Faculty Bibliography

The accumulation of amyloid-beta (Abeta) plaques is a central feature of Alzheimer's disease (AD). First reported in animal models, it remains uncertain if peripheral inflammatory and/or infectious conditions in humans can promote Abeta 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 Alzheimer's 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 Abeta load using 11C-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 Abeta vulnerable brain regions (p = 0.002). We show for the first time in humans an association between periodontal disease and brain Abeta load. These data are consistent with the previous animal studies showing that peripheral inflammation/infections are sufficient to produce brain Abeta accumulations.

Papillon-Lefevre syndrome (PLS) is a genetically inherited disorder characterized by palmoplantar hyperkeratosis and severe early onset periodontitis. Oral symptoms begin to appear when primary teeth are in the process of erupting. A defect in the cathepsin C gene causes a dysfunction of the immune response occurring 1 to 3 times in 1 million births. Varying degrees of severity have been reported, ranging from complete edentulism at a young age to complete retention of teeth with a good prognosis.

CONTEXT: Surgery-induced neuroinflammation has been implicated in the development of postoperative cognitive dysfunction (POCD). OBJECTIVE: To test the hypothesis that meloxicam, a selective cyclooxygenase (COX)-2 inhibitor, preserves postoperative cognitive function and inhibits surgery-induced neuroinflammation in a mouse model. DESIGN: A mouse model of splenectomy-induced inflammation. METHODS: Sixty Swiss Webster male mice (6-8 week old) were randomised into six groups that underwent splenectomy. Animals in groups 1-4 were tested once on day 1, 5, 9 or 14 to determine the time course of delayed transient cognitive dysfunction associated with splenectomy. Animals in groups 5 and 6 were tested once on day 5 or 9 to determine the ability of the NSAID meloxicam to attenuate cognitive dysfunction. INTERVENTION: Animals in groups 1-4 received one dose 500 mul intraperitoneal physiological saline 24 h after splenectomy. Animals in groups 5 and 6 received one dose of intraperitoneal meloxicam (60 mg kg in 500 mul saline) 24 h after splenectomy. MAIN OUTCOME MEASURES: Short-term working memory as determined by Object Recognition Test (ORT) index on days 1, 5, 9 and 14 was the first main outcome. Tomato lectin staining histochemistry of glial cells was assessed on days 1, 5, 9 and 14 as a second main outcome. RESULTS: Compared with day 1 (group 1), the mean ORT indices at day 5 (group 2) and day 9 (group 3) were decreased by 27.5% [95% confidence interval (CI): 0.9 to 54.1%, P = 0.04] and 23.8% (95% CI, 4.3 to 51.9%, P = 0.09), respectively. At day 5 (group 5) and day 9 (group 6), the ORT indices in the meloxicam groups were reduced by 6.6% (95% CI: -11.4 to 24.5%) and 4.3% (95% CI: -25.3 to 34.0). Thus, the administration of meloxicam attenuated the decrease in ORT indices (P = 0.031). Histochemical staining with tomato lectin showed features of microglia activation at day 5 and 9, which was reduced by the administration of meloxicam. CONCLUSION: These findings suggest that COX-2-dependent mechanisms may play a role in the development of POCD. This effect may be dependent on the modulation of glial cell activation.

Inflammation plays a significant role in Alzheimer's disease (AD) pathogenesis. Studies have shown that systemic, peripheral infections affect AD patients. Cognitive dysfunction is a consistent finding in AD and periodontal disease is a chronic, peripheral infection often resulting in tooth loss. We hypothesized that older adults with periodontal inflammation (PI) or many missing teeth would show impaired cognition compared to subjects without PI or with few missing teeth, and among subjects with PI, those with many missing teeth would show impaired cognition compared to those with few missing teeth. The effect of PI/tooth loss on cognitive function [measured by Digit Symbol (DST) and Block Design (BDT) tests] was assessed in 70-year old Danish subjects. We found: 1) subjects with PI obtained lower mean DST scores compared to subjects without PI (p < 0.05); 2) subjects with many missing teeth had lower mean DST and BDT scores compared to subjects with few missing teeth (p < 0.05); 3) the association of PI with DST and BDT scores was dependant on the number of missing teeth (interaction: p = 0.03 and p = 0.06); and 4) education and previous cognitive scores (age 50) were important covariates. Subjects with PI had significantly lower adjusted mean DST scores compared to subjects without PI. However for adjusted BDT, the significance held only for subjects with few missing teeth. No difference in the adjusted DST and BDT scores was seen between subjects with many missing teeth compared to those with few missing teeth. These results support the hypothesis that PI may affect cognition

Background: The etiology and pathogenic mechanisms for AD have not been defined, although peripheral inflammation is thought to play a role. Periodontal disease is a prevalent, peripheral infection associated with gram negative, anaerobic bacteria that through localized and systemic inflammatory pathways could contribute to cognitive dysfunction.We hypothesized that subjects with periodontal inflammation (PI) having a genetic profile indicative of a proinflammatory phenotype have lower cognition compared to those lacking this genetic profile or subjects without PI. Methods: We analyzed in cross-section 45, 70-year-old Danish subjects with periodontal data as well as data on, cognitive function and single nucleotide polymorphism (SNP) within the Il-10 gene promoter region. Results: The combined effect of periodontal inflammation and IL-10-1082 genotype on Digit Symbol Test (DST) was assessed by analysis of variance that showed a significant interaction between the two independent variables even after adjustments for DST at age 50 and education [F (Interaction) = 3.8, p = 0.03]. This interaction was due to the differential effect of AA/ AG and GG genotype combined with periodontal condition on the cognitive scores: subjects with IL-1082 AA/AG genotype and periodontal inflammation tested lower on the DST (33 -/+ 6.5 and 30 -/+ 8.0) compared to periodontal subjects with IL-1082 GG genotype (41 -/+ 7.9) and subjects without periodontal inflammation (42 -/+ 612). Conclusions: These results are consistent with the literature showing that subjects with IL-10-1082 GG genotype have increased production of the anti-inflammatory cytokine IL-10 compared to subjects with IL-10-1082 AA/AG genotype. These results also support our general hypothesis that periodontal disease may be associated with cognitive dysfunction through its inflammatory component