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Murray Grossman, MD; Elisabeth M. Wood, MS; Peachie Moore, BA; Manuela Neumann, MD, PhD; Linda Kwong, PhD; Mark S. Forman, MD, PhD; Christopher M. Clark, MD; Leo F. McCluskey, MD; Bruce L. Miller, MD; Virginia M.-Y. Lee, PhD, MBA; John Q. Trojanowski, MD, PhD

Arch Neurol. 2007;64(10):1449-1454.

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.

Author Affiliations: Departments of Neurology (Drs Grossman, Clark, and McCluskey and Ms Moore) and Pathology and Laboratory Medicine (Ms Wood and Drs Kwong, Forman, Lee, and Trojanowski), Center for Neurodegenerative Disease Research (Ms Wood and Drs Neumann, Kwong, Forman, Lee, and Trojanowski), and Alzheimer's Disease Center (Dr Clark), University of Pennsylvania School of Medicine, Philadelphia; Center for Neuropathology and Prion Research, Ludwig Maximilian University of Munich, Munich, Germany (Dr Neumann); and Department of Neurology, University of California, San Francisco (Dr Miller).

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