Porphyromonas gingivalis and Alzheimer disease: Recent findings and potential therapies.

Epidemiological studies have identified an association between periodontitis and Alzheimer disease (AD); however, the nature of this association has been unclear. Recent work suggests that brain colonization by the periodontal pathogen Porphyromonas gingivalis may link these two inflammatory and degenerative conditions. Evidence of P. gingivalis infiltration has been detected in autopsy specimens from the brains of people with AD and in cerebrospinal fluid of individuals diagnosed with AD. Gingipains, a class of P. gingivalis proteases, are found in association with neurons, tau tangles, and beta-amyloid in specimens from the brains of individuals with AD. The brains of mice orally infected with P. gingivalis show evidence of P. gingivalis infiltration, along with various neuropathological hallmarks of AD. Oral administration of gingipain inhibitors to mice with established brain infections decreases the abundance of P. gingivalis DNA in brain and mitigates the neurotoxic effects of P. gingivalis infection. Thus, gingipain inhibition could provide a potential approach to the treatment of both periodontitis and AD.

Treatment of Porphyromonas gulae infection and downstream pathology in the aged dog by lysine-gingipain inhibitor COR388.

COR388, a small-molecule lysine-gingipain inhibitor, is currently being investigated in a Phase 2/3 clinical trial for Alzheimer's disease (AD) with exploratory endpoints in periodontal disease. Gingipains are produced by two species of bacteria, Porphyromonas gingivalis and Porphyromonas gulae, typically associated with periodontal disease and systemic infections in humans and dogs, respectively. P. gulae infection in dogs is associated with periodontal disease, which provides a physiologically relevant model to investigate the pharmacology of COR388. In the current study, aged dogs with a natural oral infection of P. gulae and periodontal disease were treated with COR388 by oral administration for up to 90 days to assess lysine-gingipain target engagement and reduction of bacterial load and downstream pathology. In a 28-day dose-response study, COR388 inhibited the lysine-gingipain target and reduced P. gulae load in saliva, buccal cells, and gingival crevicular fluid. The lowest effective dose was continued for 90 days and was efficacious in continuous reduction of bacterial load and downstream periodontal disease pathology. In a separate histology study, dog brain tissue showed evidence of P. gulae DNA and neuronal lysine-gingipain, demonstrating that P. gulae infection is systemic and spreads beyond its oral reservoir, similar to recent observations of P. gingivalis in humans. Together, the pharmacokinetics and pharmacodynamics of COR388 lysine-gingipain inhibition, along with reduction of bacterial load and periodontal disease in naturally occurring P. gulae infection in the dog, support the use of COR388 in targeting lysine-gingipain and eliminating P. gingivalis infection in humans.

Biomarkers of oral inflammation in perinatally HIV-infected and perinatally HIV-exposed, uninfected youth.

AIM: To examine oral biomarkers that have been associated with periodontal disease progression in HIV-infected adults in perinatally HIV-infected and HIV-exposed but uninfected youth. MATERIAL AND METHODS: This was a cross-sectional, multicentre substudy of youth participating in the Oral Health Pediatric HIV/AIDS Cohort study. Gingival crevicular fluid repository samples from participants with and without periodontal disease (using Gingival Index [GI] and Bleeding on Probing [BOP] parameters on dental examination) were tested for concentration levels of inflammatory biomarkers. Associations were assessed using Wilcoxon test and Spearman correlation. RESULTS: For perinatal HIV youth (n = 129), the markers consistently elevated (p < .05) in sites with GI ≥2 and in sites with BOP were interleukin-1ß, 6 and 13, macrophage inflammatory protein-1α and metalloproteinase-9. Serum tumour necrosis factor-α and soluble CD14 were positively correlated with a summary count of elevated cytokines. No associations were seen among HIV-uninfected subjects (n = 71). CONCLUSIONS: The association of oral biomarkers of inflammation with clinical indicators of periodontal inflammation and systemic immune activation suggests that perinatal HIV-infected youth may be at higher risk for developing significant periodontal disease, associated with tooth loss and HIV progression. More frequent dental care of this group is needed to prevent potential periodontal progression.

Porphyromonas gingivalis in Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors.

Porphyromonas gingivalis, the keystone pathogen in chronic periodontitis, was identified in the brain of Alzheimer's disease patients. Toxic proteases from the bacterium called gingipains were also identified in the brain of Alzheimer's patients, and levels correlated with tau and ubiquitin pathology. Oral P. gingivalis infection in mice resulted in brain colonization and increased production of Aß1-42, a component of amyloid plaques. Further, gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau, a protein needed for normal neuronal function. To block this neurotoxicity, we designed and synthesized small-molecule inhibitors targeting gingipains. Gingipain inhibition reduced the bacterial load of an established P. gingivalis brain infection, blocked Aß1-42 production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipain inhibitors could be valuable for treating P. gingivalis brain colonization and neurodegeneration in Alzheimer's disease.

Personalized periodontal treatment for the tobacco- and alcohol-using patient.

The use of various forms of tobacco is one of the most important preventable risk factors for the incidence and progression of periodontal disease. Tobacco use negatively affects treatment outcomes for both periodontal diseases and conditions, and for dental implants. Tobacco-cessation programs can mitigate these adverse dental treatment outcomes and may be the most effective component of a personalized periodontal treatment approach. In addition, heavy alcohol consumption may exacerbate the adverse effects of tobacco use. In this review, the microbiology, host/inflammatory responses and genetic characteristics of the tobacco-using patient are presented as a framework to aid the practitioner in developing personalized treatment strategies for these patients. These personalized approaches can be used for patients who use a variety of tobacco products, including cigarettes, cigars, pipes, smokeless tobacco products, e-cigarettes and other tobacco forms, as well as patients who consume large amounts of alcohol. In addition, principles for developing personalized tobacco-cessation programs, using both traditional and newer motivational and pharmacological approaches, are presented.

Advanced platelet-rich fibrin and freeze-dried bone allograft for ridge preservation: A randomized controlled clinical trial.

BACKGROUND: Advanced platelet-rich fibrin (A-PRF) is an autogenous blood product with applications in dento-alveolar surgery. However, there is minimal information regarding its optimal clinical application or efficacy. The aim of this multi-arm parallel randomized controlled clinical trial was to evaluate the efficacy of A-PRF alone or with freeze-dried bone allograft (FDBA) in improving vital bone formation and alveolar dimensional stability during ridge preservation. METHODS: Forty patients requiring extraction of non-molar teeth and replacement with dental implants were randomized into one of four ridge preservation approaches: A-PRF, A-PRF+FDBA, FDBA, or blood clot. A-PRF was prepared at 1,300 rpm for 8 minutes. Non-traumatic extractions and ridge preservation was performed. After an average of 15 weeks healing, bone core samples were harvested at the time of implant placement for micro-CT and histomorphometric analysis. Ridge dimensions were measured immediately after extraction and before implant placement. RESULTS: Significantly greater loss of ridge height was noted in the blood clot group (3.8 ± 2.0 mm) compared to A-PRF (1.8 ± 2.1 mm) and A-PRF+FDBA (1.0 ± 2.3 mm) groups (P < 0.05). No significant differences in ridge width reduction were noted between groups. Significantly more vital bone was present in the A-PRF group (46% ± 18%) compared to the FDBA group (29% ± 14%) (P < 0.05). Bone mineral density was significantly greater in the FDBA group (551 ± 58 mg/cm3 ) compared to blood clot (487 ± 64 mg/cm3 ) (P < 0.05). CONCLUSIONS: This study demonstrates A-PRF alone or augmented with FDBA is a suitable biomaterial for ridge preservation. This study represents the first randomized controlled clinical trial comparing A-PRF with and without FDBA to FDBA alone for ridge preservation.

The Kidney and Periodontal Disease (KAPD) study: A pilot randomized controlled trial testing the effect of non-surgical periodontal therapy on chronic kidney disease.

INTRODUCTION: Chronic kidney disease (CKD) remains a prevalent public health problem that disproportionately affects minorities and the poor, despite intense efforts targeting traditional risk factors. Periodontal diseases are common bacterial plaque-induced inflammatory conditions that can respond to treatment and have been implicated as a CKD risk factor. However there is limited evidence that treatment of periodontal disease slows the progression of CKD. METHODS/DESIGN: We describe the protocol of the Kidney and Periodontal Disease (KAPD) study, a 12-month un-blinded, randomized, controlled pilot trial with two intent-to-treat treatment arms: 1. immediate intensive non-surgical periodontal treatment or 2. rescue treatment with delayed intensive treatment. The goals of this pilot study are to test the feasibility of conducting a larger trial in an ethnically and racially diverse, underserved population (mostly poor and/or low literacy) with both CKD and significant periodontal disease to determine the effect of intensive periodontal treatment on renal and inflammatory biomarkers over a 12-month period. RESULTS: To date, KAPD has identified 634 potentially eligible patients who were invited to in-person screening. Of the 83 (13.1%) of potentially eligible patients who attended in-person screening, 51 (61.4%) were eligible for participation and 46 enrolled in the study. The mean age of participants is 59.2years (range 34 to 73). Twenty of the participants (43.5%) are Black and 22 (47.8%) are Hispanic. DISCUSSION: Results from the KAPD study will provide needed preliminary evidence of the effectiveness of non-surgical periodontal treatment to slow CKD progression and inform the design future clinical research trials.

Oral Human Papillomavirus in Youth From the Pediatric HIV/AIDS Cohort Study.

In contrast to high rates of oral human papillomavirus (HPV) found in human immunodeficiency virus (HIV)-infected adults, only 2% of 209 perinatally HIV-infected youth had oral HPV. This rate was similar in HIV-exposed but uninfected youth. No association was found with sexual activity; however, low CD4 counts were associated with oral HPV.

The Burden of Oral Disease among Perinatally HIV-Infected and HIV-Exposed Uninfected Youth.

OBJECTIVE: To compare oral health parameters in perinatally HIV-infected (PHIV) and perinatally HIV-exposed but uninfected youth (PHEU). METHODS: In a cross-sectional substudy within the Pediatric HIV/AIDS Cohort Study, participants were examined for number of decayed teeth (DT), Decayed, Missing, and Filled Teeth (DMFT), oral mucosal disease, and periodontal disease (PD). Covariates for oral health parameters were examined using zero-inflated negative binomial regression and ordinal logistic regression models. RESULTS: Eleven sites enrolled 209 PHIV and 126 PHEU. Higher DT scores were observed in participants who were PHIV [Adjusted Mean Ratio (aMR) = 1.7 (95% CI 1.2-2.5)], female [aMR = 1.4 (1.0-1.9)], had no source of regular dental care [aMR = 2.3 (1.5-3.4)], and had a high frequency of meals/snacks [≥5 /day vs 0-3, aMR = 1.9 (1.1-3.1)] and juice/soda [≥5 /day vs 0-3, aMR = 1.6 (1.1-2.4)]. Higher DMFT scores were observed in participants who were older [≥19, aMR = 1.9 (1.2-2.9)], had biological parent as caregiver [aMR = 1.2 (1.0-1.3)], had a high frequency of juice/soda [≥5 /day vs 0-3, aMR = 1.4 (1.1-1.7)] and a low saliva flow rate [mL/min, aMR = 0.8 per unit higher (0.6-1.0)]. Eighty percent had PD; no differences were seen by HIV status using the patient-based classifications of health, gingivitis or mild, moderate, or severe periodontitis. No associations were observed of CD4 count and viral load with oral health outcomes after adjustment. CONCLUSIONS: Oral health was poor in PHIV and PHEU youth. This was dismaying since most HIV infected children in the U.S. are carefully followed at medical health care clinics. This data underscore the need for regular dental care. As PHIV youth were at higher risk for cavities, it will be important to better understand this relationship in order to develop targeted interventions.

Minimally invasive periodontal therapy for general practitioners.

There remains a high prevalence of mild-to-moderate forms of periodontal diseases in both developed and developing countries. Although many periodontal specialty practices currently place strong emphasis on implant surgery, periodontal plastic surgery and esthetics, general dentists and hygienists have often assumed more responsibility than periodontal specialty practices for the diagnosis, treatment, assessment and maintenance, and possible referral, of their patients. To address these current trends and challenges, this volume of Periodontology 2000 presents a series of topics on the basic biological principles of periodontal disease, as well as on approaches to diagnosis, treatment planning and treatment, in what is called 'conservative' or 'noninvasive' periodontal therapy. These topics include risk assessment of the periodontal condition; reduction, elimination and/or control of etiologies and risk factors, including mechanical, antimicrobial and host-modulation approaches; considerations for evaluation of clinical outcomes based on treatment approaches; and selected topics in laser therapy, halitosis and gingival recession.

The tobacco-using periodontal patient: role of the dental practitioner in tobacco cessation and periodontal disease management.

Although the prevalence of tobacco use has declined in some parts of the world, tobacco use remains a persistent and, in some cases, growing problem that will continue to be a fundamental challenge facing dental practitioners in the decades ahead. Dental practitioners have a unique opportunity and professional obligation to be a positive influence in reducing the economic and social burden inflicted by tobacco use on dental and general health. In this article, the current noninvasive, evidence-based approaches are presented for dental practitioners to help patients avoid initiating tobacco use, to encourage and assist patients in ceasing tobacco use and to address tobacco-induced damage to periodontal supporting tissues.

Periodontal disease in HIV/AIDS.

Since the early 1990's, the death rate from AIDS among adults has declined in most developed countries, largely because of newer antiretroviral therapies and improved access to these therapies. In addition, from 2006 to 2011, the total number of new cases of HIV infection worldwide has declined somewhat and has remained relatively constant. Nevertheless, because of the large numbers of existing and new cases of HIV infection, the dental practitioner and other healthcare practitioners will still be required to treat oral and periodontal conditions unique to HIV/AIDS as well as conventional periodontal diseases in HIV-infected adults and children. The oral and periodontal conditions most closely associated with HIV infection include oral candidiasis, oral hairy leukoplakia, Kaposi's sarcoma, salivary gland diseases, oral warts, other oral viral infections, linear gingival erythema and necrotizing gingival and periodontal diseases. While the incidence and prevalence of these oral lesions and conditions appear to be declining, in part because of antiretroviral therapy, dental and healthcare practitioners will need to continue to diagnose and treat the more conventional periodontal diseases in these HIV-infected populations. Finding low-cost and easily accessible and acceptable diagnostic and treatment approaches for both the microbiological and the inflammatory aspects of periodontal diseases in these populations are of particular importance, as the systemic spread of the local microbiota and inflammatory products of periodontal diseases may have adverse effects on both the progression of HIV infection and the effectiveness of antiretroviral therapy approaches. Developing and assessing low-cost and accessible diagnostic and treatment approaches to periodontal diseases, particularly in developing countries, will require an internationally coordinated effort to design and conduct standardized clinical trials.

Alterations of neutrophil f-actin kinetics by tobacco smoke: implications for periodontal diseases.

Tobacco smoking is a major risk factor in the incidence and severity of periodontal diseases. Alterations of neutrophil function by short-term high levels of smoke during the act of smoking (acute smoke exposure) as well as long-term exposure to lower levels of tobacco substances in the bloodstream (chronic smoke exposure) may play a role in the pathogenesis of periodontal diseases in smokers. The polymerization and depolymerization of f-actin in response to infectious agents or inflammatory mediators is a critical process in a variety of neutrophil functions. In this study, we examined the effects of in vitro smoke exposure on neutrophils from smokers and non-smokers (which may be comparable to in vivo acute smoke exposure) and neutrophils from smokers not exposed to further in vitro smoke (which may be comparable to chronic smoke exposure) on f-actin kinetics. Peripheral neutrophils were isolated from seven healthy smoking subjects and seven healthy age-matched non-smoking subjects and exposed to 1-5 min of acute smoke in a smoke box system or not exposed to further smoke (baseline controls). Selected aliquots of neutrophils from control and 5-min exposures of acute smoke were then stimulated with the chemotactic peptide F-met-leu-phe at 10(-7) M for an additional 30-360 s. Cells were fixed and permeabilized, stained for f-actin with NBD phallacidin, and analyzed by flow cytometry. From baseline to 5 min of in vitro smoke exposure, there was a 38% decline in f-actin stain in non-smokers and a 30% decline in f-actin stain in smokers (p > 0.05) with f-actin values slightly higher in smokers than-non-smokers (p > 0.05). With F-met-leu-phe stimulation, both smokers and-non-smokers demonstrated a characteristic rise in f-actin stain from 0 to 120 s with a subsequent decline to baseline at 360 s and no significant differences in f-actin levels at any time of stimulation between groups. After preincubation with 5 min of in vitro smoke, the magnitude of rise in f-actin was less in both smokers and non-smokers when compared to cells not incubated with 5 min of smoke (p < 0.05 at 120 s for both smokers and non-smokers). F-actin values in smokers were higher than-non-smokers from 30 to 360 s of F-met-leu-phe exposure (p > 0.05). These results demonstrate that in vitro smoke exposure may impair normal f-actin kinetics. These alterations in f-actin kinetics may in turn affect other neutrophil functions which may impact on the pathogenesis of periodontal diseases in smokers.