Animal studies and the brain atrophy pattern of neurodegenerative dementias suggest that misfolded proteins may propagate in a manner similar to infectious prions, spreading through brain networks. However, this propagation has not been demonstrated in vivo in humans. Alzheimer’s disease affects the resting network, which is too complex to study tau propagation. In contrast, non-fluent primary progressive aphasia (nfPPA) affects the simpler syntactic network, with two major nodes, Broca’s area and the temporal syntactic area, connected by the arcuate fasciculus. Damage in nfPPA begins in Broca’s area. This study aimed to determine whether tau deposition in nfPPA follows a network pattern.


      Seven nfPPA patients, all PET amyloid-negative, and eight healthy controls had 18F-AV-1451 PET. The SUV ratio over the cerebellar gray matter was calculated for t = 80–100 min. The two groups were compared using SPM. MRI tractography was performed in the nfPPA group. Additionally, in a different group of 35 healthy subjects, we determined normal network functional connectivity with BOLD MRI using the voxels with greatest 18F-AV-1451 uptake in the nfPPA group as seed.


      nfPPA patients had impaired language production and increased 18F-AV-1451 uptake in two major clusters (p < 0.05 FWE corrected): the larger in Broca’s area and the smaller in the syntactic comprehension area of the left temporal lobe, which was also the area most heavily connected to Broca’s area in the MRI connectivity analysis in healthy subjects. Furthermore, MR tractography revealed abnormal thinning, most pronounced anteriorly, of the left arcuate fasciculus, connecting the frontal and temporal nodes of the language network.


      Increased 18F-AV-14510 signal in nfPPA most likely reflects binding to either abnormal tau or a form of TDP-43; aggregates of either protein have a beta-pleated structure. Binding was greatest in Broca’s area, where degeneration begins in nfPPA, and, to a lesser extent, in the posterior node of the syntactic network. The arcuate fasciculus was thinned in the left hemisphere suggesting that it is the pathway traveled by misfolded proteins associated with neuronal and axonal degeneration. Our findings provide in vivo evidence that, in neurodegenerative dementia, misfolded proteins propagate in a prion-like manner.