Association between cognitive health and masticatory conditions: a descriptive study of the national database of the universal healthcare system in Japan

Introduction

Dementia is a degenerative disease characterized by progressive deterioration in mental abilities affecting behavior, cognition, and function. Alzheimer’s disease (AD) is the leading cause of dementia in the geriatric population and the fifth leading cause of death in people over the age of 65 in the US [1]. With the aging population growing as people live longer, globally up to 131.5 million people are projected to be diagnosed with dementia by 2050 [1, 2]. Age related chronic disease has become a global health concern and financial burden that impact individuals with dementia, their family and friends, as well as society as a whole.

The pathologic hallmarks of AD, based on autopsy, are characterized by aggregates of extracellular β-amyloid peptide (Aβ), and intracellular neurofibrillary tangles of tau protein. In addition to pathophysiologic mechanisms, recent studies have focused on factors that lead to neuronal damage prior to cognitive decline and prevention strategies using physical and/or cognitive training. For example, participation in leisure activities, playing board games, musical instruments, or social network activity are essential factors for the maintenance of cognitive health [3–5]. Regular exercise and dietary intake of antioxidants or foods rich in anti-inflammatory components are also believed to help maintain cognitive function [6–9]. These preventative measures are additionally beneficial to improve comorbid conditions that accelerate brain aging in AD patients such as cardiovascular disease, and diabetes [10, 11].

In the field of dentistry, several studies have investigated the relationship between oral function and cognitive function. Tooth loss effects spatial memory and increases the risk of diminished cognitive function suggesting that reduced masticatory function may be a risk factor for dementia [12–14]. Animal studies indicate that reduced masticatory ability due to missing molars leads to impaired spatial memory and degeneration of hippocampal neurons [15–17]. A study of 16 patients with mild Alzheimer’s disease (AD) had reduced masticatory and cognitive function when compared to healthy non-AD patients [13]. Another study indicated that the risk of developing AD and dementia was 1.63 times greater in the elderly with no teeth when compared to those with 20 or more teeth [14]. A longitudinal study found that the higher the number of teeth lost, the faster cognitive function declined [18]. Though an inverse association between the number of remaining teeth and cognitive function was suggested, the subjects of these studies were either of a small sample or from a limited geographic area.

Rising evidence on the effects of chewing in increased attention, memory, and cognitive processing demonstrates that masticatory condition has a link to cognitive health [19]. Since exosomes can translocate from muscle cells to nerve cells as cargo vehicles, our hypothetic mechanism for connecting mastication and cognitive health is that muscle activity can directly affect amyloid β burden. In our recently published study [20, 21], we tested our hypothesis that muscle cells can package neprilysin in exosomes in response to a neuromuscular signal and retrograde axonal transport to the brain. Neprilysin (NEP), a member of metalloproteases, aids with clearance of Aβ, plays another role in the pathogenesis of AD and serves as molecular marker of disease [22]. In vitro experiments, cholinergic stimulation of myotube cells increases quantities of both the exosome secreted into the culture medium and the amount of exosomal NEP. In the presence of carbachol, a cholinergic stimulant, muscle cytosolic NEP decreased while exosomal-NEP secretion increased, which proved that exosomes packaged and secreted NEP protein in muscle cells. In vivo experiments, fluorescent labeled myotube cells derived exosomes were injected into masseter muscle of euthanized mice and were found in both trigeminal and hippocampal tissue lysate. Results showed that the hippocampus and cerebrum contained NEP protein in the absence of mRNA, which suggested that NEP is not native to the brain, and NEP is transported into the brain via retrograde axonal transport. It was also confirmed that transgenically expressed NEP was transferred to the hippocampus via the trigeminal nerve. If these NEP rich exosomes were able to gain access to the brain via retrograde transport, then there is the possibility that masticatory activity could contribute to reducing the Aβ plaque burden in the brain. The trigeminal nerve is the largest cranial nerve, and it innervates the masseter muscles, which are the strongest among the muscles of mastication. This anatomical fact led to our tested hypothesis that masseter muscles send exosomal NEP to the brain in response to cholinergic stimulation during chewing, thus bypassing the blood-brain barrier (BBB).

These findings demonstrate that a novel mechanism for the connection of the oral cavity to the brain exists. Neuroprotective agents synthesized by the muscles of mastication on stimulation can travel to the brain [20, 21]. These findings then led us to generate the current hypothesis that a lack of mastication with natural teeth, due to tooth loss, may negatively affect cognitive health. The field of Prosthodontics supports this hypothesis based on the determinants of maximally attainable bite force, which is an increased bite force with an increased number of teeth and occlusal tooth contacts [23]. The masticatory/chewing forces generated by a removable prosthesis is 30~60% of what the natural dentition is and 10~40% of it for compete dentures. Other studies also indicate that when the function of the masticatory system is reduced due to loss of occlusal support, removable prostheses do not compensate sufficiently to attain the previous maximum bite force [24–26].

Here, we report oral function, especially masticatory function, is associated with cognitive function in patients with Alzheimer’s’ disease and other dementias in a Japanese population. Japan has a Universal Healthcare System (UHCS) where medical and dental care are recorded together. In 2011, the Japanese government, Ministry of Health, Labor and Welfare established that third parties can access the UHCS database under government guidelines. Our global team was the first dental research group whose research proposal was approved to assess the association between mastication and cognitive impairment. This study is a descriptive data analysis to examine if there is an association between cognitive function and masticatory conditions, which we hope will lead to future case-controlled or cohort studies.

Results

Discussion

In the cognitive impairment group for both age groups, a higher percentage of patients exhibiting no natural tooth-tooth contacts (Classification D+E+F) was identified and compared to the control group (Figure 1). This reveals that individuals with signs of cognitive deterioration at the time of data collection had reduced masticatory function with the loss of some or all-natural tooth-tooth contacts. On the other hand, individuals with no signs of cognitive deterioration, at the time of data collection, had better masticatory function with more natural tooth-tooth contacts. This data is in consistent with the findings that a lack of posterior occlusion predicted the incidence of cognitive decline [27, 28]. Our result is additionally convincing and significant because the dataset consists of a large sample size, where almost all of the dental and medical treatments within one healthcare system were recorded and analyzed and not data from self-reports or surveys.

In mouse model studies, evidence suggests the negative effects of masticatory deficiency and tooth loss on neurogenesis, present as a risk factor for cognitive dysfunction [29, 30]. A systematic and meta-analytic review also concludes a 20% higher risk for developing cognitive decline in individuals with suboptimal dentitions (<20 teeth) and draws the links between oral and general health [12]. Though the mechanism of this relationship is not clearly understood, studies have found that during mastication, there is an increase of cortical blood flow in somatosensory cortical areas as well as increased oxygen levels in the prefrontal cortex and hippocampus [31]. The neurovascular aspects of AD pathophysiology, cerebral hypoperfusion and reduced glucose transport progresses to cognitive decline and hippocampal atrophy in the early stages of AD [31]. A most recent MRI study also showed significantly smaller total gray matter volume and regional reduction of gray matter in the left hippocampus and parahippocampus associated with an increased number of missing teeth in subjects with mild cognitive impairment of Alzheimer’s disease [32]. Moreover, a 9-year longitudinal study found that individuals with complete or partial tooth loss had significantly lower total brain volume and gray matter volume [33].

A possible explanation for the mechanism relating the brain to the oral cavity is that cranial nerves bypass the blood-brain barrier. This is possible via the trigeminal nerve which innervates the masseter muscles. The masseter muscles are responsible for chewing and forming food boluses for swallowing with masticatory movement generated by the neuronal network in the brainstem [34]. The trigeminal nerve is the largest cranial nerve that exits the cranium carrying motor innervation to the muscles of mastication and receiving sensory inputs from proprioceptors of the teeth. Based on our previously published study [20, 21], we hypothesize that brain housekeeping molecules may travel from the masticatory muscles to the brain through the trigeminal nerve after stimulation from mastication. Clearance of amyloid-β reduces toxicity and results in maintenance of neuronal health, thereby, possibly preventing cognitive decline.

The action of mastication involves movements of the jaw, translation and rotation. When teeth are biting in functional contacts, mechanoreceptors within the periodontium activate sensorimotor circuits and the signals of feedback and feedforward promote rhythmic jaw movements [34]. In response to repetitive oral motor tasks, the associated cortical network undergoes structural and function change overtime, which is called neuroplasticity [34]. As a result of tooth loss, mass and strength of masticatory muscles decrease, leading to difficulty in chewing while diminished afferent signals reduce neuroplasticity [35]. In addition, with aging, the number of teeth present, occlusal force and masseter muscle thickness all decrease [36]. Complete denture wearers are essentially in a state of masticatory incapacity while removable partial dentures offer only a poor addition to occlusion [37]. After complete denture rehabilitation, studies have observed a subsequent increase in muscle thickness, though remaining thinner than that of dentate individuals [38]. Reduced masticatory ability was found to impair spatial memory and learning ability linked to morphological changes, decreased neurotrophic protein expression and activities in the hippocampus [39].

In the present study, we found the crude odds ratio with a significance level of p<0.0001 which strongly supports the hypothesis that a lack of mastication by the natural teeth due to tooth loss may negatively impact cognitive health. Although a removable prosthesis contributes to reproducing some mastication with denture teeth, maintaining all-natural tooth contact is the ideal for obtaining maximum bilateral bite force. In both groupings (A+B+C vs. D+E+F and A vs. F), the odds ratio in advanced elderly groups is smaller than early elderly group. This can be explained by the fact that the bite/occlusal force continuously decreases after age 50 [23, 40].

A major limitation of this study is the lack of information on confounding variables such as population demographics, other systematic diseases, and socioeconomic status. There is also a lack of information regarding other diseases causing cognitive impairment such as stroke, schizophrenia, alcohol, or drug-induced mental disorders. In future studies, known risk factors should be included to eliminate potential bias. However, we were able to detect an association between cognitive function and masticatory condition among elderly adults. Although removable prosthesis wear serves as a marker for tooth loss and a good predictor of cognitive impairment, the association between tooth loss and cognitive impairment was only suggested. Direct causative roles are yet to be proven. Multiple studies have shown the association between the tooth loss and diminished cognitive function, however, there remains conflicting evidence in longitudinal studies regarding the risk of developing incident dementia and tooth loss due to methodological limitations [28, 41]. Future studies using longitudinal data with an extensive period and larger sample size are needed to confirm and test these associations.

To the best of our knowledge, this study is the first to look at a large elderly population diagnosed with multiple stages of cognitive impairment and compare their masticatory conditions. Japan’s UHCS database used for this descriptive analysis covered 33 million patients (age >65) which is more than 94% of the population, and the masticatory condition of 70% of those patients (more than 23 million patients) was investigated. Supplement to the current knowledge [42, 43], our data demonstrate a possible association between oral and cognitive health. The mechanisms of these changes require further elucidation. The implications of this study emphasize the importance of oral health throughout life and the maintenance of natural teeth to allow individuals to have a better quality of life both physically and mentally.

Materials and Methods