The authors have declared that no competing interests exist.
Conceived and designed the experiments: HS JT TM. Performed the experiments: HS JT JY KW. Analyzed the data: HS JT S. Kinase KO NW HT. Contributed reagents/materials/analysis tools: TM S. Kinuya KK RA MF. Wrote the paper: HS JT KW TM.
The aim of this study was to assess whether migration of thallium-201 (201Tl) to the olfactory bulb were reduced in patients with olfactory impairments in comparison to healthy volunteers after nasal administration of 201Tl.
10 healthy volunteers and 21 patients enrolled in the study (19 males and 12 females; 26–71 years old). The causes of olfactory dysfunction in the patients were head trauma (n = 7), upper respiratory tract infection (n = 7), and chronic rhinosinusitis (n = 7). 201TlCl was administered unilaterally to the olfactory cleft, and SPECT-CT was conducted 24 h later. Separate MRI images were merged with the SPECT images. 201Tl olfactory migration was also correlated with the volume of the olfactory bulb determined from MRI images, as well as with odor recognition thresholds measured by using T&T olfactometry.
Nasal 201Tl migration to the olfactory bulb was significantly lower in the olfactory-impaired patients than in healthy volunteers. The migration of 201Tl to the olfactory bulb was significantly correlated with odor recognition thresholds obtained with T&T olfactometry and correlated with the volume of the olfactory bulb determined from MRI images when all subjects were included.
Assessment of the 201Tl migration to the olfactory bulb was the new method for the evaluation of the olfactory nerve connectivity in patients with impaired olfaction.
Many physicians find it difficult to detect malingering among olfaction-impaired patients. Current olfactory function tests (the University of Pennsylvania Smell Identification Test
The radioisotope thallium-201 (201Tl) migrates to the olfactory bulb after nasal administration in rodents
Nasally administered thallium-201 (201Tl) migrates to the olfactory bulb 24 h after 201Tl administration in subjects, as has been shown in healthy volunteers using a combination of single photon emission computed tomography (SPECT), X-ray computed tomography (CT), and magnetic resonance imaging (MRI)
In this study, we applied the technique of nasal administration of 201Tl followed by SPECT-CT and MRI imaging to patients with hyposmia due to head trauma, upper respiratory tract infection, or chronic rhinosinusitis, which are major causes of olfactory dysfunction
Participants were 10 healthy volunteers (7 males and 3 females, 30–66 years old;
Subject Group | Age, years(Mean ± S.D.) | Gender(Male/Female) | Non-smokers/Smokersor ex-smokers | Odor recognition threshold (Mean ± S.D.) |
Healthy volunteer (n = 10) | 44.7±11.9 | 7/3 | 7/3 | 0.9±0.6 |
Head trauma (n = 7) | 43.0±13.3 | 3/4 | 3/4 | 4.9±0.9 |
Upper respiratory tract infection (n = 7) | 50.4±10.0 | 4/3 | 6/1 | 3.4±1.5 |
Chronic rhinosinusitis (n = 7) | 54.7±15.1 | 5/2 | 4/3 | 4.4±1.4 |
Causes of olfactory dysfunction in the patients were head trauma (n = 7), upper respiratory tract infection (n = 7), and chronic rhinosinusitis (n = 7). For head trauma subjects, types of head trauma were concussion (n = 2), cerebral contusion (n = 2), and cerebral contusion with intracranial hemorrhage (n = 3). One patient with hyposmia due to head trauma showed a shallow olfactory sulcus. Another patients with hyposmia due to head trauma showed no abnormal frontal lobe findings on MRI.
The duration of olfactory deficits at the time of the examination ranged from 4 weeks to 10 years (58 months ±53 months [mean ± S.D.]). Patients with chronic rhinosinusitis were assessed in this trial if they continued to suffer olfactory impairments even though receiving medical and/or surgical treatment. Olfactory clefts were open in all subjects.
All participants were informed of the objectives of the study and possible side effects (allergic reactions to 201TlCl, irritation of the digestive system, blood pressure fluctuation, or asthmatic crisis), and have given written informed consent. Subjects were excluded if they were pregnant or lactating. Exclusion criteria also included a history of kidney disease, liver injury, or other serious illness. Healthy volunteers who might have olfactory dysfunction due to head trauma, upper respiratory tract infection, or chronic rhinosinusitis were excluded in this study. Both groups of healthy volunteers (medical workers) and patients did not include nuclear medicine specialists. Therefore, their knowledge about 201Tl imaging may be same. The Medical Ethics Committees of Kanazawa Medical University and Kanazawa University approved this trial in advance.
Each odorant was dissolved in mineral oil to form a graded series of concentrations, and then applied liberally to blotting paper and presented to subjects by using T&T olfactometry (Daiichi Yakuhin Sangyo, Tokyo, Japan). In Japan, T&T olfactometry is now a standard means of measuring olfactory thresholds. The normal odor recognition threshold score of each nostril is less than 2.0. The recognition threshold was obtained with T&T olfactometry on the side 201Tl nasally administered in this study.
All procedures involving the handling of radioisotopic materials were performed in the Division of Radiology at Kanazawa Medical University or the Division of Radioisotopes at Kanazawa University Hospital. A solution of 201TlCl in saline (74 MBq/mL) was obtained from Nihon Medi-Physics (Tokyo, Japan). For each subject, 0.3 mL 201TlCl saline solution (22 MBq) was instilled via syringe into the olfactory cleft in the right or left larger nasal cavity. The unilateral 201Tl nasal administration was performed in this study, because uptake of 201Tl in the right or left distinction may be unclear in the case of bilateral 201Tl nasal administration. Under endoscopic findings, we choose the side of larger olfactory cleft to be assessed for the certain nasal administration to the olfactory cleft. After 201Tl nasal administration, subjects laid on their sides for 30 min. Uptake of 201Tl was assessed from SPECT scans performed 24 h after 201Tl administration. It has been shown that 201Tl migration from the olfactory epithelium to the olfactory bulb is visible 24 h after 201Tl nasal administration in healthy volunteers
For each subject, MRI T2 weighted images (Syngo MR B17 3.0T; Siemens Japan Healthcare, Japan, or Signa HDx 3.0T; GE Healthcare-Japan, Japan) were collected separately from the SPECT scan, one day before. Each MRI image was merged with the corresponding SPECT image through fusion with the CT part of the SPECT-CT by using the mutual information–based registration method
Two regions of interest for the nasal turbinate area and the anterior skull base (olfactory bulb area) were set on the 201Tl SPECT–MRI fusion image. On 3 sequential fused images in both sagittal and coronal planes, large regions of interest were tentatively set manually on the nasal turbinate area to cover all of the residual 201Tl activity in the nasal cavity. The nasal cavity region of interest was defined as the area bounded by the 50% threshold of the peak 201Tl count and delineated. Then, oval regions of interest were set manually to delineate the olfactory bulb on the side of nasal administration of the tracer by referencing the MRI T2 weighted images. The size of the oval olfactory bulb region of interest was approximately 8 to 9 pixels on the long axis and 3 to 4 pixels on the short axis in the sagittal image and 5 to 6 pixels by 2 to 3 pixels in the coronal image. The regions of interest were set excluding the sphenoidal sinus area and the nasopharyngeal area.
The index of 201Tl migration from the olfactory epithelium to the olfactory bulb was determined as the ratio of the total 201Tl counts in the olfactory bulb region of interest to the total 201Tl counts in the nasal turbinate region of interest, expressed as a mean percentage of the values calculated from both sagittal and coronal images. Experienced nuclear radiologists (J.T. and K.O.) who were blind to the olfactory test data determined separately the two regions of interest on the SPECT-MRI image. The average scores of those were used for the statistical analysis.
A phantom study was performed with the same data acquisition and reconstruction method used in the clinical study. In a cylindrical phantom (20 cm in diameter) filled with water, a 201Tl (40 µCi) spherical source (4 mm in diameter) was positioned on the center of the rotation. Then the counts of pixels on the line passing through the center of the source and at a right angle to the axis of camera rotation were measured. Full width at half maximum (FWHM) was 7.0 mm. When normalized by the maximum pixel count (7972 counts) of the spherical source, pixel counts at 1 (2.1 mm), 2 (4.2 mm), 3 (6.3 mm), 4 (8.4 mm), and 5 (10.5 mm) pixels from the center of the source were 0.76, 0.34, 0.09, 0.016, 0.001, respectively. Thus, when the olfactory bulb is located more than 4 pixels (8.4 mm) from the high radioactivity in the nasal cavity, the count contamination to the olfactory bulb will be less than 2% of the activity of the nasal cavity.
Two-tailed Spearman correlations, unpaired t-tests, Bonferroni’s multiple comparison test, and Kruskal-Wallis tests were performed using Prism 5 software (GraphPad, San Diego, CA, USA).
To determine whether the viability or function of the peripheral olfactory nerve was reduced in the patients with impaired olfaction, we assessed migration of nasally administered 201Tl to the olfactory bulb in the patients and healthy volunteers. Migration of nasal 201Tl to the olfactory bulb was significantly lower in the patients with head trauma, upper respiratory infection, or chronic sinusitis than in the healthy volunteers (
Nasal 201Tl migration to the olfactory bulb in healthy volunteers (n = 10) and patients with impaired olfaction due to head trauma (n = 7), upper respiratory tract infection (respiratory infection; n = 7), or chronic rhinosinusitis (n = 7).
Representative cases are shown in
White arrows indicate the olfactory bulb and olfactory nerve. (A) A 60-year-old healthy male volunteer. (B) A 44-year-old female with hyposmia after head trauma. (C) A 42-year-old female with hyposmia after upper respiratory tract infection. (D) A 67-year-old female with hyposmia due to chronic rhinosinusitis. The index of 201Tl migration from the olfactory epithelium to the olfactory bulb in the selected subjects was shown in
White arrows indicate the olfactory bulb and olfactory nerve. (A) A 60-year-old healthy male volunteer. (B) A 44-year-old female with hyposmia after head trauma. (C) A 42-year-old female with hyposmia after upper respiratory tract infection. (D) A 67-year-old female with hyposmia due to chronic rhinosinusitis.
Selected subjects | Nasal 201Tl migration to the olfactory bulb, % | Odor recognition threshold |
60-year-old healthy male volunteer | 29.0 | 1.4 |
44-year-old female with hyposmia after head trauma | 4.2 | 5.8 |
42-year-old female with hyposmia after upper respiratory tract infection | 4.5 | 4.8 |
67-year-old female with hyposmia due to chronic rhinosinusitis | 5.0 | 3.2 |
To assess whether nasal 201Tl migration to the olfactory bulb reflects olfactory function, we examined the relationships between the recognition threshold obtained with T&T olfactometry and the amount of nasal 201Tl that migrated to the olfactory bulb in the subjects.
Nasal 201Tl migration to the olfactory bulb was correlated with the odor recognition threshold obtained by T&T olfactometry (Spearman
Nasal 201Tl migration to the olfactory bulb as a function of odor recognition threshold in patients and healthy volunteers (n = 31). Spearman
To assess whether nasal 201Tl migration to the olfactory bulb reflects olfactory bulb size, we examined the relationships between the olfactory bulb volume determined from MRI images and the amount of nasal 201Tl that migrated to the olfactory bulb in the subjects. Olfactory bulb volume was significantly lower in the patients with head trauma, upper respiratory infection, or chronic sinusitis than in the healthy volunteers (
Subject Group | Olfactory bulb volume, mm3 (Mean ± S.D.) |
Healthy volunteer (n = 10) | 83.2±25.5 |
Head trauma (n = 7) | 22.4±7.5 |
Upper respiratory tract infection (n = 7) | 35.8±12.3 |
Chronic rhinosinusitis (n = 7) | 33.3±10.5 |
Nasal 201Tl migration to the olfactory bulb was correlated with the olfactory bulb volume determined from MRI images (Spearman
Nasal 201Tl migration to the olfactory bulb as a volume of olfactory bulb in patients and healthy volunteers (n = 31). Spearman
Nasal 201Tl migration to the olfactory bulb was reduced in the patients with impaired olfaction due to head trauma, upper respiratory tract infection, and chronic rhinosinusitis, which are major causes of olfactory dysfunction
The migration of 201Tl to the olfactory bulb was correlated with odor recognition thresholds obtained with T&T olfactometry when all subjects were included. Furthermore, the volume of the olfactory bulb determined by using MR images was positively correlated with the level of 201Tl migration from the nasal turbinate area to the olfactory bulb on SPECT-MRI fusion images in both the healthy volunteers and patients with impaired olfaction. Our results suggest that the connectivity of olfactory neurons between the olfactory bulb and olfactory mucosa reflect the volume of the olfactory bulb. Increasing olfactory stimulation leads to decreased cell mortality in the olfactory bulb
The nasal 201Tl migration to the olfactory bulb was not significantly correlated with olfactory bulb volume determined by using MR images in the healthy volunteers or in the patients with impaired olfaction evaluated as separate groups (data not shown), likely because of the small number of subjects in each group. It has been shown that olfactory bulb volume is larger in men than in women
In this study, the decrease of the migration of 201Tl to the olfactory bulb was not significantly different among the patients with head trauma, upper respiratory tract infection, or chronic sinusitis. The degree of peripheral olfactory nerve degeneration may be similar in the patient groups included in this study, because we observed no significant different olfactory thresholds among the patient groups.
In this study, we observed no adverse effects in the subjects. Unlike intravenous administration of radiopharmaceutical agents, which would deliver only small amounts of radiation to the nasal cavity, nasal administration of 201Tl delivers a high radiation dose to the nasal cavity. Therefore, the estimation of the absorbed dose in the nasal cavity and neighboring organ such as brain and lens are important. We calculated the absorbed dose of 201Tl in the nasal cavity in a previous clinical study, and its dose was too low for acute radiation effects
The majority of 201Tl administered intranasally in this study migrated to the nasopharyngeal region and then was swallowed. It has been shown that intravenously administered 201Tl is hardly absorbed by the central nervous system, including the olfactory bulb,
It will be important to study whether an increase in 201Tl migration to the olfactory bulb during treatment is correlated with a decrease in odor recognition thresholds in patients with olfactory disorders. The recovery rate of olfactory function in patients with traumatic olfactory dysfunction is less than 30%
Nasal 201Tl migration to the olfactory bulb was reduced in patients with impaired olfaction due to head trauma, upper respiratory tract infection, and chronic rhinosinusitis, which are major causes of olfactory dysfunction when compared to the 201Tl migration in healthy volunteers. Assessment of the 201Tl migration to the olfactory bulb was the new method for the evaluation of the olfactory nerve connectivity in patients with olfactory disorders.
We are grateful to the staff in the Division of Radioisotopes, Kanazawa University, and the Division of Radiology, Kanazawa Medical University, for their technical support.