and glycemic control.

If such therapeutic effects are possible, periodontal therapy should decrease the level of systemic inammatory markers and improve glycemic control. Nonsurgical periodontal therapy plus local minocycline has reduced the circulating levels of TNF-a in patients with diabetes and periodontitis. A strong correlation between reduced serum levels of TNF-a and a signicant decline in mean glycated hemoglobin (HbA1c) values was also shown in one study, which indicates better glycemic control. However, mechanical treatment of periodontal disease did not signicantly lower serum TNF-a levels. CRP and soluble E-selectin levels were also reduced signicantly after nonsurgical periodontal debridement. A meta-analysis of 10 intervention trials showed an average decline in HbA1c levels by 0.38% overall, by 0.66% in subjects with type 2 diabetes, and by 0.71% when antibiotics were also given. These results are not statistically signicant, but the clinical signicance should not be overlooked. Oral glucose-lowering agents in the less potent class only lower HbA1c levels between 0.5% and 1.0%. Other studies have noted signicant improvement of glycemic control with periodontal therapy. Therefore, periodontal treatment may represent an alternative or adjunctive therapy to improve insulin sensitivity and glycemic control for patients who have periodontitis plus diabetes. Discussion.Cytokine-induced inammatory state of periodontitis can contribute to a low-grade inammatory

state occurring in patients with diabetes. Low-grade inammation may aggravate insulin resistance and complicate glycemic control. On the basis of the anti-inammatory effects produced in cytokine levels, periodontal treatment may restore insulin sensitivity and improve glycemic control.

Clinical Signicance.Dentists may want to add opportunistic diabetes screening to their list of health-related assessments, basing a suspicion of diabetes on patient-reported data and clinical periodontal parameters. Therapy to improve insulin sensitivity and glycemic control may eventually include preventing recurrent periodontal disease and tooth mortality in patients with diabetes. Interactions between physicians and oral health practitioners should be encouraged to promote patients overall health and prevent complications associated with diabetes.

Tunes RS, Foss-Freitas MC, da Rocha Nogueira-Filho G: Impact of periodontitis on the diabetes-related inammatory status. J Can Dent Assoc 76:a35, 2010 Reprints available from G Nogueira, D344-790 Bannatyne Ave, Winnipeg, MB R3E 0W2; e-mail: nogueira@cc.umanitoba.ca

Mastication and cognitive function

Background.Mastication promotes and preserves general health, particularly cognitive function. Mastication increases cortical blood ow and activates many cortical areas of the somatosensory, supplementary motor, and insular cortices, along with the striatum, thalamus, and cerebellum. When subjects chewed immediately before a cognitive task, blood oxygen levels increased in the prefrontal cortex and hippocampus while they worked. This is essential for learning and memory and improves performance on the task itself. Thus, mastication may provide a drug-free, simple method for preventing senile dementia and stress-related disorders that often are accompanied by cognitive dysfunction such as impaired spatial memory and amnesia. Having fewer teeth, using dentures infrequently, and small maximal biting force are directly linked to developing dementia. The interactions between mastication and the cognitive processes of learning and memory were investigated, especially with respect to aging. Mastication, Learning, and Memory.Studies in rats show that occlusal hypofunction causes degenerative and abnormal changes in the periodontal mechanoreceptors that indicate sensory feedback from the periodontal ligaments is suppressed. Adult rats that have their molar teeth removed lose their ability to learn within 2 to 30 months. Lack of molars also affects fear-conditioned passive avoidance learning, indicating that reduced mastication suppresses overall hippocampal-related learning ability. The regular sensory stimulation provided by mastication appears to be especially critical for maintaining learning and memory function in senile rats. It was also noted that when the missing molars were replaced with articial crowns, even aged mice recovered learning ability. Reduced mastication also impairs spatial learning and suppresses cell proliferation in the dentate gyrus. The resulting increased production of cytokines, such as interleukins

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from the microglia, causes morphologic changes and functional deterioration of hippocampal astrocytes and neurons. Such changes are typical in the senile hippocampus, probably causing age-related cognitive decline. Better hippocampal function can be maintained if it is kept busy processing

peripheral sensory input from the environment. With age, reduced locomotor activity and senescent peripheral organs provide insufcient sensory input, leading to a decline in hippocampal function. Eliminating the sensory input provided through mastication may accelerate the process of

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senility. Attenuated hippocampal function may also lead to a lack of control of corticosteroid secretion. Excessive corticosterone suppresses hippocampal-dependent learning and memory processes, which could also explain the decline in spatial memory in aged molarless animals. When functional teeth are lost for months, the digestive and absorptive functions are impaired because of changes in maxillomandibular relationships and reduced secretion of saliva and gastric acid. In human beings, the loss of teeth or disuse of dentures induces malnutrition in many cases. However, moderately restricting calories helps to protect against age-related hippocampal decits. The relationship of motor or sensory events during mastication and hippocampal function suppression requires further clarication, especially with the several confounding factors that may play a role. In human beings, chewing or sucking on a piece of sugarfree gum improved immediate or delayed word recall, sensitivity of a spatial working-memory task, and reaction time of a numeric working-memory task. Chewing increased the blood ow to various cortical and cerebellar regions and perhaps the availability of blood-borne glucose, which improves cognitive performance. The effects of chewing gum and consuming glucose were additive in improving memory task performance. Chewing also increased heart rate, reecting enhanced sympathetic activity to increase blood glucose level and/or arousal level during a cognitive task. Sustained cognitive task performance may benet particularly from mastication. Masticatory sensory input may maintain concentration levels by activating the reticular formation arousal centers. Gum chewing alone, without performing a specic cognitive task, helps to recruit the hippocampus and the prefrontal cortex, which plays a very important role in learning arbitrary associations between sensory cues and determining voluntary actions needed to accomplish a task. This may help compensate for the cognitive performance decline that comes with aging. Mastication and Stress.The hippocampus is not only one of the rst areas to be affected by aging but also one of the rst to be structurally and functionally altered by severe and inescapable stress. With excessive or prolonged stress, the hypothalamic-pituitary-adrenal (HPA) axis is stimulated and

causes the adrenal cortex to secrete corticosterone, which suppresses synaptic plasticity, the ability to change the electrical connectivity between neurons in the hippocampus, because of which learning and memory are impaired. Mastication may inhibit this systemic stress response. It suppresses stress-related increases in core body temperature, blood pressure, and plasma adrenaline levels. Mastication also prevents immune activation of interleukin-1b and interleukin-6, which prevents stress ulcers from developing in the stomach. In addition, mastication suppresses the expression of corticotropin-releasing factor and c-Fos, the phosphorylation of extracellular signal-regulated kinases 1 and 2, oxidative stress, and nitric oxide production in the paraventricular nucleus of the hypothalamus. These reductions in brain markers correlate with reduced levels of circulating corticosterone, cortisol, and adrenocorticotropic hormone, reducing the development of temporomandibular disorders and orofacial pain. A mastication-induced increase in the level of brain histamine helps to restore stress-attenuated synaptic plasticity in the hippocampal neurons and aids memory function. Mastication may also modulate the catecholaminergic neurotransmission in brain areas where the perception of stress is regulated, altering affective states and behavior and decreasing anxiety after stress exposure. In human beings, chewing was noted to improve alertness, reduce anxiety, diminish stress, and lower salivary cortisol levels. Various studies indicate that the perception of daily stress may be reduced by mastication. Senile cognitive decits may also be reduced through this stresselimination because increased cortisol levels in elderly persons accompany impaired cognitive abilities. Increased serotonin levels have accompanied mastication, contributing to a reduction in stress perception. Chewing and other oral-buccal movements activate serotonin neurons. Serotonin receptors are seen throughout the hypothalamus and hippocampus and regulate circulating corticosteroid levels. Selective serotonin reuptake inhibitors are used as antidepressants to treat depression and anxiety disorders, lending support to the role of mastication in reducing stress-induced corticosteroid secretion and stress-related anxiety. Occlusal Disharmony.When there is abnormal sensory input derived from occlusal disharmony, learning and memory abilities are suppressed. This is similar to the reduced

:
Fig 1.Possible neuronal and humoral pathways from the oral cavity to the hippocampus. Arrows indicate neuronal or humoral connections. A, Major signaling pathways of somatosensory stimuli from the oral cavity. B, Modulation of the hippocampus via reticular formation. C, Modulation of the hippocampus via HPA axis activation. D, Modulation of the hippocampus via saliva-derived NGF. Note that only focused pathways are represented. Abbreviations: ACTH, Adrenocorticotropic hormone; Adr, adrenal cortex; CORT, corticosteroids; CRF, corticotropin releasing factor; Ent, entorhinal cortex; Hip, hippocampus; Hyp, hypothalamus; PF, prefrontal cortex; PM, premotor cortex; Me5, mesencephalic trigeminal nucleus; ME, median eminence; Mo5, trigeminal motor nucleus; NGF, nerve growth factor; OC, oral cavity; Pit, pituitary; Pr5, principal sensory trigeminal nucleus; RF, reticular formation; S1, primary somatosensory cortex; SA, somatosensory association area; Su5, supratrigeminal nucleus; SG, salivary gland; TG, trigeminal ganglion; VP, ventral posterior thalamic nucleus. (Courtesy of Ono Y, Yamamoto T, Kubo K-Y, et al: Occlusion and brain function: Mastication as a prevention of cognitive dysfunction. J Oral Rehab 37:624-640, 2010.)

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mastication. In rodents and monkeys, experimental occlusal disharmony produces higher plasma corticosterone and urine cortisol levels, reecting acute stress. These responses persist for weeks. When the occlusal disharmony is returned to normal, the cortisol levels returned to basal values. Learning decits in mice can be avoided by administering metyrapone, which suppresses corticosterone synthesis. Occlusal disharmony also triggers changes in monoaminergic responses. This can manifest as altered hippocampal function or accelerated stress response of the HPA axis, thereby resulting in greater corticosteroid secretion. Occlusal disharmony in human beings is not an acute but a chronic stress. Higher levels of corticosteroids or other stress-activated neuronal responses can trigger cognitive impairments, especially in elderly persons. Thus, denture design is particularly important for these patients to avoid producing cognitive decits. Oral CavityHippocampus Connections.Although no direct interactions have been identied between the oral cavity and the hippocampus, two indirect pathways are possible: neuronal and humoral. The trigeminal sensory system conducts sensory information from the oral cavity to the central nervous system through various routes (Fig 1). In addition, various growth factors produced in the salivary glands respond to mastication. These may affect the central nervous system in various ways. Discussion.Evidence suggests that mastication sends signicant amounts of information to the brain and can

inuence the processes of learning and memory based in the hippocampus. Mastication helps to maintain cognitive function, particularly in elderly persons whose function has been altered by aging or stress. Future studies are needed to clarify the pathways by which mastication interferes with the HPA axis, particularly in human subjects.

Clinical Signicance.If mastication is linked to cognitive function, especially in the elderly people, dentists may serve as particularly important facilitators of cognitive health. Occlusal disharmony can produce stress, which seems to interfere with cognitive abilities. Ensuring that the dentures and other restorations in the patients in this study provide a comfortable occlusion will help reduce stress and enhance the ability of these persons to learn and maintain memory functions. Helping patients maintain their teeth in proper occlusal relationships throughout their lifetime takes on greater signicance as well. Further research may identify even more important linkages between mastication and cognition.

Ono Y, Yamamoto T, Kubo K-Y, et al: Occlusion and brain function: Mastication as a prevention of cognitive dysfunction. J Oral Rehab 37:624-640, 2010 Reprints available from Y Ono, Dept of Physiology and Neuroscience, Kanagawa Dental College, 82 Inaoka-cho Yokosuka Kanagawa, 238-8580, Japan; e-mail: yumic@kdcnet.ac.jp

Oral-Systemic Health
Periodontitis and systemic disease
Background.Studies have linked periodontitis with various cardiovascular and autoimmune diseases. The relationship could reect the disease predisposing to periodontitis, the periodontitis predisposing to the disease, coincidental ndings related to an unknown confounding factor, or periodontitis causing the disease only when combined with a confounding factor. All these mechanisms may also be present to various degrees. The fact remains that any link between systemic disease and periodontitis has important implications for treatment and prevention. To avoid selection bias, which could skew the results of studies focused on links between periodontitis and other diseases, the existence of relationships between periodontitis and cardiovascular and autoimmune diseases was investigated using randomly selected dental records from a dental or periodontal clinic. Methods.The 1276 dental records represented 588 patients attending a dental clinic and 688 attending a periodontal clinic. A health questionnaire was used to evaluate data on the prevalence of cardiovascular and autoimmune diseases in the population. Periodontitis prevalence was determined from the dental records. Results.Using uncontrolled analysis data from the periodontal clinics, patients with periodontitis tended to have signicantly higher prevalence of hypertension, diabetes mellitus (DM), and rheumatoid arthritis (RA) than patients without periodontitis. Data from the dental clinics

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