Abstract
Background
Pathogenic mutations in the TANK-binding kinase 1 (TBK1) gene have been associated with progressive supranuclear palsy (PSP)-like extrapyramidal symptoms, amyotrophic lateral sclerosis (ALS), as well as cognitive and behavioral alterations. However, the question as to whether TBK1 mutations may be associated with tau burden remains unanswered.
Methods
To investigate whether patients presenting with PSP-like extrapyramidal symptoms caused by TBK1 mutations have evidence of tau deposition as reflected by positive 18F-APN-1607 tau PET imaging findings. Four patients who showed PSP-like extrapyramidal symptoms, ALS, and cognitive/behavioral alterations were consecutively enrolled between August 2019 and August 2020. Patients underwent TBK1 gene sequencing and 18F-APN-1607 tau PET imaging. All PET images were interpreted in a blinded fashion with respect to genetic results. Brain structural changes were investigated with MRI, whereas 11C-CFT or 18F-DTBZ PET imaging was performed to identify dopaminergic degeneration.
Results
Pathogenic TBK1 mutations were identified in three of the four study patients. The three mutation carriers – but not the case without – showed positive 18F-APN-1607 binding in PSP-related regions, suggesting the presence of tau pathology. Mesencephalic atrophy (hummingbird sign) was observed in all TBK1 mutation carriers, and two of them also had evidence of frontotemporal atrophy. Dopaminergic degeneration was evident in all cases, regardless of TBK1 mutations.
Conclusions
Pathogenic TBK1 mutations in patients with PSP-like extrapyramidal symptoms are associated with positive 18F-APN-1607 tau PET imaging findings. Our data should prompt additional investigations on the potential role of tau accumulation in the pathogenesis of disease conditions associated with TBK1 mutations.
Clinical Routine FDG-PET Imaging of Suspected Progressive Supranuclear Palsy and Corticobasal Degeneration: A Gatekeeper for Subsequent Tau-PET Imaging?