Olfactory dysfunction and its related molecular mechanisms in Parkinson’s disease

Changes in olfactory function are considered to be early biomarkers of Parkinson’s disease.Olfactory dysfunction is one of the earliest non-motor features of Parkinson’s disease,appearing in about 90%of patients with early-stage Parkinson’s disease,and can often predate the diagnosis by years.Therefore,olfactory dysfunction should be considered a reliable marker of the disease.However,the mechanisms responsible for olfactory dysfunction are currently unknown.In this article,we clearly explain the pathology and medical definition of olfactory function as a biomarker for early-stage Parkinson’s disease.On the basis of the findings of clinical olfactory function tests and animal model experiments as well as neurotransmitter expression levels,we further characterize the relationship between olfactory dysfunction and neurodegenerative diseases as well as the molecular mechanisms underlying olfactory dysfunction in the pathology of early-stage Parkinson’s disease.The findings highlighted in this review suggest that olfactory dysfunction is an important biomarker for preclinical-stage Parkinson’s disease.Therefore,therapeutic drugs targeting non-motor symptoms such as olfactory dysfunction in the early stage of Parkinson’s disease may prevent or delay dopaminergic neurodegeneration and reduce motor symptoms,highlighting the potential of identifying effective targets for treating Parkinson’s disease by inhibiting the deterioration of olfactory dysfunction.

Acupuncture for olfactory dysfunction in infected COVID-19 patients:Study protocol for a randomized,sham-controlled clinical trial

Background:Olfactory dysfunction(OD)is a common symptom of Corona Virus Disease 2019(COVID-19).It is defined as the reduced or distorted ability to smell during sniffing(orthonasal olfaction)and represents one of the early symptoms in the clinical course of COVID-19 infection.A large online questionnaire-based survey has shown that some post-COVID-19 patients had no improvement 1 month after discharge from the hospital.Objective:To explore the efficacy of acupuncture for OD in COVID-19 infected patients and to determine whether acupuncture could have benefits over sham acupuncture for OD in post-COVID-19 patients.Methods:This is a single-blind,randomized controlled,cross-over trial.We plan to recruit 40 post-COVID-19 patients with smell loss or smell distortions lasting for more than 1 month.Qualified patients will be randomly allocated to the intervention group(real acupuncture)or the control group(sham acupuncture)at a 1:1 ratio.Each patient will receive 8 sessions of treatment over 4 weeks(Cycle 1)and a 2-week follow-up.After the follow-up,the control group will be subjected to real acupuncture for another 4 weeks(Cycle 2),and the real acupuncture group will undergo the 4-week sham acupuncture.The primary outcomes will be the score changes on the questionnaire of olfactory functioning and olfaction-related quality of life at week 6,8,12,and 14 from the baseline.The secondary outcomes will be the changes in the olfactory test score at week 6 and 12 from the baseline measured by using the Traditional Chinese version of the University of Pennsylvania Smell Identification Test(UPSIT-TC).Discussion:The results of this trial will help to determine the effectiveness of acupuncture for OD in post-COVID-19 patients.This may provide a new treatment option for patients.

Olfactory dysfunction in antineutrophil cytoplasmic antibodyassociated vasculitides: A review of the literature

Olfactory dysfunction(OD)has been described in patients with antineutrophil cytoplasmic antibody-associated vasculitides(AAV),but the underlying mechanisms are not completely understood.The causes of altered smell function can generally be divided into conductive,sensorineural or others.To date no specific treatment is available for AAV-related OD and the efficacy of currently available options has not been explored.The aim of this review is to provide an overview of the causes that may lead to OD in patients with AAV.Current available treatments for OD and possible options in patients with AAV presenting with smell impairment are also mentioned.

Long COVID:From olfactory dysfunctions to viral Parkinsonism

Neurological and psychiatric complications continue to be a public health concern in long coronavirus disease 2019(COVID-19).This varies from olfactory dysfunctions such as parosmia to cognitive and emotional challenges.Historically,the surge of neurological disorders followed the viral pandemics,for example,the emergence of Encephalitis Lethargica after the outbreak of Spanish Influenza.During and after COVID-19 infection,the problems associated with the sense of smell and the reports of affected olfactory and limbic brain areas are leading to a growing concern about the similarity with the symptoms and the pattern of degeneration observed at the onset of Parkinson's disease and Alzheimer's disease.These reports reveal the essentiality of long-term studies of olfactory and cognitive functions in the post-COVID era and the experiments using animal models to dissect the neural basis of these complications.In this manuscript,we summarize the research reporting the potential correlation between neurological disorders and viral pandemic outbreaks with a historical perspective.Further,we discuss the studies providing evidence of neurodegeneration due to severe acute respiratory syndrome coronavirus 2 infection by focusing on viral Parkinsonism.

Utilization of RNA sequencing to investigate olfactory dysfunction in chronic rhinosinusitis without nasal polyps:A pilot study

Objectives:Prior research on olfactory dysfunction in chronic rhinosinusitis(CRS)has focused on patients with polyps and suggests that direct inflammation of the olfactory cleft mucosa plays a contributory role.The purpose of this study was to evaluate gene expression in superior turbinate mucosal specimens,comparing normosmic and dysosmic CRS patients without polyps(CRSsNP).Methods:Tissue samples were obtained from the superior turbinates of patients with CRSsNP at the time of endoscopic sinus surgery.Samples subsequently underwent RNA sequencing and functional analysis to investigate biological pathways associated with differentially expressed genes between dysosmic(n=7)and normosmic(n=4)patients.Results:Differential gene expression analysis comparing dysosmic and normosmic CRSsNP patients showed upregulation of 563 genes and downregulation of 327 genes.Using stringent criteria for multiple comparisons,one upregulated gene(Immediate Early Response 3[IER3])had an false discovery rate(FDR)correction adjustedP value considered statistically significant(P<0.001,fold change 2.69).Reactome functional analysis revealed eight biological pathways significantly different between dysosmic and normosmic patients(P<0.05,FDR correction)including IL-4 and IL-13 signaling,IL-10 signaling,and rhodopsin-like receptors.Conclusions:RNA sequencing of the superior turbinates in patients with CRSsNP can provide valuable information regarding biological pathways and genes involved in olfactory dysfunction.This study supports literature suggesting that Type 2 inflammation may play a role in olfactory dysfunction in at least some patients with CRSsNP.This study also prompts questions regarding the role of IL-10,rhodopsin-like receptors,andIER3 in the pathogenesis of olfactory dysfunction.

Discordance between olfactory psychophysical measurements and olfactory event related potentials in five patients with olfactory dysfunction following upper respiratory infection

Background Subjective olfactory tests are easy to perform and popularly applied in the clinic, but using only these, it is difficult to diagnose all disorders of the olfactory system. The olfactory event related potentials technique offers further insight into the olfactory system and is an ideal objective test. This analysis was of subjective and objective data on the olfactory function of twelve patients with loss of smell associated with an upper respiratory infection （URI）. Methods We tested the twelve patients with URI induced olfactory loss by medical history, physical examination of the head and neck, olfactory tests and medical imaging. Olfactory function was assessed by Toyota and Takagi olfactometry including olfactory detection and recognition thresholds and olfactory event-related potentials （OERPs） recorded with OEP-98C Olfactometer. Results An unusual phenomenon was observed in five patients in whom the subjective detection and recognition thresholds were normal, while the expected OERPs were not detectable. Conclusions We suggest that the discordance between olfactory psychophysical measurements and OERPs might be the results of abnormal electrophysiology related with olfactory neuropathy caused by viral URI. In addition, the measurement of OERPs might play a significant role in evaluating olfactory dysfunction.

Olfactory Dysfunction in Parkinson＇s Disease Patients with the LRRK2 G2385R Variant

Abstract Olfactory dysfunction has been reported in Parkinson＇s disease （PD） patients carrying the LRRK2 G2019S variant in Caucasians but rarely in those with the LRRK2 G2385R variant. In this study, we performed genotyping for the LRRK2 G2385R variant in PD patients recruited from the Movement Disorder ClttliC of Xualwu Hospital in Beijing and in healthy controls randomly selected from the Beijing Longitudinal Study on Aging cohort. The ＂five-odor olfactory detection array＂, an olfactory threshold test, was used to assess olfactory function. One hundred and eighty-six participants were enrolled, comprising 43 PD patients without （iPD） and 25 with （LRRK2-PD） the LRRK2 G2385R variant, and 118 healthy controls. Our results showed that the threshold of olfactory identification was significantly worse in PD patients than in controls, but not significantly different between the iPD and LRRK2-PD groups. These findings suggested that although olfactory function in LRRK2-PD patients is impaired, it is similar to that in iPD patients.

Is SARS-CoV-2 (COVID-19) postviral olfactory dysfunction (PVOD) different from other PVOD?

Background:The SARS-CoV-2 virus continues to spread rapidly across the globe af-flicting many with Coronavirus Disease 2019(COVID-19).As the infection rates rise,a growing number of SARS-CoV-2 positive individuals have been reported to complain of olfactory distur-bances at an alarming rate.Postviral olfactory dysfunction(PVOD)is a well-known phenome-non that may explain the olfactory dysfunction reported by SARS-CoV-2 infected individuals.Methods:A scoping literature review was performed to identify studies that investigated the mechanisms of postviral olfactory dysfunction.Studies demonstrating pathophysiological,his-tological,immunochemical,and epidemiological outcomes of PVOD were included.Results:Fourteen studies were included in addition to one international news article.Three studies reported destruction of the olfactory epithelium following intranasal inoculation of various viral strains in mice.Three studies isolated pathogenic,anosmia inciting viruses(Para-influenza virus,Human Coronavirus,Rhinovirus)through nucleic acid amplification.Eleven studies demonstrated female predilection in patients with PVOD and COVID-19 associated ol-factory dysfunction,of which the majority were over 50 years old.Conclusions:PVOD and COVID-19 associated olfactory dysfunction demonstrates considerable similarities in epidemiological trends and disease sequela of other viruses to suggest identical pathophysiological mechanisms.Further studies such as intranasal inoculation and histological biopsies are needed to support our hypothesis.

Clinical studies in COVID-related olfactory disorders:Review of an institutional experience

Objective:To share a single institutional experience with clinical research on COVID-related olfactory dysfunction(OD).Data Source/Method:Narrative review of published original data and ongoing clinical trials on COVID-related OD at Washington University from 2020 to 2023.Results:There were three new diagnostic-/patient-reported outcome measures developed and tested.We report five clinical trials of interventions for COVID-related olfactory disorders:combined Visual-Olfactory Training(VOLT)with patient-preferred scents versus standard olfactory training(VOLT trial),oral gabapentin versus placebo(Gabapentin for the Relief of Acquired Chemosensory Experience trial),nasal theophylline irrigations versus placebo(Smell Changes and Efficacy of Nasal Theophylline trial),stellate ganglion block(single-arm),and mindfulness-based stress reduction(MBSR)versus lifestyle intervention(MBSR trial).Conclusions:Initial intervention trials for COVID-related OD have shown potential for improving subjective and objective olfactory outcomes.However,there remains no gold standard treatment that definitively outperforms placebo in controlled trials.Therefore,continued investigation of novel therapeutic strategies for COVID-related OD is necessary to maximize olfactory outcomes for affected patients.

Magnetic resonance imaging markers for early diagnosis of Parkinson's disease

Parkinson＇s disease （PD） is a neurodegenerative disorder characterized by selective and progressive degeneration, as well as loss of dopaminergic neurons in the substantia nigra. In PD, approximately 60-70% of nigrostriatal neurons are degenerated and 80% of content of the striatal dopamine is reduced before the diagnosis can be established according to widely accepted clinical diagnostic criteria. This condition describes a stage of disease called ＂prodromal＂, where non-motor symptoms, such as olfactory dysfunction, constipation, rapid eye movement behaviour disorder, depression, precede motor sign of PD. Detection of prodromal phase of PD is becoming an important goal for determining the prognosis and choosing a suitable treatment strategy. In this review, we present some non-invasive instrumental approaches that could be useful to identify patients in the prodromal phase of PD or in an early clinical phase, when the first motor symptoms begin to be apparent. Conventional magnetic resonance imaging （MRI） and advanced MRI techniques, such as magnetic resonance spectroscopy imaging, diffusion-weighted and diffusion tensor imaging and functional MRI, are useful to differentiate early PD with initial motor symptoms from atypical parkinsonian disorders, thus, making easier early diagnosis. Functional MRI and diffusion tensor imaging techniques can show abnormalities in the olfactory system in prodromal PD.

Differences in olfactory functional connectivity in early-onset depression and late-onset depression

Background:Late-onset depression(LOD)and early-onset depression(EOD)exhibit different pathological mechanisms and clinical phenotypes,including different extents of olfactory dysfunction.However,the brain abnormalities underlying the differences in ol-factory dysfunction between EOD and LOD remain unclear.Objective:The aim of this study was to compare the functional connectivity(FC)patterns of olfactory regions between EOD patients and LOD patients and examine their relationship with cognitive function.Methods:One hundred and five patients with EOD,101 patients with LOD and 160 normal controls(NCs)were recruited for the present study.Participants underwent clinical assessment,olfactory testing,cognitive assessments,and magnetic resonance imaging.Eight regions of the primary and secondary olfactory regions were selected to investigate olfactory FC.Results:Patients with LOD exhibited decreased odor identification(OI)compared with patients with EOD and NCs.The LOD group exhibited decreased FC compared with the EOD and NC groups when primary and secondary olfactory regions were selected as the regions of interest(the piriform cortex,lateral entorhinal cortex,and orbital-frontal cortex).Additionally,these abnormal olfactory FCs were associated with decreased cognitive function scores and OI,and the FC between the left orbital-frontal cortex and left amygdala was a partial mediator of the relationship between global cognitive scores and OI.Conclusion:Overall,patients with LOD exhibited decreased FC in both the primary and secondary olfactory cortices compared with patients with EOD,and abnormal olfactory FC was associated with OI dysfunction and cognitive impairment.The FC between the orbital-frontal cortex and amygdala mediated the relationship between global cognitive function and OI.

Variables associated with olfactory disorders in adults: A U.S.population-based analysis

Objective:Olfactory dysfunction is known to have significant social,psychological,and safety implications.Despite increasingly recognized prevalence,potential risk factors for olfactory loss have been arbitrarily documented and knowledge is limited in scale.The aim of this study is to identify potential demographic and exposure variables correlating with olfactory dysfunction.Methods:Cross-sectional analysis of the 2011-2012 and 2013-2014 editions of the National Health Examination and Nutrition Survey was performed.The utilized survey reports from a nationally representative sample of about 5000 persons each year located in counties across the United States.There is an interview and physical examination component which includes demographic,socioeconomic,dietary,and health-related questions as well as medical,dental,physiologic measurements,and laboratory tests.3594 adult respondents from 2011 to 2012 and 3708 respondents from 2013 to 2014 were identified from the above population-based database.The frequency of self-reported disorders as well as performance on odor identification testing was determined in relation to demographic factors,occupational or environmental exposures,and urinary levels of environmental and industrial compounds.Results:In both subjective and objective analysis,smell disorders were significantly more common with increasing age.While the non-Hispanic Black and non-Hispanic Asian populations were less likely to report subjective olfactory loss,they,along with Hispanics,performed more poorly on odor identification than Caucasians.Those with limited education had a decreased prevalence of hyposmia.Women outperformed men on smell testing.Those reporting exposure to vapors were more likely to experience olfactory dysfunction,and urinary levels of manganese,2-Thioxothiazolidine-4-carboxylic acid,and 2-Aminothiazoline-4-carboxylic acid were lower among respondents with subjective smell disturbance.In odor detection,elevated serum levels of lead and urinary levels of 2,4 dichlorophenol were associated with anosmia and hyposmia,respectively.Conclusions:This study provides current,population-based data identifying demographic and exposure elements related to smell disturbances in U.S.adults.Age,race,gender,education,exposure to vapors,urinary levels of manganese,2-Thioxothiazolidine-4-carboxylic acid,2-Aminothiazoline-4-carboxylic acid,2,4 dichlorophenol,and serum lead levels were all implicated in smell disturbance.Care should be taken in interpretation due to lack of consistency between subjective and objective measures of olfaction as well as limitations related to population-based data.Prospective trials are indicated to further elucidate these relationships.