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.

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