In Vivo Topographic Associations Between Tau Pathology, Atrophy, and Symptom Domains in Patients with Progressive Supranuclear Palsy

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Abstract Background and Objectives Progressive supranuclear palsy (PSP) is a four-repeat tauopathy characterized by subcortical atrophy and distinctive motor impairments. Although tau pathology is thought to drive neuronal loss, the spatial relationships among tau deposition, regional atrophy, and domain-specific symptoms remain incompletely understood. We aimed to determine how the topographic distribution of tau pathology and regional brain atrophy relate to distinct motor symptom domains in PSP and to clarify their contributions to clinical manifestations. Methods A single-center, cross-sectional study was conducted. Patients with PSP were recruited after diagnosis at neurology departments and were referred to our institution. All PSP cases underwent neurological assessments, including PSP Rating Scale. Tau positron emission tomography (PET) imaging with florzolotau (18F) and T1-weighted magnetic resonance imaging were obtained from patients and healthy controls to assess associations between domain scores, tau accumulation, and regional brain volumes. Path analysis was used to examine whether cross-sectional associations were consistent with hypothesized relationships among tau deposits, regional atrophy, and symptom domains. Results Fifty-eight patients with PSP (mean age, 71.6 years; 43.1% female; Richardson’s syndrome, n = 43) and 52 healthy controls (mean age, 60.8 years; 45.3% female) were included. Subcortical tau accumulation and atrophy demonstrated significant spatial overlap and were associated with motor deficits. “Ocular motor” domain scores were associated with tau deposition in the midbrain tegmentum and globus pallidus. “Gait and midline” domain scores were associated with tau in the globus pallidus, thalamus, and subthalamic nucleus. “Limb motor” domain scores were associated with tau in the primary motor and somatosensory cortices, as well as atrophy in the angular, supramarginal, and temporal cortices. These findings were identified at a family-wise error corrected cluster-level threshold of p < 0.05. Path analysis indicated that tau in subcortical structures was associated with local neuronal loss and with impairments in the “ocular motor” and “gait and midline” domains. Discussion High-contrast tau imaging clarifies the neuropathological basis of key symptoms and underscores distinct tau-induced neurotoxic effects in subcortical versus neocortical regions. Specifically, tau deposition in the neocortex may contribute to “limb motor” impairments through local effects and potentially through more distributed neurodegenerative processes. These findings support anatomically distinct tau–neurodegeneration pathways underlying key PSP symptom domains.

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