Loss of Olfactory Function-Early Indicator for Covid-19, Other Viral Infections and Neurodegenerative Disorders Heike Rebholz, Ralf Braun, Dennis Ladage, Wolfgang Knoll, Christoph Kleber, Achim Hassel To cite this version: Heike Rebholz, Ralf Braun, Dennis Ladage, Wolfgang Knoll, Christoph Kleber, et al.. Loss of Olfactory Function-Early Indicator for Covid-19, Other Viral Infections and Neurodegenerative Disorders. Fron- tiers in Neurology, Frontiers, 2020, 11, pp.569333. 10.3389/fneur.2020.569333. inserm-02982034 HAL Id: inserm-02982034 https://www.hal.inserm.fr/inserm-02982034 Submitted on 28 Oct 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. REVIEW published: 26 October 2020 doi: 10.3389/fneur.2020.569333 Loss of Olfactory Function—Early Indicator for Covid-19, Other Viral Infections and Neurodegenerative Disorders Heike Rebholz 1,2,3, Ralf J. Braun 1, Dennis Ladage 4,5, Wolfgang Knoll 6, Christoph Kleber 4,7* and Achim W. Hassel 7 1 Center of Neurodegeneration, Faculty of Medicine/Dental Medicine, Danube Private University, Krems, Austria, 2 Institut de Psychiatrie et Neurosciences de Paris (IPNP), UMR S1266, INSERM, Université de Paris, Paris, France, 3 GHU Psychiatrie et Neurosciences, Paris, France, 4 Center of Chemistry and Physics of Materials, Faculty of Medicine/Dental Medicine, Danube Private University, Krems, Austria, 5 Universitaetsklinikum Köln, Cologne, Germany, 6 Austrian Institute of Technology, Vienna, Austria, 7 Institute of Chemical Technology of Inorganic Materials, Johannes Kepler University Linz, Linz, Austria Edited by: The loss of the senses of smell (anosmia) and taste (ageusia) are rather common Görsev Yener, disorders, affecting up to 20% of the adult population. Yet, this condition has not Dokuz Eylul University, Turkey received the attention it deserves, most probably because per se such a disorder is Reviewed by: not life threatening. However, loss of olfactory function significantly reduces the quality Sven Saussez, University of Mons, Belgium of life of the affected patients, leading to dislike in food and insufficient, exaggerated Athanasia Warnecke, or unbalanced food intake, unintentional exposure to toxins such as household gas, Hannover Medical School, Germany social isolation, depression, and an overall insecurity. Not only is olfactory dysfunction *Correspondence: Christoph Kleber rather prevalent in the healthy population, it is, in many instances, also a correlate or an [email protected] early indicator of a panoply of diseases. Importantly, olfactory dysfunction is linked to the two most prominent neurodegenerative disorders, Parkinson’s disease and Alzheimer’s Specialty section: This article was submitted to disease. Anosmia and hyposmia (reduced sense of smell) affect a majority of patients Dementia and Neurodegenerative years before the onset of cognitive or motor symptoms, establishing olfactory dysfunction Diseases, as early biomarker that can enable earlier diagnosis and preventative treatments. In the a section of the journal Frontiers in Neurology current health crisis caused by SARS-CoV2, anosmia and dysgeusia as early-onset Received: 04 June 2020 symptoms in virus-positive patients may prove to be highly relevant and crucial for Accepted: 15 September 2020 pre-symptomatic Covid-19 detection from a public health perspective, preceding by Published: 26 October 2020 days the more classical respiratory tract symptoms such as cough, tightness of the Citation: Rebholz H, Braun RJ, Ladage D, chest or fever. Thus, the olfactory system seems to be at the frontline of pathologic Knoll W, Kleber C and Hassel AW assault, be it through pathogens or insults that can lead to or at least associate (2020) Loss of Olfactory with neurodegeneration. The aim of this review is to assemble current knowledge Function—Early Indicator for Covid-19, Other Viral Infections and from different medical fields that all share a common denominator, olfactory/gustatory Neurodegenerative Disorders. dysfunction, and to distill overarching etiologies and disease progression mechanisms. Front. Neurol. 11:569333. doi: 10.3389/fneur.2020.569333 Keywords: COVID-19, anosmia, hyposmia, SARS–CoV-2, normosmia Frontiers in Neurology | www.frontiersin.org 1 October 2020 | Volume 11 | Article 569333 Rebholz et al. Loss of Olfactory Function INTRODUCTION via a series of interconnected neurons and brain structures which then compute various concomitant stimuli into the notion of a The current Covid-19 pandemic is reaching more and more specific smell (Figure 1). regions, countries and tens of thousands of new patients daily. An odor is either a single molecule (e.g., hydrogen sulfide One symptom of the disease has not been fully recognized until that smells of rotten eggs) or is composed of a combination of the end of April at which point, the reduction or the loss of molecules termed odorants with specific chemical and structural olfactory function caused by the SARS-CoV2 virus was added properties which are recognized and bound with varying degrees to the list of Covid-19 symptoms by the WHO, in addition to of affinity by the so-called odorant receptors located in the nasal the well-defined symptoms such as fever, cough and shortness cavity (13)(Figures 1A,B). of breath (https://www.who.int/health-topics/coronavirus# The mammalian odorant receptor (OR) gene family tab=tab_3). comprises more than 1,000 members, which represents the Since other coronaviruses have been shown to be largest G-protein coupled receptor (GPCR) gene family in neuroinvasive, the question arises if SARS-CoV2 uses the the mammalian genomes (14). The human OR gene family neuroepithelium as a port of entry to the brain, causing olfactory encompasses 857 members (15) (https://genome.weizmann.ac.il/ dysfunction through action on the peripheral or the central horde/). Thereof up to 391 encode functional olfactory receptors components of the olfactory system. According to the so-called (ORs), whereas 466 OR gene family members are pseudogenes, vector hypothesis, it is also possible that this virus will cause i.e., non-functional sections of DNA (15). The Ca2+ influx neuronal damage in other non-olfaction-related parts of the in turn opens a Ca2+-activated Cl− channel leading to efflux brain, a hypothesis that needs to be thoroughly addressed in of Cl−, further depolarizing the cell and triggering an action the future. potential (Figure 1C). Olfactory cells usually react only briefly This review assembles relevant studies on changes in to stimulation with odorants. Even if odorant molecules are the senses of smell and taste as indicators of peripheral continuously offered, the cells only react for a few seconds, then and central pathologies induced by various pathogens or they become silent—they adapt. The adaptation itself is inhibited environmental toxins. by various mediating processes that terminate the receptor flow. The loss of normal olfactory function is categorized according These processes are controlled by the Ca2+ ions which enter by to whether a loss is complete (anosmia) or partial (hyposmia), cyclic nucleotide-gated ion channel (CNG) into the cilia. So this compared to the norm (normosmia). Often co-affected is the isaCa2+-mediated feedback inhibition. The olfactory cells’ CNG sense of taste which, when lost, is termed ageusia and, when channels are continuously Calmodulin bound. If Ca2+ enters the disturbed, dysgeusia. The majority of persistent anosmia or cell, it binds to calmodulin and causes a change in conformation. hyposmia is caused by upper respiratory tract infections, head This, in turn, leads to a closing of CNG channels: The signaling injury or nasal sinus pathology (1). In rarer cases, exposure cascade is therefore interrupted. Calmodulin also mediates other to environmental chemicals (2), medical interventions such adaptive mechanisms. The enzyme phosphodiesterase (PDE) is as radiation or chemo-therapy (3, 4), surgical procedures in produced by Ca2+ /Calmodulin activation. Phosphodiesterase the nasal areas such as septoplasty, rhinoplasty, can be at splits cAMP and reduces second messenger concentration the origin of olfactory dysfunction (5, 6). Finally, medical (Figure 1C)(16). conditions such as intranasal growths, epilepsy, psychiatric The reason for the large number of different odor receptors disorders, hypothyroidism, renal and liver disease can cause is to provide a system for discriminating between as many anosmia/hyposmia (7). It is important to distinguish between a different odors as possible (17). Odorants themselves are volatile preexisting disability and an acquired loss of the sense of smell, substances, members of different chemical classes (e.g., alcohols, as some substances (e.g., products of asparagusic acid) may not aldehydes, ketones, carboxylic acids, esters, aromatic, and sulfur- be smelled or tasted due to a genetic condition (8). containing compounds). Upon binding and being activated by At first glance, the loss of smell may not be life-threatening, the specific odorants, all neurons expressing the same