Resting-State Changes in Aging and Parkinson’s Disease Are Shaped by Underlying Neurotransmission: A Normative Modeling Study

Human healthy and pathological aging is linked to a steady decline in brain resting state activity and connectivity measures. The neurophysiological mechanisms underlying these changes remain poorly understood. Making use of recent developments in normative modeling and availability of in vivo maps for various neurochemical systems, we test in the UK Biobank cohort (N=25917) if and how age- and Parkinson's disease related resting state changes in commonly applied local and global activity and connectivity measures co-localize with underlying neurotransmitter systems. We find the distributions of several major neurotransmitter systems including serotonergic, dopaminergic, noradrenergic, and glutamatergic neurotransmission to correlate with age-related changes as observed across functional activity and connectivity measures. Co-localization patterns in Parkinson's disease deviate from normative aging trajectories for these, as well as for cholinergic and GABAergic, neurotransmission. The deviation from normal co-localization of brain function and GABAa correlates with disease duration. These findings provide new insights into molecular mechanisms underlying age- and Parkinson's related brain functional changes by extending the existing evidence elucidating the vulnerability of specific neurochemical attributes to normal aging and Parkinson's disease. The results particularly indicate that alongside dopamine and serotonin, increased vulnerability of glutamatergic, cholinergic, and GABAergic systems may also contribute to Parkinson's disease-related functional alterations. Combining normative modeling and neurotransmitter mapping may aid future research and drug development through deeper understanding of neurophysiological mechanisms underlying specific clinical conditions.