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Contents lists available at ScienceDirect

Journal of Prosthodontic Research

journal homepage: www.elsevier.com/locate/jpor

Original article

Effects of tooth loss on brain structure: a voxel-based morphometry

study
Takuya Kobayashia , Masafumi Kubotaa , Toshiyuki Takahashia , Ayaka Nakasatoa ,
Taro Nomuraa , Junichi Furuyab , Hisatomo Kondoa,*
a
Department of Prosthodontics and Oral Implantology, School of Dentistry, Iwate Medical University, Morioka, Japan,
b
Department of Oral Health Science for Community Welfare, Faculty of Dentistry, Tokyo Medical and Dental University, Tokyo, Japan

A R T I C L E I N F O A B S T R A C T

Article history: Purpose: One of the most prominent issues in a super-aging society is the rapid increase in dementia
Received 19 July 2017 patients. Cross-sectional studies in dentistry have indicated that patients with dementia have worse oral
Received in revised form 24 December 2017 health compared to healthy people. The purpose of this study was to clarify the influence of tooth loss on
Accepted 26 December 2017
brain structure by comparing the volumes of gray matter (GM) and white matter (WM) between
Available online xxx
edentulous and dentulous subjects.
Methods: Subjects were recruited from the Denture Clinic at Iwate Medical University Hospital Dental
Keyword:
Center. Experiments were performed on edentulous (5 males, 8 females, 81.8  1.24 years) and dentulous
Loss of teeth
Brain structure
subjects (4 males, 7 females, 77.1  4.25 years). Patients with dementia were excluded from this study.
Edentulous elderly Brain volumes of GM and WM in edentulous and dentulous subjects were compared using intracranial
Voxel-based morphometry volume, age, gender and history of hypertension as covariates. Analyzed brain areas were identified by
Three-dimensional magnetic resonance transforming the Montreal Neurological Institute coordinate into the anatomical coordinate in
imaging edentulous subjects.
Results: The analysis of WM structural images found no morphological differences between dentulous
and edentulous subjects. However, significant atrophy of GM was observed in the hippocampus, caudate
nucleus and temporal pole of the right hemisphere in edentulous subjects.
Conclusions: The results of this study suggest that tooth loss was a causal factor for volume reduction in
brain areas related to memory, learning and cognition.
© 2018 Japan Prosthodontic Society. Published by Elsevier Ltd. All rights reserved.

1. Introduction could be attributed to the patient’s inability to obtain routine oral

Recently, it has become a big issue that rapid increase in the
need for nursing care due to the extension of the average life
expectancy in advanced countries. Dementia is one of the main
causes of being in needs of care. According to the 2015 World
Alzheimer Report, the total number of patients with dementia is
estimated to reach 132 million people in 2050, that will be 3 times
the current population. Cross-sectional studies in dentistry have
been conducted to investigate the relationship between oral
condition and dementia. It has been previously reported that
patients with dementia had more carious teeth, missing teeth,
periodontal disease, unstable dentures and unclean oral cavities
than healthy subjects [1–8]. These unfavorable oral conditions
* Corresponding author at: Department of Prosthodontics and Oral Implantology,
School of Dentistry, Iwate Medical University, 1-19 Uchimaru, Morioka, Iwate 020-
8505, Japan.
E-mail address: hkondo@iwate-med.ac.jp (H. Kondo).
care [3,4,8,9]. Kikutani et al. reported the relationship between oral
condition and dementia, suggesting that oral care and rehabilita-
tion could inhibit the decline of cognitive function in dementia
patients [10]. Another study also indicated that there was a
negative correlation between the number of residual teeth and the
risk of acquiring dementia [11]. In addition, it was shown that few
teeth without dentures and lack of regular dental care were related
to dementia onset in the elderly [12]. However, cross-sectional
studies do not show a causal relationship between dental health
status and factors for the development of dementia.
Animal studies have suggested that molar tooth loss might
produce neuronal cell loss in the hippocampus and consequently
induce memory impairment [13]. Moreover, Riviere et al. pointed
out the relationship between oral infection and Alzheimer’s
disease (AD), on basis of the detection of oral Treponema in the
human brain [14]. Although there are a large number of studies
showing close relationships between oral and brain function
[15–19], its association with dementia remains unknown.

https://doi.org/10.1016/j.jpor.2017.12.007
1883-1958/ © 2018 Japan Prosthodontic Society. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: T. Kobayashi, et al., Effects of tooth loss on brain structure: a voxel-based morphometry study, J Prosthodont
Res (2018), https://doi.org/10.1016/j.jpor.2017.12.007
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Table 1
Characteristics of the subjects.

Dentulous Edentulous
Subjects n = 13 n = 11
Age 81.8  1.24 77.1  4.25
Sex (male/female) 5/8 4/7
Weight (kg) 55.0  6.1 55.4  10.7
ICV  S.D. 1417717.7  135227.5 1425501.6  136498.8

Hypertension n=2 n=1

Diabetes 0 0
Cranial disease 0 0
Nervous disease 0 0

In contrast, Onozuka et al. have investigated the effects of

recovery of oral condition and function on higher brain function.
Elderly people activate more brain areas while masticating,
compared to younger adults [20]. Furthermore, in our preliminary
study normal activations of the basal nucleus and cerebellum were
observed in dentate subjects, which are related to adjustment of
masticatory patterns and cognitive functions, but no activations
were found during mastication in edentulous subjects.
With the expansion of medical imaging technology, voxel-
based morphometric (VBM) studies have recently gained attention Fig. 1. Flow diagram of the selection of subjects and exclusion criteria.

as a method to investigate changes in brain morphology. The VBM

method is used as a morphological diagnostic imaging technique
based on three-dimensional magnetic resonance imaging (MRI)
and is capable of detecting both gray matter (GM) and white
matter (WM) alterations by evaluating each voxel. Previous studies
employing VBM showed atrophy of the hippocampus, para-
hippocampal gyrus, entorhinal cortex, middle temporal gyrus
and anterior and posterior cingulate gyrus in Alzheimer’s disease
patients [21–23]. Moreover, another VBM study showed atrophy in
the area from the hippocampus to the parahippocampal gyrus in
patients with mild cognitive impairment [24]. Thus, VBM can be
used to assess brain atrophy, and is a minimally invasive and
observational method to assess dementia. In this study, we
attempted to elucidate the effects of tooth loss on brain tissue,
comparing the volume of GM and WM between edentulous and
dentulous subjects by VBM. Results of this study might propose
importance of teeth maintenance to prevent brain atrophy.
2. Materials and methods
2.1. Subjects
Subjects were recruited from the Denture Clinic at the Iwate
Medical University Hospital Dental Center. They were divided into
edentulous who have been in edentulous condition at least for 10
years (6 males, 8 females, 78.5  4.90 years [mean  SD]) and
dentulous subjects who have more than 20 teeth and belong to
type A of Eichner classification (5 males, 9 females, 81.1  2.62
years). Exclusion criteria included subjects showing diffuse
marked atrophy or enlargement of the perivascular space over
10 mm from a MRI brain image. In addition, subjects were
questioned about hypertension, diabetes, encephalopathy and
neurological disease. No subjects had past histories of diabetes,
encephalopathy or neurological disease, but some had past
histories of hypertension. For this reason, hypertension was used
as a covariate. To exclude patients with dementia, the mini-mental
state examination (MMSE) was performed (Table 1).
Three subjects were consequently excluded from this study;
therefore, experiments were performed on 13 edentulous (5 males,
8 females, 81.8  1.24 years) and 11 dentulous subjects (4 males, 7
females, 77.1  4.25 years) (Fig. 1). All the edentulous subjects have
worn upper and lower complete dentures with stable occlusal
condition. This study was approved by the Ethical Committee for
Human Research of the Faculty of Iwate Medical University (No.
01071) and the subjects gave informed consent according to
institutional guidelines.
2.2. Brain MRI scans and data analysis
The MRI scans were performed using a 3.0 T MR scanner (Signa
EXCITE HD, GE, Medical Systems, Milwaukee, WI, USA). Structural
data were captured by T1-weighted imaging according to image
acquisition protocol, repetition time (TR): 7.6 ms, echo time (TE):
1.56 ms, flip angle (FA): 15 , field of view (FOV): 240  240 mm,
slice thickness: 1.4 mm, slice gap: 1.4 mm, matrix size: 256  256
and voxel size 0.94  0.94  1.40. Using statistical parametric
mapping (SPM) 12 (Wellcome Department of Imaging Neurosci-
ence, University College, London, UK), the brain volume of
edentulous subjects was compared to dentulous subjects, applying
VBM analysis.
The following processes were preparatory for VBM in SPM12.
Digital imaging and communications in medicine (DICOM)
acquired by the MR scanner was transferred from imaging data
to the Neuroimaging Informatics Technology Initiative (NIfTI) file,
and three-dimensional T1-weighted images were segmented into
GM, WM and cerebrospinal fluid. To achieve higher registration
accuracy, the diffeomorphic anatomical registration through
exponentiated Lie algebra (DARTEL) was used to calibrate a group
template. Finally, the images were smoothed with a Gaussian
kernel of 8 mm full-width at half maximum to reduce individual
variability. Brain volumes of GM and WM in edentulous and
dentulous subjects were statistically compared in the point of view
from intracranial volume, age, gender and history of hypertension
as covariates. Analyzed brain areas were identified by super-
imposing the Montreal Neurological Institute coordinate on the
anatomical coordinate.
3. Results
The mean MMSE scores of dentulous and edentulous subjects
were 28.5 and 28.8 points, respectively (Fig. 2).
The analysis of WM structural images showed no morphologi-
cal differences between dentulous and edentulous subjects. In

Please cite this article in press as: T. Kobayashi, et al., Effects of tooth loss on brain structure: a voxel-based morphometry study, J Prosthodont
Res (2018), https://doi.org/10.1016/j.jpor.2017.12.007
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Fig. 2. Mini-mental state examination (MMSE) scores. Mean value and 1 standard
deviation (vertical bar) of MMSE scores are classified as follows: normal ( 25
points), suspicion of dementia (< 24 points). There were no subjects with suspected
dementia.
contrast, significant atrophy of GM was detected in the hippocam-
pus, caudate nucleus and temporal pole of the right hemisphere
(P < 0.001, uncorrected, cluster size > 10 voxels) (Fig. 3). The
median gray matter densities in the hippocampus of dentulous and
edentulous subjects were 0.55 and 0.49 (Fig. 4), 0.52 and 0.46 in
the caudate nucleus (Fig. 5), and 0.36 and 0.30 in temporal pole
Fig. 3. Volume change in brain region with tooth loss. Significant volume reductions were observed in the hippocampus, caudate nucleus and temporal pole of the right
hemisphere.
Please cite this article in press as: T. Kobayashi, et al., Effects of tooth loss on brain structure: a voxel-based morphometry study, J Prosthodont
Res (2018), https://doi.org/10.1016/j.jpor.2017.12.007
3
(Fig. 6), respectively. Significant reductions were observed in those
areas of edentulous subjects compared to dentulous subjects
(P < 0.001).
4. Discussion
VBM is applied to both neuroimaging studies and clinical
diagnostic imaging [25,26]. For example, VBM was utilized as a tool
for the early detection of dementia because selective atrophy was
observed in the middle temporal area in dementia patients. VBM
has been recently used in a large number of case control studies,
and meta-analysis of whole-brain VBM revealed the gray matter
abnormalities in semantic dementia [27]. To examine the effects of
tooth loss on structural changes of brain tissue, a case control study
was performed, comparing edentulous subjects to dentulous
subjects.
The present results indicate that there was no subject with
suspected dementia. There were no significant differences in WM
volume between dentulous and edentulous subjects. It is known
that the degree of reduction in WM volume has a positive
correlation with the severity of dementia in mild cognitive
impairment and AD. In general, the lesioning of WM is influenced
by ischemic diseases such as small vessel disease, and it has been
reported that WM changes are correlated with hypertension [28].
However, the subjects in this study had no past histories of
encephalopathy, brain atrophy or enlargement of perivascular
space over 10 mm; a few subjects only had past histories of
hypertension. Since the VBM analysis with covariate included
hypertension showed no significant difference of WM volume
between edentulous and dentulous subjects, ischemic disease
should not influence on the present results. Therefore, those
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Fig. 4. Comparison of gray matter density in the right hippocampus between edentulous and dentulous subjects. Box pots show the gray matter density with the maximum t-
value in the right hippocampus after covariate adjustment. Significant reductions of gray matter density were observed in the right hippocampus.

Fig. 5. Comparison of gray matter density in the right caudate nucleus between edentulous and dentulous subjects. Box pots show the gray matter density with the maximum
t-value in the right caudate nucleus after covariate adjustment. Significant reductions of gray matter density were observed in the right caudate nucleus.

Fig. 6. Comparison of gray matter density in the right temporal pole between edentulous and dentulous subjects. Box pots show the gray matter density with the maximum t-
value in the right temporal pole after covariate adjustment. Significant reductions of gray matter density were observed in the right temporal pole.

results demonstrated that tooth loss should not influence on the
structural changes in WM. In contrast, the GM volume of the
hippocampus, caudate nucleus and temporal pole of the right
hemisphere in edentulous subjects was lower than in dentulous
subjects. Ferreira et al. found that the GM volume of the left
hippocampus and parahippocampal gyrus in Alzheimer’s patients
was lower than in healthy subjects. Jiji et al. reported a reduction of
caudate nucleus volume in AD patients and suggested that the
changes in the volume of caudate nucleus could be useful for early
diagnosis of AD [29]. In addition, other previous studies, related to
cause of AD, revealed that the atrophy of hippocampus and
amygdala were directly affected in AD [30,31]. A recent study
expected that the thalamus and basal ganglion might be not only
indirectly involved in AD, but also the predicator of AD [32]. The
brain atrophy in frontotemporal lobar degeneration occurred in the
caudate nucleus and temporal lobe of the right hemisphere
[33,34]. Additionally, the atrophy of the caudate nucleus was
observed in corticobasal degeneration patients [35]. As previously
described, it is interesting that the area of brain atrophy in
dementia patients is similar to the one in edentulous subjects in
this study. However, there is a contradiction between previous
reports and the results of our study. At the beginning of this
research, MMSE scores were within normal limits, suggesting that
there were no subjects with suspected dementia but subsequent
VBM study revealed reduced volume of the hippocampus, caudate
nucleus and temporal lobe in edentulous subjects.
Many studies involved in brain and masticatory function have
discussed the possibility that tooth loss results in a degenerative
change of cognitive function [36–38]. Tsakos et al. found a
significant correlation between tooth loss and cognitive im-
pairment, and suggested that being edentulous might be an early
marker of cognitive impairment [39]. Those previous reports might
support our results that tooth loss in the elderly reduced the
volume of brain regions involved in cognitive function. Yoshihara
et al. reported that there was a close relationship between tooth
loss in the elderly and the intake of nutrients, such as total protein,
animal protein, sodium, vitamin D, vitamin B1, vitamin B6, niacin
and pantothenic acid [40]. Moreover, Marcenes et al. noted that
edentulous elderly subjects consumed lower amounts of protein,
calcium, iron, niacin and vitamin C than dentulous subjects, in
particular serum vitamin C and vitamin A were significantly lower
[41]. At the same time, Ramesh et al. found that brain atrophy was
associated with the reduction in serum vitamin C and a decrease in
the intake of vitamin E, vitamin B and folic acid [42]. Based on

Please cite this article in press as: T. Kobayashi, et al., Effects of tooth loss on brain structure: a voxel-based morphometry study, J Prosthodont
Res (2018), https://doi.org/10.1016/j.jpor.2017.12.007
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those reports, tooth loss might result in reduction in nutrient
intake, and the subsequent or simultaneous lacking in nutrition
might gain the brain atrophy. In other words, overlapping those
disorders might increase the risks of brain atrophy and dementia
onset. Although further studies must be required to clarify
whether the main cause of brain atrophy is the reduction of
neural input to the brain or the lack of specific nutrients owing to
tooth loss, the results of our study partially explained the
mechanism where tooth loss might cause brain atrophy and
future risk for dementia.
5. Conclusion
VBM analysis for brain atrophy revealed that morphological
differences in the hippocampus, the caudate nucleus and temporal
pole of the right hemisphere between dentulous and edentulous
subjects. The results of the present study suggest that tooth loss
might be a causal factor for volume reductions of brain areas
related to memory, learning and cognition.
Acknowledgments
We also express our deep gratitude to Dr. Makoto Sasaki and Mr.
Fumio Yamashita for their encouragement, cooperation and
excellent assistance during the course of this work. This study
was supported by the Grant-in-Aid for Strategic Medical Science
Research (S1491001, 2014–2018) from the Ministry of Education,
Culture, Sports, Science and Technology of Japan.
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