Resting state changes in aging and Parkinson’s disease are shaped by underlying neurotransmission – a normative modeling study

Abstract

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=25,917) 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 explain 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. Combining normative modeling and neurotransmitter mapping may aid future research and drug development through deeper understanding of neurophysiological mechanisms underlying specific clinical conditions.

Regional patterns of human cortex development correlate with underlying neurobiology

“…The spatial colocalization framework constitutes a powerful and flexible tool to study biological underpinnings of both typical and atypical human brain processes in vivo . While its application in a wide range of neuroimaging contexts has brought valuable insights into the neurobiology of structural 76,32,31 and functional 77 brain development, as well as brain organization in health 25 and disease 26,40,41 , inferences from spatial colocalization analyses are usually limited to an associative, non-causal level. Notably, this also is the case for our present study, in which all reported associations can only provide indirect evidence for involvement of specific neurobiological markers in cortical development and aging, not providing actual mechanistic explanations.…”