Anatomical Progression of Neuropathology in FTLD-TDP Type C and Linkage to Annexin A11

Frontotemporal lobar degenerations (FTLD)-TDP type C (TDP-C) is distinguished from other FTLD-TDP subtypes by 3 unique features: (1) invariable onset in the anterior temporal lobe (ATL), (2) phosphorylated TDP-43 (pTDP) neurites in cortex, and (3) colocalization of all pTDP deposits with annexin A11 (ANXA11). This article provides a whole-brain anatomical account of TDP-C disease progression in relation to clinical, imaging, and neuropathologic patterns.

Thirty-two cases with TDP-C were studied, including neuropathologic findings and longitudinal magnetic resonance imaging. In 6 of these cases, cortical and subcortical areas were analyzed using whole hemisphere sections. Five control cases were used for comparison.

Progression was reconstructed with the assumption that regions displaying more severe neurodegeneration at postmortem represented earlier onset sites, an assumption supported by longitudinal imaging. Four stages of cortical TDP-C neuropathology were identified. Subcortically, the fascia dentata contained dense round bodies of pTDP, which did not seem to cause neuronal loss. These deposits were also seen in the nucleus accumbens, islands of Calleja, and the nucleus of the stria terminalis. Cortical predilection sites had higher densities of neurites especially in cases without much tissue destruction. However, cases with more severe overall neurodegeneration displayed a paradoxical scarcity of pTDP deposits at predilection sites. Neurodegeneration patterns identified in whole-hemisphere cases were corroborated by 26 additional cases processed for neuropathologic diagnosis. All pTDP inclusions contained ANXA11. In control cases, the distribution of ANXA11-rich neurons was largely concordant with the pattern of susceptibility to TDP-C.

Neurodegeneration originates in upper cortical layers of ATL and spreads posteriorly along paralimbic mediodorsal and associative ventrolateral pathways. In normal cortex, nuclear TDP-43 is distributed throughout the cortex, whereas normal ANXA11 shows variations that largely mirror TDP-C predilection patterns. The possibility is raised that ANXA11 may be a factor in determining the distribution of TDP-C neurodegeneration. ANN NEUROL 2026;99:639-655.