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

Background: Human healthy and pathological aging is linked to a steady decline in brain resting-state activity and connectivity measures. The neurophysiological mechanisms that underlie these changes remain poorly understood.

Methods: Making use of recent developments in normative modeling and availability of in vivo maps for various neurochemical systems, we tested in the UK Biobank cohort (n = 25,917) whether and how age- and Parkinson's disease-related resting-state changes in commonly applied local and global activity and connectivity measures colocalize with underlying neurotransmitter systems.

Results: We found that the distributions of several major neurotransmitter systems including serotonergic, dopaminergic, noradrenergic, and glutamatergic neurotransmission correlated with age-related changes across functional activity and connectivity measures. Colocalization patterns in Parkinson's disease deviated from normative aging trajectories for these, as well as for cholinergic and GABAergic (gamma-aminobutyric acidergic) neurotransmission. The deviation from normal colocalization of brain function and GABA_A correlated with disease duration.

Conclusions: 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 that underlie specific clinical conditions.