TDP-43 pathologic lesions and clinical phenotype in frontotemporal lobar degeneration with ubiquitin-positive inclusions

Background: TDP-43 is a major ubiquitinated disease protein in the pathologic condition of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Objective: To investigate the demographic, clinical, and neuropsychological features associated with subtypes of FTLD-U with TDP-43 inclusions (FTLD-U/TDP-43). Design: Retrospective clinical-pathologic study. Setting: Academic medical center. Patients: Twenty-three patients with histopathologically proven FTLD-U. Main Outcome Measures: Demographic, symptom, neuropsychological, and autopsy characteristics. Results: There are notably different clinical and neuropsychological patterns of impairment in FTLD-U subtypes. Patients with FTLD-U/TDP-43 characterized by numerous neuronal intracytoplasmic inclusions have shorter survival; patients with FTLD-U/TDP-43 featuring numerous neurites have difficulty with object naming; and patients with FTLD-U/TDP-43 in whom neuronal intranuclear inclusions are present have substantial executive deficits. There are also different anatomical distributions of ubiquitin pathologic features in FTLD-U subgroups, consistent with their cognitive deficits. Conclusion: Distinct TDP-43 profiles may affect clinical phenotypes differentially in patients with FTLD-U.