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Correlation between regional brain volume and olfactory function in very mild amnestic patients
Journal of the Neurological Sciences 411 (2020) 116686
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Correlation between regional brain volume and olfactory function in very mild amnestic patients
T
Tetsuo Kashibayashia, , Ryuichi Takahashib, Jun Fujitab, Naoto Kamimuraa, Fumino Okutanic, Hiroaki Kazuia ⁎
a
Kochi Medical School, Department of Neuropsychiatry, Kohasu Oko-cho, Nankoku, Kochi, Japan Hyogo Prefectural Rehabilitation Hospital at Nishi-Harima, Nishi-Harima Dementia-Related Disease Medical Center, 1-7-1, Kouto, Shingu-cho, Tatsuno, Hyogo, Japan c Kochi Medical School, Department of Occupational Health, Kohasu Oko-cho, Nankoku, Kochi, Japan b
ARTICLE INFO
ABSTRACT
Keywords: Olfactory identification Olfactory detection Mild cognitive impairment Alzheimer's disease Voxel-based morphometry
Background & aims: We aimed to determine neural correlates of olfactory detection and identification and analyze associations between cognitive function and olfactory identification or detection in very mild amnestic patients. Methods: We recruited 70 patients with chief complaints of memory impairment diagnosed as amnestic mild cognitive impairment (MCI) or Alzheimer's disease (AD) with a clinical dementia rating of 0.5. Olfactory detection and identification were assessed using T&T olfactometry. A voxel-wise correlation analysis of gray matter volume and olfactometry scores was performed. We also analyzed correlations between neuropsychological results and olfactometry scores. Results: A significant negative correlation was observed between detection scores and nucleus accumbens and left parahippocampal gyrus volumes and between identification scores and orbitofrontal, right frontal, and right anterior temporal cortex volumes (p < .001). No significant correlation existed between detection and cognitive assessment scores. Identification score was significantly correlated with the Alzheimer's Disease Assessment Scale-Cognitive Part word recall score (r = 0.305, p = .01). Conclusions: Olfactory detection and identification dysfunction were attributable to impairments in different regions in MCI and very early AD; the former was attributed to the olfactory circuit, while the latter to neocortices. The dysfunction of identification of olfactory information was associated with episodic memory in those patients.
1. Introduction Olfactory dysfunction is frequently observed in patients with Alzheimer's disease (AD) [1]. The sense of smell involves the detection and identification of chemical signals. The former refers to recognition of a smell even without its identification, while the latter refers to its identification. Olfactory identification begins to decrease during the early stages of AD, and the damage becomes more severe as symptoms progress. In contrast, olfactory detection is disturbed only once patients have reached advanced stages of the disease [2,3]. The relationship between olfactory detection/identification impairment and cognitive dysfunction has been investigated among
patients with AD or mild cognitive impairment (MCI) [4–8]. Such studies demonstrated that verbal and visual memories are closely associated with olfactory detection and identification. Moreover, olfactory identification is associated with attention, working memory, and visual spatial function [4,8]. However, the association between olfactory identification and neocortices has rarely been investigated, although associations between olfactory detection/identification and the hippocampus and parahippocampal gyrus have been reported. [9,10] Previous studies used the region of interest method to identify regions responsible for the detection and identification of olfactory information; however, whole-brain analyses have never been performed. In this study, we assessed the association between olfactory
Abbreviation list: MCI, mild cognitive impairment; AD, Alzheimer's disease; MRI, magnetic resonance imaging; CDR, clinical dementia rating; MMSE, Mini-Mental State Examination; FAB, Frontal Assessment Battery; IADL, Instrumental Activities of Daily Living; DARTEL, VBM; Voxel Based Morphometry, Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra; ADAS-cog, Alzheimer's Disease Assessment Scale – Cognitive Part; DLBFC, dorsolateral prefrontal cortex ⁎ Corresponding author at: Kochi Medical School, Department of Neuropsychiatry, Kohasu Oko-cho, Nankoku, Kochi 783-8505, Japan. E-mail address: [email protected] (T. Kashibayashi). https://doi.org/10.1016/j.jns.2020.116686 Received 1 July 2019; Received in revised form 11 January 2020; Accepted 13 January 2020 Available online 14 January 2020 0022-510X/ © 2020 Elsevier B.V. All rights reserved.
Journal of the Neurological Sciences 411 (2020) 116686
T. Kashibayashi, et al.
detection/identification impairment and cognitive impairment in a series of patients with early amnesia. We also determined the respective regions responsible for olfactory detection and identification with voxel-based morphometry in these patients.
follows: grade 1 (normal), 0–1.0; grade 2 (mild impairment), 1.1–2.5; grade 3 (moderate impairment), 2.6–4.0; grade 4 (severe impairment), 4.1–5.5; and grade 5 (olfactory loss), ≥5.6. 2.2. MRI data analysis
2. Methods
In this study, the Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra (DARTEL) algorithm implemented in Statistical Parametric Mapping 8 (SPM 8; Wellcome Department of Cognitive Neurology, London, United Kingdom) was used to normalize the magnetic resonance (MR) images. Briefly, the MR images were segmented into gray matter, white matter, and cerebrospinal fluid space according to the tissue probability maps. A DARTEL template was created using the segmented gray matter images for all participants. Subsequently, each original MR image was transformed into a stereotactic anatomical space using deformation parameters and templates that were created in the DARTEL deformation process.
This study was conducted at the neuropsychological clinic of the Hyogo Prefectural Rehabilitation Hospital at Nishi-Harima. Neuropsychological examinations, routine laboratory tests, and 1.5 Tesla cranial magnetic resonance imaging (MRI) were performed for all patients. The clinical and investigative data were prospectively collected in a standardized manner, after which the data were entered into our dementia registry. And the olfactory evaluation performed prospectively. Here, we included the data of 70 patients who met the following inclusion criteria between February 1, 2013 and July 31, 2015: (1) chief complaint of memory impairment by the patient or primary caregiver; (2) clinical dementia rating (CDR) of 0.5; and (3) amnestic MCI or early AD diagnosed based on clinical evaluation. The diagnosis of amnestic MCI was based on Petersen's criteria [11], while the diagnosis of early AD was based on the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria [12]. All clinical diagnoses were made by a specialist. We did not use the memory tests to identify MCI subjects. The exclusion criteria were as follows: (1) history of major functional psychiatric disorders such as schizophrenia, bipolar disorder, or depression (Geriatric Depression Scale 15-item short version score > 6) [13]; (2) nasal disorders (e.g., empyema or sinusitis); (3) head injury or nasal fracture; (4) inability to complete cognitive or odor identification tests; and (5) presence of visual hallucinations or extrapyramidal symptoms. This study was approved by the Regional Committee of Medical Research Ethics for the Hyogo Prefectural Rehabilitation Hospital at Nishi-Harima, and written informed consent was obtained from all patients or their caregivers.
2.3. Statistical analysis 2.3.1. Correlation analysis between olfactory tests and the neuropsychiatric examinations We analyzed the correlations between neuropsychological examination results and olfactory detection and perception scores. The correlations are significant at Bonferroni critical value of p < .01. 2.3.2. Voxel-wise correlation analysis of gray matter volume After smoothing of the gray matter images with an 8-mm Gaussian filter, SPM8 was used for voxel-wise correlation analysis between gray matter volume and detection/identification scores. The level of statistical significance was set at p < .001, uncorrected for family-wise error because of multiple comparisons, and the voxel extent threshold was set to 300. We also analyzed the correlation between gray matter volume on MR images and the detection and identification scores with sex, age, and total intracranial volume as covariates. The statistical threshold was set to p < .001 uncorrected for family-wise multiple comparison error. The voxel extent threshold was set to 150 voxels.
2.1. Measures
3. Results
2.1.1. Neurocognitive assessment All patients underwent physical, neurological, and neuropsychological examinations performed by senior neuropsychiatrists and clinical neuropsychologists. The patients underwent a comprehensive battery of neuropsychiatric and neuropsychological tests, including the MiniMental State Examination (MMSE) [14], Alzheimer's Disease Assessment Scale-Cognitive Part [15], Digit span, Frontal Assessment Battery (FAB) [16], and CDR [17]. Activities of daily living were assessed using the Instrumental Activities of Daily Living (IADL) scale [18]. The ADASCog consists of items regarding memory language praxis and orientation. Among the cognitive factors, we assessed memory function using ADAS word recall, orientation by ADAS orientation, language by ADAS language, construction by ADAS construction, and attention by digit span forward and backward.
3.1. Subject demographics and clinical evaluation results Demographic variables such as age, sex, educational level, Geriatric Depression Scale scores, and IADL scores are summarized in Table 1. The CDR of all patients was 0.5. The mean (standard deviation) grade of odor detection was 1.7 (1.2) (mild impairment) and that of identification was 3.4 (1.2) (moderate impairment). Of the 70 patients, 46 had a Table 1 Demographic data (n = 70). Age Sex (m/f) Education (year) GDS (/15) MMSE (/30) Recall ADAS - cog (/70) IADL M (/5) F (/8) Detection (1:normal/2:mild/3:moderate/4:severe/5:loss)
2.1.2. Assessment of odor identification Odor identification was assessed using T&T olfactometry (Daiichi Yakuhin Sangyo) [19,20], which measures thresholds for detection and identification. The test consists of five standard odors: (A) roses, (B) caramel, (C) rotten, (D) fruits, and (E) dung. The concentrations of all odors were prepared at 8 degrees, with the exception of (B), which was prepared at 7 degrees. The concentration of the odor was increased until the patients provided the correct response. During the detection test, patients were required to state whether they experienced a smell. During the identification test, they were required to identify the odors. In this study, detection scores and identification scores were defined based on the mean recognition thresholds for the five odorants as
Perception
77.4 ± 6.8 18/52 11.2 ± 9.6 3.2 ± 3.8 24.3 ± 3.1 1.37 ± 0.97 10.0 ± 3.7 4.5 ± 0.6 7.0 ± 1.1 46/14/3/2/5 1.7 ± 1.2 3/13/23/18/13 3.4 ± 1.2
Data are given as the mean ± SD; figures in parentheses indicate range. GDS: Geriatric Depression Scale, MMSE: Mini-Mental State Examination, ADAS: Alzheimer's Disease Assessment Scale, IADL: Instrumental Activities of Daily Living. 2
Journal of the Neurological Sciences 411 (2020) 116686
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Table 2 Correlation between olfactory evaluation and cognitive function (two-sided test). Cognitive function
Memory (ADAS word recall) Orientation (ADAS orientation) Language (ADAS naming) Construction (ADAS constrution) Attention (Digit span follow + back)
Average
(/10) (/5) (/12) (/5)
SD
4.89 0.73 0.01 0.29 9.03
1.44 0.99 0.12 0.46 1.66
Detection
Perception
r
p
r
p
0.087 −0.090 −0.042 −0.217 0.110
0.476 0.457 0.731 0.071 0.364
0.312 0.207 0.072 −0.117 −0.205
0.009⁎ 0.085 0.555 0.335 0.088
Deta are presented as ± SD. P < .05 with adjustment according to the Bonferroni method. ⁎ p < 0.05/5.
detection score of grades 1 and 34 scored more than grade 2 (mild impairment) (Table 1). In particular, 15 patients scored grade 5 (olfactory loss). Of the 70 patients, 67 had a identification score of more than grade 2 (mild impairment). There was no significant correlation between detection score and memory (r = 0.087, p = .476), orientation (r = −0.090, p = .459), language (r = −0.042, p = .731), construction (r = 0.217, p = .071) or attention (r = 0.217, p = .071). There was also no significant correlation between identification score and orientation (r = 0.207, p = .085), language (r = 0.072, p = .555), construction (r = −0.117, p = .335) or attention (r = 0.205, p = .088). However, the identification score was significantly correlated with memory (the ADAS-cog word recall score) (r = 0.312, p = .009), while the detection score was not (Table 2). Figs. 1 and 2 show the correlation between olfactory evaluation and regional gray matter volume. There was a significant negative correlation between the detection score and the volumes of the left nucleus accumbens and left parahippocampal gyrus. There was also a significant negative correlation between identification score and volumes of the right middle frontal gyrus, the right orbitofrontal gyrus, and the right anterior temporal pole (p < .001) (Table 3).
Fig. 2. Correlation between olfactory identification score and regional gray matter volume. SPM8 was used for voxel-wise correlation analysis between gray matter volume and T&T olfactometry scores. The level of statistical significance was set at p < .001.
The olfactory tests used in previous studies gathered in the meta-analysis were screening tests such as the Sniffin’ Sticks [22] and Brief-Smell Identification Test [23]. In these screening tests, the detection of only one fragrance at only one concentration is examined. In contrast, the T &T olfactometry test used in our study measured the olfactory detection and identification of five standard odors at eight graded concentrations (except for caramel, which is prepared at seven degrees). Thus, our study confirmed the results of the meta-analysis using a more reliable method.
4. Discussion 4.1. Detection and identification test results In our study, the mean detection score was grade 2 (mild impairment), while the mean identification score was grade 3 (moderate impairment). Some previous studies reported that olfactory detection remains in the normal range [2,10]. However, the result of a recent metaanalysis indicated that olfactory detection and identification were impaired in patients with MCI [21]. In addition, in the previous metaanalysis, the severity of the olfactory detection was milder than that of olfactory identification in MCI, consistent with the result of our study.
4.2. Regions responsible for olfactory dysfunction 4.2.1. Detection dysfunction We analyzed the correlation between gray matter volume on MR images and the olfactometry detection and identification scores of Using T&T olfactometry in detail in the present study. Our study findings demonstrated that the volumes of the left nucleus accumbens and the left parahippocampal gyrus were associated with olfactory detection. The parahippocampal gyrus is one region of the olfactory neural circuit, which includes the olfactory bulbs, orbitofrontal cortex, medial temporal cortices (hippocampus, parahippocampal gyrus, entorhinal cortex and amygdala), and thalamus [24]. Neuroimaging findings demonstrated an important role of the hippocampus in odor discrimination [25,26]. The entorhinal cortex [27] is involved in odor intensity processing. The parahippocampal cortex has a dense fiber connection with the amygdala and may be involved in olfactory detection. The nucleus accumbens is not included in the olfactory neural circuit; rather, it is one of the structures that constitutes the reward circuit and has many fiber connections to the regions included in the olfactory neural circuit, such as the amygdala, orbitofrontal cortex, hippocampus, and thalamus [28]. No study has indicated a significant correlation between olfactory dysfunction and the nucleus accumbens in MCI or AD. However, gray matter volume in the nucleus accumbens was reportedly decreased in patients with anosmia [29]. In MCI and
Fig. 1. Correlation between olfactory detection score and regional gray matter volume. SPM8 was used for voxel-wise correlation analysis between gray matter volume and T&T olfactometry scores. The level of statistical significance was set at p < .001. 3
Journal of the Neurological Sciences 411 (2020) 116686
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Table 3 MNI coordinates of the regions showing significant correlation with the detection or identification scores. Brain region
Detection Identification
Nucleus accumbens Parahippocampal gyrus Middle frontal gyrus Orbitofrontal gyrus Temporal pole
Tarairach coordinates Side
x
y
z
rt. lt. rt. rt rt
−8 −20 42 6 45
20 −39 12 28 15
−8 −8 33 −18 −28
t-value
Cluster size (voxels)
4.16 3.96 4.21 3.93 3.87
184 169 551 770 284
semantic memory in amnestic MCI [6]. ADAS-cog word recall requires episodic and semantic memory for words, while identification requires that the episodic memory of detected olfactory information to be checked against the semantic memory of olfactory information [4]. Conversely, there was no correlation between the detection and neuropsychological examination results in this study. The olfactory identification was associated with memory disturbance [6] and several cognitive functions, including verbal and visual memory, attention, working memory, and visual spatial function [4,5], in previous studies with patients with MCI and AD as well as normal controls. This failure to clarify the association in our study might be because of its weak statistical power. In previous studies, a decline in olfactory ability is associated with the atrophy of right or bilateral hemisphere. For example, a further volume loss could be found in areas known to be involved in olfaction like the right orbitofrontal cortex [37] or areas involved in olfactory memory like bilateral DLPFC [38]. In our study, olfactory identification is correlated with right hemisphere and olfactory detection is correlated with left hemisphere. The reason for this left volume correlation with nucleus accumbens and parahippocampal gyrus remains unclear. An extension of our study with a larger number of patients may show bilateral correlation.
early AD, it is assumed that the odor detected in the olfactory neural circuit may not stimulate the reward circuit as a result of the atrophy of nucleus accumbens. This assumption was evident in our results which revealed a correlation between volume of nucleus accumbens and scores of olfactory detections. Otherwise, the emotionally evaluation of olfactory information occurs without and before cognitive processing occurs [30]. Therefore, it is possible that the nucleus accumbens could be activated before olfactory identification. Our findings also suggest that the preferred odors are judged during the detection stage by patients with MCI and early AD. In our study, amygdala was not associated with olfactory detection, although the parahippocampal gyrus and the amygdala were associated with olfactory detection in Murphy's study. [10] The discrepancy of the results of Murphy's and our studies may be attributable to differences in disease stage between the patients of the two studies. In patients with AD, the parahippocampal gyrus is damaged earlier than the amygdala [31,32]. The mean MMSE score of the patients in Murphy's study was 22.9 ± 1.0, whereas that of our study was 24.3 ± 3.1. 4.2.2. Identification dysfunction In this study, gray matter volume loss of the right anterior temporal lobes, right frontal cortex, and orbitofrontal cortex were associated with impaired olfactory identification in groups of MCI or early AD. The former two regions are not included in the olfactory neural circuit, while the latter region is part of this neural circuit. The association between the anterior temporal lobe and olfactory identification has not been reported. Olfactory identification requires that detected olfactory information be checked against semantic memory of olfactory information [4]. The anterior temporal lobe may play the central role in semantic memory of various modalities, including olfaction [33]. The association between the right frontal cortex and olfactory identification revealed in this study has never been noted in AD patients. However, no study has shown an association between olfactory identification and dorsolateral prefrontal cortex (DLPFC) brain volume in patients with AD and MCI. Since a correlation between chronic olfactory disorders and DLPFC brain volume was indicated in Bitter's study [29] using VBM, which is the same method used in our study, olfactory identification and DLPFC could be associated. The progression of atrophy in DLPFC in patients with MCI and early-stage AD has been reported [34]. Our results suggested that olfactory identification is associated with DLPFC. The orbitofrontal cortex, which was associated with olfactory identification in this study, is the region that the final information in the olfactory recognition system reaches [25]. The association was reported in a study of 106 patients with cerebral excision [35]. A previous functional MRI study also showed the association between the posterior orbital cortex and olfactory identification in healthy elderly people [36]. Moreover, the activity of the posterior orbital cortex among olfactory identification decreased to a greater degree in individuals with early AD than in healthy persons [36]. This study revealed a significant positive correlation between olfactory identification score and memory (ADAS-cog word recall). Olfactory identification is reportedly correlated with both episodic and
5. Limitations This study has three main limitations. First, its sample size was small. Second, there might be a difference in the detection/identification score among odors, but we did not analyze the score of each odor. Third, genetic testing and tests for amyloid deposition were not performed in patients with AD and MCI; thus, it is possible that the subjects of this study constituted a heterogeneous group. 6. Conclusion The present study found that olfactory detection and identification dysfunctions were attributable to impairments in different brain regions in individuals with MCI and very early AD. The former was attributable to the olfactory circuit, including the nucleus accumbens and left parahippocampal gyrus, while the latter was attributable to the orbitofrontal, right frontal, and right anterior temporal cortices. In addition, the olfactory information identification dysfunction was associated with episodic memory in those patients. Description of authors' roles T. Kashibayashi designed the study, supervised the data collection, and drafted the manuscript. R Takahashi collected the data and assisted with writing the manuscript. J. Fujita collected the data. N. Kamimura and F. Okutani assisted with writing the manuscript. H. Kazui had major roles in writing the manuscript and revising it critically for important intellectual content. 4
Journal of the Neurological Sciences 411 (2020) 116686
T. Kashibayashi, et al.
Declaration of Competing Interest [16]
None.
[17]
Acknowledgements
[18]
The present study was supported by a grant provided by the Japan Agency for Medical research and Development (Science Research Grants for Dementia R&D) to Hiroaki Kazui (grant number: 17930173).
[19] [20] [21]
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Correlation between regional brain volume and olfactory function in very mild amnestic patients
T
Tetsuo Kashibayashia, , Ryuichi Takahashib, Jun Fujitab, Naoto Kamimuraa, Fumino Okutanic, Hiroaki Kazuia ⁎
a
Kochi Medical School, Department of Neuropsychiatry, Kohasu Oko-cho, Nankoku, Kochi, Japan Hyogo Prefectural Rehabilitation Hospital at Nishi-Harima, Nishi-Harima Dementia-Related Disease Medical Center, 1-7-1, Kouto, Shingu-cho, Tatsuno, Hyogo, Japan c Kochi Medical School, Department of Occupational Health, Kohasu Oko-cho, Nankoku, Kochi, Japan b
ARTICLE INFO
ABSTRACT
Keywords: Olfactory identification Olfactory detection Mild cognitive impairment Alzheimer's disease Voxel-based morphometry
Background & aims: We aimed to determine neural correlates of olfactory detection and identification and analyze associations between cognitive function and olfactory identification or detection in very mild amnestic patients. Methods: We recruited 70 patients with chief complaints of memory impairment diagnosed as amnestic mild cognitive impairment (MCI) or Alzheimer's disease (AD) with a clinical dementia rating of 0.5. Olfactory detection and identification were assessed using T&T olfactometry. A voxel-wise correlation analysis of gray matter volume and olfactometry scores was performed. We also analyzed correlations between neuropsychological results and olfactometry scores. Results: A significant negative correlation was observed between detection scores and nucleus accumbens and left parahippocampal gyrus volumes and between identification scores and orbitofrontal, right frontal, and right anterior temporal cortex volumes (p < .001). No significant correlation existed between detection and cognitive assessment scores. Identification score was significantly correlated with the Alzheimer's Disease Assessment Scale-Cognitive Part word recall score (r = 0.305, p = .01). Conclusions: Olfactory detection and identification dysfunction were attributable to impairments in different regions in MCI and very early AD; the former was attributed to the olfactory circuit, while the latter to neocortices. The dysfunction of identification of olfactory information was associated with episodic memory in those patients.
1. Introduction Olfactory dysfunction is frequently observed in patients with Alzheimer's disease (AD) [1]. The sense of smell involves the detection and identification of chemical signals. The former refers to recognition of a smell even without its identification, while the latter refers to its identification. Olfactory identification begins to decrease during the early stages of AD, and the damage becomes more severe as symptoms progress. In contrast, olfactory detection is disturbed only once patients have reached advanced stages of the disease [2,3]. The relationship between olfactory detection/identification impairment and cognitive dysfunction has been investigated among
patients with AD or mild cognitive impairment (MCI) [4–8]. Such studies demonstrated that verbal and visual memories are closely associated with olfactory detection and identification. Moreover, olfactory identification is associated with attention, working memory, and visual spatial function [4,8]. However, the association between olfactory identification and neocortices has rarely been investigated, although associations between olfactory detection/identification and the hippocampus and parahippocampal gyrus have been reported. [9,10] Previous studies used the region of interest method to identify regions responsible for the detection and identification of olfactory information; however, whole-brain analyses have never been performed. In this study, we assessed the association between olfactory
Abbreviation list: MCI, mild cognitive impairment; AD, Alzheimer's disease; MRI, magnetic resonance imaging; CDR, clinical dementia rating; MMSE, Mini-Mental State Examination; FAB, Frontal Assessment Battery; IADL, Instrumental Activities of Daily Living; DARTEL, VBM; Voxel Based Morphometry, Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra; ADAS-cog, Alzheimer's Disease Assessment Scale – Cognitive Part; DLBFC, dorsolateral prefrontal cortex ⁎ Corresponding author at: Kochi Medical School, Department of Neuropsychiatry, Kohasu Oko-cho, Nankoku, Kochi 783-8505, Japan. E-mail address: [email protected] (T. Kashibayashi). https://doi.org/10.1016/j.jns.2020.116686 Received 1 July 2019; Received in revised form 11 January 2020; Accepted 13 January 2020 Available online 14 January 2020 0022-510X/ © 2020 Elsevier B.V. All rights reserved.
Journal of the Neurological Sciences 411 (2020) 116686
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detection/identification impairment and cognitive impairment in a series of patients with early amnesia. We also determined the respective regions responsible for olfactory detection and identification with voxel-based morphometry in these patients.
follows: grade 1 (normal), 0–1.0; grade 2 (mild impairment), 1.1–2.5; grade 3 (moderate impairment), 2.6–4.0; grade 4 (severe impairment), 4.1–5.5; and grade 5 (olfactory loss), ≥5.6. 2.2. MRI data analysis
2. Methods
In this study, the Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra (DARTEL) algorithm implemented in Statistical Parametric Mapping 8 (SPM 8; Wellcome Department of Cognitive Neurology, London, United Kingdom) was used to normalize the magnetic resonance (MR) images. Briefly, the MR images were segmented into gray matter, white matter, and cerebrospinal fluid space according to the tissue probability maps. A DARTEL template was created using the segmented gray matter images for all participants. Subsequently, each original MR image was transformed into a stereotactic anatomical space using deformation parameters and templates that were created in the DARTEL deformation process.
This study was conducted at the neuropsychological clinic of the Hyogo Prefectural Rehabilitation Hospital at Nishi-Harima. Neuropsychological examinations, routine laboratory tests, and 1.5 Tesla cranial magnetic resonance imaging (MRI) were performed for all patients. The clinical and investigative data were prospectively collected in a standardized manner, after which the data were entered into our dementia registry. And the olfactory evaluation performed prospectively. Here, we included the data of 70 patients who met the following inclusion criteria between February 1, 2013 and July 31, 2015: (1) chief complaint of memory impairment by the patient or primary caregiver; (2) clinical dementia rating (CDR) of 0.5; and (3) amnestic MCI or early AD diagnosed based on clinical evaluation. The diagnosis of amnestic MCI was based on Petersen's criteria [11], while the diagnosis of early AD was based on the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria [12]. All clinical diagnoses were made by a specialist. We did not use the memory tests to identify MCI subjects. The exclusion criteria were as follows: (1) history of major functional psychiatric disorders such as schizophrenia, bipolar disorder, or depression (Geriatric Depression Scale 15-item short version score > 6) [13]; (2) nasal disorders (e.g., empyema or sinusitis); (3) head injury or nasal fracture; (4) inability to complete cognitive or odor identification tests; and (5) presence of visual hallucinations or extrapyramidal symptoms. This study was approved by the Regional Committee of Medical Research Ethics for the Hyogo Prefectural Rehabilitation Hospital at Nishi-Harima, and written informed consent was obtained from all patients or their caregivers.
2.3. Statistical analysis 2.3.1. Correlation analysis between olfactory tests and the neuropsychiatric examinations We analyzed the correlations between neuropsychological examination results and olfactory detection and perception scores. The correlations are significant at Bonferroni critical value of p < .01. 2.3.2. Voxel-wise correlation analysis of gray matter volume After smoothing of the gray matter images with an 8-mm Gaussian filter, SPM8 was used for voxel-wise correlation analysis between gray matter volume and detection/identification scores. The level of statistical significance was set at p < .001, uncorrected for family-wise error because of multiple comparisons, and the voxel extent threshold was set to 300. We also analyzed the correlation between gray matter volume on MR images and the detection and identification scores with sex, age, and total intracranial volume as covariates. The statistical threshold was set to p < .001 uncorrected for family-wise multiple comparison error. The voxel extent threshold was set to 150 voxels.
2.1. Measures
3. Results
2.1.1. Neurocognitive assessment All patients underwent physical, neurological, and neuropsychological examinations performed by senior neuropsychiatrists and clinical neuropsychologists. The patients underwent a comprehensive battery of neuropsychiatric and neuropsychological tests, including the MiniMental State Examination (MMSE) [14], Alzheimer's Disease Assessment Scale-Cognitive Part [15], Digit span, Frontal Assessment Battery (FAB) [16], and CDR [17]. Activities of daily living were assessed using the Instrumental Activities of Daily Living (IADL) scale [18]. The ADASCog consists of items regarding memory language praxis and orientation. Among the cognitive factors, we assessed memory function using ADAS word recall, orientation by ADAS orientation, language by ADAS language, construction by ADAS construction, and attention by digit span forward and backward.
3.1. Subject demographics and clinical evaluation results Demographic variables such as age, sex, educational level, Geriatric Depression Scale scores, and IADL scores are summarized in Table 1. The CDR of all patients was 0.5. The mean (standard deviation) grade of odor detection was 1.7 (1.2) (mild impairment) and that of identification was 3.4 (1.2) (moderate impairment). Of the 70 patients, 46 had a Table 1 Demographic data (n = 70). Age Sex (m/f) Education (year) GDS (/15) MMSE (/30) Recall ADAS - cog (/70) IADL M (/5) F (/8) Detection (1:normal/2:mild/3:moderate/4:severe/5:loss)
2.1.2. Assessment of odor identification Odor identification was assessed using T&T olfactometry (Daiichi Yakuhin Sangyo) [19,20], which measures thresholds for detection and identification. The test consists of five standard odors: (A) roses, (B) caramel, (C) rotten, (D) fruits, and (E) dung. The concentrations of all odors were prepared at 8 degrees, with the exception of (B), which was prepared at 7 degrees. The concentration of the odor was increased until the patients provided the correct response. During the detection test, patients were required to state whether they experienced a smell. During the identification test, they were required to identify the odors. In this study, detection scores and identification scores were defined based on the mean recognition thresholds for the five odorants as
Perception
77.4 ± 6.8 18/52 11.2 ± 9.6 3.2 ± 3.8 24.3 ± 3.1 1.37 ± 0.97 10.0 ± 3.7 4.5 ± 0.6 7.0 ± 1.1 46/14/3/2/5 1.7 ± 1.2 3/13/23/18/13 3.4 ± 1.2
Data are given as the mean ± SD; figures in parentheses indicate range. GDS: Geriatric Depression Scale, MMSE: Mini-Mental State Examination, ADAS: Alzheimer's Disease Assessment Scale, IADL: Instrumental Activities of Daily Living. 2
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Table 2 Correlation between olfactory evaluation and cognitive function (two-sided test). Cognitive function
Memory (ADAS word recall) Orientation (ADAS orientation) Language (ADAS naming) Construction (ADAS constrution) Attention (Digit span follow + back)
Average
(/10) (/5) (/12) (/5)
SD
4.89 0.73 0.01 0.29 9.03
1.44 0.99 0.12 0.46 1.66
Detection
Perception
r
p
r
p
0.087 −0.090 −0.042 −0.217 0.110
0.476 0.457 0.731 0.071 0.364
0.312 0.207 0.072 −0.117 −0.205
0.009⁎ 0.085 0.555 0.335 0.088
Deta are presented as ± SD. P < .05 with adjustment according to the Bonferroni method. ⁎ p < 0.05/5.
detection score of grades 1 and 34 scored more than grade 2 (mild impairment) (Table 1). In particular, 15 patients scored grade 5 (olfactory loss). Of the 70 patients, 67 had a identification score of more than grade 2 (mild impairment). There was no significant correlation between detection score and memory (r = 0.087, p = .476), orientation (r = −0.090, p = .459), language (r = −0.042, p = .731), construction (r = 0.217, p = .071) or attention (r = 0.217, p = .071). There was also no significant correlation between identification score and orientation (r = 0.207, p = .085), language (r = 0.072, p = .555), construction (r = −0.117, p = .335) or attention (r = 0.205, p = .088). However, the identification score was significantly correlated with memory (the ADAS-cog word recall score) (r = 0.312, p = .009), while the detection score was not (Table 2). Figs. 1 and 2 show the correlation between olfactory evaluation and regional gray matter volume. There was a significant negative correlation between the detection score and the volumes of the left nucleus accumbens and left parahippocampal gyrus. There was also a significant negative correlation between identification score and volumes of the right middle frontal gyrus, the right orbitofrontal gyrus, and the right anterior temporal pole (p < .001) (Table 3).
Fig. 2. Correlation between olfactory identification score and regional gray matter volume. SPM8 was used for voxel-wise correlation analysis between gray matter volume and T&T olfactometry scores. The level of statistical significance was set at p < .001.
The olfactory tests used in previous studies gathered in the meta-analysis were screening tests such as the Sniffin’ Sticks [22] and Brief-Smell Identification Test [23]. In these screening tests, the detection of only one fragrance at only one concentration is examined. In contrast, the T &T olfactometry test used in our study measured the olfactory detection and identification of five standard odors at eight graded concentrations (except for caramel, which is prepared at seven degrees). Thus, our study confirmed the results of the meta-analysis using a more reliable method.
4. Discussion 4.1. Detection and identification test results In our study, the mean detection score was grade 2 (mild impairment), while the mean identification score was grade 3 (moderate impairment). Some previous studies reported that olfactory detection remains in the normal range [2,10]. However, the result of a recent metaanalysis indicated that olfactory detection and identification were impaired in patients with MCI [21]. In addition, in the previous metaanalysis, the severity of the olfactory detection was milder than that of olfactory identification in MCI, consistent with the result of our study.
4.2. Regions responsible for olfactory dysfunction 4.2.1. Detection dysfunction We analyzed the correlation between gray matter volume on MR images and the olfactometry detection and identification scores of Using T&T olfactometry in detail in the present study. Our study findings demonstrated that the volumes of the left nucleus accumbens and the left parahippocampal gyrus were associated with olfactory detection. The parahippocampal gyrus is one region of the olfactory neural circuit, which includes the olfactory bulbs, orbitofrontal cortex, medial temporal cortices (hippocampus, parahippocampal gyrus, entorhinal cortex and amygdala), and thalamus [24]. Neuroimaging findings demonstrated an important role of the hippocampus in odor discrimination [25,26]. The entorhinal cortex [27] is involved in odor intensity processing. The parahippocampal cortex has a dense fiber connection with the amygdala and may be involved in olfactory detection. The nucleus accumbens is not included in the olfactory neural circuit; rather, it is one of the structures that constitutes the reward circuit and has many fiber connections to the regions included in the olfactory neural circuit, such as the amygdala, orbitofrontal cortex, hippocampus, and thalamus [28]. No study has indicated a significant correlation between olfactory dysfunction and the nucleus accumbens in MCI or AD. However, gray matter volume in the nucleus accumbens was reportedly decreased in patients with anosmia [29]. In MCI and
Fig. 1. Correlation between olfactory detection score and regional gray matter volume. SPM8 was used for voxel-wise correlation analysis between gray matter volume and T&T olfactometry scores. The level of statistical significance was set at p < .001. 3
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Table 3 MNI coordinates of the regions showing significant correlation with the detection or identification scores. Brain region
Detection Identification
Nucleus accumbens Parahippocampal gyrus Middle frontal gyrus Orbitofrontal gyrus Temporal pole
Tarairach coordinates Side
x
y
z
rt. lt. rt. rt rt
−8 −20 42 6 45
20 −39 12 28 15
−8 −8 33 −18 −28
t-value
Cluster size (voxels)
4.16 3.96 4.21 3.93 3.87
184 169 551 770 284
semantic memory in amnestic MCI [6]. ADAS-cog word recall requires episodic and semantic memory for words, while identification requires that the episodic memory of detected olfactory information to be checked against the semantic memory of olfactory information [4]. Conversely, there was no correlation between the detection and neuropsychological examination results in this study. The olfactory identification was associated with memory disturbance [6] and several cognitive functions, including verbal and visual memory, attention, working memory, and visual spatial function [4,5], in previous studies with patients with MCI and AD as well as normal controls. This failure to clarify the association in our study might be because of its weak statistical power. In previous studies, a decline in olfactory ability is associated with the atrophy of right or bilateral hemisphere. For example, a further volume loss could be found in areas known to be involved in olfaction like the right orbitofrontal cortex [37] or areas involved in olfactory memory like bilateral DLPFC [38]. In our study, olfactory identification is correlated with right hemisphere and olfactory detection is correlated with left hemisphere. The reason for this left volume correlation with nucleus accumbens and parahippocampal gyrus remains unclear. An extension of our study with a larger number of patients may show bilateral correlation.
early AD, it is assumed that the odor detected in the olfactory neural circuit may not stimulate the reward circuit as a result of the atrophy of nucleus accumbens. This assumption was evident in our results which revealed a correlation between volume of nucleus accumbens and scores of olfactory detections. Otherwise, the emotionally evaluation of olfactory information occurs without and before cognitive processing occurs [30]. Therefore, it is possible that the nucleus accumbens could be activated before olfactory identification. Our findings also suggest that the preferred odors are judged during the detection stage by patients with MCI and early AD. In our study, amygdala was not associated with olfactory detection, although the parahippocampal gyrus and the amygdala were associated with olfactory detection in Murphy's study. [10] The discrepancy of the results of Murphy's and our studies may be attributable to differences in disease stage between the patients of the two studies. In patients with AD, the parahippocampal gyrus is damaged earlier than the amygdala [31,32]. The mean MMSE score of the patients in Murphy's study was 22.9 ± 1.0, whereas that of our study was 24.3 ± 3.1. 4.2.2. Identification dysfunction In this study, gray matter volume loss of the right anterior temporal lobes, right frontal cortex, and orbitofrontal cortex were associated with impaired olfactory identification in groups of MCI or early AD. The former two regions are not included in the olfactory neural circuit, while the latter region is part of this neural circuit. The association between the anterior temporal lobe and olfactory identification has not been reported. Olfactory identification requires that detected olfactory information be checked against semantic memory of olfactory information [4]. The anterior temporal lobe may play the central role in semantic memory of various modalities, including olfaction [33]. The association between the right frontal cortex and olfactory identification revealed in this study has never been noted in AD patients. However, no study has shown an association between olfactory identification and dorsolateral prefrontal cortex (DLPFC) brain volume in patients with AD and MCI. Since a correlation between chronic olfactory disorders and DLPFC brain volume was indicated in Bitter's study [29] using VBM, which is the same method used in our study, olfactory identification and DLPFC could be associated. The progression of atrophy in DLPFC in patients with MCI and early-stage AD has been reported [34]. Our results suggested that olfactory identification is associated with DLPFC. The orbitofrontal cortex, which was associated with olfactory identification in this study, is the region that the final information in the olfactory recognition system reaches [25]. The association was reported in a study of 106 patients with cerebral excision [35]. A previous functional MRI study also showed the association between the posterior orbital cortex and olfactory identification in healthy elderly people [36]. Moreover, the activity of the posterior orbital cortex among olfactory identification decreased to a greater degree in individuals with early AD than in healthy persons [36]. This study revealed a significant positive correlation between olfactory identification score and memory (ADAS-cog word recall). Olfactory identification is reportedly correlated with both episodic and
5. Limitations This study has three main limitations. First, its sample size was small. Second, there might be a difference in the detection/identification score among odors, but we did not analyze the score of each odor. Third, genetic testing and tests for amyloid deposition were not performed in patients with AD and MCI; thus, it is possible that the subjects of this study constituted a heterogeneous group. 6. Conclusion The present study found that olfactory detection and identification dysfunctions were attributable to impairments in different brain regions in individuals with MCI and very early AD. The former was attributable to the olfactory circuit, including the nucleus accumbens and left parahippocampal gyrus, while the latter was attributable to the orbitofrontal, right frontal, and right anterior temporal cortices. In addition, the olfactory information identification dysfunction was associated with episodic memory in those patients. Description of authors' roles T. Kashibayashi designed the study, supervised the data collection, and drafted the manuscript. R Takahashi collected the data and assisted with writing the manuscript. J. Fujita collected the data. N. Kamimura and F. Okutani assisted with writing the manuscript. H. Kazui had major roles in writing the manuscript and revising it critically for important intellectual content. 4
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Declaration of Competing Interest [16]
None.
[17]
Acknowledgements
[18]
The present study was supported by a grant provided by the Japan Agency for Medical research and Development (Science Research Grants for Dementia R&D) to Hiroaki Kazui (grant number: 17930173).
[19] [20] [21]
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