Type 2 and Non-type 2 Inflammation in the Upper Airways: Cellular and Molecular Alterations in Olfactory Neuroepithelium Cell Populations.

PURPOSE OF REVIEW: Neurogenesis occurring in the olfactory epithelium is critical to continuously replace olfactory neurons to maintain olfactory function, but is impaired during chronic type 2 and non-type 2 inflammation of the upper airways. In this review, we describe the neurobiology of olfaction and the olfactory alterations in chronic rhinosinusitis with nasal polyps (type 2 inflammation) and post-viral acute rhinosinusitis (non-type 2 inflammation), highlighting the role of immune response attenuating olfactory neurogenesis as a possibly mechanism for the loss of smell in these diseases. RECENT FINDINGS: Several studies have provided relevant insights into the role of basal stem cells as direct participants in the progression of chronic inflammation identifying a functional switch away from a neuro-regenerative phenotype to one contributing to immune defense, a process that induces a deficient replacement of olfactory neurons. The interaction between olfactory stem cells and immune system might critically underlie ongoing loss of smell in type 2 and non-type 2 inflammatory upper airway diseases. In this review, we describe the neurobiology of olfaction and the olfactory alterations in type 2 and non-type 2 inflammatory upper airway diseases, highlighting the role of immune response attenuating olfactory neurogenesis, as a possibly mechanism for the lack of loss of smell recovery.

Olfactory Dysfunction in Mental Illness.

PURPOSE OF REVIEW: Olfactory dysfunction contributes to the psychopathology of mental illness. In this review, we describe the neurobiology of olfaction, and the most common olfactory alterations in several mental illnesses. We also highlight the role, hitherto underestimated, that the olfactory pathways play in the regulation of higher brain functions and its involvement in the pathophysiology of psychiatric disorders, as well as the effect of inflammation on neurogenesis as a possible mechanism involved in olfactory dysfunction in psychiatric conditions. RECENT FINDINGS: The olfactory deficits present in anxiety, depression, schizophrenia or bipolar disorder consist of specific alterations of different components of the sense of smell, mainly the identification of odours, as well as the qualifications of their hedonic valence (pleasant or unpleasant). Epidemiological findings have shown that both environmental factors, such as air pollutants, and inflammatory disease of the upper respiratory tract, can contribute to an increased risk of mental illness, at least in part, due to peripheral inflammatory mechanisms of the olfactory system. In this review, we describe the neurobiology of olfaction, and the most common olfactory function alterations in several psychiatric conditions and its role as a useful symptom for the differential diagnosis. We also highlight the effect of inflammation on neurogenesis as a possible mechanism involved in olfactory dysfunction in these psychiatric conditions.

Chronic Rhinosinusitis and COVID-19.

The COVID-19 pandemic has raised awareness about olfactory dysfunction, although a loss of smell was present in the general population before COVID-19. Chronic rhinosinusitis (CRS) is a common upper airway chronic inflammatory disease that is also one of the most common causes of olfactory dysfunction. It can be classified into different phenotypes (ie, with and without nasal polyps) and endotypes (ie, type 2 and non-type 2 inflammation). However, scientific information regarding CRS within the context of COVID-19 is still scarce. This review focuses on (1) the potential effects of severe acute respiratory syndrome coronavirus 2 infection on CRS symptoms, including a loss of smell, and comorbidities; (2) the pathophysiologic mechanisms involved in the olfactory dysfunction; (3) CRS diagnosis in the context of COVID-19, including telemedicine; (4) the protective hypothesis of CRS in COVID-19; and (5) the efficacy and safety of therapeutic options for CRS within the context of COVID-19.

Olfactory Bulb Excitotoxicity as a Gap-Filling Mechanism Underlying the Link Between Traumatic Brain Injury-Induced Secondary Neuronal Degeneration and Parkinson's Disease-Like Pathology.

There is increasing preclinical and clinical data supporting a potential association between Traumatic Brain Injury (TBI) and Parkinson's disease (PD). It has been suggested that the glutamate-induced excitotoxicity underlying TBI secondary neuronal degeneration (SND) might be associated with further development of PD. Interestingly, an accumulation of extracellular glutamate and olfactory dysfunction are both sharing pathological conditions in TBI and PD. The possible involvement of glutamate excitotoxicity in olfactory dysfunction has been recently described, however, the role of olfactory bulbs (OB) glutamate excitotoxicity as a possible mechanism involved in the association between TBI and PD-related neurodegeneration has not been investigated yet. We examined the number of nigral dopaminergic neurons (TH +), nigral α-synuclein expression, the striatal dopamine transporter (DAT) expression, and motor performance after bilateral OB N-Methyl-D-Aspartate (NMDA)-induced excitotoxic lesions in rodents. Bulbar NMDA administration induced a decrease in the number of correct choices in the discrimination tests one week after lesions (p < 0.01) and a significant decrease in the number of nigral DAergic neurons (p < 0.01) associated with an increase in α-synuclein expression (p < 0.01). No significant striatal changes in DAT expression or motor alterations were observed. Our results show an association between TBI-induced SND and PD-related neurodegeneration suggesting that the OB excitotoxicity occurring in TBI SND may be a filling gap mechanism underlying the link between TBI and PD-like pathology.

Loss of smell in patients with traumatic brain injury is associated with neuropsychiatric behavioral alterations.

OBJECTIVE: We sought to identify and correlate the severity of traumatic brain injuries (TBIs) associated with olfactory dysfunction with cognitive and behavioral profiles. PARTICIPANTS AND SETTING: Patients with TBI undergoing treatment in a specialized neuro-rehabilitation hospital. DESIGN: Prospective study. MAIN MEASURES: Glasgow Coma Scale (GCS) at the time of injury and during posttraumatic amnesia. Motor functions were assessed with the Functional Instrument Measure and Disability Rating Scales. The Wechsler Adult Intelligence test was used for neuropsychologic assessment and the Neuropsychiatric Inventory was used to assess behavioral changes. The Barcelona Smell Test-24 was used to study subjective smell loss. RESULTS: A total of 111 patients with TBI were enrolled (33 females; mean age 32.86 years); 38.73% exhibited smell loss. Patients with no olfactory impairment (OI) had worse TBIs than those with OI (GCS scores 5.65 and 7.74, respectively); no significant differences in cognitive behaviors, such as attention memory, visuoperception, and visuoconstruction, were observed. However, patients with TBI and olfactory dysfunction showed statistically significant alterations in neuropsychiatric behavioral performances such as feeding when compared with patients with TBI without smell loss. CONCLUSION: Olfactory dysfunction in patients with a TBI correlates with altered neuropsychiatric behavioral performances such as feeding, sleeping, and motor behavior.

Role of microRNAs in inflammatory upper airway diseases.

MicroRNAs (miRNAs) are a conserved family of small endogenous noncoding RNA molecules that modulate post-transcriptional gene expression in physiological and pathological processes. miRNAs can silence target mRNAs through degradation or inhibition of translation, showing their pivotal role in the pathogenesis of many human diseases. miRNAs play a role in regulating immune functions and inflammation and are implicated in controlling the development and activation of T and B cells. Inflammatory chronic upper airway diseases, such as rhinitis and rhinosinusitis, are spread all over the world and characterized by an exaggerated inflammation involving a complex interaction between immune and resident cells. Until now and despite allergy, little is known about their etiology and the processes implicated in the immune response and tuning inflammation of these diseases. This review highlights the knowledge of the current literature about miRNAs in inflammatory chronic upper airways diseases and how this may be exploited in the development of new clinical and therapeutic strategies.

The Loss of Smell and Taste in the COVID-19 Outbreak: a Tale of Many Countries.

PURPOSE OF REVIEW: Olfactory dysfunction in upper airway viral infections (common cold, acute rhinosinusitis) is common (> 60%). During the COVID-19 outbreak, frequency of sensory disorders (smell and/or taste) in affected patients has shown a high variability from 5 to 98%, depending on the methodology, country, and study. RECENT FINDINGS: A sudden, severe, isolated loss of smell and/or taste, in the absence of other upper airway inflammatory diseases (allergic rhinitis, chronic rhinosinusitis, nasal polyposis), should alert individuals and physicians on being potentially affected by COVID-19. The evaluation of smell/taste disorders with a visual analogue scale or an individual olfactory or gustatory test, at the hospital or by telemedicine, to prevent contamination might facilitate an early detection of infected patients and reduce the transmission of SARS-CoV-2. During the COVID-19 outbreak, patients with sudden loss of smell should initiate social distancing and home isolation measures and be tested for SARS-CoV-2 diagnostic test when available. Olfactory training is recommended when smell does not come back after 1 month but can be started earlier.

Globus pallidus, but not entopeduncular nucleus, 6-OHDA-induced lesion attenuates L-Dopa-induced dyskinesia in the rat model of Parkinson's disease.

Although extrastriatal dopaminergic (DAergic) systems are being recognized as contributors to Parkinson's disease (PD) pathophysiology, the role of extrastriatal DA depletion in L-Dopa-induced dyskinesia (LID) is still unknown. In view of the physiologic actions of DA on pallidal neuronal activity and the effects on motor behavior of local injection of DA drugs, the loss of the external (GPe, GP in rodents) and internal (GPi, entopeduncular nucleus (EP) in rodents) pallidal DAergic innervation might differentially contribute to LID. A role of pallidal serotonergic (SER) terminals in LID has been highlighted, however, the effect of DAergic innervation is unknown. We investigated the role of DAergic pallidal depletion on LID. Rats were distributed in groups which were concomitantly lesioned with 6-OHDA or vehicle (sham) in the GP, or EP, and in the medial forebrain bundle (MFB) as follows: a) MFB-sham+GP-sham, b) MFB-sham+GP-lesion, c) MFB-lesion+GP-sham, d) MFB-lesion+GP-lesion, e) MFB-sham+EP-sham, f) MFB-sham+EP-lesion, g) MFB-lesion+EP-sham, and h) MFB-lesion+EP-lesion. Four weeks later, animals were treated with L-Dopa (6 mg/kg) twice daily for 22 days.. Immunohistochemical studies were performed in order to investigate the changes in pallidal SER and serotonin transporter (SERT) levels. GP, but not EP, DAergic denervation attenuated LID in rats with a concomitant MFB lesion (p < 0.01). No differences were found in GP SERT expression between groups of animals developing or not LID. These results provide evidence of the relevance of GP DAergic innervation in LID. The conversion of levodopa to DA in GP serotonergic nerve fibers appears not to be the major mechanism underlying LID.

Lack of correlation between dyskinesia and pallidal serotonin transporter expression-induced by L-Dopa and Pramipexole in hemiparkinsonian rats.

The role of pallidal serotonergic terminals in the development of L-Dopa-induced dyskinesias (LIDs) in Parkinson's disease (PD) has been recently highlighted correlating pallidal serotonin transporter (SERT) expression levels with dyskinesias severity. However, the role of external globus pallidus (GPe, GP in rodents) serotonergic function in LIDs is still controversial since several studies have shown no differences in GPe serotonin (SER) and SERT levels between dyskinetic and non-dyskinetic PD patients. In addition, the increase in pallidal SERT/dopamine transporter (DAT) binding ratio obtained in positron emission tomography studies has been shown similar in both subtypes of PD patients. Based on these controversial results, further studies are required to clarify the possible involvement of GPe serotonergic activity in LIDs expression. We investigated the pallidal SER and SERT expression changes and the abnormal involuntary movements (AIMs) induced by L-Dopa or the D3/D2 dopamine (DA) agonist, Pramipexole, in partial unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats. L-Dopa treatment led to an increment of axial (p < 0.01), limb (p < 0.01), and orolingual (p < 0.01) AIMs. However, Pramipexole treatment did not induce AIMs. The number of GP SERT-positive axon varicosities was increased in L-Dopa (p < 0.05) and Pramipexole (p < 0.01) treated rats. No differences were observed in the number of GP SERT-positive varicosities between L-Dopa and Pramipexole treatments. Our results indicate a lack of correlation between GP SERT expression levels and the development of AIMs suggesting that pallidal serotonergic fibers are not responsible for LIDs. The possible involvement of the SER system in dyskinesia may include other mechanisms.

Correction to: Motor impulsivity and delay intolerance are elicited in a dose-dependent manner with a dopaminergic agonist in parkinsonian rats.

In the original version of this article, the Figure 3 was published in an incorrect format, even though the data and the related information in the text are correct.

Olfactory Dysfunction in Traumatic Brain Injury: the Role of Neurogenesis.

PURPOSE OF REVIEW: Olfactory functioning disturbances are common following traumatic brain injury (TBI) having a significant impact on quality of life. A spontaneous recovery of the olfactory function over time may occur in TBI patients. Although there is no standard treatment for patients with posttraumatic olfactory loss, olfactory training (OT) has shown some promise beneficial effects. However, the mechanisms underlying spontaneous recovery and olfactory improvement induced by OT are not completely known. RECENT FINDINGS: The spontaneous recovery of the olfactory function and the improvement of olfactory function after OT have recently been associated with an increase in subventricular (SVZ) neurogenesis and an increase in olfactory bulb (OB) glomerular dopaminergic (DAergic) interneurons. In addition, after OT, an increase in electrophysiological responses at the olfactory epithelium (OE) level has been reported, indicating that recovery of olfactory function not only affects olfactory processing at the central level, but also at peripheral level. However, the role of OE stem cells in the spontaneous recovery and in the improvement of olfactory function after OT in TBI is still unknown. In this review, we describe the physiology of the olfactory system, and the olfactory dysfunction after TBI. We highlight the possible role for the SVZ neurogenesis and DAergic OB interneurons in the recovery of the olfactory function. In addition, we point out the relevance of the OE neurogenesis process as a future target for the research in the pathophysiological mechanisms involved in the olfactory dysfunction in TBI. The potential of basal stem cells as a promising candidate for replacement therapies is also described.

Motor impulsivity and delay intolerance are elicited in a dose-dependent manner with a dopaminergic agonist in parkinsonian rats.

RATIONALE: Impulse control disorders (ICD) and other impulsive-compulsive behaviours are frequently found in Parkinson's disease (PD) patients treated with dopaminergic agonists. To date, there are no available animal models to investigate their pathophysiology and determine whether they can be elicited by varying doses of dopaminergic drugs. In addition, there is some controversy regarding the predispositional pattern of striatal dopaminergic depletion. OBJECTIVES: To study the effect of two doses of pramipexole (PPX) on motor impulsivity, delay intolerance and compulsive-like behaviour. METHODS: Male rats with mild dopaminergic denervation in the dorsolateral striatum (bilateral injections of 6-hydroxidopamine (6-OHDA)) treated with two doses of PPX (0.25 mg/kg and 3 mg/kg) and tested in the variable delay-to-signal paradigm. RESULTS: Partial (50%) dopaminergic depletion did not induce significant changes in motor impulsivity or delay intolerance. However, 0.25 mg/kg of PPX increased motor impulsivity, while 3 mg/kg of PPX increased both motor impulsivity and delay intolerance. These effects were independent of the drug's antiparkinsonian effects. Importantly, impulsivity scores before and after dopaminergic lesion were positively associated with the impulsivity observed after administering 3 mg/kg of PPX. No compulsive-like behaviour was induced by PPX administration. CONCLUSIONS: We described a rat model, with a moderate dorsolateral dopaminergic lesion resembling that suffered by patients with early PD, that develops different types of impulsivity in a dose-dependent manner dissociated from motor benefits when treated with PPX. This model recapitulates key features of abnormal impulsivity in PD and may be useful for deepening our understanding of the pathophysiology of ICD.

Olfactory Training Prevents Olfactory Dysfunction Induced by Bulbar Excitotoxic Lesions: Role of Neurogenesis and Dopaminergic Interneurons.

Glutamatergic excitotoxicity is involved in pathologies affecting the central nervous system, including traumatic brain injury (TBI) and neurodegenerative diseases, such as Parkinson's disease (PD), in which olfactory dysfunction is an early symptom. Interestingly, our group has recently shown that bilateral administration of the glutamate agonist, N-methyl-D-aspartate (NMDA) in the olfactory bulbs (OBs) induces an olfactory dysfunction 1 week after lesions. Although a wide range of treatments have been attempted, no standard therapy has been established to treat olfactory disorders. Increasing evidence suggests a beneficial effect of olfactory training (OT) in olfactory function. However, the mechanisms underlying OT effects remain unknown. We investigated the effects of OT on the olfactory dysfunction induced by excitotoxicity in bilateral OB NMDA-lesioned animals. We compared OT effects with the ones obtained with neuroprotective therapies (pramipexole and MK801). We studied the underlying mechanisms involved in OT effects investigating the changes in the subventricular zone (SVZ) neurogenesis and in the number of periglomerular dopaminergic interneurons. One week after lesion, NMDA decreased the number of correct trials in the olfactory discrimination tests in the non-trained group (p < 0.01). However, OT performed for 1 week after lesions prevented olfactory dysfunction (p < 0.01). Pramipexole did not prevent olfactory dysfunction, whereas MK801 treatment showed a partial recovery (p < 0.05). An increase in SVZ neurogenesis (p < 0.05) associated with an increase in OB dopaminergic interneurons (p < 0.05) was related to olfactory function prevention induced by OT. The present results suggest a role for dopaminergic OB interneurons underlying the beneficial effects of OT improving olfactory dysfunction in bilaterally OB NMDA-lesioned animals.

Recovery of Olfactory Function After Excitotoxic Lesion of the Olfactory Bulbs Is Associated with Increases in Bulbar SIRT1 and SIRT4 Expressions.

Excitotoxicity consists in a cascade of intracellular events initiated by an excessive release of glutamate and hyperactivation of glutamatergic receptors that is involved in several pathologies, including traumatic brain injury and neurodegenerative diseases such as Parkinson's disease. Both disorders are a common cause of olfactory dysfunction. We previously reported a role for glutamate excitotoxicity in olfactory dysfunction showing an olfactory deficit 1 week after lesion and a spontaneous recovery 2 weeks after excitotoxicity lesion of the olfactory bulbs (OBs). The olfactory dysfunction recovery was associated with an increase in subventricular zone neurogenesis and an increase in the OB glomerular dopaminergic interneurons. However, the underlying molecular mechanisms involved in the OB dopaminergic differentiation and olfactory recovery are still unknown. To investigate the role of silent information regulator family proteins sirtuins (SIRTs), a family of NAD+-dependent histone deacetylases, on the olfactory function recovery, we examined the OB SIRT (SIRT1, SIRT2, and SIRT4) expressions after OB excitotoxic lesions in rodents. N-methyl-D-aspartate (NMDA) OB administration induced a decrease in the number of correct choices in the discrimination tests 1 week after lesions (p < 0.01) and a spontaneous recovery of the olfactory deficit 2 weeks after lesions (p < 0.01) associated with an increase in OB SIRT1 and SIRT4 expression. Our results point out for the first time the association between recovery of olfactory function and the increase in bulbar SIRT1 and SIRT4 expression suggesting a role for these SIRTs in the pathophysiology of recovery of loss of smell.

Pramipexole-induced impulsivity in mildparkinsonian rats: a model of impulse control disorders in Parkinson's disease.

Treatment with dopaminergic agonists such as pramipexole (PPX) contributes to the development of impulse control disorders (ICDs) in patients with Parkinson's disease (PD). As such, animal models of abnormal impulse control in PD are needed to better study the pathophysiology of these behaviors. Thus, we investigated impulsivity and related behaviors using the 5-choice serial reaction time task, as well as FosB/ΔFosB expression, in rats with mild parkinsonism induced by viral-mediated substantia nigra overexpression of human A53T mutated α-synuclein, and following chronic PPX treatment (0.25 mg/kg/d) for 4 weeks. The bilateral loss of striatal dopamine transporters (64%) increased the premature response rate of these rats, indicating enhanced waiting impulsivity. This behavior persisted in the OFF state after the second week of PPX treatment and it was further exacerbated in the ON state throughout the treatment period. The enhanced rate of premature responses following dopaminergic denervation was positively correlated with the premature response rate following PPX treatment (both in the ON and OFF states). Moreover, the striatal dopaminergic deficit was negatively correlated with the premature response rate at all times (pretreatment, ON and OFF states) and it was positively correlated with the striatal FosB/ΔFosB expression. By contrast, PPX treatment was not associated with changes in compulsivity (perseverative responses rate). This model recapitulates some features of PD with ICD, namely the dopaminergic deficit of early PD and the impulsivity traits provoked by dopaminergic loss in association with PPX treatment, making this model a useful tool to study the pathophysiology of ICDs.

Olfactory Dysfunction in Neurodegenerative Diseases.

PURPOSE OF REVIEW: The sense of smell is today one of the focuses of interest in aging and neurodegenerative disease research. In several neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease, the olfactory dysfunction is one of the initial symptoms appearing years before motor symptoms and cognitive decline, being considered a clinical marker of these diseases' early stages and a marker of disease progression and cognitive decline. Overall and under the umbrella of precision medicine, attention to olfactory function may help to improve chances of success for neuroprotective and disease-modifying therapeutic strategies. RECENT FINDINGS: The use of olfaction, as clinical marker for neurodegenerative diseases is helpful in the characterization of prodromal stages of these diseases, early diagnostic strategies, differential diagnosis, and potentially prediction of treatment success. Understanding the mechanisms underlying olfactory dysfunction is central to determine its association with neurodegenerative disorders. Several anatomical systems and environmental factors may underlie or contribute to olfactory loss associated with neurological diseases, although the direct biological link to each disorder remains unclear and, thus, requires further investigation. In this review, we describe the neurobiology of olfaction, and the most common olfactory function measurements in neurodegenerative diseases. We also highlight the evidence for the presence of olfactory dysfunction in several neurodegenerative diseases, its value as a clinical marker for early stages of the diseases when combined with other clinical, biological, and neuroimage markers, and its role as a useful symptom for the differential diagnosis and follow-up of disease. The neuropathological correlations and the changes in neurotransmitter systems related with olfactory dysfunction in the neurodegenerative diseases are also described.

Olfactory Training in Post-Traumatic Smell Impairment: Mild Improvement in Threshold Performances: Results from a Randomized Controlled Trial.

Traumatic Brain Injury (TBI) can be associated with partial or total smell loss. Recent studies have suggested that olfactory outcome can be positively modulated after olfactory training (OT). This study's aim was to investigate OT's potential role in smell recovery after TBI-induced olfactory loss. A prospective, randomized, and controlled study was developed. Patients with TBI-induced olfactory dysfunction (n = 42) were randomized into an experimental group with OT and a control group without (nOT). OT was performed twice daily with a six odor training set during 12 weeks. Olfactory loss was assessed using subjective olfactometry (Barcelona Smell Test [BAST] 24), a visual analogue scale (VAS), and n-butanol threshold (n-BTt) at baseline at 4, 12, and 24 weeks. Additionally, patients underwent MRI of the olfactory brain and olfactory bulbs (OB). Based on the MRI results, an overall score (0-16) was developed to associate the structural neurological damage with olfactory outcomes. The primary outcome was the change in olfactory measurements (VAS and BAST-24) between baseline and 12 weeks. The secondary outcome was the association of the MRI score with olfactory outcomes at baseline, and the impact on quality of life (QoL). After 12 weeks of training, OT patients showed a significant improvement in n-BTt (0.6 ± 1.7 OT vs. -0.6 ± 1.8 nOT, p < 0.05), but not in the smell VAS and BAST-24 scores. Olfactory outcomes (VAS, BAST-24, and n-BTt) were significantly associated with MRI structural findings (p < 0.001), but not with the OB volume or olfactory sulcus length. The present study suggests that 12 weeks of OT mildly improves the olfactory threshold in TBI, whereas the overall MRI score may be used as an imaging marker of olfactory dysfunction and disease severity in TBI patients.