Clinicoanatomic Localization of Iron-Rich Gliosis in Aphasic Presentations of Globular Glial Tauopathy

Globular glial tauopathy is a 4-repeat tauopathy associated with heterogenous clinical syndromes, including primary progressive aphasia. Iron-reactive gliosis in mid-to-deep cortical layers has previously been reported in this disorder, but detailed anatomic localization and its relationship to clinical symptoms is understudied, particularly within the anatomic framework of primary progressive aphasia. In a series of five autopsy-confirmed patients with globular glial tauopathy and one healthy control, we utilize ultra-high-resolution whole-hemisphere ex vivo 7 Telsa MRI and digital pathology to study whole-hemisphere and local laminar/cellular patterns of pathology within affected cortex. We find signature laminar patterns of iron-rich gliosis localized to brain regions implicated in distinct clinical aphasia syndromes between patients: patients who presented with non-fluent aphasia had iron-rich gliosis pathology localized to inferior and superior frontal and motor regions while iron-rich pathology was largely localized to the anterior temporal lobe in a patient with the semantic variant. Moreover, in one patient with non-fluent aphasia and additional iron-sensitive 7 Telsa MRI during life, we find evidence of antemortem iron-rich pathology in the same frontal regions observed post-mortem. These data suggest that focal neuroinflammation and iron dysregulation may contribute to the clinical expression of tauopathies and be detectable during life to improve diagnosis.