[¹⁸F]AV-1451 binding in vivo mirrors the expected distribution of TDP-43 pathology in the semantic variant of primary progressive aphasia

<jats:sec><jats:title>Introduction</jats:title><jats:p>Semantic dementia, including the semantic variant of primary progressive aphasia (svPPA), is strongly associated with TAR-DNA binding protein 43 (TDP-43) type C pathology. It provides a useful model in which to test the specificity of in vivo binding of the putative tau ligand [<jats:sup>18</jats:sup>F]AV-1451, which is elevated in frontotemporal lobar degeneration tauopathies.</jats:p></jats:sec><jats:sec><jats:title>Methods and results</jats:title><jats:p>Seven patients (five with svPPA and two with ‘right’ semantic dementia) and 12 healthy controls underwent positron emission tomography brain imaging with [<jats:sup>18</jats:sup>F]AV-1451. Two independent preprocessing methods were used. For both methods, all patients had clearly elevated binding potential (BP<jats:sub>ND</jats:sub>(non-displaceable binding potential)) in temporal lobes, lateralising according to their clinical syndrome and evident in raw images. Region of interest analyses confirmed that BP<jats:sub>ND</jats:sub>was significantly increased in temporal regions, insula and fusiform gyrus, consistent with those areas known to be most affected in semantic dementia. Hierarchical cluster analysis, based on the distribution of [<jats:sup>18</jats:sup>F]AV-1451 binding potential, separated semantic dementia from controls with 86% sensitivity and 100% specificity.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>[<jats:sup>18</jats:sup>F]AV-1451 binds in vivo regions that are likely to contain TDP-43 and not significant tau pathology. While this suggests a non-tau target for [<jats:sup>18</jats:sup>F]AV-1451, the pathological regions in semantic dementia do not normally contain significant levels of recently proposed ‘off target’ binding sites for [<jats:sup>18</jats:sup>F]AV-1451, such as neuronal monoamine oxidase or neuromelanin. Postmortem and longitudinal data will be useful to assess the utility of [<jats:sup>18</jats:sup>F]AV-1451 to differentiate and track different types of frontotemporal lobar degeneration.</jats:p></jats:sec>