The telltale sign in Parkinson’s disease: olfactory dysfunction from the prodromal to the clinical stages

The aim of this thesis is to increase our understanding of olfactory dysfunction in Parkinson’s disease (PD) across the clinical continuum, from the prodromal phase—when characteristic motor symptoms are absent—to the later clinical stages. The studies included in this thesis examined the prevalence of olfactory and other prodromal symptoms in the general population, as well as cross-sectional and longitudinal associations between olfactory function and motor and non-motor symptoms, including cognition. In addition, the potential contribution of olfactory and gustatory dysfunction to malnutrition in PD was explored. A central focus was the longitudinal course of olfactory function and its potential value as a clinical marker of disease progression. First, we investigated the prevalence of prodromal PD symptoms—including olfactory dysfunction, cognitive impairment, constipation, probable REM sleep behavior disorder (RBD), depression, and anxiety—in a late middle-aged Dutch population using data from the Longitudinal Aging Study Amsterdam (LASA). The prevalence of individual risk factors ranged from 3 to 13%, and approximately 11% of individuals aged 55–65 had two or more established PD risk factors, most commonly the combination of depression and anxiety. Individuals with multiple prodromal symptoms reported more subtle motor symptoms suggestive of parkinsonism, had poorer physical performance, and experienced greater functional limitations in daily life. These findings suggest that a subset of these individuals may be in an early phase of PD, although longitudinal follow-up is required to confirm this and to identify the most predictive combinations of risk factors. In a cohort of 295 patients with PD, reduced olfactory function, measured using the University of Pennsylvania Smell Identification Test (UPSIT®), was associated with greater motor symptom severity and a range of non-motor symptoms, including cognitive impairment, depression, anxiety, autonomic dysfunction, and sleep disturbances. These associations remained significant after adjustment for age, sex, and disease duration. In a subgroup of patients who underwent dopamine transporter (DAT)-SPECT imaging, lower olfactory scores were also associated with reduced dopamine transporter binding in the putamen and caudate nucleus. Together, these findings indicate that olfactory dysfunction may reflect broader disease severity and underlying neurodegeneration in PD. To examine whether sensory deficits contribute to weight loss and malnutrition in PD, we conducted a pilot study in 63 patients assessing olfactory function with the Sniffin’ Sticks test and gustatory function with the Taste Strips test. Hyposmia was common and modestly associated with lower body weight, whereas taste dysfunction was less prevalent and showed no such association. Although preliminary, these results suggest that olfactory rather than gustatory impairment may contribute to weight loss and malnutrition, a clinically relevant issue in later stages of PD. Finally, in a ten-year longitudinal study of 90 PD patients, olfactory function declined over time in more than 80% of patients, independent of age or cognitive decline. This finding indicates that olfactory dysfunction is not a static early feature but continues to worsen as the disease progresses, possibly reflecting advancing or spreading neuropathology. Given its progressive nature, clinical relevance, and ease of assessment, olfactory function may serve as a valuable non-invasive marker of disease progression. In the same cohort, greater decline in olfactory function was associated with greater decline in global cognition. In a subgroup with extensive cognitive testing, this relationship was particularly strong for semantic fluency, and baseline olfactory function predicted semantic fluency at follow-up. These findings suggest that olfactory dysfunction may have prognostic value for later cognitive decline, especially within the semantic domain.