Selective hyposmia in Parkinson disease: association with hippocampal dopamine activity

Abstract

Olfactory dysfunction is common in patients with Parkinson disease (PD) and has been attributed to early pathological deposition of Lewy bodies and Lewy neurites in primary olfactory centers. However, olfactory deficits do not always worsen over time despite progression of disease raising the possibility of additional pathobiological mechanisms contributing to olfactory functions in PD, such as changes in olfactory neurotransmitter functions. Neurotransmitter changes, such as altered dopaminergic status, may also better explain the selective nature of odor identification deficits in PD. Proper odor identification depends on higher order structures, such as the hippocampus, for olfactory cognitive or memory processing. Using the University of Pennsylvania Smell Identification Test (UPSIT), we previously identified three odors (banana, licorice, dill pickle, labeled as UPSIT-3) that PD subjects most frequently failed to recognize compared to age- and gender-matched controls. We also identified six odors that were equally successfully identified by controls and PD subjects (NPD-Olf6). A ratio of UPSIT-3 divided by NPD-Olf6 scores provides another descriptor of selective hyposmia in PD ("olfactory ratio"). In this study we investigated the pathophysiology of hyposmia in PD using dopamine transporter (DAT) PET. Twenty-nine PD patients (Hoehn and Yahr stages I-III; 7f/22m; age 60.2+/-10.8) underwent olfactory testing using the UPSIT and [(11)C]beta-CFT DAT PET. DAT binding potentials (BP) were assessed in the hippocampus, amygdala, ventral and dorsal striatum. We found that correlation coefficients between total UPSIT scores and regional brain DAT BP were highest for the hippocampus (Rs=0.54, P=0.002) and lower for the amygdala (Rs=0.44, P=0.02), ventral (Rs=0.48, P=0.008) and dorsal striatum (Rs=0.39, P=0.03). Correlations were most significant for the selective hyposmia measures and hippocampal DAT: UPSIT-3 (Rs=0.65, P=0.0001) and the olfactory ratio (Rs=0.74, P<0.0001). We conclude that selective hyposmia in PD is more robustly correlated with hippocampal rather than amygdala, ventral or dorsal striatal dopamine innervation as shown by DAT binding. These findings indicate that mesolimbic dopamine innervation of the hippocampus may be a determinant of selective hyposmia in PD.

Figure 1

Scatter plot of the relationship between hippocampal DAT activity and total UPSIT score.

Figure 2

Diagram showing the pathways involved in olfactory discrimination in the UPSIT. The subject is presented with an odor. This activates olfactory receptors and processing of information through the olfactory pathways. For recall of the odor name, hippocampus and prefrontal cortex are required and the verbal response requires Broca’s area and motor cortex. This process also requires mesolimbic dopamine neuron innervation of the hippocampus and prefrontal cortex, which is altered in PD (dashed lines).