Syndrome-specific vulnerability of neuronal and glial 4-repeat frontotemporal lobar degeneration-tau.

Corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) comprise the majority of 4-repeat (4R) tauopathy cases of frontotemporal lobar degeneration (FTLD-tau). Both pathologic entities can underlie clinical syndromes such as primary progressive aphasia (PPA), characterized by an isolated, progressive impairment of language and left-predominant atrophy, and behavioral variant frontotemporal dementia (bvFTD), marked by progressive personality changes and more symmetric frontotemporal atrophy. In this study, we investigated the neocortical and hippocampal distributions of neuronal and glial tau inclusions in CBD and PSP to establish clinicopathologic concordance between tau pathology and the aphasic versus behavioral phenotype. Twenty-eight right-handed cases with autopsy-confirmed CBD (n=14) or PSP (n=14) were identified from the Northwestern University Alzheimer's Disease Research Center brain bank (PPA, n=16; bvFTD, n=12). Paraffin-embedded sections were immunohistochemically stained with AT8 to visualize tau pathology, and modified unbiased stereological analysis was performed in up to eight regions, including the middle frontal gyrus (MFG), superior temporal gyrus (STG), inferior parietal lobule (IPL), anterior temporal lobe (ATL), dentate gyrus (DG), CA1 of the hippocampus, and primary visual cortex (V1). In PPA, pathology was significantly left-lateralized, with the ATL showing the highest overall tau burden, while bvFTD cases showed more symmetric or rightward distributions with peak pathology in the MFG. Across both syndromes, CBD cases exhibited greater neuronal tau pathology, and PSP cases exhibited greater glial tau pathology, with this double-dissociation reaching significance across neocortex. Hippocampal regions, particularly CA1, showed higher neuronal tau burden than neocortical regions regardless of clinical phenotype, and DG tau burden was significantly greater in CBD than PSP (p<0.01). Inclusion-to-neuron analyses revealed disproportionately higher tau burden in the DG compared to neocortex, especially in CBD (p<0.001). These findings reveal syndrome- and pathology- specific patterns of selective cellular and regional vulnerability in 4R-tauopathies and support clinicopathologic concordance in PPA and bvFTD.