Non-motor asymmetry and dopamine degeneration in Parkinson’s disease
Authors: Hansen Frederik O , Knudsen Karoline , Damholdt Malene F , Bek Toke , Borghammer Per , Okkels Niels 
Published: January 2025

Abstract
Asymmetric dopaminergic degeneration of the striatum is a characteristic feature of Parkinson’s disease, associated with right–left asymmetry in motor function. As such, studying asymmetry provides insights into progressive neurodegeneration between cerebral hemispheres. Given the impact of Lewy pathology on various neurotransmitter systems beyond the dopaminergic, it may be that other neuronal systems in the predominantly affected hemisphere are similarly affected. According to this hypothesis, asymmetry in dopaminergic degeneration would be expected to coincide with asymmetry in other neurotransmitter systems. Consequently, asymmetry in functions primarily dependent on dopaminergic integrity, such as motor function, should correlate with asymmetry in bilateral non-motor functions that rely on other cerebral systems, such as pupillary function. Therefore, this study tested whether right–left asymmetry in bilateral non-motor measures correlates with asymmetry in dopaminergic striatal integrity. We also tested whether asymmetric striatal degeneration is associated with greater asymmetry in non-motor measures overall. Using a comparative cross-sectional design, we recruited newly diagnosed patients with Parkinson’s disease with predominantly right-sided (n = 18), left-sided (n = 15) or symmetric nigrostriatal denervation (n = 15) assessed on dopamine PET. Detailed examinations of lateralized non-motor function included lacrimation, hand skin wrinkling, salivation, olfaction and pupillary function. Healthy controls were recruited for comparison. We observed a moderate-to-strong correlation between right–left asymmetry of putamen dopamine binding and asymmetry in pupillary redilation speed [Spearman’s rank correlation coefficient (rs) = −0.53, 95% confidence interval (−0.77; −0.14), P = 0.0084]. We also observed moderate correlations between non-negative putaminal asymmetry and lacrimation [rs = 0.35, (−0.00; 0.62), P = 0.0464] and word recognition [rs = 0.36, (0.01; 0.63), P = 0.0410]. However, none were significant after false discovery rate correction. We observed significant group differences in non-negative asymmetry in salivation (P = 0.0390, ANOVA) and a trend towards greater asymmetric lacrimation in participants with asymmetric striatal dopamine loss compared with healthy controls (P = 0.0330, unadjusted). Additionally, participants with asymmetric striatal dopaminergic binding showed greater, though non-significant, asymmetry in all pupillary measures compared with those with symmetric dopaminergic binding. In conclusion, this study contributes to our understanding of neurodegeneration progression in Parkinson’s disease and suggests a link between dopaminergic degeneration and non-motor measures related to autonomic function, particularly salivation, lacrimation and pupillary function. While our findings do not support a strict right–left hemispheric association between non-motor functions and dopaminergic degeneration, potential relationships may exist between these features and asymmetrical degeneration in other neuronal systems, such as the cholinergic.