Tau deposition in non-fluent primary progressive aphasia follows the language network

Objectives: Animal studies and the brain atrophy pattern in patients with tau-related neurodegenerative dementias suggest that tau protein aggregates may propagate in a manner similar to infectious prions, spreading through brain networks. However, tau propagation in this manner has not been demonstrated in vivo in humans. This may now become feasible, given the availability of tau PET imaging agents. Alzheimer’s disease affects the complex resting network and therefore is not a good model to study tau propagation. By contrast, the non-fluent variant of primary progressive aphasia (nfvPPA) is a neurodegenerative disorder that affects the much simpler syntactic network, the core component of the language network. This network has two major nodes, Broca’s area of the frontal lobe and the language area of the temporal lobe, the two connected by the arcuate fasciculus. Damage in nfvPPA is known to begin in Broca’s area. The aim of this study was to determine whether tau deposition in nfvPPA follows a network pattern.

Methods: Six nfvPPA patients, all PET amyloid-negative, and eight healthy controls of similar age and sex as the patients were scanned with ¹⁸F-AV-1451 PET. The SUV ratio over the cerebellar gray matter was calculated for t = 80-100 min. Comparison between the two groups was done with SPM. MRI tractography was performed in the nfvPPA group. Additionally, a different group of 35 healthy controls was studied to determine normal network functional connectivity with BOLD MRI, using as seed the volume with greatest tau load in the nfvPPA group.

Results: nfvPPA patients had impaired language production and increased ¹⁸F-AV-1451 uptake, reflecting tau deposition, in two major clusters (p <0.05 FWE corrected). The larger cluster was in Broca’s area (posterior portion of the inferior frontal gyrus) and the smaller was centered in the syntactic comprehension area of the left temporal lobe, located in the middle temporal gyrus, which was also the area most heavily connected to Broca’s area in the MRI connectivity analysis in healthy controls. Furthermore, MR tractography revealed a thinning, most pronounced anteriorly, of the left arcuate fasciculus, which connects the frontal and temporal nodes of the language network.

Conclusion: nfvPPA patients showed a high tau concentration in the anterior node of the language network (Broca’s area), where degeneration begins in nfvPPA, and a lesser tau increase in the posterior node of the language network, in the temporal cortex, indicating that initial tau deposition in the frontal lobe, corroborated by the clinical findings, spread through the arcuate fasciculus to the temporal language area. As expected, the arcuate fasciculus was thinned out on the left hemisphere, suggesting that it is the pathway traveled by tau, associated with neuronal and axonal degeneration. This finding is the first in vivo demonstration that, in neurodegenerative dementia, tau propagates in a prion-like manner Research Support: N/A