Najwane Said-Sadier, Batoul Sayegh, Raymond Farah, Linda Abou Abbas, Rania Dweik, Norina Tang and David M. Ojcius
Introduction: #Periodontitis is a severe oral infection that can contribute to systemic #inflammation. A large body of evidence suggests a role for systemic inflammation in the initiation of neurodegenerative disease. This systematic review synthesized data from observational studies to investigate the association between periodontitis and #neuroinflammation in adults. Methods and materials: A systematic literature search of PubMed, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) was performed for studies published from the date of inception up to September 2021. Search terms for the exposure “oral disease” and outcome “dementia”, “neuroinflammation” and “cognitive decline” were used. Study selection and data extraction were independently undertaken by two reviewers. The final eligible articles were included only if the exposure is periodontitis and the outcome is cognitive impairment or dementia or a topic related to this condition, and if the study was conducted in an adult population. The quality and risk of bias were assessed by Newcastle Ottawa Scale (NOS). Qualitative synthesis was used to narratively synthesize the results. Six cohort studies, three cross-sectional studies, and two case-control studies met the inclusion criteria. These eleven studies were only narratively synthesized. Meta-analysis was not performed due to the methodological heterogeneity of the studies. Results: The results of included studies show that chronic periodontitis patients with at least eight years of exposure are at higher risk of developing cognitive decline and dementia. Oral health measures such as gingival inflammation, attachment loss, probing depth, bleeding on probing, and alveolar bone loss are associated with cognitive impairment. The reduction of epidermal growth factor (EGF), interleukin 8 (IL-8), interferon γ-induced protein 10 (IP-10), and monocyte chemoattractant protein-1 (MCP-1) in addition to over expression of interleukin 1-β (IL-1β) are significant in patients suffering from cognitive decline with pre-existing severe periodontitis. Conclusions: All the included studies show evidence of an association between periodontitis and cognitive impairment or dementia and Alzheimer’s disease pathology. Nonetheless, the mechanisms responsible for the association between periodontitis and dementia are still unclear and warrant further investigation.
1. Introduction
Periodontal disease (PD) is a disease of periodontal tissues that results in attachment loss and destruction of alveolar bone [1]. The onset of disease is due to bacterial infection, mainly by Porphyromonas gingivalis (Pg) [2]. Until recently, it was thought that resident oral bacteria were only capable of generating disease confined within the oral cavity [3]. However, many studies have demonstrated that oral bacteria can contribute to systemic diseases, especially through their ability to cause systemic inflammation which is characterized by the induction of pro-inflammatory cytokines, chemokines, and exaggerated host immune responses [4,5]. One of the associations with systemic diseases is the one with cardiovascular diseases by promoting atheroma plaque development and progression [6]. More specifically, studies have raised the possibility that the oral microbiome could play a role in the onset of neuroinflammation in neurodegenerative diseases [7].
Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) are characterized by progressive loss of neurons [8]. Three important hypotheses were set on the etiopathogenesis of AD, the “cholinergic hypothesis” by Bartus and colleagues [9], the “amyloid cascade hypothesis” described by Hardy and Allsop [10] and more recently the “inflammation hypothesis of AD” proposed by Krstic and Knuesel. In their hypothesis, Krstic and Knuesel stated that in late-onset AD—in contrast to the familial form of the disease—chronic inflammatory conditions may represent a major trigger of pathology by inducing phospho-tau-related cytoskeletal abnormalities and concomitant impairments of axonal transport [11]. This was not the first time where neuroinflammation involvement was discussed; more than a century ago, Alzheimer and his colleagues discussed the possibility that microorganisms may be involved in the formation of senile plaques, which are hallmarks of AD [12]. This study will focus on oral microorganisms that are associated with AD, such as Porphyromonas gingivalis. Research suggested that the association between periodontal pathogens and neuroinflammation could take place directly through blood and invasion of the blood–brain barrier, or indirectly by inducing an immune response. In support of the first hypothesis, a study was conducted using molecular and immunological techniques on the brains of AD patients. Six of seven periodontal Treponema species, namely T. socranskii, T. pectinovorum, T. denticola, T. medium, T. amylovorum, and T. maltophilum, were identified in the brains of AD patients using species-specific polymerase chain reaction [13]. On the other hand, another study confirmed that bacterial lipopolysaccharides (LPS) can activate Toll-like receptors (TLRs) expressed in glial cells, and thereby induce an inflammatory response due to the overexpression of pro-inflammatory cytokines such as IL-6, IL-1, TNF-α, and IFN-γ [7].
Future projections of the global population predict that by 2030, the world’s older population (≥65 years) will reach 1 billion, equivalent to 12% of the total global population; by 2050, it is estimated that the older population will represent 16.7% (or 1.6 billion) of the total global population [14]. This global shift in demographic characteristics toward an increase in the aging population presents not only a social and economic challenge, but also a great health concern as it is associated with the increasing prevalence of age-related diseases such as dementia [15].
In fact, the largest risk factor for developing Alzheimer’s disease is age. Recent projections indicate that by 2050, 1 in 85 individuals will be diagnosed with Alzheimer’s disease, which is the most common cause of dementia among the older population [16]. In addition, a workshop organized in 1999 demonstrated that the onset of chronic periodontitis (CP) is most commonly detected in older adults [17]. Moreover, epidemiological data demonstrated that periodontal disease affects over 10% and 50% of the young and older population, respectively [18]. Thus, it is important to understand better the correlation between periodontal inflammation and systemic complications. Such studies will provide an integrated picture revealing novel mechanisms underlying the etiopathogenesis of several human diseases such as dementia, bone loss, and other systemic diseases. In this review, we will summarize the evidence of association between periodontitis and cognitive impairment.
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