Faculty Bibliography

People with Down syndrome (DS) are at an increased risk for Alzheimer's disease (AD). After 60 years of age, >50% of DS subjects acquire dementia. Nevertheless, the age of onset is highly variable possibly because of both genetic and environmental factors. Genetics cannot be modified, but environmental risk factors present a potentially relevant intervention for DS persons at risk for AD. Among them, inflammation, important in AD of DS type, is potential target. Consistent with this hypothesis, chronic peripheral inflammation and infections may contribute to AD pathogenesis in DS. People with DS have an aggressive form of periodontitis characterized by rapid progression, significant bacterial and inflammatory burden, and an onset as early as 6 years of age. This review offers a hypothetical mechanistic link between periodontitis and AD in the DS population. Because periodontitis is a treatable condition, it may be a readily modifiable risk factor for AD.

INTRODUCTION: Hypertension, hypercholesterolemia, and obesity increase the risk of dementia. Although their detection is commonly followed by an introduction of treatment, little is known about how medications frequently used to treat vascular risk affect amyloid deposition. METHODS: A cross-sectional study of 156 subjects who underwent positron emission tomography with PiB. Using linear regression, we tested whether blood pressure, cholesterol, overweight/obese status, angiotensin receptor blockers (ARBs), beta-blockers, diuretics, angiotensin converting enzyme inhibitors, and statins predicted amyloid deposition. RESULTS: The use of ARBs (beta = -.15, P = .044) and diuretics (beta = -.20, P = .006) predicted less amyloid accumulation; older age (beta = .29, P < .001) and statins (beta = .23, P = .004) were related to greater amyloid deposition. Overweight and/or obese women had more cortical amyloid than their peers. DISCUSSION: Prospective studies should confirm effects of drugs and increased body weight on amyloid accumulation and establish whether they translate into measurable clinical outcomes. Women may be more susceptible to harmful effects of obesity.

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