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 Table of Contents  
ORIGINAL HYPOTHESIS
Year : 2018  |  Volume : 9  |  Issue : 1  |  Page : 20-24

Diabetes and Periodontitis – Role in Cognitive Impairment


1 Department of Periodontology, Manipal College of Dental Sciences, Manipal University, Mangalore, Karnataka, India
2 Department of Oral Pathology and Microbiology, Manipal College of Dental Sciences, Manipal University, Mangalore, Karnataka, India

Date of Web Publication20-Apr-2018

Correspondence Address:
Ashita S Uppoor
Department of Periodontology, Manipal College of Dental Sciences, Manipal University, Mangalore 575001, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/denthyp.denthyp_40_17

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  Abstract 


Introduction: The global burden of dementia, diabetes, and periodontitis is rapidly increasing and is becoming a serious area of concern. The incidence of diabetes and periodontitis usually increases in middle age, and because they share a bidirectional relationship, they are known to worsen if not controlled. Evidence suggests that the people who have diabetes are at a significant risk of developing dementia and in the last two decades, periodontitis has been increasingly linked with dementia. Currently, there is no definitive treatment of dementia. The Hypothesis: The patients who have uncontrolled diabetes with moderate-to-severe periodontal disease may be at a greater risk for developing neurodegeneration associated with dementia. Evaluation of the Hypothesis: The chronic effects of both periodontitis and diabetes may have an uncontrollable additive effect on the body of an aging individual. Immunosenescence may add to the complexity of such effects and in such a scenario, the complete resolution of the systemic inflammation or other interrelated process responsible for directly or indirectly triggering neurodegeneration may be compromised. We have proposed various interrelated mechanisms linking diabetes and periodontitis that may be amplified in an aging individual. These mechanisms may contribute to the neurodegeneration associated with dementia. Oral cavity is a major unbarred window into the systemic environment of an individual. Treatment and maintenance therapy for periodontitis on a routine basis may help reduce a significant amount of inflammatory load, especially in the diabetic population, who are at a greater risk for the future development of dementia.

Keywords: Dementia, diabetes, periodontitis


How to cite this article:
Sharma S, Uppoor AS, Natarajan S. Diabetes and Periodontitis – Role in Cognitive Impairment. Dent Hypotheses 2018;9:20-4

How to cite this URL:
Sharma S, Uppoor AS, Natarajan S. Diabetes and Periodontitis – Role in Cognitive Impairment. Dent Hypotheses [serial online] 2018 [cited 2018 Nov 19];9:20-4. Available from: http://www.dentalhypotheses.com/text.asp?2018/9/1/20/230700




  Introduction Top


Dementia has become a major global burden in the recent years. According to Alzheimer’s disease (AD) international, every three seconds, someone is developing dementia. In 2015, about 46.8 million people were estimated worldwide to be living with dementia. These numbers are predicted to rise to 75 million by 2030 and almost triple by 2050.[1] Currently, there is no definitive cure for dementia, and recent consensus on antidementia medication has concluded that the secondary prevention and evolution of alternative modifying treatment approaches will be an imperative area on its research. However, this will require a more extensive understanding of the underlying neurodegenerative process in the brain that leads to the symptoms of dementia.[2]

Apart from dementia, the other major chronic disease that is increasing at alarming rates is type 2 diabetes mellitus (T2DM) with numbers touching 422 million worldwide in 2014.[3] Both the diseases are significantly associated to the morbidity and mortality of the aging population. Interestingly, periodontitis, which was reported as the sixth most common disease worldwide in 2010,[4] has a bidirectional relationship with T2DM and has gained new focus in the last few decades for its association with dementia and mild cognitive impairment (CI). A recent study by Lee et al.[5] has provided critical evidence for the same. An important point to note is that T2DM is an independent risk factor for dementia.[6] Therefore, it can be predicted that, in a diabetic having periodontitis, the cumulative systemic effects may augment the underlying pathological mechanisms associated with neurodegeneration leading to the CI or progression of an already existing dementia.


  The Hypothesis Top


In this paper, we hypothesize that both uncontrolled diabetes and periodontitis contribute to the neurodegenerative process, and we must remain cognizant of the underlying pathogenesis to take the appropriate preventive and treatment protocol for dementia.

We have elaborated the hypothesis on the basis of various interrelated mechanisms between T2DM and periodontitis that are likely to magnify adding to the pathology underlying the neurodegenerative disease [Figure 1].
Figure 1: Mechanisms associated with type 2 diabetes mellitus (T2DM), Periodontitis and their interrelated mechanisms leading to neurodegeneration. (a) Pathological mechanisms linking T2DM and CI. (b) Proposed Interrelated mechanisms associated with both T2DM and Periodontitis, leading to neurodegeneration (c) Pathological mechanisms linking Periodontitis and CI

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Diabetes is a multisystem disease. The complex biochemical and hormonal interplay within the body produces numerous changes in cellular metabolism. Diabetes involves hypercholesterolemia, APOE-ε4 allele genetic predisposition, hyperglycemia, hypoglycemia, hyperinsulinemia, macrovascular and microvascular pathologies, and increased systemic inflammatory mediators, all of which have been documented as possible underlying mechanisms causing neurodegeneration associated with CI[7] [[Figure 1]a]. Results from a magnetic resonance imaging study[8] had also concluded that CI in individuals with T2DM was linked to structural alterations in the brain.

There is a large body of evidence that suggests periodontitis has been linked to the systemic diseases. Possible mechanisms have been suggested wherein CI may result due to periodontitis [[Figure 1]c]:[9]
  1. Potential periodontal pathogens may directly cross the blood brain barrier and produce neurodegenerative changes.
  2. Amplified systemic inflammation, immune responses, and associated brain cytokine pool secondary to these periodontal pathogens leading to the overactivation of microglial cells consequently leading to neurodegeneration.


The immune system plays a decisive role in maintaining tissue homeostasis. It orchestrates the various events in the body’s response in the presence of infection and injury. Microglia are the key resident macrophage cells, which forms the first line of immune defense in the central nervous system. They play a crucial role in scavenging plaques, dead and damaged neurons, and infectious agents. In the presence of neuroinflammation, the normal action of neuroglial cells is compromised, and this adds to the neurodegenerative disease. They activate the proinflammatory cytokines such as interferon gamma (IFNγ), interleukin-1alpha (IL-1α) Interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNFα) which when directly injected into the CNS lead to neurodegeneration. A sustained activated state of the microglial cells further promotes the cytokine-associated neurodegeneration. Additionally, the microglia when activated induces the production of various proteolytic enzymes that cause neurodegeneration.[10] It has been found that with aging, the incidence of dystrophic microglia is elevated.[11]

Therefore, a persistent chronic systemic inflammation or immunologically mediated stimulus in aging adults having uncontrolled T2DM and periodontitis may induce neuroinflammation, adding to the cascade of neurodegeneration mediated by numerous activated microglia. The various interrelated mechanisms between T2DM and periodontitis that may have a contribution in neurodegeneration in such a scenario have been discussed below [[Figure 1]b].

Inflammaging

The term inflammaging was first introduced by Franceschi et al. in 2000 which denotes a progressive increase in the chronic proinflammatory status with age and is significantly associated with the morbidity and mortality in the aging population.[12] Immunosenescence is a potential contributing factor in inflammaging. Franceschi et al. has reviewed the role of IL-1 and IL-6 in the pathogenesis of Alzheimer’s disease in relation to inflammaging and further emphasized their implication in AD diagnosis, prevention, and therapy.[12] Oral microbiota through bacteremia and a constant antigenic exposure in periodontitis serve as a source of inflammaging. IL-1 and IL-6, related to inflammaging, are important biomarkers associated with the progression and deterioration of periodontitis in T2DM,[13] and IL-1 gene polymorphisms[14] have been linked with periodontitis and AD.

Inflammaging such as chronic inflammation is a double-edged sword, and it is beneficial to the body because it counterbalances the harmful cytokines in the early stages of life; however, it proves detrimental in the later life. The balance between adaptive and pathogenic inflammation may be more inclined toward the pathogenic end in case of a patient who have uncontrolled diabetes with moderate to severe periodontitis. In such a scenario, the anti-inflammatory response may be weak to combat the elevated proinflammatory status owing to the burden of both the diseases leading to inflammaging. This may significantly exacerbate the already existing neuroinflammation and may amplify the morbidity and mortality associated with the same. Inflammaging has been documented as prodromal to Alzheimer’s disease. The controlled status of periodontitis and T2DM and its associated balance is critical in preventing inflammaging.

Porphyromonas gingivalis

P. gingivalis is the key periodontal pathogen that is linked to the worsening of the periodontal status of the diabetic individuals.[15] In older individuals with severe periodontitis, the increased levels of serum antibodies to P. gingivalis have been observed.[16] An analysis from the National Health and Nutrition Examination Survey III had concluded that elevated P. gingivalis IgG levels in adults >60 years was significantly associated to CI.[17] Accordingly, neuronal changes can be anticipated because T2DM may boost the inflammatory response to P. gingivalis systemically through a greater response to bacteremia and dysregulated the immune-inflammatory process in the aging population. These events may also be directly associated to the pathology of neurodegeneration because periodontal pathogens and their products have been documented to cross the blood brain barrier and cause neuroglial activation.[14] Therefore, in elderly diabetics with periodontitis, an early detection of serum antibody levels to P. gingivalis needs to be evaluated. This will serve as a crucial diagnostic tool to estimate the systemic pathogenic load of the organism.

Advanced glycation end products

Advanced glycation end products (AGEs) form a significant element of aging and few age-associated chronic diseases affecting nearly every cell in the body. The increased levels of oxidative stress due to hyperglycemia are linked to the formation of AGEs. They are associated with the chronic complications in diabetics and have been reported to play a significant part in the pathogenesis of neurodegeneration. A study by Schmidt et al.[18] provided an important finding that the gingival tissues in the diabetics expressed both AGEs and the receptors for AGEs. Additionally, there is also evidence that the buildup of AGEs may interrupt the phagocytic events and migration of monocytes and neutrophils. In case of a diabetic, this may consequently escalate the destruction of periodontal tissues and may serve as a chronic stimulus for P. gingivalis, upregulating the production of cytokines and proinflammatory mediators further adding to the load of systemic inflammation.[19] These events may reversibly elevate the accumulation of AGEs with the hyper-expression of receptor for advanced glycation end products (RAGE), leading to the formation of a vicious cycle. Because AGE is a common factor associated with aging, diabetes, neurodegeneration, and periodontitis, the treatment and maintenance of periodontitis in a diabetic individual may lower the combined hyper-expression of RAGEs and AGEs associated with both the diseases and its impact on the brain.

Physiological function and wound healing

With aging, the manual dexterity is reduced, thus compromising an individual’s ability to practice regular oral hygiene practices. As a result of reduced physiological functioning and the inability to seek timely dental treatment, oral care is ignored both by the elderly patients and their caretakers. Aging is also independently associated with impaired wound healing, especially in the elderly diabetics, and this ignorance may prove detrimental by compromising the periodontal healing. There is evidence that the formation of AGEs and their interaction to RAGE also may be associated with impaired wound healing in diabetics.[19] These factors may lead to the episodes of acute exacerbation of already existing chronic inflammation, adding to the vicious cycle of systemic inflammation and its effects on the brain. Therefore, a routine periodontal check-up/treatment should be mandatory in the elderly diabetics to prevent the worsening on periodontal disease.

Along with the diverse evidence supporting the hypothesis, there also exists research that may create areas of uncertainties against the hypothesis. The precise pathogenic mechanisms documented to exist between periodontitis and neurodegeneration are not proven. There is no evidence that suggests comparison guidelines between periodontitis and dementia of any kind. Most studies that have concluded a positive correlation are difficult to compare because they vary in their criteria for the assessment of CI, case definition of periodontitis, and study designs. In addition, because most studies have provided results on the basis of screening tests, and this provides only crude data on the level of cognitive decline and no definitive data about the level of neurodegeneration existent as a result of the severity of periodontitis in an individual.[20] Most studies have eliminated T2DM as a confounding factor and have not discussed its potential effect on both the cognitive decline and periodontitis. However, even if T2DM is considered, it is important to understand that all the three diseases are interrelated, multifactorial in nature with multiple confounding factors, therefore the severity of which has a superior effect is questionable.

Evaluation of the Hypothesis

To test the association of CI or dementia with diabetes and periodontitis, patients with uncontrolled diabetes should be monitored for the cognitive decline and severity of periodontitis. They may be systematically followed and all the three diseases must be evaluated for any interrelationship and possible correlations. In addition, the systemic inflammatory biomarkers may also be simultaneously recorded, to assess the changes in the systemic inflammatory burden overtime. Further statistical corrections may be utilized using logistic regression analysis to adjust for the confounding as well as interactions among the multiple variables. Initial studies can be cross-sectional. However, only multicentre longitudinal studies taking different strata of population will provide the most valid information for the confirmation on the stated hypothesis.


  Conclusion Top


There is a large body of evidence providing valuable information for the link between diabetes and dementia and that between dementia and periodontitis/oral health. However, to the best of the author’s knowledge, no literature was found establishing an association between the three diseases. One of the hallmarks of successful aging is high cognitive and physical functioning capacity. With the increasing number of people having diabetes worldwide, it should be emphasized that specific treatment approaches should be tailor made specifically for them to reduce the future risk of development of dementia. The treatment of periodontitis can be an important modifying treatment approach to reduce the systemic inflammatory burden and other mechanisms in patients who have uncontrolled diabetes liable to develop neurodegeneration. Because there is currently no known cure for dementia, it is important that future studies should be conducted to have a better understanding of the hypothesis proposed in this article.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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