Histological changes in the olfactory bulb and rostral migratory stream due to interruption of olfactory input.

OBJECTIVE: Periglomerular and granule cells in the adult mammalian olfactory bulb modulate olfactory signal transmission. These cells originate from the subventricular zone, migrate to the olfactory bulb via the Rostral Migratory Stream (RMS), and differentiate into mature cells within the olfactory bulb throughout postnatal life. While the regulation of neuroblast development is known to be affected by external stimuli, there is a lack of information concerning changes that occur during the recovery process after injury caused by external stimuli. To address this gap in research, the present study conducted histological observations to investigate changes in the olfactory bulb and RMS occurring after the degeneration and regeneration of olfactory neurons. METHODS: To create a model of olfactory neurodegeneration, adult mice were administered methimazole intraperitoneally. Nasal tissue and whole brains were removed 3, 7, 14 and 28 days after methimazole administration, and EdU was administered 2 and 4 h before removal of these tissues to monitor dividing cells in the RMS. Methimazole-untreated mice were used as controls. Olfactory nerve fibers entering the olfactory glomerulus were observed immunohistochemically using anti-olfactory marker protein. In the brain tissue, the entire RMS was observed and the volume and total number of cells in the RMS were measured. In addition, the number of neuroblasts and dividing neuroblasts passing through the RMS were measured using anti-doublecortin and anti-EdU antibodies, respectively. Statistical analysis was performed using the Tukey test. RESULTS: Olfactory epithelium degenerated was observed after methimazole administration, and recovered after 28 days. In the olfactory glomeruli, degeneration of OMP fibers began after methimazole administration, and after day 14, OMP fibers were reduced or absent by day 28, and overall OMP positive fibers were less than 20%. Glomerular volume tended to decrease after methimazole administration and did not appear to recover, even 28 days after recovery of the olfactory epithelium. In the RMS, EdU-positive cells decreased on day 3 and began to increase on day 7. However, they did not recover to the same levels as the control methimazole-untreated mice even after 28 days. CONCLUSION: These results suggest that the division and maturation of neuroblasts migrating from the RMS was suppressed by olfactory nerve degeneration or the disruption of olfactory input.

Efficacy of tokishakuyakusan and mecobalamin on post-infectious olfactory dysfunction: A prospective multicenter study.

OBJECTIVE: To determine if tokishakuyakusan (TSS) is effective for treating post-infectious olfactory dysfunction (PIOD) compared with vitamin B12 (mecobalamin). METHODS: We conducted a randomized, nonblinded clinical trial. Patients with PIOD enrolled in 17 hospitals and clinics from 2016 to 2020 were randomly divided into two groups, and we administered TSS or mecobalamin for 24 weeks. Their olfactory function was examined using interviews and T&T olfactometry. The improvement of olfactory dysfunction was assessed following the criteria of the Japanese Rhinologic Society. RESULTS: Overall, 82 patients with PIOD were enrolled in this study. In the TSS and mecobalamin groups, 39 patients completed the medication regimen. In the TSS and mecobalamin groups, olfactory dysfunction was significantly improved based on self-reports and olfactory test results. The improvement rate of olfactory dysfunction was 56% in the TSS group and 59% in the mecobalamin group. Early intervention within 3 months produced a better prognosis than the treatment initiated after 4 months. Furthermore, age and sex differences were not observed. Both medications produced no severe adverse events. CONCLUSION: The present study showed that TSS and mecobalamin might be useful for treating PIOD.

Olfactory Regeneration with Nasally Administered Murine Adipose-Derived Stem Cells in Olfactory Epithelium Damaged Mice.

In this study, we aimed to determine whether nasally administered murine adipose-derived stem cells (ADSCs) could support olfactory regeneration in vivo. Olfactory epithelium damage was induced in 8-week-old C57BL/6J male mice by intraperitoneal injection of methimazole. Seven days later, OriCell adipose-derived mesenchymal stem cells obtained from green fluorescent protein (GFP) transgenic C57BL/6 mice were nasally administered to the left nostril of these mice, and their innate odor aversion behavior to butyric acid was assessed. Mice showed significant recovery of odor aversion behavior, along with improved olfactory marker protein (OMP) expression on both sides of the upper-middle part of the nasal septal epithelium assessed by immunohistochemical staining 14 d after the treatment with ADSCs compared with vehicle control animals. Nerve growth factor (NGF) was detected in the ADSC culture supernatant, NGF was increased in the nasal epithelium of mice, and GFP-positive cells were observed on the surface of the left side nasal epithelium 24 h after left side nasal administration of ADSCs. The results of this study suggest that the regeneration of olfactory epithelium can be stimulated by nasally administered ADSCs secreting neurotrophic factors, thereby promoting the recovery of odor aversion behavior in vivo.

Sarcopenia and decline in appendicular skeletal muscle mass are associated with hypoperfusion in key hubs of central autonomic network on 3DSRT in older adults with progression of normal cognition to Alzheimer's disease.

AIM: Although sarcopenia is common in patients with Alzheimer's disease (AD), the neural substrates involved remain unclear. We investigated the relationship between sarcopenia, as well as its definition components, and regional cerebral blood flow (rCBF) in older adults with progression of normal cognition to AD. METHODS: 99m Tc-ethyl-cysteinate-dimer single-photon emission computed tomography was carried out in 95 older adults with progression of normal cognition to AD (40 men and 55 women, mean ± SD age 80.9 ± 6.8 years). The associations of rCBF determined by 3-D stereotactic region of interest template software, with sarcopenia and its definition components, slower gait speed, weaker grip strength, and decline in appendicular skeletal muscle mass index (ASMI) were analyzed. RESULTS: Logistic regression analysis adjusted by age, sex, mini-mental state examination score and education showed that sarcopenia as well as ASMI less than the cut-off (men 7.0 kg/m2 , women 5.7 kg/m2 ) were associated with significantly reduced rCBF in the key hub of the central autonomic network, including the insula, anterior cingulate cortex, subcallosal area, rectal gyrus, hypothalamus, amygdala and caudate head. Sarcopenia and ASMI decline were associated with hypoperfusion in the aforementioned cortical hubs of the central autonomic network in men, but with hypoperfusion of the hypothalamus in women. Linear regression analysis showed significant correlations of ASMI/cut-off with rCBF in the bilateral medial frontal cortex, as well as rCBF in the aforementioned key hubs. CONCLUSIONS: Hypoperfusion in key hubs of central autonomic network is implicated in the emergence of sarcopenia, probably through ASMI decline in vulnerable older adults. Geriatr Gerontol Int 2023; 23: 16-24.

Thallium-201 Imaging in Intact Olfactory Sensory Neurons with Reduced Pre-Synaptic Inhibition In Vivo.

In this study, we determined whether the 201Tl (thallium-201)-based olfactory imaging is affected if olfactory sensory neurons received reduced pre-synaptic inhibition signals from dopaminergic interneurons in the olfactory bulb in vivo. The thallium-201 migration rate to the olfactory bulb and the number of action potentials of olfactory sensory neurons were assessed 3 h following left side nasal administration of rotenone, a mitochondrial respiratory chain complex I inhibitor that decreases the number of dopaminergic interneurons without damaging the olfactory sensory neurons in the olfactory bulb, in mice (6-7 animals per group). The migration rate of thallium-201 to the olfactory bulb was significantly increased following intranasal administration of thallium-201 and rotenone (10 µg rotenone, p = 0.0012; 20 µg rotenone, p = 0.0012), compared with that in control mice. The number of action potentials was significantly reduced in the olfactory sensory neurons in the rotenone treated side of 20 µg rotenone-treated mice, compared with that in control mice (p = 0.0029). The migration rate of thallium-201 to the olfactory bulb assessed with SPECT-CT was significantly increased in rats 24 h after the left intranasal administration of thallium-201 and 100 µg rotenone, compared with that in control rats (p = 0.008, 5 rats per group). Our results suggest that thallium-201 migration to the olfactory bulb is increased in intact olfactory sensory neurons with reduced pre-synaptic inhibition from dopaminergic interneurons in olfactory bulb glomeruli.

The Impact of Ovariectomy on Olfactory Neuron Regeneration in Mice.

Estrogen has been shown to affect differentiation and proliferation as a mitogen in various neural systems. Olfactory receptor cells are unique within the nervous system, and have the ability to regenerate even after an individual has reached maturity. Olfactory receptor cells also regenerate after experimentally induced degeneration. The purpose of this study is to observe the influence of estrogen depletion induced by ovariectomy on olfactory nerve regeneration. Female mice underwent bilateral ovariectomy at 8 weeks of age and received intraperitoneal administration of methimazole 1 week later. At 2, 4, and 6 weeks after methimazole administration, the olfactory mucosa was analyzed histochemically to determine olfactory epithelium (OE) thickness, olfactory marker protein distribution, and Ki-67 immunoreactivity. Furthermore, 2 weeks after ovariectomy, trkA protein distribution in the OE and nerve growth factor (NGF) levels in the olfactory bulb were determined by immunohistochemistry and enzyme-linked immunosorbent assay, respectively. Our results showed that in ovariectomized mice OMP, Ki-67, and trkA-immunopositive cells expression decreased at 2 weeks after methimazole injection, a time point at which regeneration is underway. At this same time point, although NGF production in the olfactory bulb had increased before methimazole administration, no differences were observed between the ovx and control groups. These results suggest that estrogen depletion induces a suppressive effect on regeneration of olfactory neurons, and that estrogen may have a potential use in the treatment of sensorineural olfactory dysfunction.

Relationship Between Olfactory Disturbance After Acute Ischemic Stroke and Latent Thalamic Hypoperfusion.

Odor detection, recognition, and identification were assessed in 19 acute ischemic stroke patients who had no magnetic resonance imaging-detectable thalamic lesions but in whom technetium-99m ethyl cysteinate dimer single photon emission tomography revealed thalamic hypoperfusion. Although these patients were unaware of reduced olfactory function, they exhibited significantly lower scores in tests for odor identification and recognition threshold as compared with 9 ischemic stroke controls that had normal thalamic hypoperfusion. However, absolute odor detection thresholds were similar in the 2 groups. These results demonstrate the usefulness of cerebral perfusion scintigraphy in assessing sensory loss after ischemic stroke and provide further evidence for the role of the thalamus in olfaction.

Nasal thallium-201 uptake in patients with parosmia with and without hyposmia after upper respiratory tract infection.

BACKGROUND: In this study, we aimed to determine whether nasal thallium-201 uptake of the olfactory cleft and olfactory bulb (OB) differs between patients with parosmia with and without hyposmia after upper respiratory tract infection (URTI). METHODS: Twenty patients with parosmia after URTI were enrolled in this study (15 women and 5 men, 28 to 76 years old). Nasally administered thallium-201 migration to the OB, nasal thallium-201 uptake ratio in the olfactory cleft, and OB volume were determined in 10 patients with normal T&T olfactometry (Daiichi Yakuhin Sangyo, Tokyo, Japan) odor recognition thresholds (≤2.0) who still complained of parosmia (parosmia group), and 10 patients with T&T odor recognition thresholds >2.0 (parosmia and hyposmia group). RESULTS: The nasal thallium-201 uptake ratio in the olfactory cleft was significantly higher in the parosmia group than in the parosmia and hyposmia group (p = 0.0015). Thallium-201 migration to the OB was not significantly different between the 2 groups (p = 0.31). The OB volume was significantly larger in the parosmia group than that in the parosmia and hyposmia group (p = 0.029); however, the mean OB volume in both the groups was lower than the normal threshold value in healthy individuals. CONCLUSION: Our results signify the recovery of the olfactory epithelium; however, the olfactory neural projections to the OB and regeneration of OB were not complete in patients with parosmia with normal T&T recognition thresholds after URTI.

Clinical practice guidelines for the management of olfactory dysfunction - Secondary publication.

OBJECTIVE: To provide an evidence-based recommendation for the management of olfactory dysfunction in accordance with the consensus reached by the Subcommittee of the Japanese Clinical Practice Guideline for olfactory dysfunction in the Japanese Rhinologic Society. METHODS: Seven clinical questions (CQs) regarding the management of olfactory dysfunction were formulated by the subcommittee of the Japanese Clinical Practice Guideline for olfactory dysfunction. We searched the literature published between April 1990 and September 2014 using PubMed, the Cochrane Library, and Ichushi Web databases. The main search terms were "smell disorder," "olfactory dysfunction," "olfactory loss," "olfactory disturbance," "olfactory impairments," "olfaction disorder," "smell disorder," "anosmia," "cacosmia," and "dysosmia." Based on the results of the literature review and the expert opinion of the Subcommittee, 4 levels of recommendation, from A-strongly recommended to D-not recommended, were adopted for the management of olfactory dysfunction. RESULTS: Both oral and locally administered corticosteroids have been strongly recommended for patients with olfactory dysfunction due to chronic rhinosinusitis. Nasal steroid spray and antihistamine drugs have been moderately recommended for patients with allergic rhinitis. Although no drugs have been deemed to be truly effective for post-viral olfactory dysfunction by randomized-controlled trials (RCTs) or placebo-controlled trials, olfactory training using odorants has been reported to be effective for improving olfactory function. There is considerable evidence that olfactory testing is useful for differential diagnosis, prediction of disease progression, and early detection of cognitive decline in neurodegenerative diseases. CONCLUSION: The Clinical Practice Guideline has developed recommendations for the management of various aspects of olfactory dysfunction.

Association of olfactory impairment with indexes of sarcopenia and frailty in community-dwelling older adults.

AIM: Individuals with olfactory or gustatory impairment often have associated difficulties with food-related activities. As both functions decline in older adults, we investigated the association of these impairments with sarcopenia/frailty indexes in community-dwelling older adults. METHODS: A total of 141 participants (69 men and 72 women, mean age 73.0 years) were enrolled. Odor identification was examined using the Open Essence test. Salty and sweet tastes were assessed using a whole-mouth gustatory test. Participants underwent evaluation of the appendicular skeletal muscle mass index (ASMI) by InBody720 and grip strength, and determination of the Study of Osteoporotic Fractures frailty index. RESULTS: Participants with olfactory impairment (Open Essence ≤7), but not with gustatory impairment, showed a significantly higher prevalence of ASMI and grip strength less than the cut-off values recommended by the Asian Working Group for Sarcopenia, and Study of Osteoporotic Fractures frailty and/or pre-frailty status, compared with those without impairment. Multivariate logistic regression analysis showed a significant association of olfactory impairment with ASMI less than the cut-off value, grip strength less than the cut-off value, Asian Working Group for Sarcopenia sarcopenia and pre-frailty/frailty in the Study of Osteoporotic Fractures index in the whole population, and with ASMI less than the cut-off value and Asian Working Group for Sarcopenia sarcopenia in women, after adjustment. Three (Japanese cypress, wood and roasted garlic) and four (Japanese orange, India ink, menthol and curry) Open Essence odorants were elucidated as the "sarcopenia subset" and "frailty subset," respectively, and showed higher ability to identify sarcopenia and frailty status, compared with the remaining five odorants. CONCLUSIONS: These findings suggest that olfactory impairment is closely associated with sarcopenia and/or frailty in community-dwelling older adults. Geriatr Gerontol Int 2019; 19: 384-391.

Effects of Tokishakuyakusan on Regeneration of Murine Olfactory Neurons In Vivo and In Vitro.

Post-upper respiratory tract infection related olfactory dysfunction typically occurs due to neural damage after an upper respiratory tract infection associated with a common cold or influenza. At present, Tokishakuyakusan, a Japanese traditional Kampo medicine, has been found to be effective for post-viral olfactory dysfunction. However, the pharmacodynamics of Tokishakuyakusan in the treatment of post-viral olfactory dysfunction remains unresolved. We investigated the effects of Tokishakuyakusan on the regeneration of olfactory neurons and expression of nerve growth factor (NGF) in neural systems, using in vivo murine studies and in vitro cell culture studies. Eight-week-old BALB/C female mice were fed a pellet diet with or without Tokishakuyakusan. Degeneration of cells in olfactory epithelium was induced by intraperitoneal methimazole injection. Regeneration of olfactory neurons was observed by histological and immunohistochemical procedures. NGF expression in the olfactory bulb was measured by enzyme-linked immunosorbent assay. NGF gene and protein expression were measured using rat primary cultured astrocytes by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. We found that olfactory marker protein, Ki-67, and NGF were more highly expressed in the olfactory epithelium during the regeneration period in mice receiving Tokishakuyakusan. In cultured astrocytes, Tokishakuyakusan as well as its individual components, Atractylodes lancea rhizome and Japanese angelica root, increased NGF expression. Screening assays revealed that NGF production was increased by atractylodin and levistolide A, which are ingredients in Atractylodes lancea rhizome and Japanese angelica root, respectively. These results suggest that Tokishakuyakusan promotes regeneration of olfactory neurons by increasing NGF expression in the olfactory bulb.

Prognostic value of olfactory nerve damage measured with thallium-based olfactory imaging in patients with idiopathic olfactory dysfunction.

Idiopathic olfactory disorder is resistant to treatment, and the recovery time is long. This study investigated the prognostic value of the migration of nasally administered thallium-201 to the olfactory bulb (thallium migration to the OB), a measure of olfactory nerve damage, in patients with idiopathic olfactory disorders. Twenty-four patients with idiopathic olfactory disorders were enrolled in the study (7 women and 17 men; aged 23-73 years). We retrospectively analyzed potential prognostic markers in subjects who underwent thallium-based olfactory imaging with the nasal administration of thallium-201 before conventional treatment with the Japanese herbal medicine tokishakuyakusan and compared those data with the prognosis. Log-rank tests were performed to assess the relationship between thallium migration to the OB (<4.6% [low] vs. ≥4.6% [high]; data dichotomized at the optimal cutoff value) and the duration until recovery of the odor recognition threshold determined by a standard olfactory function test (T&T olfactometry) after the treatment. Upon statistical analysis, we found that high thallium migration to the OB was significantly correlated with better prognosis in patients. Our results suggest that patients with intact olfactory nerve fibers could be selected using thallium-based imaging for the long-term follow-up of olfactory dysfunction.

Combinations of two odorants of smell identification test for screening of olfactory impairment.

OBJECTIVE: To determine whether combinations of two odorants of the Open Essence smell identification test can be used to screen for olfactory impairment in Japanese people. METHODS: A total of 243 Japanese subjects (142 males, 101 females; mean age, 37.5 years; age range, 20-62 years) were enrolled in the study. The main outcome measures were the results of olfactory testing by using the full 12 odorants (condensed milk, cooking gas, curry, cypress wood (Japanese cypress, hinoki), India ink, Japanese orange (mikan), menthol, perfume, roasted garlic, rose, sweaty-smelling clothes, and wood) of the Open Essence test as well as combinations of two odorants of the Open Essence test, and the results of self-reported questionnaires addressing awareness of a smell disorder, history of sinunasal disease, self-reported nasal obstruction, and history of smoking. RESULTS: In screening with combinations of two odorants, the highest positive likelihood ratio (19.1) was obtained with the cypress wood and India ink odorants. All subjects correctly identified the curry odorant. Combinations of other odorants also had high positive likelihood ratios (India ink and sweaty-smelling clothes, 17.6; perfume and sweaty-smelling clothes, 14.7; cypress wood and roasted garlic, 14.1; cypress wood and rose, 13.2; cypress wood and perfume, 11.0; cypress wood and wood, 10.7). CONCLUSION: The combination of cypress wood and India ink odorants may be useful for detecting individuals with olfactory impairment among subjects who can correctly identify the curry odorant.

Reduced nasal transport of insulin-like growth factor-1 to the mouse cerebrum with olfactory bulb resection.

Although the olfactory nerve is involved in nasal transport of insulin-like growth factor-1 (IGF-1) to the brain, to our knowledge there have been no direct assessments of the effects of olfactory nerve damage on this transport. To determine whether olfactory bulb resection resulted in reduced transport of nasally administered human recombinant IGF-1 (hIGF-1) to the cerebrum, we measured the uptake of nasally administered iodine-125 hIGF-1 ((125)I-hIGF-1) in the cerebrum as a percentage of that in the blood in male ICR mice subjected to left olfactory bulb resection (model mice) and in sham-operated male ICR mice (control mice). Phosphorylated extracellular signal-regulated kinase (ERK) 1/2 (Thr202/Tyr204)/(Thr185/Tyr187) as a percentage of total ERK 1/2 in the left cerebrum was also assessed by using enzyme-linked immunosorbent assay after nasal administration of hIGF-1. Uptake of nasally administered (125)I-hIGF-1 in the cerebrum as a percentage of that in the blood was significantly lower in the model group than in the control group 30min after nasal administration of hIGF-1. Unilateral olfactory bulb resection prevented nasally administered hIGF-1 from increasing the phosphorylation of ERK 1/2 in the mouse cerebrum in vivo. These findings suggest that olfactory bulb damage reduces nasal transport of hIGF-1 to the brain in vivo.

Rapamycin downregulates thymidylate synthase and potentiates the activity of pemetrexed in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancer cases, and almost half of newly diagnosed patients have metastatic disease. Pemetrexed is a widely used drug for NSCLC and inhibits several folate-dependent enzymes including thymidylate synthase (TS). Increased expression of TS confers resistance to pemetrexed in vitro and predicts poor response to pemetrexed. Rapamycin is an mTOR inhibitor and suppresses cap-dependent synthesis of specific mRNA species. Here, we show that the combination of rapamycin and pemetrexed synergistically inhibits proliferation of NSCLC cells. Although pemetrexed as a single agent induced TS, pretreatment with rapamycin suppressed pemetrexed-induced TS expression. In vivo, the combination of rapamycin and pemetrexed inhibited growth of NSCLC xenografts, which correlated with decreased mTOR activity and suppression of pemetrexed-induced TS expression. The ability of rapamycin to enhance the efficacy of pemetrexed and prevent TS expression has implications for the design of Phase I and/or Phase II NSCLC clinical trials with mTOR inhibitors in combination with pemetrexed.

Assessment of olfactory nerve by SPECT-MRI image with nasal thallium-201 administration in patients with olfactory impairments in comparison to healthy volunteers.

PURPOSE: The aim of this study was to assess whether migration of thallium-201 ((201)Tl) to the olfactory bulb were reduced in patients with olfactory impairments in comparison to healthy volunteers after nasal administration of (201)Tl. PROCEDURES: 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). (201)TlCl was administered unilaterally to the olfactory cleft, and SPECT-CT was conducted 24 h later. Separate MRI images were merged with the SPECT images. (201)Tl 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. RESULTS: Nasal (201)Tl migration to the olfactory bulb was significantly lower in the olfactory-impaired patients than in healthy volunteers. The migration of (201)Tl 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. CONCLUSIONS: Assessment of the (201)Tl migration to the olfactory bulb was the new method for the evaluation of the olfactory nerve connectivity in patients with impaired olfaction.

[Clinical diagnosis of the olfactory nerve transport function].

Nasal administration of macromolecular drugs (peptides, nanoparticles) has a possibility to enable a drug delivery system beyond the blood brain barrier via olfactory nerve transport. Basic research on nasal drug delivery to the brain has been well studied. However, evaluation of the olfactory nerve transport function in patients with olfactory disorders has yet to be done, although such an evaluation is important in selecting candidates for clinical trials. Current olfactory function tests are useful for the analysis of olfactory thresholds in olfaction-impaired patients. However, the usefulness of using the increase in olfactory thresholds in patients as an index for evaluating olfactory nerve damage has not been confirmed because of the difficulty in directly evaluating the viability of the peripheral olfactory nerves. Nasally administered thallium-201 migrates to the olfactory bulb, as has been shown in healthy volunteers. Furthermore, transection of olfactory nerve fibers in mice significantly decreases migration of nasally administered thallium-201 to the olfactory bulb. The migration of thallium-201 to the olfactory bulb is reduced in patients with impaired olfaction due to head trauma, upper respiratory tract infections, and chronic rhinosinusitis, relative to the values in healthy volunteers. Nasally administrating thallium-201 followed by single photon emission computed tomography, X-ray computed tomography and magnetic resonance imaging might be useful in choosing candidates for clinical trials of nasal drug delivery methods to the brain.

Evaluation of the olfactory nerve transport function by SPECT-MRI fusion image with nasal thallium-201 administration.

PURPOSE: The aim of this study was to visualize the human olfactory transport pathway to the brain by performing imaging after nasal thallium-201 ((201)Tl) administration. PROCEDURES: Healthy volunteers were enrolled in this study after giving informed consent (five males, 35-51 years old). The subjects were nasally administered (201)TlCl into either the olfactory cleft. Twenty-four hours later, uptake of (201)Tl was detected by a single photon emission computed tomography (SPECT)/X-ray computed tomography hybrid system. For each subject, an MRI image was obtained and merged with the SPECT image. RESULTS: The peak of the (201)Tl uptake entered into the olfactory bulb in the anterior skull base through the cribriform lamina 24 h after nasal administration of (201)Tl. No participant had olfactory disturbance after treatment. CONCLUSIONS: Nasal (201)Tl administration was safely used to assess the direct pathway to the brain via the nose in healthy volunteers with normal olfactory threshold.

Use of thallium transport to visualize functional olfactory nerve regeneration in vivo.

OBJECTIVE: To image olfactory nerve regeneration in vivo using a high-resolution gamma cam- era and radiography after nasal administration of thallium-201 (olfacto-scintigraphy). METHODS: Six Wistar rats were trained to avoid the smell of cycloheximide as a test of olfactory function. The olfactory nerve fibers of 3 rats were then carefully transected bilaterally with a Teflon knife, avoiding damage to the olfactory bulbs. The remaining 3 rats underwent sham operations and were used as controls. Steel wires were implanted in the left olfactory bulb of each rat for locating the bulbs with plain X-rays. The rats were assessed 2, 14, 28, and 42 d after the olfactory nerve transection or sham operation for their ability to detect odours and for transport of 201Tl to the olfactory bulb area 8 h after nasal administration of 201Tl. RESULTS: Both transport of 201Tl to the olfactory bulb area (p < 0.04) and ability to detect odours (p < 0.04) significantly increased with a time course after olfactory nerve transection. CONCLUSION: 201Tl transport to the olfactory bulb may be useful to visually assess olfactory ability in vivo. We plan to test olfacto-scintigraphy clinically by nasal administration of 201Tl in patients with posttraumatic olfactory loss.