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Background: The mechanisms by which any upper respiratory virus, including SARS-CoV-2, impairs chemosensory function are not known. COVID-19 is frequently associated with olfactory dysfunction after viral infection, which provides a research opportunity to evaluate the natural course of this neurological finding. Clinical trials and prospective and histological studies of new-onset post-viral olfactory dysfunction have been limited by small sample sizes and a paucity of advanced neuroimaging data and neuropathological samples. Although data from neuropathological specimens are now available, neuroimaging of the olfactory system during the acute phase of infection is still rare due to infection control concerns and critical illness and represents a substantial gap in knowledge., Recent Developments: The active replication of SARS-CoV-2 within the brain parenchyma (ie, in neurons and glia) has not been proven. Nevertheless, post-viral olfactory dysfunction can be viewed as a focal neurological deficit in patients with COVID-19. Evidence is also sparse for a direct causal relation between SARS-CoV-2 infection and abnormal brain findings at autopsy, and for trans-synaptic spread of the virus from the olfactory epithelium to the olfactory bulb. Taken together, clinical, radiological, histological, ultrastructural, and molecular data implicate inflammation, with or without infection, in either the olfactory epithelium, the olfactory bulb, or both. This inflammation leads to persistent olfactory deficits in a subset of people who have recovered from COVID-19. Neuroimaging has revealed localised inflammation in intracranial olfactory structures. To date, histopathological, ultrastructural, and molecular evidence does not suggest that SARS-CoV-2 is an obligate neuropathogen. WHERE NEXT?: The prevalence of CNS and olfactory bulb pathosis in patients with COVID-19 is not known. We postulate that, in people who have recovered from COVID-19, a chronic, recrudescent, or permanent olfactory deficit could be prognostic for an increased likelihood of neurological sequelae or neurodegenerative disorders in the long term. An inflammatory stimulus from the nasal olfactory epithelium to the olfactory bulbs and connected brain regions might accelerate pathological processes and symptomatic progression of neurodegenerative disease. Persistent olfactory impairment with or without perceptual distortions (ie, parosmias or phantosmias) after SARS-CoV-2 infection could, therefore, serve as a marker to identify people with an increased long-term risk of neurological disease., Competing Interests: Declaration of interests SP reports grants from the US National Institutes of Health. AP reports grants from the German Ministry of Education and Research. MWA reports non-financial support from International Flavor & Fragrances, funding from the US National Institutes of Health Rapid Acceleration of Diagnostics (RADx), and a pending COVID-19 smell test patent. All other authors declare no competing interests. The views expressed in this manuscript do not necessarily reflect the official position of the US Department of Defense., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Olfactory dysfunction (OD) affects a majority of COVID-19 patients, is atypical in duration and recovery, and is associated with focal opacification and inflammation of the olfactory epithelium. Given recent increased emphasis on airborne transmission of SARS-CoV-2, the purpose of the present study was to experimentally characterize aerosol dispersion within olfactory epithelium (OE) and respiratory epithelium (RE) in human subjects, to determine if small (sub 5μm) airborne aerosols selectively deposit in the OE., Methods: Healthy adult volunteers inhaled fluorescein-labeled nebulized 0.5-5μm airborne aerosol or atomized larger aerosolized droplets (30-100μm). Particulate deposition in the OE and RE was assessed by blue-light filter modified rigid endoscopic evaluation with subsequent image randomization, processing and quantification by a blinded reviewer., Results: 0.5-5μm airborne aerosol deposition, as assessed by fluorescence gray value, was significantly higher in the OE than the RE bilaterally, with minimal to no deposition observed in the RE (maximum fluorescence: OE 19.5(IQR 22.5), RE 1(IQR 3.2), p<0.001; average fluorescence: OE 2.3(IQR 4.5), RE 0.1(IQR 0.2), p<0.01). Conversely, larger 30-100μm aerosolized droplet deposition was significantly greater in the RE than the OE (maximum fluorescence: OE 13(IQR 14.3), RE 38(IQR 45.5), p<0.01; average fluorescence: OE 1.9(IQR 2.1), RE 5.9(IQR 5.9), p<0.01)., Conclusions: Our data experimentally confirm that despite bypassing the majority of the upper airway, small-sized (0.5-5μm) airborne aerosols differentially deposit in significant concentrations within the olfactory epithelium. This provides a compelling aerodynamic mechanism to explain atypical OD in COVID-19., Competing Interests: The authors do not have competing interests that could bias this work.

Objectives/hypothesis: The aim of the study was to develop a test for the assessment of retronasal olfaction in healthy participants and patients with olfactory disorders using "tasteless" powders., Study Design: Prospective case-control series., Methods: A total of 150 participants (110 women, 40 men, mean age = 40 ± 16 years) were recruited for this study; 100 were healthy controls and 50 were patients with olfactory loss due to infections of the upper respiratory tract (n = 25), idiopathic causes (n = 12), sinonasal disease (n = 7), and head trauma (n = 6). Orthonasal olfactory function was evaluated using the Sniffin' Sticks test battery, and retronasal olfaction was evaluated using powders lacking distinctive tastes administered to the oral cavity. To establish test-retest reliability, healthy participants had their orthonasal and retronasal function tested twice., Results: The validity analyses revealed that the selected 16 stimuli differentiated between normosmic participants and patients with olfactory loss, and that retronasal and orthonasal olfaction were highly correlated., Conclusions: The results of the present study indicate that patients with olfactory loss and controls can be clearly separated using a reliable test of retronasal olfaction based on 16 retronasal stimuli., Level of Evidence: 2b Laryngoscope, 131:E324-E330, 2021., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

Three mechanisms have been proposed to account for COVID-19 associated olfactory dysfunction; obstruction of the olfactory cleft; epithelial injury and infection of the sustentacular supporting cells, which are known to express ACE2, or injury to the olfactory bulb due to axonal transport through olfactory sensory neurones. The absence of ACE2 expression by olfactory sensory neurones has led to the neurotropic potential of COVID-19 to be discounted. While an accumulating body of evidence supports olfactory epithelial injury as an important mechanism, this does not account for all the features of olfactory dysfunction seen in COVID-19; for example the duration of loss in some patients, evidence of changes within the olfactory bulb on MRI imaging, identification of viral particles within the olfactory bulb in post-mortem specimens and the inverse association between severity of COVID-19 and the prevalence of olfactory loss. The recent identification of a second route of viral entry mediated by NRP1 addresses many of these inconsistencies. Expression by the olfactory sensory neurones and their progenitor cells may facilitate direct injury and axonal transport to the olfactory bulb as well as a mechanism for delayed or absent recovery. Expression by regulatory T cells may play a central role in the cytokine storm. Variability in expression by age, race or gender may explain differing morbidity of infection and inverse association between anosmia and severity; in the case of higher expression there may be a higher risk of olfactory function but greater activation of regulatory T cells that may suppress the cytokine storm., (Copyright © 2020. Published by Elsevier Ltd.)

Just before 2020 began, a novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), brought for humans a potentially fatal disease known as coronavirus disease 2019 (COVID-19). The world has thoroughly been affected by COVID-19, while there has been little progress towards understanding the pathogenesis of COVID-19. Patients with a severe phenotype of disease and those who died from the disease have shown hyperinflammation and were more likely to develop neurological manifestations, linking the clinical disease with neuroimmunological features. Anosmia frequently occurs early in the course of COVID-19. The prevalence of anosmia would be influenced by self-diagnosis as well as self-misdiagnosis in patients with COVID-19. Despite this, the association between anosmia and COVID-19 has been a hope for research, aiming to understand the pathogenesis of COVID-19. Studies have suggested differently probable mechanisms for the development of anosmia in COVID-19, including olfactory cleft syndrome, postviral anosmia syndrome, cytokine storm, direct damage of olfactory sensory neurons, and impairment of the olfactory perception center in the brain. Thus, the observation of anosmia would direct us to find the pathogenesis of COVID-19 in the central nervous system, and this is consistent with numerous neurological manifestations related to COVID-19. Like other neurotropic viruses, SARS-CoV-2 might be able to enter the central nervous system via the olfactory epithelium and induce innate immune responses at the site of entry. Viral replication in the nonneural olfactory cells indirectly causes damage to the olfactory receptor nerves, and as a consequence, anosmia occurs. Further studies are required to investigate the neuroimmunology of COVID-19 in relation to anosmia.

The main neurological manifestation of COVID-19 is loss of smell or taste. The high incidence of smell loss without significant rhinorrhea or nasal congestion suggests that SARS-CoV-2 targets the chemical senses through mechanisms distinct from those used by endemic coronaviruses or other common cold-causing agents. Here we review recently developed hypotheses about how SARS-CoV-2 might alter the cells and circuits involved in chemosensory processing and thereby change perception. Given our limited understanding of SARS-CoV-2 pathogenesis, we propose future experiments to elucidate disease mechanisms and highlight the relevance of this ongoing work to understanding how the virus might alter brain function more broadly., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Despite clinical evidence indicating a close relationship between olfactory dysfunction and Alzheimer's disease (AD), further investigations are warranted to determine the diagnostic potential of nasal surrogate biomarkers for AD. In this study, we first identified soluble amyloid-β (Aβ), the key biomarker of AD, in patient nasal discharge using proteomic analysis. Then, we profiled the significant differences in Aβ oligomers level between patient groups with mild or moderate cognitive decline (n = 39) and an age-matched normal control group (n = 21) by immunoblot analysis and comparing the levels of Aβ by a self-standard method with interdigitated microelectrode sensor systems. All subjects received the Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and the Global Deterioration Scale (GDS) for grouping. We observed higher levels of Aβ oligomers in probable AD subjects with lower MMSE, higher CDR, and higher GDS compared to the normal control group. Moreover, mild and moderate subject groups could be distinguished based on the increased composition of two oligomers, 12-mer Aβ*56 and 15-mer AβO, respectively. The longitudinal cohort study confirmed that the cognitive decline of mild AD patients with high nasal discharge Aβ*56 levels advanced to the moderate stage within three years. Our clinical evidence strongly supports the view that the presence of oligomeric Aβ proteins in nasal discharge is a potential surrogate biomarker of AD and an indicator of cognitive decline progression.

During the initial pandemic wave of COVID-19, apart from common presenting symptoms (cough, fever, and fatigue), many countries have reported a sudden increase in the number of smell and taste dysfunction patients. Smell dysfunction has been reported in other viral infections (parainfluenza, rhinovirus, SARS, and others), but the incidence is much lower than SARS-CoV-2 infection. The pathophysiology of post-infectious olfactory loss was hypothesized that viruses may produce an inflammatory reaction of the nasal mucosa or damage the olfactory neuroepithelium directly. However, loss of smell could be presented in COVID-19 patients without other rhinologic symptoms or significant nasal inflammation. This review aims to provide a brief overview of recent evidence for epidemiology, pathological mechanisms for the smell, and taste dysfunction in SARS-CoV-2 infected patients. Furthermore, prognosis and treatments are reviewed with scanty evidence. We also discuss the possibility of using "smell and taste loss" as a screening tool for COVID-19 and treatment options in the post-SARS-CoV-2 infectious olfactory loss.

The novel coronavirus SARS-CoV-2, which was identified after a recent outbreak in Wuhan, China, in December 2019, has kept the whole world in tenterhooks due to its severe life-threatening nature of the infection. The virus is unlike its previous counterparts, SARS-CoV and MERS-CoV, or anything the world has encountered before both in terms of virulence and severity of the infection. If scientific reports relevant to the SARS-CoV-2 virus are noted, it can be seen that the virus owes much of its killer properties to its unique structure that has a stronger binding affinity with the human angiotensin-converting enzyme 2 (hACE2) protein, which the viruses utilize as an entry point to gain accesses to its hosts. Recent reports suggest that it is not just the lung that the virus may be targeting; the human brain may soon emerge as the new abode of the virus. Already instances of patients with COVID-19 have been reported with mild (anosmia and ageusia) to severe (encephalopathy) neurological manifestations, and if that is so, then it gives us more reasons to be frightened of this killer virus. Keeping in mind that the situation does not worsen from here, immediate awareness and more thorough research regarding the neuroinvasive nature of the virus is the immediate need of the hour. Scientists globally also need to up their game to design more specific therapeutic strategies with the available information to counteract the pandemic. In this Viewpoint, we provide a brief outline of the currently known neurological manifestations of COVID-19 and discuss some probable ways to design therapeutic strategies to overcome the present global crisis.

Objective: To observe the effect of olfactory training on mice with olfactory dysfunction induced by 3-methylindole (3-MI). Methods: Thirty-one male BALB/c mice were randomly divided into 3 groups by random digits table: control group (group A, n= 10), olfactory dysfunction group (group B, n= 10) and olfactory dysfunction+olfactory training group (group C, n= 11). Mice in group B and group C were intraperitoneally injected with 150 mg/kg 3-MI to induce olfactory dysfunction model, while mice in group A were intraperitoneally injected with corn oil of the same volume. From the first day after injection, mice in group C were treated with 4 kinds of odors by inhalation, while mice in group B were treated with distilled water by inhalation, with 2 times/d, 30 min/time/kind of odor, and continuous training for 28 d. Group A was not treated. Buried food pellet tests were conducted before injection and at 7, 14, 21 and 28 days after injection, respectively. The olfactory epithelium was harvested for observation of the number of olfactory marker protein (OMP) and the thickness of olfactory epithelium on the 28th day after injection. SPSS 23.0 software was used for statistical analysis. Results: Before injection, all mice in each group had no olfactory dysfunction. At the 7th, 14th, 21st and 28th days after injection, the food finding time of mice in group C was shorter than that in group B, and the difference was statistically significant ((175.88±100.50) s vs (266.73±46.83) s, (132.00±84.62) s vs (264.10±48.50) s, (103.57±77.43) s vs (197.43±69.78) s, (67.79±32.54) s vs (176.63±61.06) s, all P< 0.05), but food finding time of mice in group B and C was longer than that in group A (the food finding time of group A at the 7th, 14th, 21st and 28th days after injection was (27.13±5.36) s, (25.83±7.28) s, (23.13±2.72) s, (26.63±7.60) s, respectively, all P< 0.05). At the 28th day after olfactory training, the number of OMP positive cells in group B and C were fewer than that in group A, and the difference was statistically significant ((108.00±28.19)/HP vs (288.22±84.06)/HP, (199.33±58.55)/HP vs (288.22±84.06)/HP, all P< 0.05). The number of OMP positive cells in group C were higher than that in group B ( P< 0.05). The number of OMP positive cells had negative correlation with food finding time ( r =-0.886, P< 0.01). As for the thickness of the olfactory epithelium, the thickness of group B was thinner than that in group A and C, and the difference was statistically significant ((59.57±31.27) μm vs (114.55±40.70)μm vs (90.54±37.72) μm, all P< 0.05). Conclusion: Olfactory training can accelerate the recovery of olfactory function in 3-MI-induced olfactory impaired mice.

Background: Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is a chronic inflammatory disease often accompanied by impairment of sense of smell. This symptom has been somewhat overlooked, and its relationship to inflammatory cytokines, tissue compression, neuronal loss, and neurogenesis is still unclear., Methods: In order to elucidate potential mechanisms leading to CRS in humans, we have established a type 2/T helper type 2 cell (Th2)-mediated allergic CRS mouse model, based on house dust mite (HDM) and Staphylococcus aureus enterotoxin B (SEB) sensitization. The inflammatory status of the olfactory epithelium (OE) was assessed using histology, biochemistry, and transcriptomics. The sense of smell was evaluated by studying olfactory behavior and recording electro-olfactograms (EOGs)., Results: After 22 weeks, a typical type 2/Th2-mediated inflammatory profile was obtained, as demonstrated by increased interleukin (IL)-4, IL-5, and IL-13 in the OE. The number of mast cells and eosinophils was increased, and infiltration of these cells into the olfactory mucosa was also observed. In parallel, transcriptomic and histology analyses indicated a decreased number of immature olfactory neurons, possibly due to decreased renewal. However, the number of mature sensory neurons was not affected and neither the EOG nor olfactory behavior was impaired., Conclusion: Our mouse model of CRS displayed an allergic response to HDM + SEB administration, including the type 2/Th2 inflammatory profile characteristic of human eosinophilic CRSwNP. Although the sense of smell did not appear to be altered in these conditions, the data reveal the influence of chronic inflammation on olfactory neurogenesis, suggesting that factors unique to humans may be involved in CRSwNP-associated anosmia., (© 2018 The Authors. Allergy Published by John Wiley & Sons Ltd.)

Background: Olfactory training (OT) has been shown to increase olfactory performance in healthy subjects and patients with post-traumatic or post-infectious olfactory loss. Morphological correlates such as olfactory bulb volume increase and gray matter changes suggest central changes in olfactory brain areas following olfactory exposure. Some evidence from animal studies indicates peripheral changes upon OT whereas no such data exist in humans. This study explores the question whether changes in olfaction following OT are associated with alterations of the electro-olfactogram (EOG) derived from the olfactory epithelium., Methodology: We compared electrophysiological EOG responses to a pleasant, rose-like odor (phenylethyl alcohol, PEA) and to an unpleasant odor (rotten eggs, H2S) in patients and controls. EOG were recorded in smell impaired patients before and after OT for a period of 4-6 months., Results: EOG recordings following PEA and H2S stimulation were significantly more often obtained in controls than in patients. OT was associated with a significantly higher number of EOG recordings., Conclusions: OT is associated with an increase in EOG responses implicating stimulus-induced plasticity to start at the level of the olfactory epithelium.

Olfactory dysfunction is an early sign of neuroinflammation of the central nervous system (CNS). Microgliosis and astrogliosis are representative pathological changes that develop during neuroinflammation of CNS tissues. Autoimmune CNS inflammation, including human multiple sclerosis, is an occasional cause of olfactory disorders. We evaluated whether gliosis and olfactory dysfunction developed in animals with experimental autoimmune encephalomyelitis (EAE), a model of human multiple sclerosis. Neuroinflammatory lesions characterized by infiltration of inflammatory cells and microglial cell activation were occasionally found in the olfactory bulbs of EAE-affected rats. Microglial activation, visualized by immunohistochemical staining of ionized calcium binding protein (Iba)-1, and astrogliosis in the olfactory bulb were also evident in the olfactory bulb of EAE rats. Inflammatory cells were found along the olfactory nerves and in the olfactory submucosa. Western blot analysis of olfactory marker protein (OMP) levels showed that OMP expression was significantly downregulated in the olfactory mucosa of EAE rats. On the buried food test, EAE-affected mice required significantly more time to find a bait pellet. Collectively, the results suggest that the olfactory dysfunction of EAE is closely linked to downregulation of OMP and the development of inflammatory foci in the olfactory system in an animal model of human multiple sclerosis.

Objective: In this study, we introduce an extension of previous work by Soler et al. (Int Forum Allergy Rhinol 6(3):293-298, 2016) on a modified endoscopic scoring system of the Lund-Kennedy Score (focusing on the olfactory cleft) to evaluate its correlation with the olfactory function in patients with various smell disorders., Study Design: A prospective cohort study., Methods: Two-hundred and eighty-eight participants were included and categorized in five groups according to the cause of their olfactory disorder: (0) control, (1) idiopathic, (2) sino-nasal, (3) postinfectious and (4) post traumatic olfactory loss. Olfaction was evaluated using the "Sniffin' Sticks" test. The classical Lund-Kennedy scoring and a new olfactory cleft specific Lund-Kennedy scoring (OC-LK) were performed to evaluate mucosal changes., Results: Significantly higher OC-LK scores on both sides were found in smell-impaired patients as compared to normosmic controls. When comparing the 4 groups, a significant difference of the OC-LK score were present between the sino-nasal and all other groups. Most importantly, significant negative correlations with strong effects were shown in the sino-nasal group between the OC-LK score and odor discrimination and odor identification. However, no such correlation emerged between the classical LK score and smell function., Conclusion: Olfactory cleft evaluation using the OC-LK score correlates with the olfactory function in patients with sino-nasal smell disorder. This diagnostic tool may reflect the underlying pathophysiological mechanism of sino-nasal smell loss, and therefore, should complement olfactory diagnostics in patients with sino-nasal smell disorder.

Apolipoprotein E (ApoE) is highly expressed in the central nervous system including the olfactory epithelium (OE) and olfactory bulb (OB). ApoE induction is beneficial for Alzheimer's disease (AD) treatment, whereas ApoE deficiency results in impaired olfaction, but the timing and underlying molecular and cellular mechanisms of these effects remain unclear. Uncovering the mechanisms underlying olfactory dysfunction in ApoE-deficient mice might provide a potential avenue for the early diagnosis of AD. We used an ApoE knockout (ApoE -/- ) mouse model and a cookie-finding test to reveal an olfactory deficit in 3- to 5-month-old, but not 1- to 2-month-old, ApoE -/- mice. Electrophysiological experiments indicated a significant decline in the electroolfactogram (EOG) amplitude, which was associated with an increase in rise time in ApoE -/- mice. Knockout mice also exhibited compromised olfactory adaptation, as well as a reduced number of mature olfactory sensory neurons in the OE. Local field potential recording in the OB showed that gamma oscillation power was enhanced, which might be attributed to an increase in GABAergic inhibition mediated by parvalbumin-expressing (PV) interneurons. This study demonstrates the critical involvement of ApoE in olfactory information processing in the OE and OB. ApoE deficiency results in olfaction deficits in mice as young as 3 months old, which has implications for AD pathogenesis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Olfactory dysfunction is a robust and early sign for Parkinson's disease (PD). Previous studies have revealed its association with dementia and related neural changes in PD. Yet, how olfactory dysfunction affects white matter (WM) microstructure in newly diagnosed and untreated PD remains unclear. Here we comprehensively examined WM features using unbiased whole-brain analyses. 88 newly diagnosed PD patients without dementia (70 with hyposmia and 18 without hyposmia) and 33 healthy controls underwent clinical assessment and diffusion tensor imaging (DTI) scanning. Tract-based special statistics (TBSS), graph-theoretic methods and network-based statistics (NBS) were used to compare regional and network-related WM features between groups. TBSS analysis did not show any differences in fractional anisotropy and mean diffusivity between groups. Compared with controls, PD patients without hyposmia showed a significant decrease in global efficiency, whilst PD patients with hyposmia exhibited significantly reduced global and local efficiency and additionally a disrupted connection between the right medial orbitofrontal cortex and left rectus and had poorer frontal-related cognitive functioning. These results demonstrate that hyposmia-related WM changes in early PD only occur at the network level. The confined disconnectivity between the bilateral olfactory circuitry may serve as a biomarker for olfactory dysfunction in early PD.

Objectives/hypothesis: Others have reported olfactory disturbances following endoscopic approaches to the skull base. However, there is a lack of consensus on the extent and duration of dysfunction. This study aimed to compare our results with previously published work and to validate the olfactory strip-sparing approach., Study Design: Prospective study to assess olfaction in 50 patients scheduled to undergo resection of skull base tumors via extended endoscopic approaches., Methods: Patients were divided into two groups. Group I had a nasoseptal flap (NSF), and group II included patients in whom rescue flaps were performed bilaterally. Olfactory outcomes were assessed using repeated University of Pennsylvania Smell Identification Test at baseline, 6 weeks, 3 months, and 6 months following surgery., Results: Ultimately, 42 patients (seven group I and 35 group II) were available for assessment. Scores for group I were lower than at baseline at 6 weeks postoperatively (30.71 ± 5.5 vs. 24.5 ± 5.4; P = .05). However, by the third postoperative month the scores had improved to a level that was not significantly different from baseline (29.0 ± 3.7; P = .5). At 6 months, the score was 30.0 ± 3.9. Patients in group II showed no difference between their baseline and 6-week scores (31.5 ± 5.3 vs. 29.7 ± 5.9; P = .16). Six months postoperatively, the score was significantly higher (33.78 ± 3.6; P = .04)., Conclusions: Expanded endoscopic approaches to skull base tumors involving reconstruction with an NSF are associated with a short-term negative impact on olfaction. Olfaction does not seem to be affected by the surgical resection of pituitary adenomas associated with rescue flaps. Identification of the olfactory epithelium and meticulous harvesting of the NSF are critical to preserve olfaction., Level of Evidence: 4. Laryngoscope, 127:1970-1975, 2017., (© 2017 The American Laryngological, Rhinological and Otological Society, Inc.)

The olfactory system is a unique part of the mammalian nervous system due to its capacity for neurogenesis and the replacement of degenerating receptor neurons. Cigarette smoking is a major cause of olfactory dysfunction. However, the mechanisms by which cigarette smoke impairs the regenerative olfactory receptor neurons (ORNs) remain unclear. Here, we investigated the influence of cigarette smoke on ORN regeneration following methimazole-induced ORN injury. Administration of methimazole caused detachment of the olfactory epithelium from the basement membrane and induced olfactory dysfunction, thus enabling us to analyze the process of ORN regeneration. We found that intranasal administration of cigarette smoke solution (CSS) suppressed the recovery of ORNs and olfaction following ORN injury. Defective ORN recovery in CSS-treated mice was not associated with any change in the number of SOX2(+) ORN progenitor cells in the basal layer of the OE, but was associated with impaired recovery of GAP43(+) immature ORNs. In the nasal mucosa, mRNA expression levels of neurotrophic factors such as brain-derived neurotrophic factor, neurotrophin-3, neurotrophin-5, glial cell-derived neurotrophic factor, and insulin-like growth factor-1 (IGF-1) were increased following OE injury, whereas CSS administration decreased the ORN injury-induced IGF-1 expression. Administration of recombinant human IGF-1 prevented the CSS-induced suppression of ORN recovery following injury. These results suggest that CSS impairs regeneration of ORNs by suppressing the development of immature ORNs from ORN progenitors, at least partly by reducing IGF-1 in the nasal mucosa.

Background: Viral infection is a common cause of olfactory dysfunction. The complexities of studying post-viral olfactory loss in humans have impaired further progress in understanding the underlying mechanism. Recently, evidence from clinical studies has implicated Parainfluenza virus 3 as a causal agent. An animal model of post viral olfactory disorders (PVOD) would allow better understanding of disease pathogenesis and represent a major advance in the field., Objective: To develop a mouse model of PVOD by evaluating the effects of Sendai virus (SeV), the murine counterpart of Parainfluenza virus, on olfactory function and regenerative ability of the olfactory epithelium., Methods: C57BL/6 mice (6-8 months old) were inoculated intranasally with SeV or ultraviolet (UV)-inactivated virus (UV-SeV). On days 3, 10, 15, 30 and 60 post-infection, olfactory epithelium was harvested and analyzed by histopathology and immunohistochemical detection of S-phase nuclei. We also measured apoptosis by TUNEL assay and viral load by real-time PCR. The buried food test (BFT) was used to measure olfactory function of mice at day 60. In parallel, cultured murine olfactory sensory neurons (OSNs) infected with SeV or UV-SeV were tested for odorant-mixture response by measuring changes in intracellular calcium concentrations indicated by fura-4 AM assay., Results: Mice infected with SeV suffered from olfactory dysfunction, peaking on day 15, with no loss observed with UV-SeV. At 60 days, four out of 12 mice infected with SeV still had not recovered, with continued normal function in controls. Viral copies of SeV persisted in both the olfactory epithelium (OE) and the olfactory bulb (OB) for at least 60 days. At day 10 and after, both unit length labeling index (ULLI) of apoptosis and ULLI of proliferation in the SeV group was markedly less than the UV-SeV group. In primary cultured OSNs infected by SeV, the percentage of cells responding to mixed odors was markedly lower in the SeV group compared to UV-SeV (P = 0.007)., Conclusion: We demonstrate that SeV impairs olfaction, persists in OE and OB tissue, reduces their regenerative ability, and impairs the normal physiological function of OSNs without gross cytopathology. This mouse model shares key features of human post-viral olfactory loss, supporting its future use in studies of PVOD. Further testing and development of this model should allow us to clarify the pathophysiology of PVOD.

Exposure to cigarette smoke is a major cause of olfactory dysfunction. However, the underlying mechanisms by which cigarette smoke interferes with the highly regenerative olfactory nerve system remain unclear. To investigate whether cigarette smoke induces olfactory dysfunction by disrupting cell proliferation and cell survival in the olfactory epithelium (OE), we developed a mouse model of smoking that involved intranasal administration of a cigarette smoke solution (CSS). Immunohistological analyses and behavioral testing showed that CSS administration during a period of 24 days reduced the number of olfactory marker protein-positive mature olfactory receptor neurons (ORNs) in the OE and induced olfactory dysfunction. These changes coincided with a reduction in the number of SOX2(+) ORN progenitors and Ki-67(+) proliferating cells in the basal layer of the OE, an increase in the number of caspase-3(+) apoptotic cells, and an increase in the expression of mRNA for the inflammatory cytokines IL-1β and IL-6. Notably, the proliferating ORN progenitor population recovered after cessation of treatment with CSS, resulting in the subsequent restoration of mature ORN numbers and olfaction. These results suggest that SOX2(+) ORN progenitors are targets of CSS-induced impairment of the OE, and that by damaging the ORN progenitor population and increasing ORN death, CSS exposure eventually overwhelms the regenerative capacity of the epithelium, resulting in reduced numbers of mature ORNs and olfactory dysfunction., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The purpose of the study was to investigate the effect of bone marrow-derived mesenchymal stem cells (BMSCs) transplantation on olfactory epithelium (OE) of morphologic and functional restoration following neural Sensorineural Disorder in rats. Except the Normal group, twenty-one rats underwent Triton X-100 (TX-100) irrigation to induce degeneration of OE, and then BMSCs and PBS were treated from the both medial canthus to the rear part of the both nasal cavity into the experimental group and then were observed for restoration according to time point. At two and four weeks after transplantation with BMSCs, restoration of OE was observed with olfactory marker protein (OMP) and behavioral test. And we observed the expression of OMP, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). After TX-100 irrigation, the OE almost disappeared in 3 days. At four weeks after transplantation with BMSCs, the thickness and cellular composition of OE was considerably restored to normal group and expression of OMP was markedly increased when compared with PBS group and reduced the searching time in the behavioral test. Furthermore at two weeks after treatment with BMSCs, expression of NGF and BDNF was greatly increased when compared with PBS group. However at four weeks after treatment with BMSCs, expression of NGF and BDNF was slightly decreased. Our results suggest the BMSCs transplantation affect restoration of OE and olfaction, most likely via regulation of the neurotrophic factor expression, especially the expression of NGF and BDNF and has a possibility of a new therapeutic strategy for the treatment of olfactory disorder caused by the degeneration of OE., (Copyright © 2015 Elsevier Inc. All rights reserved.)

For most animal species, olfaction plays a paramount role in their perception of the environment. Odours are initially detected in neurons located in the olfactory mucosa. This tissue is regulated by several physiological signals and can be altered in pathology. A number of clinical studies suggest an association between depressive disorders and olfactory sensory loss. In rodents, depressive-like states can be observed in models of chronic stress. We tested the hypothesis that olfactory function might be altered in a rat model of depression, induced by chronic variable stress (CVS). While CVS rats exhibited several symptoms consistent with chronic stress exposure and depressive-like states (increased sucrose intake in sucrose preference test, increased immobility in forced swim test, hyperlocomotion), their odorant responses recorded at the olfactory mucosa level by electro-olfactogram were decreased. In addition we observed increased apoptosis markers in the olfactory mucosa using Western Blot. Our data are consistent with reduced olfactory capacities in a laboratory rat model of chronic stress and depression, in agreement with human clinical data; this warrants further mechanistic studies. Furthermore, this works raises the possibility that altered olfactory function might be a confounding factor in the behavioural testing of chronically stressed or depressed rats., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Damage to the eye from blast exposure can occur as a result of the overpressure air-wave (primary injury), flying debris (secondary injury), blunt force trauma (tertiary injury), and/or chemical/thermal burns (quaternary injury). In this study, we investigated damage in the contralateral eye after a blast directed at the ipsilateral eye in the C57Bl/6J and DBA/2J mouse. Assessments of ocular health (gross pathology, electroretinogram recordings, optokinetic tracking, optical coherence tomography and histology) were performed at 3, 7, 14 and 28 days post-trauma. Olfactory epithelium and optic nerves were also examined. Anterior pathologies were more common in the DBA/2J than in the C57Bl/6 and could be prevented with non-medicated viscous eye drops. Visual acuity decreased over time in both strains, but was more rapid and severe in the DBA/2J. Retinal cell death was present in approximately 10% of the retina at 7 and 28 days post-blast in both strains. Approximately 60% of the cell death occurred in photoreceptors. Increased oxidative stress and microglial reactivity was detected in both strains, beginning at 3 days post-injury. However, there was no sign of injury to the olfactory epithelium or optic nerve in either strain. Although our model directs an overpressure air-wave at the left eye in a restrained and otherwise protected mouse, retinal damage was detected in the contralateral eye. The lack of damage to the olfactory epithelium and optic nerve, as well as the different timing of cell death as compared to the blast-exposed eye, suggests that the injuries were due to physical contact between the contralateral eye and the housing chamber of the blast device and not propagation of the blast wave through the head. Thus we describe a model of mild blunt eye trauma.

Purpose: Transcanalicular diode laser dacryocystorhinostomy (TCL-DCR) is used much in recent years for the surgery of nasolacrimal duct obstruction (NLDO). Although TCL-DCR is accepted to be minimally invasive, safe, and effective, there is no report focusing on postoperative changes in olfactory function after this procedure. Hence, the aim of this current study was to investigate the changes in olfactory function after TCL-DCR procedure., Materials and Methods: This study was carried out in 42 volunteers (16 men and 26 women) between the ages of 20 and 81 years. All participants received detailed lateralized olfactory tests preoperatively and at the postoperative first week, first month, third month, and sixth month. After lateralized olfactory tests were performed, the results were grouped according to the side of the nasal passage where the operation was performed for NLDO: the nonoperated side served as the control., Results: The current investigation produced 2 major findings: (1) olfactory function decreased significantly after TCL-DCR procedure at the operated side of the nose compared with the nonoperated side; (2) olfactory abilities of the patients returned to normal within 3 months., Conclusion: The results of this study showed that transcanalicular diode laser could be used safely in terms of olfactory function for dacryocystorhinostomy. Temporary decrease of olfactory function on the side having TCL-DCR should be taken into account when obtaining informed patient consent.

Olfactory epithelium has the capability to continuously regenerate olfactory receptor neurons throughout life. Adult neurogenesis results from proliferation and differentiation of neural stem cells, and consequently, olfactory neuroepithelium offers an excellent opportunity to study neural regeneration and the factors involved in the maintenance and regeneration of all their cell types. We analyzed the expression of BDNF in the olfactory system under normal physiological conditions as well as during a massive regeneration induced by chemical destruction of the olfactory epithelium in Xenopus laevis larvae. We described the expression and presence of BDNF in the olfactory epithelium and bulb. In normal physiological conditions, sustentacular (glial) cells and a few scattered basal (stem) cells express BDNF in the olfactory epithelium as well as the granular cells in the olfactory bulb. Moreover, during massive regeneration, we demonstrated a drastic increase in basal cells expressing BDNF as well as an increase in BDNF in the olfactory bulb and nerve. Together these results suggest an important role of BDNF in the maintenance and regeneration of the olfactory system., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

The zebrafish olfactory system is a valuable model for examining neural regeneration after damage due to the remarkable plasticity of this sensory system and of fish species. We applied detergent to the olfactory organ and examined the effects on both morphology and function of the olfactory system in adult zebrafish. Olfactory organs were treated once with Triton X-100 unilaterally to study glomerular innervation patterns or bilaterally to study odor detection. Fish were allowed to recover for 4-10 days and were compared to untreated control fish. Axonal projections were analyzed using whole mount immunocytochemistry with anti-keyhole limpet hemocyanin, a marker of olfactory axons in teleosts. Chemical lesioning of the olfactory organ with a single dose of Triton X-100 had profound effects on glomerular distribution in the olfactory bulb at 4 days after treatment, with the most significant effects in the medial region of the bulb. Glomeruli had returned by 7 days post-treatment. Analysis of the ability of the fish to detect cocktails of amino acids or bile salts consisted of counting the number of turns the fish made before and after odorant delivery. Control fish turned more after exposure to both odorants. Fish tested 4 and 7 days after chemical lesioning made more turns in response to amino acids but did not respond to bile salts. At 10 days post-lesion, these fish had regained the ability to detect bile salts. Thus, the changes seen in bulbar innervation patterns correlated to odorant-mediated behavior. We show that the adult zebrafish brain has the capacity to recover rapidly from detergent damage of the olfactory epithelium, with both glomerular distribution and odorant-mediated behavior returning in 10 days., (Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.)

In subterranean rodents, which dig down the passages with frontal teeth, adaptation to the underground mode of life presumes forming of mechanisms that provide protection against inhaling dust particles of different size when digging. One of such mechanisms can be specific pattern of air flow organization in the nasal cavity. To test this assumption, comparative study of geometry and aerodynamics of nasal passages has been conducted with regard to typical representative of subterranean rodents, the mole vole, and a representative of ground rodents, the house mouse. Numerical modeling of air flows and deposition of micro- and nanoparticle aerosols indicates that sedimentation of model particles over the whole surface of nasal cavity is higher in mole vole than in house mouse. On the contrary, particles deposition on the surface of olfactory epithelium turns out to be substantially less in the burrowing rodent as compared to the ground one. Adaptive significance of the latter observation has been substantiated by experimental study on the uptake ofnanoparticles of hydrated manganese oxide MnO x (H2O)x and Mn ions from nasal cavity into brain. It has been shown with use of magnetic resonance tomography method that there is no difference between studied species with respect to intake of particles or ions by olfactory bulb when they are introduced intranasally. Meanwhile, when inhaling nanoparticle aerosol of MnCl2, deposition of Mn in mouse's olfactory bulbs surpasses markedly that in vole's bulbs. Thereby, the morphology of nasal passages as a factor determining the aerodynamics of upper respiratory tract ensures for burrowing rodents more efficient protection of both lungs and brain against inhaled aerosols than for ground ones.

Background: Niemann-Pick type C disease (NPC) is a rare autosomal recessive lipid storage disease characterized by progressive neurodegeneration. As only a few studies have been conducted on the impact of NPC on sensory systems, we used a mutant mouse model (NPC1(-/-)) to examine the effects of this disorder to morphologically distinct regions of the olfactory system, namely the olfactory epithelium (OE) and olfactory bulb (OB)., Methodology/principal Findings: For structural and functional analysis immunohistochemistry, electron microscopy, western blotting, and electrophysiology have been applied. For histochemistry and western blotting, we used antibodies against a series of neuronal and glia marker proteins, as well as macrophage markers. NPC1(-/-) animals present myelin-like lysosomal deposits in virtually all types of cells of the peripheral and central olfactory system. Especially supporting cells of the OE and central glia cells are affected, resulting in pronounced astrocytosis and microgliosis in the OB and other olfactory cortices. Up-regulation of Galectin-3, Cathepsin D and GFAP in the cortical layers of the OB underlines the critical role and location of the OB as a possible entrance gate for noxious substances. Unmyelinated olfactory afferents of the lamina propria seem less affected than ensheathing cells. Supporting the structural findings, electro-olfactometry of the olfactory mucosa suggests that NPC1(-/-) animals exhibit olfactory and trigeminal deficits., Conclusions/significance: Our data demonstrate a pronounced neurodegeneration and glia activation in the olfactory system of NPC1(-/-), which is accompanied by sensory deficits.

Background: Olfactory loss is a debilitating symptom of chronic rhinosinusitis (CRS). The pathophysiology of inflammatory olfactory dysfunction likely involves both conductive and sensorineural components. To study the interaction of CRS-associated inflammatory cytokines with the olfactory epithelium (OE), a transgenic mouse model was developed that allows temporally-controlled local gene expression. Interferon-gamma (IFN-γ) is a prototypical T helper 1 (Th1) cytokine linked to nonpolypoid CRS (CRSsNP), as well as sinonasal viral and bacterial infections. In this study, the effects of chronic IFN-γ expression on olfactory histology and function were investigated., Methods: IFN-γ secretion by olfactory sustentacular cells was induced in the transgenic mouse. Viability and gross behavior were unaffected. Mice were euthanized after 6 weeks of IFN-γ expression, and olfactory tissue was studied by histology, immunohistochemistry, and electro-olfactography (EOG). Findings were compared with uninduced littermates., Results: IFN-γ expression did not result in alteration of the normal histologic architecture of the neuroepithelium or lamina propria. However, EOG recordings demonstrated a significant decrease in odorant responses after IFN-γ expression. In addition, a marked increase in submucosal CD45-positive cells was observed, the majority of which were CD3-positive and CD4-positive lymphocytes., Conclusion: Chronic IFN-γ expression in the mouse OE results in diminished odorant responsiveness, despite the absence of inflammatory tissue damage. This suggests a direct effect of IFN-γ on olfactory neuron function that may underlie olfactory loss in CRSsNP or viral infections. The infiltration of submucosal lymphocytes raises the possibility that other downstream cytokines also contribute to olfactory dysfunction., (© 2013 ARS-AAOA, LLC.)

Phantosmia, the perception of an odor when there are no odorants in the environment, can be a very debilitating symptom. In the 1960s, Zilstorff reported olfactory distortions could be treated by the topical application of a cocaine solution to the olfactory epithelium. In evaluating this treatment, we observed no long-term benefit using cocaine on 6 patients with phantosmia. Based on our observations, the patient's olfactory ability was not a determining factor in the initiation or quality of their phantosmia. Following topical cocainization, we observed a remarkable delay of hours to days in the return of olfactory ability, and when cocaine was applied to only 1 nostril, there was a decreased olfactory ability on the noncocainized side. These results may suggest the possibility that phantosmia is related to a central processing problem.

Various genetic or toxin-induced mouse models are frequently used for investigation of early PD pathology. Although olfactory impairment is known to precede motor symptoms by years, it is not known whether it is caused by impairments in the brain, the olfactory epithelium, or both. In this study, we investigated the olfactory function in three genetic Parkinson's disease (PD) mouse models and mice treated with MPTP intraperitoneally and intranasally. To investigate olfactory function, we performed electro-olfactogram recordings (EOGs) and an olfactory behavior test (cookie-finding test). We show that neither a parkin knockout mouse strain, nor intraperitoneal MPTP treated animals display any olfactory impairment in EOG recordings and the applied behavior test. We also found no difference in the responses of the olfactory epithelium to odorants in a mouse strain over-expressing doubly mutated α-synuclein, while this mouse strain was not suitable to test olfaction in a cookie-finding test as it displays a mobility impairment. A transgenic mouse expressing mutated α-synuclein in dopaminergic neurons performed equal to control animals in the cookie-finding test. Further we show that intranasal MPTP application can cause functional damage of the olfactory epithelium.

Olfactory dysfunction is an early 'pre-clinical' sign of Parkinson's disease (PD). The present review is a comprehensive and up-to-date assessment of such dysfunction in PD and related disorders. The olfactory bulb is implicated in the dysfunction, since only those syndromes with olfactory bulb pathology exhibit significant smell loss. The role of dopamine in the production of olfactory system pathology is enigmatic, as overexpression of dopaminergic cells within the bulb's glomerular layer is a common feature of PD and most animal models of PD. Damage to cholinergic, serotonergic, and noradrenergic systems is likely involved, since such damage is most marked in those diseases with the most smell loss. When compromised, these systems, which regulate microglial activity, can influence the induction of localized brain inflammation, oxidative damage, and cytosolic disruption of cellular processes. In monogenetic forms of PD, olfactory dysfunction is rarely observed in asymptomatic gene carriers, but is present in many of those that exhibit the motor phenotype. This suggests that such gene-related influences on olfaction, when present, take time to develop and depend upon additional factors, such as those from aging, other genes, formation of α-synuclein- and tau-related pathology, or lowered thresholds to oxidative stress from toxic insults. The limited data available suggest that the physiological determinants of the early changes in PD-related olfactory function are likely multifactorial and may include the same determinants as those responsible for a number of other non-motor symptoms of PD, such as dysautonomia and sleep disturbances., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The relationship between chronic rhinosinusitis (CRS) and asthma has been known for a long time. However, no large studies on the relationship between CRS and lower airway diseases have been reported to date in Japan. Additionally, eosinophilic chronic rhinosinusitis (ECRS) in Japan is considered to be a subgroup of CRS with nasal polyps (CRSwNP) characterized by eosinophil-dominant inflammation. However, the diagnostic criteria of ECRS have not been established., Methods: To investigate clinical and epidemiological features of patients with CRS from the aspect of their associations with lower airway diseases, 553 patients with CRS who visited one of six local university hospitals were examined and interviewed. Local eosinophilic infiltration was evaluated pathologically by examining NPs., Results: The prevalences of olfactory dysfunction (OD) in the patients with nasal polyps (NPs) and those without NPs were 57.0% and 13.7%, respectively (p < 0.0001). The prevalence of asthma in all patients was 23.1%. Furthermore, the prevalences of NPs and OD in the patients with asthma and those without asthma were 81.0% and 50.1% (p < 0.0001) and 64.2% and 35.7% (p < 0.0001), respectively. 97.4% of the patients with asthma had ≥ 15% mucosal eosinophils, and 87.9% of the patients without asthma had <15% mucosal eosinophils., Conclusions: Similar to the relationship between nasal allergy and asthma, CRSwNP may be applicable to the concept of "one airway, one disease".

Background: Despite the significant health impact of olfactory loss in chronic rhinosinusitis (CRS), the underlying pathophysiology is incompletely understood. A transgenic mouse model of olfactory inflammation induced by tumor necrosis factor-alpha (TNF-α) has provided new insights into the cellular and molecular basis of inflammatory olfactory loss. Here, we utilize systemic corticosteroids to suppress downstream cytokine expression, in order to study the direct role of TNF-α in CRS-associated olfactory dysfunction., Methods: Transgenic mice were induced to express TNF-α in the olfactory epithelium for 6 weeks. In a subset of mice, 1 mg/kg prednisolone was administered concurrently to inhibit downstream inflammatory responses. The olfactory epithelium (OE) was analyzed by histology and electro-olfactogram (EOG) recordings., Results: Treatment with prednisolone successfully prevented inflammatory infiltration over significant regions of the OE. In areas where significant subepithelial inflammation was present, a corresponding loss of olfactory neurons was observed. In contrast, areas without major inflammatory changes had normal olfactory neuron layers, despite chronic local expression of TNF-α. Prednisolone partially reversed the complete loss of olfaction in the mouse model, preserving odorant responses that were significantly diminished compared to controls, but not absent., Conclusions: The addition of prednisolone to the transgenic model of olfactory inflammation isolates the direct effects of induced TNF-α expression on the OE. The finding that prednisolone treatment prevents neuronal loss in some regions of the OE suggests that TNF-α does not directly cause neuronal apoptosis--rather, that subepithelial inflammation or other downstream mediators may be responsible. At the same time, EOG results imply that TNF-α directly causes physiologic dysfunction of olfactory neurons, independent of the inflammatory state. An understanding of the role of TNF-α and other inflammatory cytokines may suggest novel therapeutic strategies for CRS-associated olfactory loss., (Copyright © 2011 The American Laryngological, Rhinological, and Otological Society, Inc.)

Intranasal exposure to cadmium has been related to olfactory dysfunction in humans and to nasal epithelial damage and altered odorant-guided behavior in rodent models. The pathophysiology underlying these deficits has not been fully elucidated. Here we use optical imaging techniques to visualize odorant-evoked neurotransmitter release from the olfactory nerve into the brain's olfactory bulbs in vivo in mice. Intranasal cadmium chloride instillations reduced this sensory activity by up to 91% in a dose-dependent manner. In the olfactory bulbs, afferents from the olfactory epithelium could be quantified by their expression of a genetically encoded fluorescent marker for olfactory marker protein. At the highest dose tested, cadmium exposure reduced the density of these projections by 20%. In a behavioral psychophysical task, mice were trained to sample from an odor port and make a response when they detected an odorant against a background of room air. After intranasal cadmium exposure, mice were unable to detect the target odor. These experiments serve as proof of concept for a new approach to the study of the neural effects of inhaled toxicants. The use of in vivo functional imaging of the neuronal populations exposed to the toxicant permits the direct observation of primary pathophysiology. In this study optical imaging revealed significant reductions in odorant-evoked release from the olfactory nerve at a cadmium chloride dose two orders of magnitude less than that required to induce morphological changes in the nerve in the same animals, demonstrating that it is a more sensitive technique for assessing the consequences of intranasal neurotoxicant exposure. This approach is potentially useful in exploring the effects of any putative neurotoxicant that can be delivered intranasally., (Copyright © 2011. Published by Elsevier B.V.)

Atrophy of the olfactory epithelium (OE) associated with impaired olfaction and dry nose represents one of the most common phenotypes of human aging. Impairment in regeneration of a functional olfactory epithelium can also occur in response to injury due to infection or nasal surgery. These complications occur more frequently in aged patients. Although age is the most unifying risk factor for atrophic changes and functional decline of the olfactory epithelium, little is known about molecular mechanisms that could influence maintenance and repair of the olfactory epithelium. Here, we analyzed the influence of telomere shortening (a basic mechanism of cellular aging) on homeostasis and regenerative reserve in response to chemical induced injury of the OE in late generation telomere knockout mice (G3 mTerc(-/-)) with short telomeres compared to wild type mice (mTerc(+/+)) with long telomeres. The study revealed no significant influence of telomere shortening on homeostatic maintenance of the OE during mouse aging. In contrast, the regenerative response to chemical induced injury of the OE was significantly impaired in G3 mTerc(-/-) mice compared to mTerc(+/+) mice. Seven days after chemical induced damage, G3 mTerc(-/-) mice exhibited significantly enlarged areas of persisting atrophy compared to mTerc(+/+) mice (p = 0.031). Telomere dysfunction was associated with impairments in cell proliferation in the regenerating epithelium. Deletion of the cell cycle inhibitor, Cdkn1a (p21) rescued defects in OE regeneration in telomere dysfunctional mice. Together, these data indicate that telomere shortening impairs the regenerative capacity of the OE by impairing cell cycle progression in a p21-dependent manner. These findings could be relevant for the impairment in OE function in elderly people.

Objectives: Patients with Parkinson's disease (PD) commonly show olfactory deficits in the early stages of the disease. These deficits can be verified psychophysically or electrophysiologically using olfactory event-related potentials (OERP). While psychophysical olfactory function in PD patients can improve over time, the course of OERPs in PD has not yet been investigated., Methods: Olfactory function was investigated twice in 19 patients at 5-year intervals. Psychophysical tests included the "Sniffin' Sticks" test battery. In addition, OERPs were recorded in response to two odors on each side (phenyl-ethyl-alcohol: 40% (v/v), H(2)S, 6ppm). OERPs were evaluated regarding existence (yes/no). Average disease duration at follow-up was 9.0 years and the average Hoehn and Yahr score (disease stage) was 2.2., Results: Psychophysically, 1 patient was normosmic, 14 were hyposmic, and 4 were functionally anosmic at the initial visit. Re-examination revealed 1 normosmic, 9 hyposmic, and 8 functionally anosmic patients. Mean olfactory function decreased significantly in all patients. OERPs were initially existent in 3 out of 19 patients. At follow-up, OERPs were no longer present in these patients, but were detectable in 3 other patients., Conclusions: Overall, mean olfactory function decreased, although improvements were observed at the individual level. We confirmed previous findings regarding psychophysical follow-up results. Electrophysiological measures showed a pattern of fluctuation in olfactory function comparable to that of the psychophysical results. These fluctuations do not seem to predict the course of the disease., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Primary acquired nasolacrimal duct obstruction results from inflammation of unknown cause that eventually leads to fibrosis and occlusion. The nasolacrimal duct is within the medial wall of maxillary sinus and open into the nasal cavity. It may be affected by gasteroesophageal reflux disease (GERD) by the possible direct noxious effect of the refluxate on the nasal mucosal cavity surrounding of the nasolacrimal duct opening at the inferior meatous and ascending of inflammation to the mucosa of the duct may leads to chronic inflammation and fibrosis. In addition to, the GERD may induce autonomic nervous system hyperactivity resulting in hyperemia of venous plexus surrounding nasolacrimal duct leading to secondary mucosal edema of nasolacrimal duct and dacryostenosis., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)

Options for the treatment of hyposmia are limited;available therapies do not provide a long-lasting effect.A recent study suggests that an unspecific phosphodiesterase inhibitor (PDE-I) increases olfactory sensitivity due to interaction with the signal transduction in the olfactory epithelium. The aim of the present study was to investigate whether theophylline, an unspecific PDE-I, evokes changes in the electro-olfactogram (EOG) which would support the hypothesis of a drug-related impact on signal transduction.In addition, the uptake of topically administered theophylline in the olfactory epithelium should be investigated. EOG was obtained in 29 samples of supravital mouse olfactory epithelia. Olfactory stimulation (phenylethyl alcohol, PEA and hydrogen sulfide, H2S) was performed using an air dilution olfactometer. Theophylline concentration in the olfactory epithelium of five samples was measured by means of high pressure liquid chromatography. Administration of theophylline resulted in a tendency towards smaller EOG amplitudes (p = 0.055), being reduced by 13 and 25% in response to stimulation with PEA or H2S,respectively. In comparison to the application of Ringer's solution, theophylline resulted in a significant (p = 0.031)decrease of the EOG amplitude. Latency was not significantly(p = 0.10) influenced by drug administration. The theophylline concentration in the olfactory epithelium ranged from 0.21 to 1.53 microg/mg. Theophylline seems to be taken up into the olfactory epithelium of supravital mice and to interact with the olfactory signal transduction.

The olfactory epithelium (OE) is unique in regenerating throughout life and thus is an attractive target for examining neurogenesis. The nestin protein was shown to be expressed in the OE of rodents and is suggested to be essentially involved in the process of regeneration. Here we report the expression and distribution of nestin in the human OE at RNA and protein level. Moreover, we analysed the expression profiles in dependence on age and olfactory capacity. After sinus surgery, biopsies were taken from the olfactory epithelium of 16 patients aged 20-80 years with documented differences in their olfactory function. Our studies revealed that nestin is constantly detectable in the apical protuberances of sustentacular cells within the human OE of healthy adults. Its expression is not dependent on age, but rather appears to be related to the olfactory function, as a comparison with specimens obtained from patients suffering either from persistent anosmia or hyposmia suggests. Particularly, in the course of dystrophy, often accompanied with impaired olfaction, nestin expression was occasionally decreased. Contrarily, the expression of the p75-NGFR protein, a marker for human OE basal cells, was not altered, indicating that at least in the tested samples olfactory impairment is not connected with abnormalities at the basal cell level. These observations emphasize an essential role of nestin for the process of regeneration, and also highlight this factor as a candidate marker for sustentacular cells in the human olfactory epithelium.

Object: The olfactory mucosa (OM) consists of 2 layers, the epithelium and the lamina propria. Attempts have been made to restore motor function in rat models of spinal cord injury (SCI) by transplanting olfactory ensheathing cells from the lamina propria, but there has been no attempt to transplant the OM in animal models. To investigate the potential of the OM to restore motor function, the authors developed a rat model of SCI and delayed transplantation of syngenic OM., Methods: Two weeks after complete transection of the spinal cord at the T-10 level in Wistar rats, pieces of syngenic whole-layer OM were transplanted into the lesion. Rats that underwent respiratory mucosa transplantation were used as controls. The authors evaluated the locomotor activity according to the Basso-Beattie-Bresnahan scale for 8 weeks after transplantation. Obtained spinal cords were analyzed histologically. Results The OM transplantation rats showed significantly greater hindlimb locomotor recovery than the respiratory mucosa-transplanted rats. However, the recovery was limited according to the Basso-Beattie-Bresnahan scale. In the histological examination, the serotonergic raphespinal tract was regenerated. The pseudocyst cavity volume in the vicinity of the SCI lesion correlated negatively with the functional recovery., Conclusions: Transplantation of whole-layer OM in rats contributes to functional recovery from SCI, but the effect is limited. In addition to OM transplantation, other means would be necessary for better outcomes in clinical situations.

Among the sensory modalities, olfaction is most closely associated with the frontal and temporal brain regions that are implicated in schizophrenia and most intimately related to the affective and mnemonic functions that these regions subserve. Olfactory probes may therefore be ideal tools through which to assess the structural and functional integrity of the neural substrates that underlie disease-related cognitive and emotional disturbances. Perhaps more importantly, to the extent that early sensory afferents are also disrupted in schizophrenia, the olfactory system-owing to its strategic anatomic location-may be especially vulnerable to such disruption. Olfactory dysfunction may therefore be a sensitive indicator of schizophrenia pathology and may even serve as an "early warning" sign of disease vulnerability or onset. In this article, we review the evidence supporting a primary olfactory sensory disturbance in schizophrenia. Convergent data indicate that structural and functional abnormalities extend from the cortex to the most peripheral elements of the olfactory system. These reflect, in part, a genetically mediated neurodevelopmental etiology. Gross structural and functional anomalies are mirrored by cellular and molecular abnormalities that suggest decreased or faulty innervation and/or dysregulation of intracellular signaling. A unifying mechanistic hypothesis may be the epigenetic regulation of gene expression. With the opportunity to obtain olfactory neural tissue from live patients through nasal epithelial biopsy, the peripheral olfactory system offers a uniquely accessible window through which the pathophysiological antecedents and sequelae of schizophrenia may be observed. This could help to clarify underlying brain mechanisms and facilitate identification of clinically relevant biomarkers.

Studies of the tissues of the human olfactory mucosa have been performed to investigate olfactory dysfunction and, more recently, olfactory mucosa has attracted a novel interest of investigators because it can be used as an early marker of neurodegenerative conditions of the brain and as a source of multipotent neural stem cells, with applications in regenerative medicine. The olfactory mucosa is readily available to the otolaryngologist, but the harvesting of this tissue must be safe, effective, and reliable, obtaining as little tissue as necessary, while avoiding unnecessary harm to the remaining olfactory tissue and function. The purpose of this review is to summarize the results of the most important studies and knowledge with regard to the human olfactory mucosa and its applications, emphasizing the issue of the distribution of the olfactory mucosa in the nasal cavities.

The mucopolysaccharidoses (MPS) are a family of lysosomal storage diseases resulting in developmental defects and, in some types, mental retardation and other neurological symptoms. To gain insight into the neurological dysfunction in MPS, we examined the morphology of olfactory epithelia (OE) and physiology of olfactory receptor neurons (ORNs) in cat models of MPS I, a type in which neuronal lesions are prominent, and MPS VI, in which they are essentially absent. Histopathology showed that both groups of MPS-affected cats had significantly thinner OE than controls. Although immature and mature ORNs were present in both MPS I and VI affected OE, the OE of MPS I-affected cats was structurally disorganized. ORN function was assessed with calcium imaging and patch-clamp recording. Few viable ORNs were recovered from MPS VI cats, but these exhibited normal responses to odors and pharmacological stimuli. In contrast, viable ORNs were as prevalent in MPS I as in controls but were significantly less likely to respond to odor stimuli, although other responses were normal. Disrupted OE organization and impaired ORN function in MPS I, but not MPS VI, corresponds to the central nervous system lesions found in MPS I but not MPS VI. These data represent the first neurophysiological correlate of this correspondence and have implications both for understanding the role of glycosaminoglycans in maintenance of the OE and for targeting further research into the basis for and treatment of the neurological consequences of MPS disorders., ((c) 2008 Wiley-Liss, Inc.)

Environmental agents, including viruses, prions, and toxins, have been implicated in the cause of a number of neurodegenerative diseases, most notably Alzheimer's and Parkinson's diseases. The presence of smell loss and the pathological involvement of the olfactory pathways in the formative stages of Alzheimer's and Parkinson's diseases, together with evidence that xenobiotics, some epidemiologically linked to these diseases, can readily enter the brain via the olfactory mucosa, have led to the hypothesis that Alzheimer's and Parkinson's diseases may be caused or catalyzed by agents that enter the brain via this route. Evidence for and against this concept, the "olfactory vector hypothesis," is addressed in this review.

In normal nasal epithelium, the olfactory receptor neurons (ORNs) are continuously replaced through the differentiation of progenitor cells. The olfactory epithelium (OE) of the cystic fibrosis (CF) mouse appears normal at birth, yet by 6 mo of age, a marked dysmorphology of sustentacular cells and a dramatic reduction in olfactory receptor neurons are evident. Electroolfactograms revealed that the odor-evoked response in 30-day-old CF mice was reduced approximately 45%; in older CF mice, a approximately 70% reduction was observed compared with the wild type (WT) response. Consistent with studies of CF airway epithelia, Ussing chamber studies of OE isolated from CF mice showed a lack of forskolin-stimulated Cl(-) secretion and an approximately 12-fold increase in amiloride-sensitive sodium absorption compared with WT mice. We hypothesize that the marked hyperabsorption of Na(+), most likely by olfactory sustentacular cells, leads to desiccation of the surface layer in which the sensory cilia reside, followed by degeneration of the ORNs. The CF mouse thus provides a novel model to examine the mechanisms of disease-associated loss of olfactory function.