Imaging-based Topographic Association and Dissociation between Tau Pathology and Atrophy Correlated with Impairments of Key Motor Domains in Progressive Supranuclear Palsy

Background and ObjectivesProgressive supranuclear palsy (PSP) is a four-repeat tauopathy characterized by subcortical atrophy and distinctive motor impairments. Although tau pathology is presumed to drive neuronal loss, the spatial relationships between tau deposition, regional atrophy, and domain-specific symptoms remain incompletely understood. This study aimed to compare the distributions of tau pathology and atrophy related to key motor symptom domains in PSP, and to clarify their distinct contributions to clinical manifestations. MethodsWe conducted a prospective, single-center observational study. PSP cases underwent neurological assessments, including the PSP Rating Scale, which covers six domains. Tau positron emission tomography (PET) with florzolotau (18F) and T1-weighted magnetic resonance imaging were acquired from these patients and healthy controls to assess correlations of domain scores with tau accumulation and local brain volumes. Path analysis was performed to explore spatiotemporal relationships between tau deposits and volume loss leading to individual domains. ResultsFifty-eight PSP patients (mean age 60.8 years; 45.3% female) and 52 healthy controls (71.6 years; 43.1% female) were included. Subcortical tau accumulation and atrophy showed significant spatial overlap and were closely associated with motor deficits. The "ocular motor" domain scores correlated with tau in the midbrain tegmentum and globus pallidus, and the "gait and midline" domain scores correlated with tau in the globus pallidus, thalamus, and subthalamic nucleus. In contrast, tau deposits and volume reductions in separate neocortical regions were linked to the manifestations. Indeed, the "limb motor" domain scores correlated with tau in the primary motor and somatosensory cortices, and atrophy in the angular, supramarginal, and temporal cortices. Path analysis suggested that tau in subcortical structures may elicit local neuronal loss, impairing the "ocular motor" and "gait and midline" domains, while tau in the neocortex likely affects the "limb motor" domain through local and subsequent network-mediated neurotoxicity. DiscussionHigh-contrast tau imaging clarifies the neuropathological basis of key symptoms in living PSP patients and highlights distinct tau-induced neurotoxic effects in subcortical versus neocortical regions. These findings indicate that PSP key symptoms arise from anatomically and mechanistically distinct tau-neurodegeneration pathways, underscoring the significance of PET-detectable regional tau depositions as surrogates for and predictors of clinical manifestations.