The prevalence of smell loss in Parkinson’s Disease (PD) patients greatly exceeds that of the characteristic motor symptoms defining the disease by several years. One hypothesis of the cause of PD states that it is initiated in the olfactory bulb — the critical first central processing stage of the olfactory system — and that the olfactory nerve might serve as an entry point to the OB for pathogens or environmental components. But what if there was no OB to start with? Recent data demonstrate that cortical, but not peripheral, blindness acts as a protective factor against schizophrenia and other psychotic disorders. We hypothesize that individuals with the rare diagnose Isolated Congential Anosmia (ICA) are immune to PD given that they are born without OBs. If true, it would strongly support the theory that PD might start in the bulb. However, if one could identify even one single PD patient with an established ICA diagnosis with non-existing OBs, a so-called black swan, this would effectively falsify the hypothesis. In this commentary, we model the likely occurrence of such potential comorbidity and we postulate that it is possible to find this black swan; a finding that would falsify a salient hypothesis within the PD research community.
It has been suggested that congenital blindness could be protective against schizophrenia and other psychotic disorders where the resulting cortical reorganization might prevent disturbances of the eye later in life1, a known risk factor for schizophrenia2. We postulate that another rare congenital sensory disorder may protect from a central disorder, in this case Parkinson’s disease (PD). In PD, the reported prevalence of smell loss varies but larger studies using objective sensory tests commonly report the prevalence as 90–96%3,4, thereby exceeded the prevalence of the characteristic motor symptoms defining the disease and a clear olfactory loss often occurs years prior to most other prodromal symptoms5. One of several hypotheses of the cause of PD states that within the brain, the disease is initiated in the olfactory bulb (OB)6 the critical first central stage of the olfactory system and only entry point for olfactory signals to the brain. It is not known why the OB is an early area of insult in PD but it has been proposed that the olfactory nerve serves as an entry point for pathogens or environmental components, through which they gain OB access through the blood brain barrier7. Indeed, the olfactory nerve is known to transport such heavy particles as soluble metals8 and this mechanism is, among others, a known entryway to the OB for the SARS-CoV-2 virus9. Once there, it has been proposed that the pathogens trigger intraneuronal Lewy Bodies (LB) which aggregate and spread from the OB and subsequently cause the progression of PD’s pathology6. But what if there was no OB to start with and therefore no entryway for pathogens or environmental components to use the olfactory nerve to gain entry to the brain?
Isolated congenital anosmia (ICA) is a rare condition where otherwise healthy individuals are born without a sense of smell and with mostly aplastic (on rare occasions, hypoplastic) OBs10,11. In addition, absence of OBs is associated with degeneration of the olfactory nerve as well as most olfactory neurons in the olfactory epithelium12, thereby excluding access via the olfactory system at multiple stages. Here we propose a novel hypothesis that individuals with ICA might be immune to PD given the absence of their OB. If true, it would strongly support the notion that this type of PD starts in the bulb. However, the opposite could serve as a so-called black swan — an event which seems impossible, but which has very far-reaching consequences. If one could identify even one single PD patient outside the atypical parkinsonism subtypes with an established ICA diagnosis and aplastic OBs, this would effectively falsify this theory of how PD is initiated.
What would be the chance of finding such a patient? Using North America as an example given the available data, combining the USA demographics and the North American PD prevalence13 (Fig. 1a, b) with the prevalence of ICA (1/10,000)14,15, we calculate that while the probability is low, it is a very much possible question to settle (Fig. 1c). For example, the probability of finding a 65-year-old individual in the general US population with both ICA and PD can be estimated to 0.18‰. While admittedly difficult to find, a multitude of rare diseases exists that display lower prevalence numbers16.
Finding this black swan would only serve to falsify the specific hypothesis that the OB serves as an initial staging area through which the disease propagates. It does not falsify the PD diagnose in general given that, for example, atypical parkinsonism subtypes do not display olfactory dysfunctions17. However, a critical notion is that because the OB is involved in PD progression in multiple ways, identifying and studying these individuals would in addition provide the community with unique insights into the OBs role in PD progression. In conclusion, although these individuals, if they exist, would be hard to find, we urge clinicians to assess their records for PD patients with both an ICA diagnosis and aplastic OBs. Finding this black swan would falsify a salient hypothesis within the PD research community and open up new research avenues.
Reporting summary
Further information on research design is available in the Nature Research Reporting Summary linked to this article.
Data availability
US demographic values was obtained from open databases with references provided within the manuscript.
Code availability
Codes to generate figures can be obtained with contact with communicating authors.
References
Silverstein, S. M. & Rosen, R. Schizophrenia and the eye. Schizophr. Res. Cogn. 2, 46–55 (2015).
Morgan, V. A. et al. Congenital blindness is protective for schizophrenia and other psychotic illness. A whole-population study. Schizophr. Res. 202, 414–416 (2018).
Haehner, A. et al. Prevalence of smell loss in Parkinson’s disease-a multicenter study. Parkinsonism Relat. Disord. 15, 490–494 (2009).
Doty, R. L. Olfaction in Parkinson’s disease and related disorders. Neurobiol. Dis. 46, 527–552 (2012).
Marras, C. et al. Smell identification ability in twin pairs discordant for Parkinson’s disease. Mov. Disord. 20, 687–693 (2005).
Braak, H. et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging 24, 197–211 (2003).
Rey, N. L., Wesson, D. W. & Brundin, P. The olfactory bulb as the entry site for prion-like propagation in neurodegenerative diseases. Neurobiol. Dis. 109, 226–248 (2018).
Henriksson, J., Tallkvist, J. & Tjälve, H. Uptake of nickel into the brain via olfactory neurons in rats. Toxicol. Lett. 91, 153–162 (1997).
de Melo, G. D. et al. COVID-19-related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters. Sci. Transl. Med. 13, eabf8396 (2021).
Abolmaali, N. D., Hietschold, V., Vogl, T. J., Hüttenbrink, K.-B. & Hummel, T. MR evaluation in patients with isolated anosmia since birth or early childhood. Am J Neuroradiol 23, 157–164 (2002).
Peter, M. G. et al. Morphological changes in secondary, but not primary, sensory cortex in individuals with life-long olfactory sensory deprivation. Neuroimage 218, 117005 (2020).
Jafek, B. W., Murrow, B., Michaels, R., Restrepo, D. & Linschoten, M. Biopsies of human olfactory epithelium. Chem. Sens. 27, 623–628 (2002).
Marras, C. et al. Prevalence of Parkinson’s disease across North America. npj Parkinsons Dis. 4, 21 (2018).
Hummel, T., Landis, B. N. & Rombaux, P. Springer handbook of odor (ed. Buettner, A.) 79–80 (Springer International Publishing, 2017).
Sailani, M. R. et al. Isolated congenital anosmia and CNGA2 mutation. Sci. Rep. 7, 2667 (2017).
ORPHANET REPORT, I. Prevalence And Incidence Of Rare Diseases: Prevalence And Incidence Of Rare Diseases (Orphanet, 2022).
Wenning, G. K. et al. Olfactory function in atypical parkinsonian syndromes. Acta Neurol. Scand. 91, 247–250 (1995).
Funding
Open access funding provided by Karolinska Institute.
Author information
Authors and Affiliations
Contributions
A.A. contributed to analyses, writing, and editing of this commentary. B.I. contributed to analyses, writing, and editing of this commentary. J.N.L. contributed to analyses, writing, and editing of this commentary. All authors have read and approved this manuscript.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Arshamian, A., Iravani, B. & Lundström, J.N. Is congenital anosmia protective for Parkinson’s disease triggered by pathogenic entrance through the nose?. npj Parkinsons Dis. 8, 152 (2022). https://doi.org/10.1038/s41531-022-00425-5
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41531-022-00425-5