Olfactory Dysfunction Research Articles

Adherence to olfactory training improves orthonasal and retronasal olfaction in post-COVID-19 olfactory loss.

Olfactory loss (OL) has emerged as one of the most prevalent and debilitating symptoms of SARS-CoV-2 infection and long-COVID-19. The present prospective observational study aimed to evaluate the efficacy of olfactory training (OT) on orthonasal and retronasal olfactory function in a cohort of individuals with persistent post-COVID-19 OL. Participants with post-COVID-19 olfactory impairment underwent 4 months of OT, self-assessing their smell perception and undergoing comprehensive psychophysical evaluation of orthonasal and retronasal olfaction at baseline and after training. Orthonasal olfactory function was assessed using the extended Sniffin' Sticks test battery. Retronasal olfactory function was tested with powdered aromas. Among 114 participants with post-COVID-19 olfactory loss, adherence to OT was 60%. In adherents, the average increase in composite TDI score was 6.0 points compared to 2.6 points in non-adherents. Fifty-seven percent of adherent participants achieved a clinically significant improvement in TDI score (≥5.5 points), compared to 22% of non-adherents. In retronasal olfactory identification, 56% of adherents achieved a clinically significant improvement (≥4 points), compared to 16% of non-adherents. Adherence to a 4-month OT regimen can yield clinically meaningful improvements in both orthonasal and retronasal olfactory function among individuals with persistent post-COVID-19 olfactory dysfunction.

Olfactory perceptual fingerprints of people with olfactory dysfunction and healthy controls.

An olfactory perceptual fingerprint (OPF) defines one's olfactory perception using perceptual descriptor ratings (such as odor pleasantness, intensity) for a set of odors. OPFs have been shown to distinguish patients with COVID-related olfactory dysfunction (OD) and healthy controls with 86% accuracy. However, all participants rated the same odorants. With the aim to evaluate whether the OPFs are indeed odorant independent, previously published dataset by Lötsch et al. was reanalyzed. Furthermore, this independent dataset was used to check whether the OPFs separate patients with OD due to various causes from controls. The study included 104 controls and 42 patients, who were randomized into four odor sets with 10 odorants each. Odorants were presented using a computer-controlled olfactometer and evaluated on scales from 1 (not at all) to 5 (very) using perceptual descriptors pleasant, intensive, familiar, edible, irritating, cold/warm, and painful. Permutational multivariate analysis of variance showed that the odor set did not have a significant effect on the OPFs, confirming that the OPFs are indeed odorant independent. On the other hand, both diagnosis and age affected the OPFs (p < .001) and explained around 11% and 5% of the variance of the OPFs, respectively. Furthermore, a supervised machine learning method, random forest classifier, showed that OPF can distinguish patients and controls with 80% accuracy. OPFs are odorant independent. Patients perceived odors as less familiar, less intense, and less edible than controls. Other perceptual descriptors were much less important for the separation of patients and controls. 3.

Investigating the efficacy of melatonin, topical sodium citrate, and multivitamin with zinc as a potential treatment for postinfectious loss of smell

ObjectivesUpper respiratory tract infections, including COVID-19, are associated with olfactory dysfunction and there is a need for novel therapeutic approaches. The aim of study was evaluating the effectiveness of adding melatonin, multivitamin and sodium citrate to olfactory training for the treatment of olfactory loss caused by COVID-19. MethodsWe evaluated olfactory function using University of Pennsylvania Smell Identification Test (UPSIT ®) scores and self-reported patient outcomes in post-infectious smell loss cases. We investigated the effectiveness involved olfactory training combined with sodium citrate, melatonin, and multivitamin supplements with zinc over a three-month period compared to an olfactory training alone. ResultsA total of 66 patients were included, with 33 in each group. There was no significant difference in the proportion of participants who showed improvement in UPSIT scores between the groups (OR = 1.43, 95% CI 0.43–4.8, p = 0.56). Both groups showed improvement in average test scores, but there were no significant differences in self-reported olfactory ability or discomfort with olfactory loss. Qualitative symptoms, such as parosmia and phantosmia, were reported by a similar proportion in both groups before and after the treatment (p = 0.11, p = 1, respectively). ConclusionsOlfactory training alone and olfactory training with associated with melatonin, multivitamins and topical sodium citrate did not show significant differences in improving olfactory function in post-COVID-19 patients. Level of evidence3.

Assessing parosmia patients: a study on the evaluation method using a self-administered odor questionnaire for parosmia.

Parosmia symptoms are difficult to quantify due to their heterogeneity among patients, and thus a clinical challenge. This study aimed to assess parosmia with Self-Administered Odor Questionnaire for Parosmia (SAOQ-P), a modification of the widely used SAOQ in Japan. The primary objective was to assess the effectiveness of SAOQ-P in identifying parosmia symptoms and its potential integration into the clinical assessment process. The study also explored traditional olfactory test differences between patients with and without parosmia. Patients at Jikei Smell Clinic that presented between May 2022 and November 2022 were recruited and administered the SAOQ-P, which had an added question about changes in the perception of 20 daily odors compared to the original SAOQ. Traditional olfactory tests utilized T&T olfactometry and Open Essence. Of 279 patients, 81 had parosmia, while 198 did not exhibit parosmic symptoms. Parosmia prevalence was influenced by the cause of olfactory dysfunction, with post-infectious and post-COVID-19 patients showing higher parosmia rates. Among parosmia patients, 87% reported changes in their perception of at least one odor assessed by SAOQ-P, with coffee, stool, and perfume most commonly affected. Traditional olfactory tests showed no significant differences between parosmia and non-parosmia groups. The number of odors causing parosmia was negatively correlated with age. SAOQ-P offers a promising approach to assess and quantify parosmia symptoms, seamlessly integrating into clinical assessments. SAOQ-P identified parosmia in 87% of patients and revealed insights into triggering factors. Traditional olfactory tests' limitations underscore the need for more accurate, patient-centric diagnostic approaches for parosmia.

A single-cell transcriptomic census of mammalian olfactory epithelium aging.

Mammalian olfactory epithelium has the capacity of self-renewal throughout life. Aging is one of the major causes leading to the olfactory dysfunction. Here, we performed single-cell RNA sequencing (scRNA-seq) analysis on young and aged murine olfactory epithelium (OE) and identified aging-related differentially expressed genes (DEGs) throughout 21 cell types. Aging led to the presence of activated horizontal basal cells (HBCs) in the OE and promoted cellular interaction between HBCs and neutrophils. Aging enhanced the expression of Egr1 and Fos in sustentacular cell differentiation from multipotent progenitors, whereas Bcl11b was downregulated during the sensory neuronal homeostasis in the aged OE. Egr1 and Cebpb were predictive core regulatory factors of the transcriptional network in the OE. Overexpression of Egr1 in aged OE organoids promoted cell proliferation and neuronal differentiation. Moreover, aging altered expression levels and frequencies of olfactory receptors. These findings provide a cellular and molecular framework of OE aging at the single-cell resolution.

Impact of Nutritional Status on COVID-19-Induced Olfactory Dysfunction.

Although olfactory dysfunction is one of the most common presenting signs of COVID-19 infection, little is known about which populations are most susceptible. The aim of this study is to evaluate the risk of COVID-19-induced chemosensory dysfunction in malnourished individuals. The N3C database was queried for adults having positive COVID-19 test result, diagnosis of chemosensory dysfunction within 2 weeks of positive test date, and overnutrition or undernutrition (i.e., deficiency or excess of micro- and macronutrients) related diagnoses prior to COVID-19 infection. Individuals previously diagnosed with chemosensory dysfunction were excluded. COVID-19-positive adults without olfactory dysfunction were similarly analyzed. Statistical analysis was performed using odds ratio calculations (95% confidence interval [CI]). Of 3,971,536 patients with COVID-19, 73,211 adults were identified with a diagnosis of undernutrition and 428,747 adults were identified with a diagnosis of overnutrition prior to infection. Of those with undernutrition, 264 (0.36%) individuals were identified with a diagnosis of olfactory dysfunction within 2 weeks of infection. Of those with overnutrition, 2851 (0.66%) individuals were identified with a diagnosis of olfactory dysfunction within 2 weeks of infection. The calculated odds ratio for undernutrition and olfactory dysfunction was 0.731 (p < 0.0001, 95% CI [0.0647, 0.0825]). The calculated odds ratio for overnutrition and olfactory dysfunction was 1.419 (p < 0.0001, 95% CI [1.3359, 1.5081]). Overnutrition may increase the risk of COVID-19-related olfactory dysfunction, while undernutrition may slightly protect. While reasons are unclear, baseline differences in metabolic, inflammatory, and structural biochemistry deserve closer inspection. 3 Laryngoscope, 134:4338-4343, 2024.

Impaired olfactory performance and anxiety-like behavior in a rat model of multiple sclerosis are associated with enhanced adenosine signaling in the olfactory bulb via A1R, A2BR, and A3R.

The present study shows that animals with experimental autoimmune encephalomyelitis (EAE) exhibit olfactory dysfunction and impaired general cognitive abilities, as well as anxiety-like behavior. Olfactory dysfunction occurs on average at 2 dpi, well before the onset of the first motor signs of EAE (8-10 dpi). After the initial olfactory dysfunction, the EAE animals show a fluctuation in olfactory performance that resembles the relapsing-remitting course of human MS. The study also shows severe neuroinflammation in the olfactory bulb (OB), with numerous infiltrated CD4+ T cells and peripheral macrophages in the superficial OB layers, marked microgliosis, and massive induction of TNF-α, IL-1β, and IL-6. Reduced tyrosine hydroxylase activity in the glomerular layer, pronounced granule cell atrophy, and reduced numbers of type B neuroblasts in the rostral migratory stream also indicate altered plasticity of the neuronal network in the OB. Considering the exceptionally high purinome expression in the OB, the possible involvement of purinergic signaling was also investigated. The study shows that macrophages infiltrating the OB overexpress A3R, while highly reactive microglia overexpress the adenosine-producing enzyme eN/CD73 as well as A2BR, A3R, and P2X4R. Given the simultaneous induction of complement component C3, the results suggest that the microglial cells develop a functional phenotype of phagocytizing microglia. The study also demonstrates transcriptional and translational upregulation of A1R in mitral and tufted cells, which likely influence resting network activity in OB and likely contribute to olfactory dysfunction in EAE. Overall, our study shows that olfactory dysfunction and altered social and cognitive behavior in EAE are associated with increased adenosine signaling via A1R, A2BR, and A3R.

Effects of Corticosteroid Treatment on Olfactory Dysfunction in LATY136F Knock-In Mice.

Immunoglobulin G4-related disease (IgG4-RD) is a systemic inflammatory condition affecting multiple organs, including the pancreas, salivary glands, lungs, kidneys, skin, and lymph nodes. Clinically, it is characterized by elevated serum IgG and IgG4 levels and tissue infiltration by IgG4-positive plasma cells, lymphocytes, fibrosis, and phlebitis obliterans. IgG4-RD is linked to increased Th2-dominant cytokines, contributing to eosinophilia, elevated serum IgG4, and fibrosis. A notable feature is its good response to corticosteroid therapy. To investigate the effects of corticosteroid treatment on olfactory dysfunction in LATY136F knock-in mice, which exhibited increased production of Th2-type IgG1 (the murine homolog of human IgG4) and developed multiorgan tissue lesions similar to those observed in IgG4-RD patients. LATY136F knock-in mice (n=24) were divided into groups that received prednisolone or saline at different ages. Olfactory function was assessed using a behavioral test with cycloheximide. Histological and immunohistochemical analyses were performed to evaluate the olfactory epithelium thickness as well as the presence of mature and immature olfactory neurons. Corticosteroid-treated mice exhibited significantly improved olfactory function compared to the controls. Histological analysis revealed a significant increase in olfactory epithelium thickness and mature (olfactory marker protein-positive) and immature (growth-associated protein 43-positive) olfactory neurons in the treated groups compared with the control group. Corticosteroid treatment effectively improved olfactory dysfunction and promoted olfactory epithelium regeneration in LATY136F knock-in mice, suggesting the potential therapeutic benefits of corticosteroid treatment for patients with IgG4-RD experiencing olfactory dysfunction. However, further research on topical nasal steroid therapy in untreated patients is warranted. The results support further investigation into topical nasal steroid therapies for treating olfactory dysfunction in untreated patients, potentially influencing clinical practice and patient management strategies for IgG4-RD globally.

Association of prior military service with olfactory function among older adults.

Olfactory dysfunction (OD) is a condition primarily affecting older adults. Several factors have been implicated in OD, such as age, socioeconomic status, and neurodegenerative disease; however, the effect of military service still requires additional investigation. Here, we aim to determine if there is an association between prior military service and OD among older adults. This cross-sectional study included 2268 adults from Round 1 of the National Social Life, Health, and Aging Project. OD was defined as 0-3 odors correctly identified on the 5-item Sniffin' Sticks test. Bivariate analysis was conducted to calculate crude odds ratios (cOR) for the association of prior military service with OD and identify covariates for regression. Associations between prior military service and OD were assessed using logistic regression, and adjusted odds ratios (aOR) were calculated controlling for age, gender, race/ethnicity, education, stroke history, dementia, diabetes, and mental health. All analyses were weighted using survey weights to account for sampling design. OD was present in 489 adults (21.6%). Among those with OD, the average age was 71.0 ± 7.9 years, whereas the average age in those without OD was 67.0 ± 7.2 years. Among adults with OD, 34.4% reported prior military service, compared to 27.7% of adults without OD (cOR = 1.37; 95% CI: 1.05-1.79). However, after adjusting for covariates, prior military service was not associated with OD (aOR: 1.09; 95% CI: 0.79-1.50). Older age (aOR: 1.07; 95% CI: 1.05-1.09) and worse mental health (aOR: 1.68; 95% CI: 1.14-2.49) were associated with OD. Prior military service was not associated with OD among older adults after controlling for covariates. More nuanced research is needed to examine correlations between OD and specific elements of military service such as duration, toxin exposure, and head trauma.Level of Evidence: Level 4.

Distinct olfactory mucosal macrophage populations mediate neuronal maintenance and pathogen defense

The olfactory mucosa is important for both the sense of smell and as a mucosal immune barrier to the upper airway and brain. However, little is known about how the immune system mediates the conflicting goals of neuronal maintenance and inflammation in this tissue. A number of immune cell populations reside within the olfactory mucosa and yet we have little understanding of how these resident olfactory immune cells functionally interact with the chemosensory environment. Identifying these interactions will allow therapeutic manipulations that treat disorders such as post-viral olfactory dysfunction. Macrophages are the most prevalent immune cell type in the uninflamed olfactory mucosa and here, we identify two distinct tissue macrophage populations in murine olfactory mucosa. P2ry12hi macrophages are transcriptionally specialized for neuron interactions, closely associated with olfactory neuron cell bodies, long-term tissue residents, and functionally specialized to phagocytose cells and debris, including olfactory neurons. Conversely, MHC Class IIhi macrophages are transcriptionally dedicated to cytokine production and antigen presentation, localized primarily within the olfactory lamina propria, more rapidly replaced by blood monocytes, and rapidly produce chemokines in response to viral infection. We further show that these macrophage signatures are present in human olfactory biopsies, and P2ry12-like olfactory macrophages are reduced in patients with long-term smell loss following COVID-19. Together, these data show that two olfactory macrophage populations regulate neurons and initiate the immune response, contributing to our understanding of both olfactory immunity and tissue-resident macrophage biology.

JAK and STAT5B mediate olfactory response of migratory locusts to their own volatiles

Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signaling affect social aggregation, mood and psychiatric disorders, nociceptive and depressive behaviors. Olfactory dysfunction is one of the distinct symptoms of these behaviors, but function and mechanism of JAK and STAT in modulating olfaction remain largely unknown. Migratory locusts show olfactory preference for their own volatiles. We thus use this animal model to explore functions and mechanisms of JAK and STAT5B in mediating olfaction response to their own volatiles. Tissue distribution study shows that JAK and STAT5B express in antennae and brains, especially in antennal lobes and mushroom bodies in locust brains, and knockdown of these two genes by RNA interference (RNAi) in antennae and brains results in the loss of olfactory preference for locust volatiles, including chemical odorants indole and β-ionone. RNA-seq analysis reveals that JAK and STAT5B RNAi knockdown downregulates a functional class of transcripts in nucleoprotein complex, including heterogeneous nuclear ribonucleoprotein C (hnRNPC) and small nuclear ribonucleoprotein polypeptide F (SNRPF). HnRNPC and SNRPF mRNAs and proteins are also expressed in antennae and brains, and RNAi knockdown of these two genes reduces the percentage of locusts preferring volatiles, including chemical odorants indole and β-ionone. Furthermore, RNAi knockdown of dopamine receptor 1 (DopR1) results in the decrease of JAK mRNA level in antennae, and JAK/STAT5B, hnRNPC and SNRPF are required for dopamine receptor 1 (DopR1) to modulate olfactory preference for their own volatiles. This study confirms that JAK/STAT5B signaling modulates olfaction by affecting expression levels of hnRNPC and SNRPF, and this pathway is also required for DopR1 to modulate olfactory preference for their own volatiles. These findings highlight novel roles of JAK and STAT5B in modulating olfactory preference. This study provides novel insights into functional links among JAK/STAT5B signaling, RNA binding proteins and DopR1 underlying the modulation of olfactory behaviors.

Unraveling olfactory subtypes in Parkinson's disease and their effect on the natural history of the disease.

Hyposmia in Parkinson's disease (PD) had been studied before but had not been detailed by its temporal progression. This study observed how each olfactory subtype evolved in terms of motor symptoms, cardiac sympathetic innervation, and cognition. Two hundred and three early PD patients were classified as normosmia, hyposmia-converter (hypo-converter), and hyposmia. Their presynaptic monoamine availability at the time of diagnosis was assessed by positron emission tomography imaging using 18F-N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane and compared across the subtypes. Motor symptoms were evaluated in all patients, cardiac denervation was examined in 183 patients, and cognition in 195 patients were assessed using a neuropsychological battery. The domains were re-assessed 2-4 times, and the longitudinal data were analyzed to discern the natural course of each subtype. Twenty-nine (14.3%) patients belonged to the normosmia group, 34 (16.7%) to the hypo-converter group, and the rest to the hyposmia (69.0%) group. 85.7% of the total population became hyposmic during an average 3years of follow-up. The baseline motor symptoms, cardiac denervation, and cognition were comparable across the olfactory subtypes. Across the subtypes, a decline in the presynaptic monoamine densities of the caudate, especially the ventral-anterior subdivisions, correlated inversely with olfaction dysfunction. Over time, motor and cardiac denervation burdens worsened regardless of olfactory subtypes, but hypo-converters experienced faster cognitive deterioration than the other two groups. The results suggest that the olfactory subtypes have differential significance along the disease course, which might reflect the involvement of different neuro-biochemical circuitries.

Hippocampus and olfactory impairment in Parkinson disease: a comparative exploratory combined volumetric/functional MRI study.

Patients with Parkinson's Disease (PD) commonly experience Olfactory Dysfunction (OD). Our exploratory study examined hippocampal volumetric and resting-state functional magnetic resonance imaging (rs-fMRI) variations in a Healthy Control (HC) group versus a cognitively normal PD group, further categorized into PD with No/Mild Hyposmia (PD-N/MH) and PD with Severe Hyposmia (PD-SH). We calculated participants' relative Total Hippocampal Volume (rTHV) and performed Spearman's partial correlations, controlled for age and gender, to examine the correlation between rTHV and olfactory performance assessed by the Odor Stick Identification Test for the Japanese (OSIT-J) score. Mann-Whitney U tests assessed rTHV differences across groups and subgroups, rejecting the null hypothesis for p < 0.05. Furthermore, a seed-based rs-fMRI analysis compared hippocampal connectivity differences using a one-way ANCOVA covariate model with controls for age and gender. Spearman's partial correlations indicated a moderate positive correlation between rTHV and OSIT-J in the whole study population (ρ = 0.406; p = 0.007), PD group (ρ = 0.493; p = 0.008), and PD-N/MH subgroup (ρ = 0.617; p = 0.025). Mann-Whitney U tests demonstrated lower rTHV in PD-SH subgroup compared to both HC group (p = 0.013) and PD-N/MH subgroup (p = 0.029). Seed-to-voxel rsfMRI analysis revealed reduced hippocampal connectivity in PD-SH subjects compared to HC subjects with a single cluster of voxels. Although the design of the study do not allow to make firm conclusions, it is reasonable to speculate that the progressive involvement of the hippocampus in PD patients is associated with the progression of OD.

Deletion in RMST lncRNA impairs hypothalamic neuronal development in a human stem cell-based model of Kallmann Syndrome

Rhabdomyosarcoma 2-associated transcript (RMST) long non-coding RNA has previously been shown to cause Kallmann syndrome (KS), a rare genetic disorder characterized by congenital hypogonadotropic hypogonadism (CHH) and olfactory dysfunction. In the present study, we generated large deletions of approximately 41.55 kb in the RMST gene in human pluripotent stem cells using CRISPR/Cas9 gene editing. To evaluate the impact of RMST deletion, these cells were differentiated into hypothalamic neurons that include 10–15% neurons that express gonadotrophin-releasing hormone (GnRH). We found that deletion in RMST did not impair the neurogenesis of GnRH neurons, however, the hypothalamic neurons were electro-physiologically hyperactive and had increased calcium influx activity compared to control. Transcriptomic and epigenetic analyses showed that RMST deletion caused altered expression of key genes involved in neuronal development, ion channels, synaptic signaling and cell adhesion. The in vitro generation of these RMST-deleted GnRH neurons provides an excellent cell-based model to dissect the molecular mechanism of RMST function in Kallmann syndrome and its role in hypothalamic neuronal development.

Long-COVID olfactory dysfunction: allele E4 of apolipoprotein E as a possible protective factor.

Olfactory dysfunction (OD) represents a frequent manifestation of the coronavirus disease 2019 (COVID-19). Apolipoprotein E (APOE) is a protein that interacts with the angiotensin-converting enzyme receptor, essential for viral entry into the cell. Previous publications have suggested a possible role of APOE in COVID-19 severity. As far as we know, no publications found significant associations between this disease's severity, OD, and APOE polymorphisms (E2, E3, and E4). To analyze the epidemiology of OD and its relationship with APOE polymorphisms in a cohort of Long-COVID patients. We conducted a prospective cohort study with patients followed in a post-COVID neurological outpatient clinic, with OD being defined as a subjective reduction of olfactory function after infection, and persistent OD being defined when the complaint lasted more than 3 months after the COVID-19 infection resolution. This cross-sectional study is part of a large research with previously reported data focusing on the cognitive performance of our sample. The final sample comprised 221 patients, among whom 186 collected blood samples for APOE genotyping. The persistent OD group was younger and had a lower hospitalization rate during the acute phase of the disease (p < 0.001). Furthermore, the APOE variant E4 allele frequency was lower in this group (p = 0.035). This study evaluated OD in an outpatient population with COVID-19. In the current literature on this disease, anosmia is associated with better clinical outcomes and the E4 allele is associated with worse outcomes. Our study provides new information to these correlations, suggesting APOE E4 as a protective factor for OD.

Incidence and influencing factors of olfactory dysfunction in patients 1 week after endoscopic transsphenoidal resection of pituitary tumor: a cross-sectional study of 158 patients.

To investigate the current situation of olfactory dysfunction in patients after endoscopic transsphenoidal resection of pituitary tumors, and analyze its influencing factors, to provide references for clinical nursing and rehabilitation. A cross-sectional study design and convenience sampling method were used to investigate 158 patients with pituitary tumors treated by endoscopic transsphenoidal pituitary tumor resection in the Department of Neurosurgery of three Grade-A general hospitals in Sichuan Province from January 2022 and June 2023. The olfactory function of patients was evaluated 1 week after surgery, and the general clinical data and olfactory related data of patients were collected, and the influencing factors of olfactory disorder were analyzed by logistic regression. The incidence of olfactory dysfunction was 73.42%. analysis revealed that the formation of blood scabs, nasal cavity adhesion, cerebrospinal fluid leakage and operation time were independent risk factors for olfactory dysfunction in patients after transsphenoidal pituitary tumor resection (p < 0.05). The incidence of olfactory dysfunction is high in patients after endoscopic transsphenoidal resection of pituitary tumors, suggesting that medical staff should pay close attention to and identify patients with olfactory dysfunction based on the guidance of disease knowledge and skills, develop targeted nursing interventions, and promote the improvement of patients' olfactory function and quality of life.

Efficacy of forskolin as a promising therapy for chronic olfactory dysfunction post COVID-19.

Olfactory dysfunction is increasingly common among COVID-19 patients, impacting their well-being. Reports have demonstrated decreased levels of cyclic adenosine monophosphate and cyclic guanosine monophosphate among patients with chronic olfactory dysfunction. A prospective randomized clinical trial was developed to demonstrate the efficacy of an oral forskolin regimen treatment, an adenylyl cyclase activator that raises intracellular levels of cyclic adenosine monophosphate, for the treatment of olfactory dysfunction following COVID-19, compared to placebo regimen. The study enrolled 285 participants with persistent olfactory dysfunction post COVID-19 infection, randomly assigning them to receive either placebo capsules (n = 120) or oral forskolin capsules (n = 165). Follow-up was conducted to track progress, with 18 participants from the placebo group and 12 from the forskolin group lost during this period. Olfactory function was assessed using the "Sniffin' Sticks" test, measuring threshold, discrimination and identification scores before and after treatment. Subjects administered forskolin capsules demonstrated a significant enhancement in their composite TDI (threshold, discrimination and identification) score, suggesting a notable amelioration in olfactory functionality. Moreover, the discrimination and identification scores notably improved within the forskolin group. Conversely, no significant alterations were observed in the threshold scores. This study suggests that forskolin can contribute potentially to improve chronic olfactory dysfunction post COVID-19. DFM-IRB00012367-23-10-001.

A novel olfactory sorting task

BackgroundThis study aimed to develop a simple self-administered screening tool for odor memory, which allowed users to self-test their olfactory function repeatedly even at home.MethodsOne hundred and ten participants were recruited (30 men, age = 50.1 ± 9.9 years; 80 women, age = 47.1 ± 11.5 years); half of them were heathy volunteers, the other half were patients with olfactory dysfunction. Fifty-one healthy participants volunteered for a retest within an interval of a maximum of 14 days. Olfactory function was assessed using the extended Sniffin’ Sticks test (SST) comprising tests for odor threshold, identification, and discrimination. All participants received the Novel Olfactory Sorting Task (NOST) which is based on the sorting of 12 matching pairs of odors involving olfactory and cognitive functions. After that, all participants rated questions related to their test performance and the practicability of the test.ResultsConsistent with the previous literature, significant effects of age were found. Results showed an acceptable test-retest reliability and a satisfactory validity of the NOST. The NOST score not only had positive correlations with SST, but also was capable of differentiating severe hyposmia/anosmia from normosmia by the score of 5.5 (sensitivity of 76.2%, specificity of 77.6%).ConclusionThe present study showed the good reliability, validity, and possible clinical usefulness of the NOST. As a self-performed screening test, it can be comprehended and conducted easily, which may provide a quick and simple approach to obtaining a global estimation of olfactory and cognitive functions.

Paper based analytical devices for ions determination in nasal secretions demonstrating association with olfactory function

Nasal ions environment plays a crucial role in maintaining nasal physiology and supports olfactory transmission. Addressing the limited research on nasal ion levels and their association with olfactory function, paper-based sensors were developed for determination of sodium, potassium, calcium and chloride in the nasal mucus of healthy volunteers and patients with olfactory dysfunction. Multi-walled carbon nanotubes and carbon quantum dots from beetroot were incorporated into paper substrate where sensors were designed with ion association complexes for sodium, potassium, calcium and chloride enhancing the recognition sensing capabilities. The sensors composition was optimized, including ion-exchange materials and plasticizers, to enhance sensitivity and selectivity. The performance of the sensors is evaluated based on Nernstian slope, dynamic range, detection limit and response time. Selectivity of the sensors was tested and the results demonstrated high selectivity for the target ions. The sensors were successfully determined sodium, potassium, calcium and chloride levels in nasal mucus of healthy volunteers and patients with olfactory dysfunction. The results revealed elevated calcium levels in patients with olfactory dysfunction, highlighting associated diagnostic implications. This suggests that the proposed sensors could serve as a diagnostic tool for olfactory evaluation, particularly in resource-constrained settings where access to advanced diagnostic tools is limited.

ErbB4 deficiency exacerbates olfactory dysfunction in an early-stage Alzheimer's disease mouse model.

Olfactory dysfunction is increasingly recognized as an early indicator of Alzheimer's disease (AD). Aberrations in GABAergic function and the excitatory/inhibitory (E/I) balance within the olfactory bulb (OB) have been implicated in olfactory impairment during the initial stages of AD. While the neuregulin 1 (NRG1)/ErbB4 signaling pathway is known to regulate GABAergic transmission in the brain and is associated with various neuropsychiatric disorders, its specific role in early AD-related olfactory impairment remains incompletely understood. This study demonstrated that olfactory dysfunction preceded cognitive decline in young adult APP/PS1 mice and was characterized by reduced levels of NRG1 and ErbB4 in the OB. Further investigation revealed that deletion of ErbB4 in parvalbumin interneurons reduced GABAergic transmission and increased hyperexcitability in mitral and tufted cells (M/Ts) in the OB, thereby accelerating olfactory dysfunction in young adult APP/PS1 mice. Additionally, ErbB4 deficiency was associated with increased accumulation of Aβ and BACE1-mediated cleavage of APP, along with enhanced CDK5 signaling in the OB. NRG1 infusion into the OB was found to enhance GABAergic transmission in M/Ts and alleviate olfactory dysfunction in young adult APP/PS1 mice. These findings underscore the critical role of NRG1/ErbB4 signaling in regulating GABAergic transmission and E/I balance within the OB, contributing to olfactory impairment in young adult APP/PS1 mice, and provide novel insights for early intervention strategies in AD. This work has shown that ErbB4 deficiency increased the burden of Aβ, impaired GABAergic transmission, and disrupted the E/I balance of mitral and tufted cells (M/Ts) in the OB, ultimately resulting in olfactory dysfunction in young adult APP/PS1 mice. NRG1 could enhance GABAergic transmission, rescue E/I imbalance in M/Ts, and alleviate olfactory dysfunction in young adult APP/PS1 mice. OB: olfactory bulb, E/I: excitation/inhibition, Pr: probability of release, PV: parvalbumin interneurons, Aβ: β-amyloid, GABA: gamma-aminobutyric acid.