Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is associated with abnormalities in white matter structural integrity and connectivity: An ex-vivo diffusion MRI and pathology investigation

Limbic predominant age -related TDP-43 encephalopathy neuropathological change (LATE -NC) is common in older adults and is associated with neurodegeneration, cognitive decline and dementia. In this MRI and pathology investigation we tested the hypothesis that LATE -NC is associated with abnormalities in white matter structural integrity and connectivity of a network of brain regions typically harboring TDP-43 inclusions in LATE, referred to here as the "LATE -NC network ". Ex -vivo diffusion MRI and detailed neuropathological data were collected on 184 community -based older adults. Linear regression revealed an independent association of higher LATE -NC stage with lower diffusion anisotropy in a set of white matter connections forming a pattern of connectivity that is consistent with the stereotypical spread of this pathology in the brain. Graph theory analysis revealed an association of higher LATE -NC stage with weaker integration and segregation in the LATE -NC network. Abnormalities were significant in stage 3, suggesting that they are detectable in later stages of the disease. Finally, LATE -NC network abnormalities were associated with faster cognitive decline, specifically in episodic and semantic memory.