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PLoS One. 2016 Nov 17;11(11):e0165112. doi: 10.1371/journal.pone.0165112. eCollection 2016.

Assessment of Olfactory Function in MAPT-Associated Neurodegenerative Disease Reveals Odor-Identification Irreproducibility as a Non-Disease-Specific, General Characteristic of Olfactory Dysfunction.

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NorthShore University Health System, Evanston, Illinois, United States of America.
Department of Biology, University of Nebraska at Omaha, Omaha, Nebraska, United States of America.
Department of Neurological and Psychiatric Nursing, Medical University of Gdańsk, Gdańsk, Poland.
Department of Neurology, St. Adalbert Hospital, Copernicus PL Sp. z o.o, Gdańsk, Poland.
Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, Florida, United States of America.
Department of Neurodegenerative Disorders, Mossakowski Medical Research Center, Polish Academy of Sciences, Warsaw, Poland.
Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany.
Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, Florida, United States of America.


Olfactory dysfunction is associated with normal aging, multiple neurodegenerative disorders, including Parkinson's disease, Lewy body disease and Alzheimer's disease, and other diseases such as diabetes, sleep apnea and the autoimmune disease myasthenia gravis. The wide spectrum of neurodegenerative disorders associated with olfactory dysfunction suggests different, potentially overlapping, underlying pathophysiologies. Studying olfactory dysfunction in presymptomatic carriers of mutations known to cause familial parkinsonism provides unique opportunities to understand the role of genetic factors, delineate the salient characteristics of the onset of olfactory dysfunction, and understand when it starts relative to motor and cognitive symptoms. We evaluated olfactory dysfunction in 28 carriers of two MAPT mutations (p.N279K, p.P301L), which cause frontotemporal dementia with parkinsonism, using the University of Pennsylvania Smell Identification Test. Olfactory dysfunction in carriers does not appear to be allele specific, but is strongly age-dependent and precedes symptomatic onset. Severe olfactory dysfunction, however, is not a fully penetrant trait at the time of symptom onset. Principal component analysis revealed that olfactory dysfunction is not odor-class specific, even though individual odor responses cluster kindred members according to genetic and disease status. Strikingly, carriers with incipient olfactory dysfunction show poor inter-test consistency among the sets of odors identified incorrectly in successive replicate tests, even before severe olfactory dysfunction appears. Furthermore, when 78 individuals without neurodegenerative disease and 14 individuals with sporadic Parkinson's disease were evaluated twice at a one-year interval using the Brief Smell Identification Test, the majority also showed inconsistency in the sets of odors they identified incorrectly, independent of age and cognitive status. While these findings may reflect the limitations of these tests used and the sample sizes, olfactory dysfunction appears to be associated with the inability to identify odors reliably and consistently, not with the loss of an ability to identify specific odors. Irreproducibility in odor identification appears to be a non-disease-specific, general feature of olfactory dysfunction that is accelerated or accentuated in neurodegenerative disease. It may reflect a fundamental organizational principle of the olfactory system, which is more "error-prone" than other sensory systems.

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Conflict of interest statement

PR, AS, EN, EJS, MBer, MBar, and MCB declare that no competing interests exist. RR received received honoraria for lectures or educational activities not funded by industry; she serves on the medical advisory board of the Association for Frontotemporal Degeneration, on the board of directors of the International Society for Frontotemporal Dementia and holds a patent on methods to screen for the hexanucleotide repeat expansion in the C9ORF72 gene. ZKW serves as Co-Editor-in-Chief of Parkinsonism and Related Disorders, Associate Editor of the European Journal of Neurology, and on the editorial boards of Neurologia i Neurochirurgia Polska, Advances in Rehabilitation, the Medical Journal of the Rzeszow University, and Clinical and Experimental Medical Letters; holds and has contractual rights for receipt of future royalty payments from patents re: A novel polynucleotide involved in heritable Parkinson's disease; receives royalties from publishing Parkinsonism and Related Disorders (Elsevier, 2013, 2014) and the European Journal of Neurology (Wiley-Blackwell, 2012, 2013). BAC is editor of the Transactions of the Nebraska Academy of Sciences. ES receives a scholarship from the Polish Ministry of Science and Higher Education. JS is a member of the editorial board of Parkinsonism & Related Disorders and Associate Editor of the Polish Journal of Neurology and Neurosurgery. KM was funded by the MJ Fox Foundation for Parkinson’s Disease Research. KH received a congress travel grant ($1000) from the Movement Disorders Society to attend the 19th International Congress of Parkinson`s Disease and Movement Disorders. CK serves as medical adviser to Centogene, received honoraria for speaking at the Annual Meeting of the American Academy of Neurology, at Biogen Idec., and is the recipient of a Career development award from the Hermann and Lilly Schilling Foundation. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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