title: Assessment of Olfactory Function in MAPT-Associated Neurodegenerative Disease Reveals Odor-Identification Irreproducibility as a Non-Disease-Specific, General Characteristic of Olfactory Dysfunction.
abstract: 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.
authors.affiliation: NorthShore University Health System, Evanston, Illinois, United States of America.
authors.forename: Katerina
authors.identifier: http://orcid.org/0000-0003-3973-5437
authors.initials: K
authors.lastname: Markopoulou
authors.affiliation: Department of Biology, University of Nebraska at Omaha, Omaha, Nebraska, United States of America.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Chase
authors.affiliation: 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.
authors.forename: Piotr
authors.initials: P
authors.lastname: Robowski
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, Florida, United States of America.
authors.forename: Audrey
authors.initials: A
authors.lastname: Strongosky
authors.affiliation: 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.
authors.forename: Ewa
authors.initials: E
authors.lastname: Narożańska
authors.affiliation: 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.
authors.forename: Emilia J
authors.initials: EJ
authors.lastname: Sitek
authors.affiliation: Department of Neurodegenerative Disorders, Mossakowski Medical Research Center, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Berdynski
authors.affiliation: Department of Neurodegenerative Disorders, Mossakowski Medical Research Center, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Barcikowska
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, Florida, United States of America.
authors.forename: Matt C
authors.initials: MC
authors.lastname: Baker
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, Florida, United States of America.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.affiliation: 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.
authors.forename: Jarosław
authors.initials: J
authors.lastname: Sławek
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.|Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Hückelheim
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.|Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Kasten
authors.affiliation: Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, Florida, United States of America.
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
mesh_terms: D000328:Adult; D017668:Age of Onset; D000483:Alleles; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000150:complications* / Q000175:diagnosis / Q000235:genetics*; D009812:Odorants; D000857:Olfaction Disorders / Q000175:diagnosis / Q000209:etiology* / Q000503:physiopathology*; D019655:Quantitative Trait, Heritable; D012720:Severity of Illness Index; D012903:Smell; D016875:tau Proteins / Q000235:genetics*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins