Association of Olfactory Loss With Cognition Is Mediated by Striatal Dopamine Loss and Cerebral Perfusion in Parkinson's Disease.

Abstract

Hyposmia is a common early non-motor symptom of Parkinson disease (PD) and has been linked to cognitive decline. This study investigated whether striatal dopaminergic degeneration and cerebral perfusion deficits mediate the relationship between hyposmia and cognition in PD. We retrospectively analyzed 343 newly diagnosed PD patients who underwent the Cross-Cultural Smell Identification Test (CCSIT) and dual-phase 18 F-FP-CIT PET. Early-phase PET was used as a surrogate of regional cerebral blood perfusion, and late-phase PET measured dopamine transporter (DAT) availability in 6 striatal subregions. A subset of 219 patients completed baseline neuropsychological testing and were followed for a mean of 4.2 years to assess dementia conversion. Baseline CCSIT scores were positively correlated with DAT availability across striatal regions, strongest in the posterior putamen (β=0.21, P <0.001). Hyposmia was associated with cortical hypoperfusion in bilateral entorhinal, inferior parietal, inferior temporal, and parieto-occipital regions. Lower CCSIT scores predicted poorer baseline cognitive performance (language, memory, executive function; all P <0.05) and a higher risk of dementia (HR=0.83, P =0.001). In models adjusted for DAT and perfusion markers, direct associations between olfaction and cognition were markedly reduced. Mediation analyses revealed that posterior cortical hypoperfusion explained the olfaction-memory link, whereas both dopaminergic loss and hypoperfusion mediated dementia conversion. Olfactory loss in PD reflects widespread neurodegeneration involving nigrostriatal and posterior cortical networks. Integrating olfactory assessment with imaging markers may better identify patients at risk for cognitive decline, supporting improved risk stratification and early intervention.