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University of Utah

Qinwen Mao, MD, PhD | Utah, United States

University of Utah

Qinwen Mao, MD, PhD | Utah, United States

Plasma pathologic TDP-43 as a biomarker for FTLD-TDP

Frontotemporal dementia (FTD) is the second most common dementia in patients younger than 65. Pathologically, most patients have frontotemporal lobar degeneration (FTLD), of which there are two main subtypes, FTLD-tau and FTLD-TDP, although FTD may also be caused by unusual presentations of Alzheimer’s disease (AD). Given that different underlying pathologies require different drugs, a biomarker—a molecule in patient samples that can be measured to indicate disease—is essential to distinguish between patients with FTLD-TDP, FTLD-tau, or AD. The goal of this study is to develop a robust biomarker for FTLD-TDP. A promising approach is to quantify disease-specific, brain-derived pathologic TDP-43 as a biochemical marker in plasma; however, no pathologic TDP-43-specific antibody has been available. To solve this issue, we recently produced a panel of monoclonal antibodies against TDP-43 and obtained one specific for pathologic TDP-43. A highly sensitive quantitative enzyme-linked immunosorbent assay (ELISA) with this antibody has also been developed, which will be essential for quantitatively detecting brain-derived pathologic TDP-43. In this study, we will determine whether plasma pathologic TDP-43 levels can be used to distinguish patients with FTLD-TDP from those with FTLD-tau or AD by first measuring plasma pathologic TDP-43 levels in cases of FTLD-tau, FTLD-TDP, AD, and controls using our ELISA, then comparing the plasma pathologic TDP-43 ranges for each group. To verify our ELISA system, we will perform mass spectrometry-based proteomic analyses to quantify plasma pathologic TDP-43 in a subset of samples. Lastly, we will determine if the pathologic TDP-43 level in plasma reflects the severity of pathology in FTLD-TDP brains. This study will define plasma pathologic TDP-43 as a sensitive and specific biomarker for distinguishing FTLD-TDP from FTLD-tau, AD, and normal aging. We expect that such a biomarker will enable the rapid diagnosis of FTLD-TDP patients, which will have direct impact on patient care.