TDP-43-negative FTLD-U is a significant new clinico-pathological subtype of FTLD
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Frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) is the most common neuropathological subtype of frontotemporal dementias. While TDP-43 is the pathologic protein in the majority of FTLD-U cases, small numbers of cases have recently been reported with TDP-43-negative FTLD-U pathology. To determine the frequency and to define the clinico-pathological spectrum of TDP-43-negative FTLD-U, we re-evaluated 44 cases with a previous diagnosis of FTLD-U or dementia lacking distinctive histopathology. We identified nine cases (20%) with TDP-43-negative FTLD-U pathology by immunohistochemistry and confirmed the absence of pathological TDP-43 by biochemical analysis. All patients presented with sporadic early-onset frontotemporal dementia with predominant behavioral and personality changes. Besides ubiquitin-positive neuronal cytoplasmic inclusions, the most intriguing neuropathological feature was the presence of ubiquitin-positive neuronal intranuclear inclusions (NIIs), often with curved or twisted morphology, in the neocortex, hippocampus, brainstem, and spinal cord. Double-label immunofluorescence revealed an unusual and distinct immunoreactivity profile for these NIIs, with ubiquitin-immunoreactivity, but absence of p62 labeling. The highly consistent clinical and neuropathological phenotype supports the concept that TDP-43-negative FTLD-U should be considered as a new clinicopathological FTLD entity.
KeywordsTDP-43 p62 Ubiquitin Intranuclear inclusions Frontotemporal dementia Frontotemporal lobar degeneration
The work was supported by grants from the German Federal Ministry of Education and Research (BrainNet 01GI0505), the Canadian Institutes of Health Research (grant # 74580) and the Pacific Alzheimer Research Foundation. We are very grateful to I. Pigur for expert technical assistance histological processing. We thank all the collaborating clinics and the donors and families of patients who made this study possible.
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