Abstract
The PET ligand [18F]AV‐1451 was developed to bind tau pathology in Alzheimer's disease, but increased binding has been shown in both genetic tauopathies and in semantic dementia, a disease strongly associated with TDP‐43 pathology. Here we assessed [18F]AV‐1451 binding in behavioral variant frontotemporal dementia due to a hexanucleotide repeat expansion in C9orf72, characterized by TDP‐43 pathology. We show that the C9orf72 mutation increases binding in frontotemporal cortex, with a distinctive distribution of binding compared with healthy controls.
Highlights
AV-1451 binding in frontotemporal regions of a magnitude greater than the 95th centile of binding in controls but within the interquartile range for binding in Alzheimer’s disease[7] and semantic dementia[9] (Fig. 2)
While [18F]AV-1451 might retain a role in tracking disease by visualising the distribution and/or severity of neuropathology in a person with frontotemporal dementia, it is unlikely to have utility for cohort selection for disease modifying trials that target tau or TAR DNA-binding Protein-43 (TDP-43)-specific disease mechanisms
The regions of elevated BPND with largest t-scores were situated within the atrophic regions but elevated BPND did not occur across all atrophic regions
Summary
[18F]AV-1451 was developed as a specific marker of paired helical filament tau (PHF-tau) pathology in Alzheimer’s disease (AD), and is selective for PHF-tau over beta-amyloid and alpha-synuclein in vitro.[1]. We describe [18F]AV1451 binding in a patient with a clear familial case of frontotemporal dementia (FTD) due to a hexanucleotide repeat expansion in the C9orf[72] gene This is the commonest genetic cause of FTD14 and it is strongly associated with TDP-43 pathology[15] without the presence of any tau. Genetic testing confirmed a hexanucleotide repeat expansion in C9orf[72] He met diagnostic criteria for definite behavioral variant frontotemporal dementia.[16,17] He underwent research structural MRI and [18F]AV-1451 positron emission tomography (PET) as part of the Neuroimaging of Inflammation in Memory and Related Other Disorders (NIMROD) study.[18] Thirteen healthy volunteers acted as controls (age range 55–80, 6 Male, ACE-R range 89–99, MMSE range 28–30) and underwent the same neuroimaging and behavioral protocol. Were there regions of the brain with increased nondisplaceable-binding potential (BPND)? Secondly, irrespective of the absolute level of ligand binding, did the distribution of binding across brain regions differ? This second question focusses on the multivariate distribution or pattern of binding, in relation to the distribution of neuropathological substrates of frontotemporal dementias
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