Protein misfolding and aggregation is associated with several devastating neurodegenerative diseases. Aggregation of proteins including beta-amyloid (Abeta), alpha-synuclein (a-syn), tau and TDP-43 have been associated with Frontal Temporal Dementia (FTD), Alzheimer's disease, Parkinson's disease and Lewy Body Dementia among others. Factors resulting in increased cellular stress can lead to misfolding and aggregation of more than one protein, therefore the presence of multiple misfolded proteins in different diseases should be expected. Characterization of which aggregated protein species are present at different stages of each disease would greatly facilitate identification of suitable biomarkers and development of better diagnostic and treatment strategies for these neurodegenerative diseases. We have developed novel technology in our lab that enables us to isolate reagents that very selectively bind different protein variants and that can distinguish neurodegenerative disease tissue from healthy tissue at a very early stage. Here we propose to generate similar reagents against variants of the protein TDP-43 which has been associated with FTD. Our long term goal is to develop selective reagents that can identify which aggregate morphologies of TDP-43 are specific for diseased human FTD brain tissue, and which of these TDP-43 species represent the best diagnostic targets. We will isolate different TDP-43 species that are uniquely found in human FTD brain tissue, and generate reagents that selectively bind these unique TDP-43 species. We will then utilize the reagents to identify which TDP-43 forms can distinguish between human FTD and healthy brain tissue. Aggregation of TDP-43 is considered to be an early event in FTD, and therefore reagents that can very selectively detect the presence of these variants can be useful to help diagnose FTD at an early stage when therapeutic interventions have the most promise.