one step further, gingipains are now a potential therapeutic target for the treatment of periodontitis and AD.
Researchers will continue to learn about the relationship periodontitis has with other systemic diseases. Regardless of whether periodontitis modulates diseases like Alzheimer’s, the dental profession endures treating periodontitis for the many concrete dental justifications we already have.
References:
Periodontal Disease, Oral Health Home, Centers for Disease Control and Prevention. Accessed
July 10, 2023.https://www.cdc.gov/oralhealth/conditions/periodontaldisease.
html#:~:text=47.2%25%20of%20adults%20aged%2030, some%20form%20of%
20periodontal%20disease.
Nadim, R., Tang, J., Dilmohamed, A. et al. Influence of periodontal disease on risk of dementia: a
systematic literature review and a meta-analysis. Eur J Epidemiol 35, 821–833 (2020).
Associations of Dental Health with the Progression of Hippocampal Atrophy in Community-
Dwelling Individuals: The Ohasama Study
Satoshi Yamaguchi, Takahisa Murakami, Michihiro Satoh, TakamasaKomiyama, Takashi Ohi, Yos
hitada Miyoshi, Kosei Endo, TakakoHiratsuka, Azusa Hara, Yukako Tatsumi, Tomoko Totsune,
KeiAsayama, Masahiro Kikuya, Kyoko Nomura, Atsushi Hozawa, Hirohito Metoki, Yutaka Ima
i, Makoto Watanabe, Takayoshi Ohkubo, Yoshinori Hattori Neurology Jul2023, 10.1212/
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https://n.neurology.org/content/early/2023/07/05/WNL.0000000000207579
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