The importance of smell: anosmias and other disorders

By Vakare B. Kucinskaite

Olfaction is a chemical sense empoyed to detect food sources or noxious substances in the environment or aid the selection of potential mates. Its importance for humans has been overlooked due to a general consensus that in comparison with other animals humans have a poor sense of smell. However, it is now being recognised that the olfaction is crucial for everyday experiences, particularly eating, as well as in clinical settings when the change in the sense of smell may be an indicator of a variety of disorders and diseases. This review will briefly summarise the structure of the olfactory system and focus on the presentation of anosmia and hyposmia and their relevance for some viral infections and neurodegenerative disorders.

Odour molecules are detected by the olfactory receptor neurons (ORNs) located in the nasal cavity. ORNs together with supporting cells which provide nutrients and secrete mucus, and basal cells which regenerate ORNs, form the olfactory epithelium. The axons of the ORNs relay signals to the olfactory bulbs where they synapse onto mitral cells in structures called glomeruli. Mitral cells subsequently signal to the pyriform and enthorhinal cortices, the amygdala and the olfactory tubercle where olfactory information processing begins. Mice studies have shown that a particular ORN expresses one type of odorant receptor protein (ORP) (Bear et al. 2020, p. 385). Humans have about 350 genes, encoding functional ORPs. Each of these receptors can bind to several different odorants with varying strength, hence, it is postulated that population encoding where the odorant is represented by the combination of ORPs activated is used in the olfactory system as a means to increase the number of odours that can be recognised (Bear, Connors, Parasido et al. 2020, p. 385, 390). 

Anosmia – the loss of smell – or hyposmia – the decreased sense of smell – can negatively affect human wellbeing and health. Total anosmia results in the patient completely losing the ability to smell, while partial anosmia makes the patient unable to identify a particular odorant or a group of scents. Total anosmia may result from severe upper respiratory tract infections or head injury leading to the axons of ORNs getting severed. In contrast, partial anosmia is thought to originate from defects in a particular ORP gene. The consequences of anosmia and, to a lesser degree of hyposmia, range from changes in personal hygiene (manifesting in excessive showering and perfume use), to decreased appetite and enjoyment of food as flavour is a combined interpretation of gustation and olfaction (Temmel et al. 2002; Boesveldt et al., 2017). These effects can subsequently lead to difficulties in maintaining social interactions, healthy eating habits and put the patients at risk of developing anxiety and depression disorders, especially if anosmia is a result of trauma, causing a sudden change (Boesveldt et al., 2017). The inability to distinguish a certain odour in partial anosmia is less likely to produce the compound effects on health and quality of life in a similar way. However, the specific impairments in olfaction resulting from defected receptors may still pose substantial inconvienences or risks, depending on which scent or scents cannot be detected.

Anosmia may be a symptom of viral infections. Increased secretion of mucus by the olfactory epithelium and congestion due to inflammatory edema in response to an infection makes it harder for odorants to reach and bind to the ORPs, resulting in hyposmia (Gonclaves & Goldstein, 2016). Moreover, some viruses target ORNs and cells in the olfactory bulb, directly interfering with the olfactory function. For example, the rabies virus in mice can infect the ORNs, then transfer to replicate in the secondary neurons in the olfactory bulb and finally in the tertiary neurons in other brain structures which receive olfactory input (Astic et al., 1993). A similar mechanism is thought to be implicated in herpes simplex encephalitis in humans (Mori et al., 2005). Viral infections that spread from ORNs to higher structures of the brain are highly likely to result in other neurological deficits alongside anosmia (Mori et al., 2005). Some viral infections may disturb olfaction indirectly by affecting the supporting cells in the olfactory epithelium. Emerging studies indicate that this could be the case for anosmia and change in the sense of smell associated with COVID-19 cause by the SARS-CoV-2 virus. Single-cell sequence has shown that ACE2 – the protein protein used by SARS-CoV-2 to enter the cells – is expressed in the supporting cells rather than ORNs (Brann et al., 2020). It may also help to explain why the anosmic symptoms resolve with time in the majority of the patients but more research is required to clarify the exact mechanisms of SARS-CoV-2 interference with the olfactory function.

Interestingly, alterations in olfaction may be indicators not only of viral infections but also neurodegenerative disorders. It is worth noting that the sense of smell gradually declines with age (Rebholz et al., 2020). In neurodegenerative disorders, such as Parkinson‘s disease (PD) and Alzheimer‘s disease (AD), the prevalence of olfactory impairments is high with the majority of patients experiencing it even at an early stage of the disease (Rebholz et al., 2020). Neuritic plaques consisting of amyloid-β protein and neurofibrillary tangles constituted of tau protein – the two characteristic neuropathological aggregates of AD – have been shown to accumulate in the olfactory bulb and the entorhinal cortex early in the disease progression (Ubeda-Bañon et al., 2020). Lewy bodies composed of α-synuclein have been shown to initially occur in the cholinergic and monoaminergic neurons in the olfactory system (Ubeda-Bañon et al., 2020). Some studies have also revealed that hyposmia may precede motor symptoms of PD by years or even decades and that developing hyposmia is associated wiht increased risk of developing PD (Doty, 2012). Together, these findings suggest that olfactory dysfunction could be an early marker of neurodegenerative disorders, providing a means to detect potential PD or AD before the clinical symptoms manifest and prevent or hinder the development of the disease once suitable therapies are available.

In conclusion, the impaired sense of smell may result from genetic defects in olfactory receptor genes or trauma or infection, damaging the olfactory receptor neurons as well as other cells in the olfactory system. Olfactory dysfunction is also a potential early indicator of neurodegenerative disorders, signifying the importance of olfaction not only in everyday but also clinical settings. 

References:

Bear, M. F., Connors, B. W. & Paradiso, M. A. (2020). Neuroscience: exploring the brain. (Enhanced 4th ed.) Burlington, Jones & Bartlett Learning, pp. 385-390

Astic, L., Saucier, D., Coulon, P., Lafay, F. & Flamand, A. 1993, “The CVS strain of rabies virus as transneuronal tracer in the olfactory system of mice”, Brain research, vol. 619, no. 1-2, pp. 146-156.

Boesveldt, S., Postma, E.M., Boak, D., Welge-Luessen, A., Schöpf, V., Mainland, J.D., Martens, J., Ngai, J. & Duffy, V.B. 2017, “Anosmia—A Clinical Review”, Chemical senses, vol. 42, no. 7, pp. 513-523.

Brann, D.H., Tsukahara, T., Weinreb, C., Lipovsek, M., Van den Berge, K., Gong, B., Chance, R., Macaulay, I.C., Chou, H., Fletcher, R.B., Das, D., Street, K., de Bezieux, H.R., Choi, Y., Risso, D., Dudoit, S., Purdom, E., Mill, J., Hachem, R.A., Matsunami, H., Logan, D.W., Goldstein, B.J., Grubb, M.S., Ngai, J. & Datta, S.R. 2020, “Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia”, Science Advances, vol. 6, no. 31, pp. eabc5801.

Doty, R.L. 2012, “Olfactory dysfunction in Parkinson disease”, Nature reviews.Neurology, vol. 8, no. 6, pp. 329-339.

Goncalves, S. & Goldstein, B.J. 2016, “Pathophysiology of Olfactory Disorders and Potential Treatment Strategies”, Current otorhinolaryngology reports, vol. 4, no. 2, pp. 115-121.

Mori, I., Nishiyama, Y., Yokochi, T. & Kimura, Y. 2005, “Olfactory transmission of neurotropic viruses”, Journal of neurovirology, vol. 11, no. 2, pp. 129-137.

Rebholz, H., Braun, R.J., Ladage, D., Knoll, W., Kleber, C. & Hassel, A.W. 2020, “Loss of Olfactory Function-Early Indicator for Covid-19, Other Viral Infections and Neurodegenerative Disorders”, Frontiers in neurology, vol. 11, pp. 569333.

Temmel, A.F.P., Quint, C., Schickinger-Fischer, B., Klimek, L., Stoller, E. & Hummel, T. 2002, “Characteristics of Olfactory Disorders in Relation to Major Causes of Olfactory Loss”, Archives of Otolaryngology–Head & Neck Surgery, vol. 128, no. 6, pp. 635-641.

Ubeda-Bañon, I., Saiz-Sanchez, D., Flores-Cuadrado, A., Rioja-Corroto, E., Gonzalez-Rodriguez, M., Villar-Conde, S., Astillero-Lopez, V., Cabello-de la Rosa, Juan Pablo, Gallardo-Alcañiz, M.J., Vaamonde-Gamo, J., Relea-Calatayud, F., Gonzalez-Lopez, L., Mohedano-Moriano, A., Rabano, A. & Martinez-Marcos, A. 2020, “The human olfactory system in two proteinopathies: Alzheimer’s and Parkinson’s diseases”, Translational Neurodegeneration, vol. 9, no. 1, pp. 22.

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