Ronald G. Craig

Inflammation and Alzheimer's disease: possible role of periodontal diseases.

The molecular and cellular mechanisms responsible for the etiology and pathogenesis of Alzheimers disease (AD) have not been defined; however, inflammation within the brain is thought to play a pivotal role. Studies suggest that peripheral infection/inflammation might affect the inflammatory state of the central nervous system. Chronic periodontitis is a prevalent peripheral infection that is associated with gram‐negative anaerobic bacteria and the elevation of serum inflammatory markers including C‐reactive protein. Recently, chronic periodontitis has been associated with several systemic diseases including AD. In this article we review the pathogenesis of chronic periodontitis and the role of inflammation in AD. In addition, we propose several potential mechanisms through which chronic periodontitis can possibly contribute to the clinical onset and progression of AD. Because chronic periodontitis is a treatable infection, it might be a readily modifiable risk factor for AD.

TNF-α and antibodies to periodontal bacteria discriminate between Alzheimer’s disease patients and normal subjects

The associations of inflammation/immune responses with clinical presentations of Alzheimers disease (AD) remain unclear. We hypothesized that TNF-alpha and elevated antibodies to periodontal bacteria would be greater in AD compared to normal controls (NL) and their combination would aid clinical diagnosis of AD. Plasma TNF-alpha and antibodies against periodontal bacteria were elevated in AD patients compared with NL and independently associated with AD. The number of positive IgG to periodontal bacteria incremented the TNF-alpha classification of clinical AD and NL. This study shows that TNF-alpha and elevated numbers of antibodies against periodontal bacteria associate with AD and contribute to the AD diagnosis.

Periodontal disease adversely affects the survival of patients with end-stage renal disease

Periodontal disease is associated with cardiovascular disease and is thought to accelerate systemic atherosclerosis. Here we examined the relationship between periodontitis and cardiovascular disease mortality in outpatients on hemodialysis using a retrospective analysis of 168 adult patients in New York City and North Carolina. During 18 months of follow-up, cardiovascular disease and all-cause mortality were determined from a centralized dialysis registry. One hundred patients had mild or no periodontal disease but the remaining 68 had moderate-to-severe disease defined as 2 or more teeth with at least 6 mm of inter-proximal attachment loss. At baseline, the proportion of males was significantly lower in the moderate-to-severe group. Compared with mild or no periodontal disease, moderate-to-severe disease was significantly associated with death from cardiovascular causes. Adjustment for age, gender, center and dialysis vintage, smoking status, and history of diabetes mellitus or hypertension did not diminish the strength of this association. Our findings suggest a need for larger studies to confirm this connection, along with intervention trials to determine if treating periodontitis reduces cardiovascular disease mortality in dialysis patients.

Interactions between chronic renal disease and periodontal disease

The incidence of end-stage renal disease (ESRD) is increasing and patients receiving renal replacement therapy including hemodialysis, peritoneal dialysis or renal transplantation will comprise an enlarging segment of the dental patient population. Renal replacement therapy can affect periodontal tissues including gingival hyperplasia in immune suppressed renal transplantation patients and increased levels of plaque, calculus and gingival inflammation and possible increased prevalence and severity of destructive periodontal diseases in ESRD patients on dialysis maintenance therapy. Also, the presence of undiagnosed periodontitis may have significant effects on the medical management of the ESRD patient. Periodontitis has been found to contribute to systemic inflammatory burden including the elevation of C-reactive protein (CRP) in the general population. Atherosclerotic complications including myocardial infarction and stroke are the primary causes of mortality in the ESRD population and, in contrast to that of the general population, the best predictor of all cause and cardiac death in this population is CRP. Consequently, periodontitis may be a covert but treatable source of systemic inflammation in the ESRD population. The objective of this review was to explore the interaction between chronic renal disease, renal replacement therapy and periodontal diseases based upon the results of studies published within the last decade.

Alzheimer's Disease and Peripheral Infections: The Possible Contribution from Periodontal Infections, Model and Hypothesis

Alzheimers disease (AD) affects approximately 4.5 million people in the U.S. and this number will increase as the population ages and the life-span increases. Therefore, of paramount importance is identifying mechanisms and factors that affect the risk of developing AD. The etiology and pathogenic mechanisms for AD have not been defined, although inflammation within the brain is thought to play a role. Consistent with this hypothesis, studies suggest that peripheral infections contribute to the inflammatory state of the central nervous system. Periodontitis is a prevalent, persistent peripheral infection associated with gram negative, anaerobic bacteria that are capable of exhibiting localized and systemic infections in the host. This review offers a hypothetical link between periodontitis and AD and will present possible mechanistic links between periodontitis related inflammation and AD. It will review the pathogenesis of periodontitis and the mechanisms by which periodontal infections may affect the onset and progression of AD. Since periodontitis is a treatable condition, it may be a readily modifiable risk factor for AD.

Periodontal Pathogens and Gestational Diabetes Mellitus

In previous cross-sectional or case-control studies, clinical periodontal disease has been associated with gestational diabetes mellitus. To test the hypothesis that, in comparison with women who do not develop gestational diabetes mellitus, those who do develop it will have had a greater exposure to clinical and other periodontal parameters, we measured clinical, bacteriological (in plaque and cervico-vaginal samples), immunological, and inflammatory mediator parameters 7 weeks before the diagnosis of gestational diabetes mellitus in 265 predominantly Hispanic (83%) women in New York. Twenty-two cases of gestational diabetes mellitus emerged from the cohort (8.3%). When the cases were compared with healthy control individuals, higher pre-pregnancy body mass index (p = 0.004), vaginal levels of Tannerella forsythia (p = 0.01), serum C-reactive protein (p = 0.01), and prior gestational diabetes mellitus (p = 0.006) emerged as risk factors, even though the clinical periodontal disease failed to reach statistical significance (50% in those with gestational diabetes mellitus vs. 37.3% in the healthy group; p = 0.38).

Predicting risk for bisphosphonate-related osteonecrosis of the jaws: CTX versus radiographic markers

BACKGROUND AND OBJECTIVE The most common risk factor for bisphosphonate-related osteonecrosis of the jaws (BRONJ) is dentoalveolar surgery. It has been suggested that reduced serum C-terminal telopeptide (CTX) can determine the degree of osteoclast suppression and may predict the development of BRONJ after dentoalveolar surgery. Although there are many radiographic appearances associated with BRONJ, there are little data that describes changes preceding dentoalveolar surgery. The objective of this retrospective study was: 1) to investigate if reduced serum CTX values (i.e., <150 pg/mL) were associated with BRONJ after dentoalveolar surgery; and 2) to determine if specific radiographic changes are associated with teeth that develop BRONJ after extraction. STUDY DESIGN A retrospective review of radiographic and/or serum CTX data was performed for 68 patients with a history of bisphosphonate therapy who either underwent dental extraction or were diagnosed with BRONJ in the Department of Oral and Maxillofacial Surgery during the period 2007-2009. Postoperative healing was assessed for 26 patients with reduced serum CTX levels (<150 pg/mL) who either underwent dental extraction or treatment for BRONJ. Preoperative radiographs were evaluated for 55 patients who either healed normally or developed BRONJ after dental extraction. RESULTS All 26 patients (100%) who had serum CTX levels <150 pg/mL healed successfully after dentoalveolar surgery (20 patients) or after treatment for BRONJ (6 patients). Among the 55 patients who underwent radiographic evaluation, 24 patients (83%) with BRONJ exhibited periodontal ligament (PDL) widening associated with extracted teeth, whereas only 3 patients (11%) who healed normally demonstrated PDL widening. CONCLUSION These data suggest that radiographic PDL widening may be a more sensitive indicator than CTX testing in predicting risk of BRONJ. Current guidelines that recommend minimal surgical intervention may need to be revised to include alternative strategies for the elimination or management of this pathology.

Severe Periodontitis Is Associated with Low Serum Albumin among Patients on Maintenance Hemodialysis Therapy

The relationship between periodontitis and two measures of systemic inflammation, serum albumin and C-reactive protein (CRP), were examined among patients who were receiving chronic outpatient hemodialysis. Adult patients at two locations, North Carolina and New York City, were evaluated by dentist examiners. Six sites per tooth (up to 32 teeth per patient) were examined. A periodontitis case was defined as > or = 60% of sites with attachment level > or = 4 mm. Multivariable logistic regression was used to determine the association of periodontitis with low serum albumin, defined as < 3.5 mg/dl, and with high CRP, defined as > 3.0 mg/dl. A total of 154 patients completed the study. The mean age was 54.6 yr (SD 13.3), and average duration of dialysis was 4.0 yr (3 mo to 16 yr). Eighty-six (54.6%) were men, and 89 (58.2%) were black. Common causes of end-stage kidney disease were hypertension (12.3%), diabetes (22.1%), glomerulonephritis (7.1%), and other (58.4%). The average number of teeth was 20.3 (SD 8.4). Thirty-five (23%) patients were periodontitis cases. Severe periodontitis was associated with low serum albumin (odds ratio 8.20; 95% confidence interval 1.61 to 41.82; P = 0.01) compared with individuals without severe periodontitis disease after adjustment for age, gender, race, diabetes, hypertension, body mass index, smoking, study site, total cholesterol, serum calcium, serum phosphorus, and normalized protein catabolic rate. There was no observed association of severe periodontitis with CRP. Investigation of the potential contribution of periodontitis to serum albumin and possibly to morbidity and mortality among patients with end-stage kidney disease seems warranted.

Importance of Periodontal Disease in the Kidney Patient

End-stage renal disease (ESRD) patients on hemodialysis experience a greatly increased rate of atherosclerotic complications. In both hemodialysis and general populations, it has become evident that inflammation plays a central role in the pathogenesis of atherosclerotic complications. C-reactive protein (CRP), the major acute phase protein in man, has been found to predict all-cause and cardiovascular mortality in ESRD patients on hemodialysis maintenance therapy. Hepatic CRP synthesis is upregulated by proinflammatory cytokines released locally at sites of infection or inflammation, although many patients experience elevated CRP values in the absence of overt infection or inflammation. Destructive periodontal diseases in the general population have been associated with both an increased prevalence of atherosclerotic complications and an elevation in serum CRP values. In view of the prevalence of destructive periodontal diseases in the general population, and since periodontal evaluations are normally not performed as part of a medical assessment, destructive periodontal diseases may be an over looked source of inflammation in ESRD patients on hemodialysis therapy. The intent of this report is to review the possible role destructive periodontal diseases and associated periodontal infections may play in the management of the ESRD patient on hemodialysis maintenance therapy.

Periodontal disease associates with higher brain amyloid load in normal elderly

The accumulation of amyloid-β (Aβ) plaques is a central feature of Alzheimers disease (AD). First reported in animal models, it remains uncertain if peripheral inflammatory and/or infectious conditions in humans can promote Aβ brain accumulation. Periodontal disease, a common chronic infection, has been previously reported to be associated with AD. Thirty-eight cognitively normal, healthy, and community-residing elderly (mean age, 61 and 68% female) were examined in an Alzheimers Disease Research Center and a University-Based Dental School. Linear regression models (adjusted for age, apolipoprotein E, and smoking) were used to test the hypothesis that periodontal disease assessed by clinical attachment loss was associated with brain Aβ load using (11)C-Pittsburgh compound B (PIB) positron emission tomography imaging. After adjusting for confounders, clinical attachment loss (≥3 mm), representing a history of periodontal inflammatory/infectious burden, was associated with increased PIB uptake in Aβ vulnerable brain regions (p = 0.002). We show for the first time in humans an association between periodontal disease and brain Aβ load. These data are consistent with the previous animal studies showing that peripheral inflammation/infections are sufficient to produce brain Aβ accumulations.