Abstract
Retention of 18F-Flortaucipir is reportedly increased in the semantic variant of primary progressive aphasia (svPPA), which is dominated by TDP-43 pathology. However, it is unclear if 18F-Flortaucipir is also increased in other TDP-43 diseases, such as bvFTD caused by a C9orf72 gene mutation. We therefore recruited six C9orf72 expansion carriers, six svPPA patients, and 54 healthy controls. All underwent 18F-Flortaucipir PET and MRI scanning. Data from 39 Alzheimer’s Disease patients were used for comparison. PET tracer retention was assessed both at the region-of-interest (ROI) and at the voxel-level. Further, autoradiography using 3H-Flortaucipir was performed. SvPPA patients exhibited higher 18F-Flortaucipir retention in the lateral temporal cortex bilaterally according to ROI- and voxel-based analyses. In C9orf72 patients, 18F-Flortaucipir binding was slightly increased in the inferior frontal lobes in the ROI based analysis, but these results were not replicated in the voxel-based analysis. Autoradiography did not show specific binding in svPPA cases or in C9orf72-mutation carriers. In conclusion, temporal lobe 18F-Flortaucipir retention was observed in some cases of svPPA, but the uptake was of a lower magnitude compared to AD dementia. C9orf72-mutation carriers exhibited none or limited 18F-Flortaucipir retention, indicating that 18F-Flortaucipir binding in TDP-43 proteinopathies is not a general TDP-43 related phenomenon.
Highlights
Ante mortem identification of the underlying pathology in frontotemporal dementias (FTD) is challenging
It is at this stage not fully clear whether the retention of radiotracer detected in semantic variant of primary progressive aphasia (svPPA) represents binding to true tau-aggregates, whether it binds to TAR DNA-binding protein 43 (TDP-43) or whether this is a retention due to non-tau, non-TDP-43 related neurodegeneration[19,20]
Since the genetic background is known in patients with C9orf72-mutations, we can assume that the mutation carriers have a more predictable TDP-43 pathology underlying their symptoms, allowing us to study the effect of TDP-43 pathology on 18F-Flortaucipir retention
Summary
Ante mortem identification of the underlying pathology in frontotemporal dementias (FTD) is challenging. Several positron emission tomography (PET) radioligands for the microtubule associated protein tau have been developed in recent years[6] These include the family of THK compounds7, 11C-PBB38 as well as the most commonly used 18F-Flortaucipir[9]. Www.nature.com/scientificreports using 18F-Flortaucipir autoradiography[12,13,15] It is at this stage not fully clear whether the retention of radiotracer detected in svPPA represents binding to true tau-aggregates, whether it binds to TDP-43 or whether this is a retention due to non-tau, non-TDP-43 related neurodegeneration[19,20]. To further study whether 18F-Flortaucipir binds to TDP-43 related pathology we recruited a group of svPPA patients along with a group of patients with bvFTD due to hexanucleotide expansions in the C9orf72-gene, known to be strongly related to TDP-43 pathology of type A and B4,5. Since the genetic background is known in patients with C9orf72-mutations, we can assume that the mutation carriers have a more predictable TDP-43 pathology underlying their symptoms, allowing us to study the effect of TDP-43 pathology on 18F-Flortaucipir retention
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