18F]AV1451 POSITRON EMISSION TOMOGRAPHY IN SEMANTIC VARIANT PRIMARY PROGRESSIVE APHASIA

Abstract

[18F]AV1451 is selective for Tau vs Beta-amyloid and vs alpha-synuclein. Binding in Alzheimer's disease shows strong correlations with phenotypic variants and severity. Studies in non-AD tauopathy are discordant, with significant binding in vivo contrasting with weak binding post mortem. Binding to TDP-43 pathology is poorly characterised. The semantic variant of primary progressive aphasia (svPPA) has a strong clinico-pathological correlation with TDP43 type C pathology at post mortem. We hypothesise that in cases clinically diagnosed with svPPA, [18F]AV1451 non-displaceable binding potential (BPND) is not increased compared with age-matched controls. 7 patients with svPPA and 12 controls underwent dynamic [18F]AV1451 PET. BPND was determined by kinetic modelling with a simplified reference tissue model (superior cerebellum). Partial volume corrected regional analysis of BPNDmaps was performed using PetSurfer following Freesurfer Desikan-Killiany cortical parcellation of 3T T1-MRI. We compared group BPND and tissue volume in each brain region using t-tests and quantifying effects with Cohen's d. We then assessed for distributional differences in BPND using hierarchical cluster analysis. Significant increases in [18F]AV1451 binding were seen in svPPA compared to controls. These were observed across left temporal lobe, in left fusiform gyrus, left insula and right amygdala (p<0.05 Bonferroni corrected). The effect size of the difference between svPPA and control binding was correlated with that of grey matter volume. Nonparametric hierarchical clustering classified svPPA with 86% sensitivity and 100% specificity. There is significantly increased [18F]AV1451 binding in regions where TDP43 pathology is known to be localised in svPPA and where atrophy was demonstrated in our cohort. Given the strong association between svPPA and TDP43 pathology it seems unlikely that all patients had undiagnosed Alzheimer's or Pick's pathology. The anatomical distribution is as expected for the clinical syndrome, undermining the previously proposed ‘off target’ binding sites, such as Iron, Calcium, Neuromelanin and Biondi ring tangles. Regardless of the molecular basis of [18F]AV1451 binding, the regionally selective binding we observe suggests a potential role as biomarker in longitudinal and therapeutic studies of svPPA. Post mortem validation will be useful in furthering our understanding of [18F]AV1451 binding in Frontotemporal lobar degeneration.