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Tooth loss is associated with mild memory impairment in the elderly: The Fujiwara-kyo study
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Research Report
Tooth loss is associated with mild memory impairment in the elderly: The Fujiwara-kyo study Nozomi Okamoto a,⁎, Masayuki Morikawa b,c , Kensuke Okamoto d,e , Noboru Habu a , Kan Hazaki f , Akihiro Harano g,h , Junko Iwamoto i , Kimiko Tomioka a , Keigo Saeki a , Norio Kurumatani a a
Department of Community Health and Epidemiology, Nara Medical University, Japan Sakai City Mental Health Center, Japan c Department of Psychiatry, Nara Medical University, Japan d Department of Oral and Maxillofacial Surgery, Nara Kasuga Hospital, Japan e Department of Oral and Maxillofacial Surgery, Nara Medical University, Japan f Department of Physical Therapy, Osaka Electro-Communication University, Japan g Department of Orthopedic Surgery, Higashiosaka City General Hospital, Japan h Department of Orthopedic Surgery, Nara Medical University, Japan i Department of Indoor Environmental Medicine, Nara Medical University, Japan b
A R T I C LE I N FO
AB S T R A C T
Article history:
It has been reported that tooth loss is associated with Alzheimer's disease (AD) and
Accepted 22 June 2010
dementia. The purpose of this study was to investigate the association between tooth loss
Available online 1 July 2010
and mild memory impairment (MMI) among the elderly. We examined 3,061 community residents aged 65 years or older who had a score of 24 or more on the Mini-Mental State
Keywords:
Examination. The subjects were divided according to their score for the three-word delayed
Tooth loss
recall test into control (score: 3 or 2) and MMI (score: 1 or 0) subjects. The subjects underwent
Memory
a dental examination, an interview to determine their medical history, a self-administered
Dementia
questionnaire (inclusive of higher-level functional capacity, drinking and smoking habits,
Community-based
and frequency of going out), and a 10-m walking test. Fewer remaining teeth, going out once a week or less frequently, and a slow walking speed on a 10-m walking test were found at a significantly higher prevalence in the MMI group (n = 101) than in the control group (n = 2,960), after adjustment for sex, age, and the level of education. Multiple logistic regression analysis using these items revealed that the odds ratio of 0–10 remaining teeth for MMI was 1.71 (95% CI 1.05–2.78), compared to individuals with 22–32 remaining teeth. A significant increase was also found in a trend test to examine the increasing odds ratios of 22–32, 11–21, and 0–10 remaining teeth. We consider that tooth loss is associated with MMI later in life. © 2010 Elsevier B.V. All rights reserved.
⁎ Corresponding author. Department of Community Health and Epidemiology, Nara Medical University, Shijo-cho 840, Kashihara city, Nara, zip code 6348521, Japan. Fax: +81 744 29 0673. E-mail address: [email protected] (N. Okamoto). Abbreviations: AD, Alzheimer's disease; MMI, mild memory impairment; MMSE, Mini-Mental State Examination; Recall, three-word delayed recall test; GDS, Geriatric Depression Scale short version; CPI, community periodontal index; MCI, mild cognitive impairment; CRP, plasma C-reactive protein; IL, interleukin; CI, confidence interval 0006-8993/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2010.06.054
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1.
Introduction
Several studies have reported that tooth loss is associated with Alzheimer's disease (AD) and dementia (Gatz et al., 2006; Stein et al., 2007). The biological bases are as mentioned below. First, it has been hypothesized (Kamer et al., 2008) that periodontal disease-derived inflammatory molecules, bacteria, and bacterial products enhance brain inflammation (Blasko and Grubeck-Loebenstein, 2003; Rogers, 2008). Tooth loss is an indicator of periodontal disease (Desvarieux et al., 2003; Humphrey et al., 2008). Second, tooth loss may induce nutritional deficits (Kim et al., 2007) and deprivation of sensory information input during mastication (Kondo et al., 1994). It has been reported that, among persons with mild memory impairment (MMI), 21.2% progress to illnesses with dementia, including AD (10.6%), vascular dementia (4.8%), or other types of dementia (5.8%), over a period of 5 years (Ishikawa and Ikeda, 2007). These individuals represent a high-risk population for dementia. MMI was defined as (Ishikawa et al., 2006): (1) no impairment of the activities of daily living (ADL); (2) normal general cognitive function, as determined using the Mini-Mental State Examination (MMSE) ≥ 24 (Folstein et al., 1975); (3) objective memory impairment, assessed by the three-word delayed recall (Recall) test (score:1 or 0) in the MMSE; (4) absence of dementia or depression, diagnosed by geriatric neuropsychiatrists according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd edn., revised (DSM-Ш R) criteria (American Psychiatric Association, 1987). We hypothesized that tooth loss may also be associated with a preclinical stage of AD and dementia. To our knowledge, few studies have examined this subject. To investigate our hypothesis in a community-based survey, subjects with MMI and elderly controls were identified operationally using the MMSE and Geriatric Depression Scale short version (GDS) (Schreiner et al., 2003). The subjects were also examined for their dental characteristics, serum albumin level, body mass index, medical history, higher-level functional capacity, drinking and smoking habits, frequency of going out, and their performance on a 10-m walking test. The purpose of this cross-sectional study was twofold: 1) to compare the number of remaining teeth of MMI subjects with those of elderly controls, and 2) to determine whether the relationship between the number of remaining teeth and MMI was modulated by other explanatory variables.
2.
Results
Among the 3,061 subjects available for analysis, MMI was found in 4.5% (69/1,544) of male subjects and 2.1% (32/1,517), a significantly lower percentage, of female subjects. The demographic characteristics of the control and MMI groups are presented in Table 1. Significant differences were found between the two groups for the median age; 71.0 (interquartile range, 7.0) years in the control group vs. 74.0 (9.0) years in the MMI group, length of education, MMSE-total, and the number of remaining teeth. Fig. 1 shows the cumulative percentages of the remaining teeth. The median number (interquartile range) of remaining teeth in the control group vs. the MMI group were 24.0 (10.0) vs.
Table 1 – Demographic characteristics of the control and MMI groups. Variables
Control (n = 2960 ) %
MMI P (n = 101 ) value ⁎ %
Sex Age (years)
50.2 37.3 33.7 20.1 7.3 1.7 25.3
31.7 21.8 28.7 30.7 12.9 5.9 36.6
< 0.01 < 0.01
28.0 (4.0)
26.0 (2.0)
< 0.01
22.0 (15.0)
16.0 (21.5)
< 0.01
Female 65–69 70–74 75–79 80–84 85 or more Length of Less than education 12 years MMSE-total Median (interquartile range) Number of Median remaining teeth (interquartile range)
0.01
Data are given as % or median (interquartile range). MMI, mild memory impairment. ⁎ Differences between the two groups were analyzed by the chi-square test or Mann–Whitney's U test.
25.0 (20.5) (Mann–Whitney's test, P = 0.79) for the 65–69 years age category, 21.0 (16.0) vs. 15.5 (18.0) (P = 0.12) for the 70– 79 years age category, and 11.0 (20.0) vs. 3.0 (17.0) (P = 0.08) for the 80 years or older age category, respectively. No significant differences were found in the distribution of the remaining teeth between the two groups for any age categories (by the Kolmogorov–Smirnov test). Table 2 shows the relationships between MMI and dental characteristics. The number of remaining teeth was categorized into three equal categories: 22–32, 11–21, and 0–10. In univariate analyses, the percentage of individuals with 22–32 remaining teeth was significantly lower in the MMI group than in the control group. No significant differences were found in the community periodontal index (CPI) code and dental uncleanliness between the two groups. After adjustment for sex, age, and length of education, the odds ratio of 0–10 to 22–32 remaining teeth for MMI was 1.72 (95% CI 1.06–2.80). A significant increase was also found in a trend test performed to examine the increase in the odds ratios of 22–32, 11–21, and 0–10 remaining teeth (P = 0.03). Table 3 shows the relationships between MMI and other explanatory variables. In univariate analyses, greater size of the household, drinking at least 1 day a week, going out once a week or less, and a slow walking speed on a 10-m walking test were found at a significantly higher prevalence, and having never smoked was found at a significant lower prevalence in the MMI group than in the control group. After adjustment for sex, age, and length of education, the odds ratio of going out once a week or less frequently was 1.96 (95% CI 1.10–3.49), this factor demonstrated a significant relationship with MMI. The relationship between the risk of MMI and the results of a 10-m walking test was marginally significant (P = 0.07). Table 4 shows the results of the multiple logistic regression analysis using variables that were significantly related even after adjustment for sex, age, and length of education. Hosmer–Lemeshow analyses provided no evidence for lack
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Fig. 1 – The cumulative percentages of the number of remaining teeth.
of fit. The odds ratio of 0–10 to 22–32 remaining teeth for MMI was 1.71 (95% CI 1.05–2.78), demonstrating a significant relationship. The relationship between the MMI risk and the number of remaining teeth was also significant when examined by the trend test for increasing odds ratios (P = 0.03).
3.
Discussion
The prevalence of MMI examined in our study was 3.0% (MMI, n = 101; participants in baseline examination, n = 3,389). The reported prevalence of community-based mild cognitive impairment (MCI), diagnosed on the criteria of Petersen et al. (1999), after several standardized memory examinations, was 4.9% according to the Tajiri Project in Japan (Meguro et al., 2004), and 2.9–4.0% according to the Monongahela Valley Independent Elders Survey (Ganguli et al., 2004). The prevalence of MMI in this study was consistent with these values. The individuals with MMI selected operationally by the simple
method are considered to represent a population approximating the community-based MCI. In the analyses conducted with adjustment for the influences of sex, age, and length of education, we observed that fewer remaining teeth and a lower frequency of going out were significantly correlated to the risk of MMI (Tables 2 and 3). Consistent with a previous report, which documented that decreased physical functions were associated with decreased cognitive functions (Tabbarah et al., 2002), we observed a marginally significant relationship between a slower speed on the 10-m walking test and the risk of MMI (Table 3). We considered that a lower frequency of going out was associated with MMI as this activity requires the maintenance of physical function, and that going out for leisure activities may be associated with a decreased risk of dementia (Karp et al., 2006; Wang et al., 2002). There were no significant relationships between the history of any disease and MMI. The relationship between the presence of MMI and subclinical cerebrovascular disease might have been
Table 2 – Relationships between MMI and dental characteristics. Variables Number of remaining teeth
22–32 11–21 0–10 CPI Ineligible ‡ Code 0 or 1 or 2 Code 3 Code 4 Any one of plaque, calculus, uncleanliness Present of dentures, and coating of tongue
Control (n = 2960) %
MMI (n = 101) %
50.4 25.3 24.3 13.2 26.3
35.6 22.8 41.6 23.8 18.7
38.3 22.2 46.5
32.7 24.8 55.4
P Adjusted odds ratio † P value ⁎ (95% CI) value † < 0.01
1 1.08 (0.63–1.85) 1.72 (1.06–2.80)
0.34
1
0.09
1.06 (0.60–1.89) 1.25 (0.68–2.32) 1.10 (0.73–1.66)
MMI, mild memory impairment; CI, confidence interval; CPI, community periodontal index. ⁎ Differences between the two groups were analyzed by the chi-square test. † Adjusted for sex, age, and length of education. ‡ Persons in whom none of the six fractions could be evaluated because of the low number of remaining teeth.
P for trend 0.03
0.79 0.03 0.47 0.84 0.48 0.65
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Table 3 – Relationships between MMI and other explanatory variables. Variables Spouse Number of household members Serum albumin Body mass index Cancer Cerebrovascular disease Myocardial infarction Diabetes mellitus Hypertension Intellectual activity Social role Drinking habit
Smoking habit
Frequency of going out 10-m walking test (s)
Control (n = 2960) %
MMI (n = 101) %
P value ⁎
Adjusted odds ratio † (95% CI)
P value †
None Median (interquartile range) Less than 3.8 g/dl Less than 18.5 Positive history Positive history
21.5 2 (1)
18.8 2 (3)
0.62 0.02
1.14 (0.65–2.01) 1.09 (0.97–1.21)
0.65 0.16
0.6 5.9 9.0 5.7
0 8.9 14.9 9.9
1.00 0.20 0.05 0.08
1.44 (0.70–2.94) 1.50 (0.85–2.66) 1.60 (0.81–3.16)
0.32 0.17 0.17
Positive history Positive history Positive history Disability Disability At least 1 day a week Ethanol intake 40 g or more per day Never Ex-smoker Current smoker Once a week or less frequent Median (interquartile range)
2.7 11.1 39.4 16.6 24.2 38.8 28.9
3.0 12.9 39.6 12.0 20.0 51.5 25.5
0.75 0.63 0.97 0.27 0.41 0.01 0.75
1.06 0.99 0.93 0.63 0.65 1.33 0.84
(0.33–3.47) (0.55–1.82) (0.62–1.40) (0.36–1.25) (0.39–1.07) (0.84–2.09) (0.43–1.62)
0.92 0.99 0.72 0.21 0.09 0.22 0.60
57.8 32.4 9.8 7.4
43.6 45.5 10.9 14.9
<0.01
0.01
1 1.13 (0.63–2.00) 1.05 (0.49–2.27) 1.96 (1.10–3.49)
0.68 0.90 0.02
5.30 (1.30)
5.58 (1.51)
0.01
1.13 (0.99–1.29)
0.07
P for trend
0.47
MMI, mild memory impairment; CI, confidence interval. ⁎ Differences between the two groups were analyzed by the chi-square test or Mann–Whitney's U test. † Adjusted for sex, age, and length of education.
underestimated because of the lack of brain imaging data (Gauthier et al., 2006). As indicated in Table 4, after adjustment for sex, age, length of education, frequency of going out, and the results of the 10-m waking test, the odds ratio of less than one-third remaining teeth for MMI was 1.71 (95% CI 1.05–2.78) compared to individuals with more than two-thirds remaining teeth. Tooth loss may partly contribute to MMI, considering that the odds ratio was not so high and no significant differences
Table 4 – Relationships between MMI and the number of remaining teeth. Variables Sex Age (years)
Women Per 1-year increase Length of Less than education 12 years Number of 22–32 remaining teeth 11–21 0–10 Frequency of Once a week going out or less frequent 10-m walking Per 1-s test (s) increase
Adjusted odds P P for ratio ⁎ 95% (CI) value ⁎ trend 0.41 (0.26–0.64) 1.06 (1.02–1.11)
< 0.01 < 0.01
1.43 (0.92–2.20)
0.11
1 1.05 (0.61–1.82) 1.71 (1.05–2.78) 1.94 (1.08–3.48)
0.85 0.03 0.03
1.10 (0.96–1.26)
0.17
0.03
MMI, mild memory impairment; CI, confidence interval. ⁎ The full model included the following: sex, age, length of education, number of remaining teeth, frequency of going out, and the result of the 10-m walking test.
were observed in the distribution of the remaining teeth between the control and MMI groups (Fig. 1). Four plausible biological explanations for the relationship between tooth loss and the risk for MMI can be proposed: 1) presence of periodontal disease; 2) genetic risk factors related to both periodontal disease and MMI; 3) a decrease in the number of periodontal mechanoreceptors due to tooth loss; and 4) further risk factors related to both tooth loss and MMI. Periodontal disease is a common cause of tooth loss in the elderly. It has been suggested that periodontal disease, a chronic infection of the tissue surrounding the teeth caused by gramnegative anaerobic bacteria, is related to not only a localized inflammatory reaction represented by alveolar bone resorption (Graves, 2008; Silva et al., 2007), but also a systemic inflammation, based on the elevation of plasma C-reactive protein (CRP) found in periodontal disease patients (Paraskevas et al., 2008) and the improvement in the blood levels of high-sensitivity CRP, interleukin (IL)-6, and fibrinogen after non-surgical therapy for periodontal disease (Marcaccini et al., 2009; Piconi et al., 2009). A model of the proposed pathways between periodontal disease and AD suggests the transmigration of proinflammatory molecules derived from periodontal tissue, pathogens, and their products from the bloodstream to the brain (Watts et al., 2008). The presence of inflammatory molecules and alterations of the immune response in the cerebrospinal fluid, plasma, and serum may be involved in the development of MCI (Galimberti et al., 2006a, 2006b; Guerreiro et al., 2007; Magaki et al., 2007, 2008). Periodontal disease may contribute to MMI through systemic inflammation. There is evidence indicating that the risk of AD is influenced by gene polymorphisms in inflammatory cytokines, e.g., IL-1, IL-
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6, and tumor necrosis factor-α (McGeer and McGeer, 2001). The risk for AD is significantly higher in subjects with the IL-1A (−889 position of the regulatory region) 2, 2 genotype in comparison to subjects with the IL-1A 1, 2 or IL-1A 1, 1 genotypes (Rainero et al., 2004). Homozygosity for allele 2 of IL-1A and allele 2 of IL-1B (+3953 position in exon 5) is associated with an increased risk for AD (Nicoll et al., 2000). On the other hand, an association between allele 2 of IL-1A, allele 2 of IL-1B, and an increased severity of periodontal disease has been reported (Galbraith et al., 1999; Kornman et al., 1997). Therefore, several polymorphic cytokine genotypes may be related to periodontal disease and the risk of MMI. Functional deterioration of the cholinergic neuronal system in the parietal cortex (Kato et al., 1997), a decrease in the number of choline acetyltransferase-positive neurons present in the nucleus of the diagonal band/medical septal nucleus (Terasawa et al., 2002) and a decrease in the number of pyramidal cells in the hippocampus (Onozuka et al., 1999) have been found in tooth crown-cut off or tooth-loss rats. A decrease in the number of periodontal mechanoreceptors, which are sensory receptors, caused by multiple tooth loss (Jacobs and Steenberghe, 2006 has been suggested to exert some influence on the brain sites involved in learning and memory function (Yamazaki et al., 2008). Tooth loss is also impacted upon by several additional factors that may provide alternative explanations for the association found in the present study. For example, tooth loss may be an indicator of low socioeconomic status and life stressors that may play a role in the progression of MMI later in life. Head trauma with maxillofacial injuries and the lack of a healthy diet may also be related to both tooth loss and MMI. Further studies are required to investigate possible risk factors related to both tooth loss and MMI. No significant relationships were found between MMI and the maximum individual CPI code, or between MMI and dental uncleanliness (Table 2). A higher prevalence of “ineligible” and a lower prevalence of “code 0 or 1 or 2” were found in the MMI group than in the control group; therefore, we considered that periodontal disease is associated with MMI. The presence or absence of dental plaque, calculus, uncleanliness of dentures, and a coating of the tongue allow for the evaluation of dental health behavior. It may be natural that no significant difference was found in dental uncleanliness between the control and MMI groups because MMI individuals had no impairment in their ADL. Several limitations of the present study merit consideration. First, the data were derived from a cross-sectional study; thus, we can only hypothesize the biological credibility of tooth loss on MMI. Second, the study participants were volunteers and not randomly selected; however, the Fujiwarakyo study participants had a similar age distribution to the participants in a national survey, and our results can be utilized for people living independently in communities. Third, markers of inflammation in gingival crevicular fluid, interproximal bone loss measurements using full mouth radiography, and the timing and causes of tooth loss, which may be important to determine the biological foundations of the relationship between tooth loss and MMI, were not investigated. Fourth, apolipoprotein E (APOE) genotyping was not examined. It has been reported that APOE ε4 carrier status
was associated with conversion from MCI to AD in older outpatients (Devanand et al., 2005). Considering the presence of APOE ε4 carriers in the MMI group, our findings could have overestimated the relationship between tooth loss and MMI. Fifth, tooth loss related to other factors, that is, socioeconomic status, life stressors, a positive history of head trauma with maxillofacial injuries, and nutrition status, were not investigated. Sixth, the number of MMI subjects was small in our study; therefore, the percentage of individuals with 0–10 remaining teeth in the MMI group could have been high by chance. Within the limitations of the study design mentioned above, this cross-sectional study revealed a significant relationship between MMI and tooth loss of more than two-thirds, while statistical significance for tooth loss was not so high. We consider that an examination of the relationship between MMI and tooth loss may help us to establish preventive strategies for dementia. Further studies are needed to investigate the specific causes of this relationship.
4.
Experimental procedures
4.1.
Subjects
We used data from the baseline examination of the Fujiwarakyo study, which was a 5-year prospective cohort study on successful aging in the elderly, conducted on volunteer men and women aged 65 years or older who were living in their homes in Nara prefecture (where the first capital of Japan, called “Fujiwara-kyo”, was established), Japan. A total of 3,389 persons gave their consent for participation in the Fujiwara-kyo study and completed the baseline examination in 2007. Among the 3,389 participants, the sex and age distribution was as follows: 49.0% (the percentage of female), 34.9% (65–69 years), 33.8% (70– 74 years), 20.9% (75–79 years), 8.0% (80–84 years), and 2.3% (85 years or more). The results from the National Oral Disease Survey in Japan, 2005 (performed by the Ministry of Health, Labor, and Welfare, Japan, using a national random sampling approach, once per 6 years) (Statistics of Oral Health 2007) were as follows: 56.2% (female), 32.9% (65–69 years), 29.7% (70–74 years), 21.3% (75– 79 years), 11.3% (80–84 years), and 4.8% (85 years or more), respectively. The Fujiwara-kyo study participants comprised a slightly lower proportion of females, but their age distribution was similar to the participants of the national survey. Interviews revealed that 3,253 of these individuals had no severe visual or hearing impairment that were likely to affect the results of the cognitive function tests, and were able to independently execute the basic ADL (eating, dressing, bathing, toileting, and walking) and the instrumental ADL (use public transportation, shop for daily necessities, pay bills, handle one's own banking). After the exclusion of 169 persons who were suspected to have cognitive impairment based on their low MMSE scores (23 or lower) (Ishizaki et al., 1998), the remaining 3,084 subjects were classified based on their Recall score into the control (high score: 3 or 2; n = 2,960) or the low score (score: 1 or 0; n = 124) groups. Furthermore, in the low score group, we excluded 23 individuals who were suspected to have depression based on their high scores in the GDS (score: 6 or more) because of excluding persons with pseudo-dementia of depression.
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Finally, the control (n = 2,960) and MMI (n = 101) groups were included for analysis in this study. This study was approved by the Ethical Review Board of Nara Medical University. Written informed consent was obtained from each of the subjects prior to their participation in the baseline examination.
4.2.
Assessment for cognitive mental status
The MMSE (score range, 0–30) is used as a screening test for cognitive impairment. The Recall test (score range, 0–3) is a sub-item of the MMSE that evaluates the impairment of recent memory. Subjects were instructed to recall three unrelated objects that they had been previously instructed to remember. The MMSE was carried out by trained medical professionals who were experts in psychology. Depression was evaluated using the GDS (score range, 0–15; cut-off score, 5/6). Responses were coded as follows: 1 = yes, symptom present and 0 = no, symptom not present. The scores for the individual items were summed to obtain the final score; higher scores indicated a greater number of depressive symptoms. GDS was included in a self-administered questionnaire survey.
4.3.
Dental examination
A dental examination was carried out by two dentists calibrated as to the techniques, with both the dentist and the subject in a sitting position under artificial lighting. The remaining teeth were defined as healthy teeth, carious teeth, or treated teeth (including crowned teeth, inlay teeth, and abutment teeth for bridge work), inclusive of completely erupted third molars. Root tips and very loose teeth that were indicated for extraction were not included as remaining teeth. The CPI code (World Health Organization, 1997) was used to evaluate the current status of the periodontal tissue. The upper and lower teeth were divided into six prescribed segments, and each segment was subjected to further examination if it contained two or more remaining teeth that did not require extraction. The prescribed 10 representative teeth (tooth position: 11, 16, 17, 26, 27, 31, 36, 37, 46, and 47) in the 6 segments were examined. Each segment was assigned to 1 of 5 code levels (code 0, healthy; code 1, gingival bleeding after probing; code 2, calculus present in the periodontal pocket; code 3, periodontal pocket 4–5 mm deep; and code 4, periodontal pocket at least 6 mm deep), or an ineligible segment (segment having one or no remaining teeth). The highest code level among the six segments examined was regarded as the maximum CPI code for the individual. The subject was examined for dental plaques, dental calculus, uncleanliness of dentures, and a coating of the tongue. The four items were judged as “present” or “absent” when more or less than onethird of the exposed surface was affected, respectively.
4.4.
73
sion), a self-administered questionnaire survey (presence or absence of a spouse, size of household, higher-level functional capacity, drinking and smoking habits, and frequency of going out), and a 10-m walking test. These examinations were carried out by medical professionals. The height and body weight of the subjects were measured with a TANITA body fat scale (TANITA Co., Tokyo, Japan), with the subject wearing an examination gown. Body mass index was calculated as weight (kg) divided by height squared (m2). Higher-level functional capacity (intellectual activity and social role) was evaluated using the Tokyo Metropolitan Institute of Gerontology Index of Competence (Fujiwara et al., 2003; Ishizaki et al., 2000; Koyano et al., 1991). Intellectual activity (four questions), and social role (four questions) are subscales of the index. The subjects were requested to choose the response option of “yes/can” (one point) or “no/cannot” (zero point) for each question. Lower scores indicate reduced higher-level functional capacity. Disability was defined as a failure to achieve full scores in the respective subscales. In regard to drinking habits, the subjects were asked about their drinking frequency (hardly drink; drink on at least 1 day a week), the type of alcohol they drank, and their average daily alcohol intake. They were also asked to report their smoking habits (never; ex-smoker; current smoker) and the frequency of going out (once or more in 2 or 3 days; once a week or less frequent). In the 10-m walking test, the subjects were instructed to walk in a straight line as quickly as possible along a 14-m pathway marked with red tape at 2 and 12 m. Modulation-type optical input units (TAKEI Co., Niigata, Japan) were placed at the 2- and 12-m points, and the time taken by the subject to walk the 10-m distance from 2 to 12 m was measured to a precision of 1/100 s. The measurement was performed twice, and the fastest time was used for analysis.
4.5.
Statistical analysis
The chi-square test and Mann–Whitney's U test were used to examine the differences between the control and the MMI groups in univariate analyses. Differences in the cumulative percentages of the remaining teeth between the two groups were analyzed by the Kolmogorov–Smirnov test. A logistic regression analysis (by the forced entry method) was carried out using the control group or the MMI group as dependent variables, and sex, age, length of education, and other variables, as independent variables. Statistical analysis included sex (Fei et al., 2009; Ganguli et al., 2004), age, and length of education (Ishizaki et al., 1998) as potential confounders. Goodness of fit was performed based on the techniques of Hosmer and Lemeshow. Tests of trend for examining the increasing odds ratios were performed using integer-coded categories of the variables. Statistical analysis was performed using SPSS (version 17.0; SPSS Japan Inc., Tokyo, Japan). We calculated two-tailed P values in all the analyses. The α level of significance was set at 0.05.
Other explanatory variables
Each subject also underwent an examination of their nutritional status (serum albumin level and body mass index), an interview to record any history of diseases (cancer, cerebrovascular disease, myocardial infarction, diabetes mellitus, or hyperten-
Acknowledgments The authors express their sincere gratitude to all participants for their cooperation in this study, the Nara Mannen Seinen
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Club Association, Yamatokoriyama Koyu Club Association, Kashihara Senior Citizens Club Association, Nara Public Health Center, Koriyama Public Health Center, Nara Dental Association, Kashihara Neighborhood Community Association board members and welfare commissioners, and the Welfare Policy Division of Kashihara City Government. This work was supported by a research grant from Nara Medical University (2006, 2007) and the Mitsui Sumitomo Insurance Welfare Foundation (Tokyo, Japan) (2007). We had no financial or any other kind of personal conflict with this paper.
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McGeer, P.L., McGeer, E.G., 2001. Polymorphisms in inflammatory genes and the risk of Alzheimer disease. Arch. Neurol. 58, 1790–1792. Meguro, K., Ishii, H., Yamaguchi, S., Ishizaki, J., Sato, M., Hashimoto, R., Meguro, M., Lee, E., Tanaka, Y., Kasuya, M., Sekita, Y., 2004. Prevalence and cognitive performances of clinical dementia rating 0.5 and mild cognitive impairment in Japan: the Tajiri Project. Alzheimer Dis. Assoc. Disord. 18, 3–10. Nicoll, J.A., Mrak, R.E., Graham, D.I., Stewart, J., Wilcock, G., MacGowan, S., Esiri, M.M., Muray, L.S., Dewar, D., Love, S., Moss, T., Griffin, W.S., 2000. Association of interleukin-1 gene polymorphisms with Alzheimer's disease. Ann. Neurol. 47, 365–368. Onozuka, M., Watanabe, K., Mirbod, S.M., Ozono, S., Nishiyama, K., Karasawa, N., Nagatsu, I., 1999. Reduced mastication stimulates impairment of spatial memory and degeneration of hippocampal neurons in aged SAMP8 mice. Brain Res. 826, 148–153. Organization, World Health, 1997. Oral Health Surveys: Basic Methods, 4th edition. Geneva, pp. 36–38. Paraskevas, S., Huizinga, J.D., Loos, B.G., 2008. A systematic review and meta-analyses on C-reactive protein in relation to periodontitis. J. Clin. Periodontol. 35, 277–290. Petersen, R.C., Smith, G.E., Waring, S.C., Ivnik, R.J., Tangalos, E.G., Kokmen, E., 1999. Mild cognitive impairment :clinical characterization and outcome. Arch. Neurol. 56, 303–308. Piconi, S., Trabattoni, D., Luraghi, C., Perilli, E., Borelli, M., Pacei, M., Rizzardini, G., Lattuada, A., Bray, D.H., Catalano, M., Sparaco, A., Clerici, M., 2009. Treatment of periodontal disease results in improvements in endothelial dysfunction and reduction of the carotid intima-media thickness. FASEB J. 23, 1196–1204. Rainero, I., Bo, M., Ferrero, M., Valfrè, W., Vaula, G., Pinessi, L., 2004. Association between the interleukin-1α gene and Alzheimer's disease: a meta-analysis. Neurobiol. Aging 25, 1293–1298. Rogers, J., 2008. The inflammatory response in Alzheimer's disease. J. Periodontol. 79, 1535–1543.
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Research Report
Tooth loss is associated with mild memory impairment in the elderly: The Fujiwara-kyo study Nozomi Okamoto a,⁎, Masayuki Morikawa b,c , Kensuke Okamoto d,e , Noboru Habu a , Kan Hazaki f , Akihiro Harano g,h , Junko Iwamoto i , Kimiko Tomioka a , Keigo Saeki a , Norio Kurumatani a a
Department of Community Health and Epidemiology, Nara Medical University, Japan Sakai City Mental Health Center, Japan c Department of Psychiatry, Nara Medical University, Japan d Department of Oral and Maxillofacial Surgery, Nara Kasuga Hospital, Japan e Department of Oral and Maxillofacial Surgery, Nara Medical University, Japan f Department of Physical Therapy, Osaka Electro-Communication University, Japan g Department of Orthopedic Surgery, Higashiosaka City General Hospital, Japan h Department of Orthopedic Surgery, Nara Medical University, Japan i Department of Indoor Environmental Medicine, Nara Medical University, Japan b
A R T I C LE I N FO
AB S T R A C T
Article history:
It has been reported that tooth loss is associated with Alzheimer's disease (AD) and
Accepted 22 June 2010
dementia. The purpose of this study was to investigate the association between tooth loss
Available online 1 July 2010
and mild memory impairment (MMI) among the elderly. We examined 3,061 community residents aged 65 years or older who had a score of 24 or more on the Mini-Mental State
Keywords:
Examination. The subjects were divided according to their score for the three-word delayed
Tooth loss
recall test into control (score: 3 or 2) and MMI (score: 1 or 0) subjects. The subjects underwent
Memory
a dental examination, an interview to determine their medical history, a self-administered
Dementia
questionnaire (inclusive of higher-level functional capacity, drinking and smoking habits,
Community-based
and frequency of going out), and a 10-m walking test. Fewer remaining teeth, going out once a week or less frequently, and a slow walking speed on a 10-m walking test were found at a significantly higher prevalence in the MMI group (n = 101) than in the control group (n = 2,960), after adjustment for sex, age, and the level of education. Multiple logistic regression analysis using these items revealed that the odds ratio of 0–10 remaining teeth for MMI was 1.71 (95% CI 1.05–2.78), compared to individuals with 22–32 remaining teeth. A significant increase was also found in a trend test to examine the increasing odds ratios of 22–32, 11–21, and 0–10 remaining teeth. We consider that tooth loss is associated with MMI later in life. © 2010 Elsevier B.V. All rights reserved.
⁎ Corresponding author. Department of Community Health and Epidemiology, Nara Medical University, Shijo-cho 840, Kashihara city, Nara, zip code 6348521, Japan. Fax: +81 744 29 0673. E-mail address: [email protected] (N. Okamoto). Abbreviations: AD, Alzheimer's disease; MMI, mild memory impairment; MMSE, Mini-Mental State Examination; Recall, three-word delayed recall test; GDS, Geriatric Depression Scale short version; CPI, community periodontal index; MCI, mild cognitive impairment; CRP, plasma C-reactive protein; IL, interleukin; CI, confidence interval 0006-8993/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2010.06.054
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1.
Introduction
Several studies have reported that tooth loss is associated with Alzheimer's disease (AD) and dementia (Gatz et al., 2006; Stein et al., 2007). The biological bases are as mentioned below. First, it has been hypothesized (Kamer et al., 2008) that periodontal disease-derived inflammatory molecules, bacteria, and bacterial products enhance brain inflammation (Blasko and Grubeck-Loebenstein, 2003; Rogers, 2008). Tooth loss is an indicator of periodontal disease (Desvarieux et al., 2003; Humphrey et al., 2008). Second, tooth loss may induce nutritional deficits (Kim et al., 2007) and deprivation of sensory information input during mastication (Kondo et al., 1994). It has been reported that, among persons with mild memory impairment (MMI), 21.2% progress to illnesses with dementia, including AD (10.6%), vascular dementia (4.8%), or other types of dementia (5.8%), over a period of 5 years (Ishikawa and Ikeda, 2007). These individuals represent a high-risk population for dementia. MMI was defined as (Ishikawa et al., 2006): (1) no impairment of the activities of daily living (ADL); (2) normal general cognitive function, as determined using the Mini-Mental State Examination (MMSE) ≥ 24 (Folstein et al., 1975); (3) objective memory impairment, assessed by the three-word delayed recall (Recall) test (score:1 or 0) in the MMSE; (4) absence of dementia or depression, diagnosed by geriatric neuropsychiatrists according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd edn., revised (DSM-Ш R) criteria (American Psychiatric Association, 1987). We hypothesized that tooth loss may also be associated with a preclinical stage of AD and dementia. To our knowledge, few studies have examined this subject. To investigate our hypothesis in a community-based survey, subjects with MMI and elderly controls were identified operationally using the MMSE and Geriatric Depression Scale short version (GDS) (Schreiner et al., 2003). The subjects were also examined for their dental characteristics, serum albumin level, body mass index, medical history, higher-level functional capacity, drinking and smoking habits, frequency of going out, and their performance on a 10-m walking test. The purpose of this cross-sectional study was twofold: 1) to compare the number of remaining teeth of MMI subjects with those of elderly controls, and 2) to determine whether the relationship between the number of remaining teeth and MMI was modulated by other explanatory variables.
2.
Results
Among the 3,061 subjects available for analysis, MMI was found in 4.5% (69/1,544) of male subjects and 2.1% (32/1,517), a significantly lower percentage, of female subjects. The demographic characteristics of the control and MMI groups are presented in Table 1. Significant differences were found between the two groups for the median age; 71.0 (interquartile range, 7.0) years in the control group vs. 74.0 (9.0) years in the MMI group, length of education, MMSE-total, and the number of remaining teeth. Fig. 1 shows the cumulative percentages of the remaining teeth. The median number (interquartile range) of remaining teeth in the control group vs. the MMI group were 24.0 (10.0) vs.
Table 1 – Demographic characteristics of the control and MMI groups. Variables
Control (n = 2960 ) %
MMI P (n = 101 ) value ⁎ %
Sex Age (years)
50.2 37.3 33.7 20.1 7.3 1.7 25.3
31.7 21.8 28.7 30.7 12.9 5.9 36.6
< 0.01 < 0.01
28.0 (4.0)
26.0 (2.0)
< 0.01
22.0 (15.0)
16.0 (21.5)
< 0.01
Female 65–69 70–74 75–79 80–84 85 or more Length of Less than education 12 years MMSE-total Median (interquartile range) Number of Median remaining teeth (interquartile range)
0.01
Data are given as % or median (interquartile range). MMI, mild memory impairment. ⁎ Differences between the two groups were analyzed by the chi-square test or Mann–Whitney's U test.
25.0 (20.5) (Mann–Whitney's test, P = 0.79) for the 65–69 years age category, 21.0 (16.0) vs. 15.5 (18.0) (P = 0.12) for the 70– 79 years age category, and 11.0 (20.0) vs. 3.0 (17.0) (P = 0.08) for the 80 years or older age category, respectively. No significant differences were found in the distribution of the remaining teeth between the two groups for any age categories (by the Kolmogorov–Smirnov test). Table 2 shows the relationships between MMI and dental characteristics. The number of remaining teeth was categorized into three equal categories: 22–32, 11–21, and 0–10. In univariate analyses, the percentage of individuals with 22–32 remaining teeth was significantly lower in the MMI group than in the control group. No significant differences were found in the community periodontal index (CPI) code and dental uncleanliness between the two groups. After adjustment for sex, age, and length of education, the odds ratio of 0–10 to 22–32 remaining teeth for MMI was 1.72 (95% CI 1.06–2.80). A significant increase was also found in a trend test performed to examine the increase in the odds ratios of 22–32, 11–21, and 0–10 remaining teeth (P = 0.03). Table 3 shows the relationships between MMI and other explanatory variables. In univariate analyses, greater size of the household, drinking at least 1 day a week, going out once a week or less, and a slow walking speed on a 10-m walking test were found at a significantly higher prevalence, and having never smoked was found at a significant lower prevalence in the MMI group than in the control group. After adjustment for sex, age, and length of education, the odds ratio of going out once a week or less frequently was 1.96 (95% CI 1.10–3.49), this factor demonstrated a significant relationship with MMI. The relationship between the risk of MMI and the results of a 10-m walking test was marginally significant (P = 0.07). Table 4 shows the results of the multiple logistic regression analysis using variables that were significantly related even after adjustment for sex, age, and length of education. Hosmer–Lemeshow analyses provided no evidence for lack
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Fig. 1 – The cumulative percentages of the number of remaining teeth.
of fit. The odds ratio of 0–10 to 22–32 remaining teeth for MMI was 1.71 (95% CI 1.05–2.78), demonstrating a significant relationship. The relationship between the MMI risk and the number of remaining teeth was also significant when examined by the trend test for increasing odds ratios (P = 0.03).
3.
Discussion
The prevalence of MMI examined in our study was 3.0% (MMI, n = 101; participants in baseline examination, n = 3,389). The reported prevalence of community-based mild cognitive impairment (MCI), diagnosed on the criteria of Petersen et al. (1999), after several standardized memory examinations, was 4.9% according to the Tajiri Project in Japan (Meguro et al., 2004), and 2.9–4.0% according to the Monongahela Valley Independent Elders Survey (Ganguli et al., 2004). The prevalence of MMI in this study was consistent with these values. The individuals with MMI selected operationally by the simple
method are considered to represent a population approximating the community-based MCI. In the analyses conducted with adjustment for the influences of sex, age, and length of education, we observed that fewer remaining teeth and a lower frequency of going out were significantly correlated to the risk of MMI (Tables 2 and 3). Consistent with a previous report, which documented that decreased physical functions were associated with decreased cognitive functions (Tabbarah et al., 2002), we observed a marginally significant relationship between a slower speed on the 10-m walking test and the risk of MMI (Table 3). We considered that a lower frequency of going out was associated with MMI as this activity requires the maintenance of physical function, and that going out for leisure activities may be associated with a decreased risk of dementia (Karp et al., 2006; Wang et al., 2002). There were no significant relationships between the history of any disease and MMI. The relationship between the presence of MMI and subclinical cerebrovascular disease might have been
Table 2 – Relationships between MMI and dental characteristics. Variables Number of remaining teeth
22–32 11–21 0–10 CPI Ineligible ‡ Code 0 or 1 or 2 Code 3 Code 4 Any one of plaque, calculus, uncleanliness Present of dentures, and coating of tongue
Control (n = 2960) %
MMI (n = 101) %
50.4 25.3 24.3 13.2 26.3
35.6 22.8 41.6 23.8 18.7
38.3 22.2 46.5
32.7 24.8 55.4
P Adjusted odds ratio † P value ⁎ (95% CI) value † < 0.01
1 1.08 (0.63–1.85) 1.72 (1.06–2.80)
0.34
1
0.09
1.06 (0.60–1.89) 1.25 (0.68–2.32) 1.10 (0.73–1.66)
MMI, mild memory impairment; CI, confidence interval; CPI, community periodontal index. ⁎ Differences between the two groups were analyzed by the chi-square test. † Adjusted for sex, age, and length of education. ‡ Persons in whom none of the six fractions could be evaluated because of the low number of remaining teeth.
P for trend 0.03
0.79 0.03 0.47 0.84 0.48 0.65
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Table 3 – Relationships between MMI and other explanatory variables. Variables Spouse Number of household members Serum albumin Body mass index Cancer Cerebrovascular disease Myocardial infarction Diabetes mellitus Hypertension Intellectual activity Social role Drinking habit
Smoking habit
Frequency of going out 10-m walking test (s)
Control (n = 2960) %
MMI (n = 101) %
P value ⁎
Adjusted odds ratio † (95% CI)
P value †
None Median (interquartile range) Less than 3.8 g/dl Less than 18.5 Positive history Positive history
21.5 2 (1)
18.8 2 (3)
0.62 0.02
1.14 (0.65–2.01) 1.09 (0.97–1.21)
0.65 0.16
0.6 5.9 9.0 5.7
0 8.9 14.9 9.9
1.00 0.20 0.05 0.08
1.44 (0.70–2.94) 1.50 (0.85–2.66) 1.60 (0.81–3.16)
0.32 0.17 0.17
Positive history Positive history Positive history Disability Disability At least 1 day a week Ethanol intake 40 g or more per day Never Ex-smoker Current smoker Once a week or less frequent Median (interquartile range)
2.7 11.1 39.4 16.6 24.2 38.8 28.9
3.0 12.9 39.6 12.0 20.0 51.5 25.5
0.75 0.63 0.97 0.27 0.41 0.01 0.75
1.06 0.99 0.93 0.63 0.65 1.33 0.84
(0.33–3.47) (0.55–1.82) (0.62–1.40) (0.36–1.25) (0.39–1.07) (0.84–2.09) (0.43–1.62)
0.92 0.99 0.72 0.21 0.09 0.22 0.60
57.8 32.4 9.8 7.4
43.6 45.5 10.9 14.9
<0.01
0.01
1 1.13 (0.63–2.00) 1.05 (0.49–2.27) 1.96 (1.10–3.49)
0.68 0.90 0.02
5.30 (1.30)
5.58 (1.51)
0.01
1.13 (0.99–1.29)
0.07
P for trend
0.47
MMI, mild memory impairment; CI, confidence interval. ⁎ Differences between the two groups were analyzed by the chi-square test or Mann–Whitney's U test. † Adjusted for sex, age, and length of education.
underestimated because of the lack of brain imaging data (Gauthier et al., 2006). As indicated in Table 4, after adjustment for sex, age, length of education, frequency of going out, and the results of the 10-m waking test, the odds ratio of less than one-third remaining teeth for MMI was 1.71 (95% CI 1.05–2.78) compared to individuals with more than two-thirds remaining teeth. Tooth loss may partly contribute to MMI, considering that the odds ratio was not so high and no significant differences
Table 4 – Relationships between MMI and the number of remaining teeth. Variables Sex Age (years)
Women Per 1-year increase Length of Less than education 12 years Number of 22–32 remaining teeth 11–21 0–10 Frequency of Once a week going out or less frequent 10-m walking Per 1-s test (s) increase
Adjusted odds P P for ratio ⁎ 95% (CI) value ⁎ trend 0.41 (0.26–0.64) 1.06 (1.02–1.11)
< 0.01 < 0.01
1.43 (0.92–2.20)
0.11
1 1.05 (0.61–1.82) 1.71 (1.05–2.78) 1.94 (1.08–3.48)
0.85 0.03 0.03
1.10 (0.96–1.26)
0.17
0.03
MMI, mild memory impairment; CI, confidence interval. ⁎ The full model included the following: sex, age, length of education, number of remaining teeth, frequency of going out, and the result of the 10-m walking test.
were observed in the distribution of the remaining teeth between the control and MMI groups (Fig. 1). Four plausible biological explanations for the relationship between tooth loss and the risk for MMI can be proposed: 1) presence of periodontal disease; 2) genetic risk factors related to both periodontal disease and MMI; 3) a decrease in the number of periodontal mechanoreceptors due to tooth loss; and 4) further risk factors related to both tooth loss and MMI. Periodontal disease is a common cause of tooth loss in the elderly. It has been suggested that periodontal disease, a chronic infection of the tissue surrounding the teeth caused by gramnegative anaerobic bacteria, is related to not only a localized inflammatory reaction represented by alveolar bone resorption (Graves, 2008; Silva et al., 2007), but also a systemic inflammation, based on the elevation of plasma C-reactive protein (CRP) found in periodontal disease patients (Paraskevas et al., 2008) and the improvement in the blood levels of high-sensitivity CRP, interleukin (IL)-6, and fibrinogen after non-surgical therapy for periodontal disease (Marcaccini et al., 2009; Piconi et al., 2009). A model of the proposed pathways between periodontal disease and AD suggests the transmigration of proinflammatory molecules derived from periodontal tissue, pathogens, and their products from the bloodstream to the brain (Watts et al., 2008). The presence of inflammatory molecules and alterations of the immune response in the cerebrospinal fluid, plasma, and serum may be involved in the development of MCI (Galimberti et al., 2006a, 2006b; Guerreiro et al., 2007; Magaki et al., 2007, 2008). Periodontal disease may contribute to MMI through systemic inflammation. There is evidence indicating that the risk of AD is influenced by gene polymorphisms in inflammatory cytokines, e.g., IL-1, IL-
72
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6, and tumor necrosis factor-α (McGeer and McGeer, 2001). The risk for AD is significantly higher in subjects with the IL-1A (−889 position of the regulatory region) 2, 2 genotype in comparison to subjects with the IL-1A 1, 2 or IL-1A 1, 1 genotypes (Rainero et al., 2004). Homozygosity for allele 2 of IL-1A and allele 2 of IL-1B (+3953 position in exon 5) is associated with an increased risk for AD (Nicoll et al., 2000). On the other hand, an association between allele 2 of IL-1A, allele 2 of IL-1B, and an increased severity of periodontal disease has been reported (Galbraith et al., 1999; Kornman et al., 1997). Therefore, several polymorphic cytokine genotypes may be related to periodontal disease and the risk of MMI. Functional deterioration of the cholinergic neuronal system in the parietal cortex (Kato et al., 1997), a decrease in the number of choline acetyltransferase-positive neurons present in the nucleus of the diagonal band/medical septal nucleus (Terasawa et al., 2002) and a decrease in the number of pyramidal cells in the hippocampus (Onozuka et al., 1999) have been found in tooth crown-cut off or tooth-loss rats. A decrease in the number of periodontal mechanoreceptors, which are sensory receptors, caused by multiple tooth loss (Jacobs and Steenberghe, 2006 has been suggested to exert some influence on the brain sites involved in learning and memory function (Yamazaki et al., 2008). Tooth loss is also impacted upon by several additional factors that may provide alternative explanations for the association found in the present study. For example, tooth loss may be an indicator of low socioeconomic status and life stressors that may play a role in the progression of MMI later in life. Head trauma with maxillofacial injuries and the lack of a healthy diet may also be related to both tooth loss and MMI. Further studies are required to investigate possible risk factors related to both tooth loss and MMI. No significant relationships were found between MMI and the maximum individual CPI code, or between MMI and dental uncleanliness (Table 2). A higher prevalence of “ineligible” and a lower prevalence of “code 0 or 1 or 2” were found in the MMI group than in the control group; therefore, we considered that periodontal disease is associated with MMI. The presence or absence of dental plaque, calculus, uncleanliness of dentures, and a coating of the tongue allow for the evaluation of dental health behavior. It may be natural that no significant difference was found in dental uncleanliness between the control and MMI groups because MMI individuals had no impairment in their ADL. Several limitations of the present study merit consideration. First, the data were derived from a cross-sectional study; thus, we can only hypothesize the biological credibility of tooth loss on MMI. Second, the study participants were volunteers and not randomly selected; however, the Fujiwarakyo study participants had a similar age distribution to the participants in a national survey, and our results can be utilized for people living independently in communities. Third, markers of inflammation in gingival crevicular fluid, interproximal bone loss measurements using full mouth radiography, and the timing and causes of tooth loss, which may be important to determine the biological foundations of the relationship between tooth loss and MMI, were not investigated. Fourth, apolipoprotein E (APOE) genotyping was not examined. It has been reported that APOE ε4 carrier status
was associated with conversion from MCI to AD in older outpatients (Devanand et al., 2005). Considering the presence of APOE ε4 carriers in the MMI group, our findings could have overestimated the relationship between tooth loss and MMI. Fifth, tooth loss related to other factors, that is, socioeconomic status, life stressors, a positive history of head trauma with maxillofacial injuries, and nutrition status, were not investigated. Sixth, the number of MMI subjects was small in our study; therefore, the percentage of individuals with 0–10 remaining teeth in the MMI group could have been high by chance. Within the limitations of the study design mentioned above, this cross-sectional study revealed a significant relationship between MMI and tooth loss of more than two-thirds, while statistical significance for tooth loss was not so high. We consider that an examination of the relationship between MMI and tooth loss may help us to establish preventive strategies for dementia. Further studies are needed to investigate the specific causes of this relationship.
4.
Experimental procedures
4.1.
Subjects
We used data from the baseline examination of the Fujiwarakyo study, which was a 5-year prospective cohort study on successful aging in the elderly, conducted on volunteer men and women aged 65 years or older who were living in their homes in Nara prefecture (where the first capital of Japan, called “Fujiwara-kyo”, was established), Japan. A total of 3,389 persons gave their consent for participation in the Fujiwara-kyo study and completed the baseline examination in 2007. Among the 3,389 participants, the sex and age distribution was as follows: 49.0% (the percentage of female), 34.9% (65–69 years), 33.8% (70– 74 years), 20.9% (75–79 years), 8.0% (80–84 years), and 2.3% (85 years or more). The results from the National Oral Disease Survey in Japan, 2005 (performed by the Ministry of Health, Labor, and Welfare, Japan, using a national random sampling approach, once per 6 years) (Statistics of Oral Health 2007) were as follows: 56.2% (female), 32.9% (65–69 years), 29.7% (70–74 years), 21.3% (75– 79 years), 11.3% (80–84 years), and 4.8% (85 years or more), respectively. The Fujiwara-kyo study participants comprised a slightly lower proportion of females, but their age distribution was similar to the participants of the national survey. Interviews revealed that 3,253 of these individuals had no severe visual or hearing impairment that were likely to affect the results of the cognitive function tests, and were able to independently execute the basic ADL (eating, dressing, bathing, toileting, and walking) and the instrumental ADL (use public transportation, shop for daily necessities, pay bills, handle one's own banking). After the exclusion of 169 persons who were suspected to have cognitive impairment based on their low MMSE scores (23 or lower) (Ishizaki et al., 1998), the remaining 3,084 subjects were classified based on their Recall score into the control (high score: 3 or 2; n = 2,960) or the low score (score: 1 or 0; n = 124) groups. Furthermore, in the low score group, we excluded 23 individuals who were suspected to have depression based on their high scores in the GDS (score: 6 or more) because of excluding persons with pseudo-dementia of depression.
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Finally, the control (n = 2,960) and MMI (n = 101) groups were included for analysis in this study. This study was approved by the Ethical Review Board of Nara Medical University. Written informed consent was obtained from each of the subjects prior to their participation in the baseline examination.
4.2.
Assessment for cognitive mental status
The MMSE (score range, 0–30) is used as a screening test for cognitive impairment. The Recall test (score range, 0–3) is a sub-item of the MMSE that evaluates the impairment of recent memory. Subjects were instructed to recall three unrelated objects that they had been previously instructed to remember. The MMSE was carried out by trained medical professionals who were experts in psychology. Depression was evaluated using the GDS (score range, 0–15; cut-off score, 5/6). Responses were coded as follows: 1 = yes, symptom present and 0 = no, symptom not present. The scores for the individual items were summed to obtain the final score; higher scores indicated a greater number of depressive symptoms. GDS was included in a self-administered questionnaire survey.
4.3.
Dental examination
A dental examination was carried out by two dentists calibrated as to the techniques, with both the dentist and the subject in a sitting position under artificial lighting. The remaining teeth were defined as healthy teeth, carious teeth, or treated teeth (including crowned teeth, inlay teeth, and abutment teeth for bridge work), inclusive of completely erupted third molars. Root tips and very loose teeth that were indicated for extraction were not included as remaining teeth. The CPI code (World Health Organization, 1997) was used to evaluate the current status of the periodontal tissue. The upper and lower teeth were divided into six prescribed segments, and each segment was subjected to further examination if it contained two or more remaining teeth that did not require extraction. The prescribed 10 representative teeth (tooth position: 11, 16, 17, 26, 27, 31, 36, 37, 46, and 47) in the 6 segments were examined. Each segment was assigned to 1 of 5 code levels (code 0, healthy; code 1, gingival bleeding after probing; code 2, calculus present in the periodontal pocket; code 3, periodontal pocket 4–5 mm deep; and code 4, periodontal pocket at least 6 mm deep), or an ineligible segment (segment having one or no remaining teeth). The highest code level among the six segments examined was regarded as the maximum CPI code for the individual. The subject was examined for dental plaques, dental calculus, uncleanliness of dentures, and a coating of the tongue. The four items were judged as “present” or “absent” when more or less than onethird of the exposed surface was affected, respectively.
4.4.
73
sion), a self-administered questionnaire survey (presence or absence of a spouse, size of household, higher-level functional capacity, drinking and smoking habits, and frequency of going out), and a 10-m walking test. These examinations were carried out by medical professionals. The height and body weight of the subjects were measured with a TANITA body fat scale (TANITA Co., Tokyo, Japan), with the subject wearing an examination gown. Body mass index was calculated as weight (kg) divided by height squared (m2). Higher-level functional capacity (intellectual activity and social role) was evaluated using the Tokyo Metropolitan Institute of Gerontology Index of Competence (Fujiwara et al., 2003; Ishizaki et al., 2000; Koyano et al., 1991). Intellectual activity (four questions), and social role (four questions) are subscales of the index. The subjects were requested to choose the response option of “yes/can” (one point) or “no/cannot” (zero point) for each question. Lower scores indicate reduced higher-level functional capacity. Disability was defined as a failure to achieve full scores in the respective subscales. In regard to drinking habits, the subjects were asked about their drinking frequency (hardly drink; drink on at least 1 day a week), the type of alcohol they drank, and their average daily alcohol intake. They were also asked to report their smoking habits (never; ex-smoker; current smoker) and the frequency of going out (once or more in 2 or 3 days; once a week or less frequent). In the 10-m walking test, the subjects were instructed to walk in a straight line as quickly as possible along a 14-m pathway marked with red tape at 2 and 12 m. Modulation-type optical input units (TAKEI Co., Niigata, Japan) were placed at the 2- and 12-m points, and the time taken by the subject to walk the 10-m distance from 2 to 12 m was measured to a precision of 1/100 s. The measurement was performed twice, and the fastest time was used for analysis.
4.5.
Statistical analysis
The chi-square test and Mann–Whitney's U test were used to examine the differences between the control and the MMI groups in univariate analyses. Differences in the cumulative percentages of the remaining teeth between the two groups were analyzed by the Kolmogorov–Smirnov test. A logistic regression analysis (by the forced entry method) was carried out using the control group or the MMI group as dependent variables, and sex, age, length of education, and other variables, as independent variables. Statistical analysis included sex (Fei et al., 2009; Ganguli et al., 2004), age, and length of education (Ishizaki et al., 1998) as potential confounders. Goodness of fit was performed based on the techniques of Hosmer and Lemeshow. Tests of trend for examining the increasing odds ratios were performed using integer-coded categories of the variables. Statistical analysis was performed using SPSS (version 17.0; SPSS Japan Inc., Tokyo, Japan). We calculated two-tailed P values in all the analyses. The α level of significance was set at 0.05.
Other explanatory variables
Each subject also underwent an examination of their nutritional status (serum albumin level and body mass index), an interview to record any history of diseases (cancer, cerebrovascular disease, myocardial infarction, diabetes mellitus, or hyperten-
Acknowledgments The authors express their sincere gratitude to all participants for their cooperation in this study, the Nara Mannen Seinen
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Club Association, Yamatokoriyama Koyu Club Association, Kashihara Senior Citizens Club Association, Nara Public Health Center, Koriyama Public Health Center, Nara Dental Association, Kashihara Neighborhood Community Association board members and welfare commissioners, and the Welfare Policy Division of Kashihara City Government. This work was supported by a research grant from Nara Medical University (2006, 2007) and the Mitsui Sumitomo Insurance Welfare Foundation (Tokyo, Japan) (2007). We had no financial or any other kind of personal conflict with this paper.
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