PSP-specific atrophy targets regions connecting the salience network and subcortical circuits

Progressive supranuclear palsy (PSP) shows a characteristic but incompletely defined pattern of neurodegeneration, in part because prior imaging studies have been limited by small and heterogeneous cohorts. Here, we consolidated evidence for PSP-related gray matter (GM) loss using a coordinate-based meta-analysis and interpreted the resulting atrophy pattern in a network and molecular framework to infer disease-relevant mechanisms. We conducted an Anatomical Likelihood Estimation (ALE) meta-analysis of whole-brain morphometry studies investigating atrophy in PSP, followed by functional decoding to evaluate the functions recruiting the atrophied regions and meta-analytic connectivity to delineate co-activation-based connectivity profiles. Finally, we explored potential neurochemical underpinnings by correlating the atrophy map with PET-derived neurotransmitter density distributions. ALE meta-analysis identified clusters of robust gray matter (GM) atrophy in PSP in the bilateral thalamus & midbrain, left anterior-dorsal insula as well as bilateral caudate nucleus. These regions were shown to be functionally associated with language, body perception, somatosensation and emotion processing. Connectivity analyses indicated coupling with fronto-insular salience-network circuitry and with key subcortical nodes, consistent with a distributed systems-level disturbance. At the molecular level, PSP-related atrophy aligned with higher densities of dopaminergic, serotonergic, and-most prominently-cholinergic markers, suggesting multi-transmitter-system vulnerability with a critical role of the cholinergic architecture. Together, these findings identify an interconnected set of cortical-subcortical targets in PSP whose functional and molecular profiles map onto core clinical features, supporting a network-based view of PSP neurodegeneration beyond isolated local atrophy with critical roles of the insula and the cholinergic system.