Persistent Hyposmia as Surrogate for α-Synuclein-Linked Brain Pathology

Abstract

ABSTRACTImpaired olfaction can be associated with neurodegenerative disorders. We examined odor identification in newly diagnosed patients with parkinsonism and those at increased risk, measured olfactory performances longitudinally, and juxtaposed results to cerebrospinal fluid (CSF) values. Using Sniffin’-Sticks-Identification Tests (SST-ID), we examined 312 age-matched individuals at a German center, including: 126 with Parkinson disease (PD), 109 healthy controls, 25 with other neurodegenerative disorders and 52 with a REM-sleep behavior disorder (RBD). As expected, PD patients had significantly lower SST-ID scores than controls. Scent identification by subjects with other neurodegenerative diseases fell between those with PD and healthy individuals. Those with isolated RBD, who subsequently converted to PD or dementia, had lower baseline scores than non-converters. When monitoring olfaction in participants up to a decade, we saw small group differences in progression rates for hyposmia. However, these variations were insignificant after controlling for age, sex and length of intervals between testing. When analyzing participants’ sense of smell versus several CSF biomarkers linked to neurodegeneration, we found no correlation with SST-ID scores. However, the means for normalized concentrations of α-synuclein, total tau, phosphorylated tau and amyloid-β peptide42were reduced in PD. We also identified significant age- and sex-linked differences in CSF values. Finally, we compared olfaction to the results of a validated α-synuclein ‘Seed Amplification Assay’ (SAA) using CSF. We found that hyposmia strongly correlated with a positive CSF α-synuclein SAA-test. We conclude that chronically impaired olfaction in older adults is strongly associated with a positive α-synuclein SAA-test from CSF but not with the concentrations of several, neuropathologically relevant CSF markers. We posit that simple-to-administer, quantitative smell tests could serve as inexpensive screening tools in future population studies for the identification of α-synuclein-related brain disorders, including Parkinson’s during its premotor phase.