18F-Flortaucipir in TDP-43 associated frontotemporal dementia

Abstract

Retention of 18 F-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 18 F-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 18 F-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 3 H-Flortaucipir was performed. SvPPA patients exhibited higher 18 F-Flortaucipir retention in the lateral temporal cortex bilaterally according to ROI- and voxel-based analyses. In C9orf72 patients, 18 F-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 18 F-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 18 F-Flortaucipir retention, indicating that 18 F-Flortaucipir binding in TDP-43 proteinopathies is not a general TDP-43 related phenomenon.

Binding of [18F]AV1451 in post mortem brain slices of semantic variant primary progressive aphasia patients

“…The absence of binding in the vitro autoradiography images of FTLD-TDP cases is in line with a recent study in which in vitro [ 3 H]AV1451 autoradiography on frontal and temporal cortical cryosections of SV PPA cases as well as C9orf72 TDP-43 type B cases also showed no binding [12]. Another independent study demonstrated the absence of in vivo [ 18 F]AV1451 PET signal during life in a patient with the C9orf72 mutation who was neuropathologically diagnosed as TDP-43 type B [21].…”

“…This made the authors conclude that MAO-B does not appear to be a significant binding target of [ 18 F]AV1451, despite tau levels being low in this patient group in the first place. Similarly, we also could not reveal any binding in vitro while in vivo, a strong signal has been consistently shown [9][10][11][12]14]. On the other hand, for [ 18 F]THK5351, in vivo reduction of tracer uptake has been demonstrated in AD and PSP using an oral dose of selegiline [25].…”

“…We and others have previously demonstrated strong PET signal of the first-generation tau-PET tracers in the anterior temporal lobe that was consistently present in patients with SV PPA [9][10][11][12][13][14][15][16]. In an effort to explain this unexpected but highly consistent finding, we conducted an in vitro autoradiography binding study with [ 18 F]AV1451 in SV PPA cases, constituting the range of underlying pathologies.…”

“…Currently, a positron emission tomography (PET) tracer to visualize TDP-43 in vivo is not available yet. However, firstgeneration tau-PET tracers such as [ 18 F]AV1451 [7] and [ 18 F]THK5351 [8] have consistently shown strong in vivo tracer retention in the anterior temporal lobe of SV PPA patients [9][10][11][12][13][14][15][16]. At the individual patient level, evidence for consistently elevated [ 18 F]AV1451 binding has been found in the anterior temporal lobe of all seven SV PPA cases and all seven "right" semantic dementia cases [10,11].…”

“…In vitro binding studies with fluorine-18 labeled and tritiated AV1451 on sections with FTLD pathology have shown heterogeneous results [12,[17][18][19][20][21]. [ 3 H]AV1451 autoradiography indicated no binding to TDP-43 type C in SV PPA nor to C9orf72 gene mutation carriers with underlying TDP-43 type B pathology [12].…”